Cardio Diabetes_2017 book

128 Cardio Diabetes Medicine 2017

Atypical Presentation of Acute
Coronary Syndrome in Diabetics

Dr. T. Neelambujan, MD., DNB., FESC., FCSI., FIAE.

Consultant Cardiologist & Interventionalist,
Sundaram Arulrhaj Hospitals, Tuticorin

INTRODUCTION Variables ODD rates (95% confiden-
tial interval
It is predicted that 366 million patients globally will Nonwhite 1.05 (1.03 - 1.07)
have diabetes mellitus by 2030. Cardiovascular mor- Women 1.06 (1.04 - 1.08)
tality is the main cause of death in diabetics. There is Diabetes mellitus 1.21 (1.19- 1.23)
an estimated two to four fold higher risk of cardiovas- Age (10 year interval) 1.28 (1.26 - 1.28)
cular events in diabetics compared to non-diabetics. Prior stroke 1.43 (1.40 - 1.47)
Prior Heart Failure 1.77 (1.74 - 1.81)
ATYPICAL SYMPTOMS OF ACUTE
CORONARY SYNDROME(ACS) : PROFILE OF PATIENTS WITH ATYPICAL
PRESENTATION
Chest pain is the cornerstone symptom of ACS.
However diabetic patients are also more frequently In the National Registry of Myocardial Infarction 2
asymptomatic with a wide range of atypical presenta- (NRMI 2) study, a prospective observational study
tions which makes the diagnosis of ACS challenging. from United States which included 4,34,8777 patients
with acute myocardial infarction, 33% were without
Atypical presentation is defined as the absence of chest pain on presentation to the hospital and were 7
chest pain before or during admission and may have years older than those with chest pain (74.2 years Vs
included gastrointestinal or respiratory symptoms. 66.9 years). Patients with atypical presentation were
The common atypical symptoms encountered in clin- more likely to be females (32.6% Vs 25.4%) or previ-
ical practice are: ous cardiac failure (26.4% Vs 12.3%) and had delayed
presentation(7.9 Vs 5.3 hrs).
1. Dyspnea (19.3%)
The Global Registry of Acute Coronary Events (GRACE
2. Diaphoresis (26.2%) Study) is the largest multinational prospective ob-
servational study. Atypical presentation was seen in
3. Nausea and Vomiting (24.3%) 5.7% of unstable angina and 12.3% non ST elevation
MI patients. Of the 20,881 patients in this study 8.4%
4. Syncope (19.1%) presented without any chest pain and 23.8% were not
initially recognized a shaving ACS. The patients with
5. Abdominal discomfort atypical presentation had higher hospital morbidity
and mortality (13% Vs 4.3% respectively ; P<0.00001)
6. Sudden cardiac death and were less likely to receive effective cardiac med-
ications than patients with typical presentation. High-
7. Silent myocardial ischaemia er inhospital mortality were seen in patients who pre-
sented with presyncope / syncope(OR=2.0), Nausea
INDEPENDENT RISK FACTORS FOR ATYPICAL PRE- or vomiting (OR=1.6) and dyspnea (OR=1.4). In addition
SENTATION

In NRMI – 2 registry, variables such as older age, gen-
der, race and co-morbidities were considered as risk
factors for atypical symptoms.

GCDC 2017

Atypical Presentation of Acute 129
Coronary Syndrome in Diabetics

patients with atypical presentation had less coronary Dobutamine stress echocardiography : This is a use-
angiography and subsequent revascularisation, anti- ful diagnostic test for detecting SMI. In a study by
coagulant, antiplatelet and B-blocker therapy. Mbaye et.al, among 79 diabetics positive test was
seen in 67.1% with a predominance of wall motion
ATYPICAL PRESENTATION IN DIABETES . abnormalities in the anterior area (83%)
Why?
SPECT Scan- DIAD study (Detection of Ischaemia in
Despite the fact that CAD is the primary vascular Asymptomatic Diabetics) identified SMI in 21 – 24%
complication of diabetes, there is a significant gap of intermediate and high cardiovascular risk patients.
in the knowledge and understanding on atypical ACS
symptom in diabetics. SILENT MYOCARDIAL ISCHAEMIA IN
DIABETICS – To screen or not ?
Diabetics may have a diminished awareness of isch-
aemic chest pain which could result in an atypical Due to greater risk of cardiovascular events and
presentation . This can be explained by autonom- more frequent silent CAD in diabetics compared to
ic neuropathy and prolongation of the angina per- non-diabetics, screening asymptomatic diabetic pa-
ceptional threshold due to sensory denervation. A tients for CAD is an attractive concept. However there
change in Beta endorphin levels has also been pro- is paucity of confirmed data that a prospectively uti-
posed as a cause of atypical presentation. lized screening programme has a positive prognostic
impact in asymptomatic diabetic patients.
Cardiac autonomic neuropathy contributes for in-
creased risk of sudden death and also for silent Long standing diabetics; patients with diabetic com-
myocardial ischaemia. plication like neuropathy and nephropathy; diabetics
with two or more cardiovascular risk factors should
SILENT MYOCARDIAL ISCHAEMIA (SMI) undergo screening for SMI. A Stress ECG may be the
initial screening test. If the exercise ECG is non-di-
Diabetes is considered as an independent risk factor agnostic or if the test is submaximal, a myocardial
for the presence of SMI. Silent Myocardial Ischaemia perfusion scan may be recommended. A Dobuta-
is seen in 28.5% of diabetics . Upto 25% of patients mine stress echocardiography may also be used as
with CAD have suffered silent SMI. The magnitude it is comparable to scintigraphy. If a large ischaemia
of the myocardium involved is on an average 10% of involving more than 20 – 25% of the myocardium is
left ventricle muscle mass. Cardiac autonomic neu- detected a coronary angiogram is justified.
ropathy is considered as the risk factor for SMI in
diabetics.

HOW TO ASSESS SILENT MYOCARDIAL
ISCHAEMIA (SMI) ?

The Primary step is to identify diabetic individuals at
high risk for SMI.

Patients with advanced age, hypertension, low HDL
and hypertriglyceridemia are considered as high risk
individuals. A high carotid intima medial thickness
also points for high risk of CAD in non-insulin de-
pendent diabetic patients even in those without ev-
ident CAD.

The presence of higher microalbuminuria also inden-
tifies patients with SMI.

Erectile dysfunction may become a possible indicator
to identify diabetic patients with SMI during screen-
ing.

TESTS USED TO EVALUATE SMI:

Exercise stress test; A Positive test for silent isch-
aemia is seen in about 19% of diabetics.

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130 Cardio Diabetes Medicine 2017

FLOW CHART OF EVAUATION OF SILENT REFERENCES:
MYOCARDIAL ISCHAEMIA
1. Hadi AR Hadi Khafaji et.al; Atypical presentation of Acute and Chronic
DIABETES No coronary artery disease in diabetics. World journal of cardiology 2014
August 26; 6(8): 802 – 813.
Long standing Diabetes
Diabetic complication >2 2. Hyun Kuk Kim et.al; Atypical presentation in patients with Acute cor-
Risk Factors onary syndrome; Acute coronary syndrome – Dr.Mariano Brizzio,ISBN:
978-953-307-827-4.
YES
3. Brieger D et.al; Acute coronary syndromes without chestpain , an un-
derdiagnosed and undertreated high risk group : Insights from the Global
Registry of Acute Coronary Events. Chest 2004: 126:461-469.

4. Canto et.al, Prevalence, clinical characteristics and mortality among
patients with myocardial infarction presenting without chest pain.
JAMA,283,3223-3229.

Stress ECG Control of Diabetes
& CV risk of factors

Non -Diagnostics /
Submaximal

Myocardial Perfusion
Scan / Dobutamine

Stess ECHO

LARGE ISCHEMIA >
20-25%

Cornorary Angiogram

CONCLUSION:

All diabetics do not have the same risk of coronary
events. Hence it is reasonable to identify patients who
require additional investigations to diagnose associ-
ated CAD. This strategy will help to adopt therapeutic
measures like tight glycaemic control, antiplatelets,
statins, ACE/ARB and also invasive interventions to
improve prognosis in high risk individuals. Future
studies are needed to identify the patient subgroups
who will benefit from screening.

GCDC 2017

Cardio Diabetes Medicine 2017 131

Cardiovascular Risk in Diabetes:
Known v/s Unknown

Dr. T.P. Weerarathna,

MBBS, MD, FCCP, FACP, FRCP
Professor in Medicine, Faculty of Medicine

Galle, Sri Lanka

Abstract T2DM living in the developing countries especially in
the south Asian region still have a rising morbidity
Type 2 diabetes increases the risk of cardiovascular and mortality from CVD2. With high incidence of di-
disease. South Asian ethnicity augments this risk abetes manifested at a relatively younger age with
with early onset and diffuse atherosclerotic disease more adverse risk factor profile favoring accelerated
especially among individuals with diabetes. atherosclerosis, health authorities in the South Asian
countries are facing several dilemmas in controlling
There are many known and unexplored facets in CVD3. Although a large body of research is being
the cardiovascular diseases among South Asians conducted in this field, there are many unknown
with diabetes. When a patient is presented with an facets in the CVD risks among patients in the de-
acute vascular catastrophe such as acute coronary veloping countries.
syndrome, screening with a more sensitive test for
detection of glucose abnormalities can improve clin- Based on studies conducted in the local setting, this
ical outcome. Recognition of cardiovascular risk fac- article addresses several issues related to CVD risks
tor profiles in groups with increased susceptibility to among patients presented to a diabetes center in
cardiovascular disease would help initiation of more Southern Sri Lanka.
targeted and specific therapy before progression of
the disease to adverse clinical events. Selection of In the first study, sensitivity of fasting plasma glu-
most appropriate screening tool for disease stratifi- cose (FPG) in comparison to glycosylated hemoglo-
cation in to low, moderate or high risk would enable bin (HbA1C) test in detecting previously non- diabetic
implementation of more cost effective preventive individuals presenting with acute coronary syndrome
therapeutic and lifestyle measures. Recognition of is explored. Second study describes the cardiovas-
individuals under specific therapy who has a resid- cular risk profile and their associations of newly di-
ual risk would pave the way to optimize individual agnosed patients with type 2 diabetes. In the third
measures to improve clinical outcomes. study, we attempted to find out the most appropriate
cardiovascular risk screening tool for patients with
This article summarizes findings of several cross type 2 diabetes without clinical evidence of estab-
sectional studies carried out in a diabetes center in lished cardiovascular disease. The final study ad-
Southern Sri Lanka highlighting many previously un- dresses prevalence and associations of suboptimal
explored aspects of cardiovascular risk in diabetes in levels of high density lipoprotein levels (HDL) among
a developing country. patients with T2DM being treated with statins.

Introduction Are we missing a lot with diabetes
presenting with acute coronary syndrome?
Cardiovascular diseases (CVD) account for a sub-
stantial morbidity and mortality in patients with type In routine clinical practice among patients admitted
2 diabetes (T2DM)1. An Individual with T2DM carries to hospital, fasting plasma glucose (FPG) is carried
three to four fold risk of developing CVD compared out to screen diabetes or impaired fasting glucose
to a healthy individual. Although developed coun- (pre-diabetes). Testing of glycosylated hemoglobin
ties can boast about a significant decline in CVD (HbA1c) level in previously undiagnosed diabetic pa-
mortality among people with diabetes, patients with

Cardio Diabetes Medicine

132 Cardiovascular Risk In Diabetes: Known v/s Unknown

tients with acute coronary syndrome (ACS) could higher CVD morbidity and mortality than the late on-
help in detecting the correct glycemic category than set patients with T2DM5. We studied the prevalence
testing them with FPG alone. We studied clinical util- and pattern of modifiable CVD risk factors including
ity of testing for HBA1c in detecting pre-diabetes and major lipid fractions and systolic and diastolic blood
diabetes among patients without the previous diag- pressure in patients with newly diagnosed T2DM and
nosis of diabetes admitted to hospital with ACS. to detect possible association of these risk factors
with gender, age at onset of diabetes, central obesity
In this cross sectional study conducted in a medical (measured as waist circumference) and global obesi-
ward of a tertiary care hospital in Southern Sri Lan- ty (measured as body mass index). (Table 1)
ka, we included all male and female patients with no
previous history of diabetes admitted over a period From a database which included demographic, clini-
of three months with any of the three types of acute cal and biochemical data of patients who underwent
coronary syndrome; ST elevation myocardial infarc- screening in a diabetes clinic at the time of first di-
tion, non-ST elevation myocardial infarction and un- agnosis of T2DM before commencing any hypogly-
stable angina. cemic, anti -hypertensive or lipid lowering therapy,
we obtained data on their demographic (gender, age)
Of the 125 patients studied, 99 (80%) had normal clinical (height, weight, waist circumference, systolic
fasting plasma glucose (< 125 mg/ dL), 20 (16%) had and diastolic blood pressure) and biochemical (to-
impaired fasting glucose (IFG) (FPG100- 124mg /dL) tal cholesterol, low density lipoproteins (LDL), tri-
and 6 (4%) were newly diagnosed to have diabetes glycerides (TG), high density lipoprotein levels (HDL)
based on FPG. HbA1c levels of all 6 newly diagnosed for analysis. Optimal cutoff levels for blood pressure
patients with diabetes according to FPG ranged from and lipids recommended by the American diabetes
7 – 8.9%. Based on HbA1c, 59 (47%) had diabetes association (ADA) were used to determine the prev-
(HbA1c > 6.5%) and 66 (53%) were in the category of alence of each cardiovascular risk factor needing
pre - diabetes (HbA1c5.5- 6.5%) and none of the study therapeutic intervention. The proportions with systolic
subjects presenting with ACS had HbA1c level below blood pressure ( SBP> 140 mm Hg), diastolic blood
5.5% to be categorized as having normal blood glu- pressure ( DBP>90 mm Hg) , low density lipoprotein
cose (Table 1). Out of the 66 in the pre-diabetes cat- level ( LDL > 100 mg/ dL) , triglycerides( TG> 150 mg/
egory according to HbA1c, only 7 subjects had FPG dL) and high density lipoprotein level ( HDL < 40
in the range of IFG (100-124mg/dL) , leaving 59 (89%) mg/ dL in males and < 50 mg/ dL in females) were
patients with pre-diabetes on HbA1C having normal estimated. Logistic regression analysis was used to
FPG (< 100 mg / dL). study the association of age, gender, body mass in-
dex (BMI) and waist circumference with each of the
Finding of eight fold (6 vs 50) increase of number modifiable cardiovascular risk factor. Age adjusted
of patients with diabetes and two and a half fold in- odds ratios were calculated for each parameter risk
crease in the category with pre-diabetes by testing and level below 0.05 was taken as statistically sig-
for HbA1c compared to FPG among patients in this nificant. Characteristics of the study sample (n=412)
study challenges the diagnostic utility of FPG in cor- and the results from regression analysis are shown
rectly recognizing the glycemic status of individuals in tables 1, 2 and 3.
presenting with ACS. It exposes the need for a test
with better diagnostic yield. Findings of our study Number of sub- Number of sub-
may not be compelling for clinicians to test HbA1c
in each and every patient with ACS with no previous jects according jects according
history of diabetes, but they serve as an eye opener
of higher prevalence of glucose abnormalities among to FPG to HbA1C
patients with ACS in the Sri Lankan setting.
Normal 99 None
Why is young onset T2DM more prone to
CVD than the late onset T2DM? IFG/pre-diabe- 20 69
tes
Pattern of cardiovascular risk factors and their asso-
ciations prevalent among the South Asians may ex- Diabetes 6 56
plain this higher CVD risk prevalent among patients
with diabetes compared to their Caucasian coun- Tables and figures
terparts4. Furthermore, studies from the west reveal
that young onset T2DM patients have an early and Table1. Number of subjects with acute coronary syn-
drome according to fasting plasma glucose (FPG)
and glycosylated hemoglobin (HbA1c)

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Cardio Diabetes Medicine 2017 133

Parameter Mean(SD) 49 (11) Parameter odds ratio P value
Age (years)* 71.30% Age 0.98 (-97 - 0.99) <0.01
Gender (male) 24.5 (3.3) Gender(Female) 7.73 (5.99 - 9.97) <0.01
BMI (kg/m2)* 91.1 (8.9) Duration of diabetes 1.00 (0.98 - 1.02) 0.93
WC (cm)* 122 (15) LDL Cholesterol 1.01 (1.00 - 1.02) 0.04
SBP (mmHg) 77 (9) Triglycerides 1.01 (1.00 - 1.02) 0.01
DBP (mmHg) 208.1 (35.5) HbA1C 1.02 (0.86 - 1.22) 0.81
TC (mg/dL)* 49.4 (7.7) Body Mass Index 1.05 (1.00 - 1.2) 0.04
HDL (mg/dL)* 133.3 (34.1) Waist circumference 0.99 (0.97 - 1.01) 0.26
LDL (mg/dL) 120.8 (53.7)
TG (mg/dL)* 17.10% Table 4 : Associations of different parameters with
Proportion of suboptimal HDL 81.20% suboptimal high density cholesterol levels among
Proportion of suboptimal LDL 18.50%
Proportion of suboptimal TG statin treated patients

Table2. Characteristics of the study sample of newly
diagnosed patients with type 2 diabetes

LDL HDL High TG SBP DBP
Odds ratio Odds ratio P Odds ratio
Clinical Odds ratio P Odds ratio P (95% CI) P (95% CI) value (95% CI) P
risk factor (95% CI) value (95% CI) value value val-
Age at 0.95 <0.01 1.062 ue
diagnosis 1.003 0.84 0.95 <0.01 (0.93- 0.98) 0.32 1.09 <0.01 (1.006- 0.03
0.36 1.121)
Gender (0.98- (0.93-0.98) 0.73 0.96 (1.05- 1.28 0.68
(male) 1.03) (0.39-1.36) 1.13) (0.39-
0.15 7.98 <0.01 4.11) 0.86
WC 2.46 1.02 1.16 0.71 1.01
(4.39- (0.98 -1.07) (0.92- 0.86
BMI (1.19- 14.49) (0.53 1.11)
5.07) 1.003 2.55) 0.98
0.4 0.95 0.03 (0.888-1.133) (0.76-
0.98 0.98 0.53 1.25)
(0.91-0.99)
(0.93- (0.92- .04)
1.03)
0.86 1.139 0.04 1.02 0.82
0.99
(1.077- (0.86
(0.87- 1.288) -1.20)
1.12)

Table 3 : Association of clinical parameters with major modifiable cardiovascular risk factors

Cardio Diabetes Medicine

134 Cardiovascular Risk In Diabetes: Known v/s Unknown

In this study, we found a high prevalence (81. 2 %) of is postulated to be associated with lower HDL lev-
adverse level of LDL cholesterol (over 100 mg / dL) el. Markedly lower percentages of individuals in the
at the time of diagnosis of diabetes. Although more CVD risk categories of > 10% with WHO risk score
males had LDL above 100 mg/ dL than females, no suggests the relative lack of sensitivity of including
significant gender variation was observed. Male gen- the total cholesterol level alone in predicting the CVD
der was associated with significantly higher odds of risk in Asian ethnicity.
having lower HDL cholesterol level. Males with newly
diagnosed T2DM compared to females have non-sig- Targeting Diabetic dyslipidemia with statins;
nificantly higher odds of possessing all major modifi- How about suboptimal HDL?
able CVD risk factors except higher TG level. Of the
clinical parameters, younger age at onset of diabetes Abnormalities in lipoproteins collectively named as di-
revealed a significant association with higher TG and abetic dyslipidemia augment the risk of CVD among
lower HDL cholesterol levels. BMI revealed a positive individuals with T2DM. Major components of diabet-
association with SBP, TG and low HDL but a statis- ic dyslipidemia include elevated level of triglycerides,
tically significant association of BMI was only seen small and dense low-density lipoproteins (LDL) and
with lower HDL cholesterol level. low levels of high-density lipoproteins (HDL)9. Statin
group of drugs substantially reduce elevated LDL
Cardiovascular risk assessment tools; what cholesterol and triglycerides with favorable clinical
suits us best? outcomes, but they have a marginal effect on HDL
level10.
Risk assessment tools used to calculate the cardio-
vascular diseases risk such as the Framingham risk We aimed to study the prevalence of suboptimal HDL
score (FRS), United Kingdom Prospective Diabetes cholesterol level and its association with gender, in-
study (UKPDS) risk engine and the World Health Or- dices of global and central obesity (body mass index
ganization (WHO) risk score have not been tested and waist circumference), age at onset and duration
on their ability to detect subclinical atherosclerosis of diabetes and glycemic control among a group of
in most developing countries6. patients with diabetes being followed up in a diabe-
tes center taking statin therapy.
We studied the associations between the calculated
CVD risk scores using each of these tools and carot- In this cross-sectional study we included patients
id intima medial thickness (CIMT), a surrogate marker (n=2416) taking statin group of drugs irrespective of
of atherosclerosis, in a group of patients with Type 2 the type and the dose for at least three months be-
diabetes (T2DM) in Sri Lanka. CVD risk scores of 68 fore the screening visit. Association of suboptimal
randomly selected patients with T2DM with no his- HDL level (HDL < 40 mg/dL in males and < 50 mg/
tory or symptoms of CVD and measured their CIMT dL in females) (dependent variable) with clinical pa-
using B mode ultrasonography. Pearson correlation rameters (age at diagnosis and duration of diabetes,
was used to study the association between CVD risk gender, BMI, WC as independent variables) were
scores with CIMT studied with logistic regression analysis.

Of the 68 patients (50% males), mean age (SD), age We found that the prevalence of suboptimal HDL of
at onset and duration of diabetes were 56.9(9.63), 17.6%. Regression analysis revealed female gender,
44.26(9) and 12.16(7.6) years respectively. Of the scor- (OR 7.73, 95% CI 5.99 to 9.97) younger age (OR 0.98
ing methods, UKPDS tool had weak, but significantly , 95% CI 0.97- 0.99 ), higher BMI (OR1.05. 95% CI 1.00
positive (r = 0.26, p < 0.05) and FRS had positive but to 1.2 ) and LDL level over 100 mg / dL ( OR 1.004,
not significant association (r= 0. 21) with CIMT. There 95% CI 1.00 to 1.007 ) have significant associations
was a negative association between CIMT and WHO with suboptimal HDL. (Table 4)
risk score(r = - 0.07).
Conclusions
The possible explanation for both UKPDS and FRS
to reveal stronger associations with a surrogate of • Several important conclusions on the CVD risks
atherosclerosis than the WHO tool could be due to in Type 2 diabetes among individuals in local
inclusion of additional variables such as HDL cho- setting can be arrived from the aforementioned
lesterol, HbA1c and duration of diabetes in them. studies. They include
Studies have shown higher prevalence rates of lower
HDL cholesterol among Indian Asians7, 8. Higher CVD • Testing for glucose abnormalities in patients
morbidity and morbidity in the South Asian region presenting with acute coronary syndrome using
HbA1c as opposed to FPG would substantially

GCDC 2017

Cardio Diabetes Medicine 2017 135

increase the number of patients detected with 9. Karim MN, Ahmed KR, Bukht MS, et al. Pattern and predictors of dyslip-
diabetes and pre-diabetes. idemia in patients with type 2 diabetes mellitus. Diabetes Metab Syndr.
2013; 7: 95-100.
• An individual with ACS has either pre diabetes or
diabetes with HBA1c. 10. Preiss D and Packard CJ. Emerging therapeutic approaches to treat dys-
lipidemia. Current cardiology reports. 2014; 16: 506.
• Younger onset of T2DM is associated with more
atherogenic lipid profile characterized by lower
levels of HDL cholesterol and high triglyceride
levels.

• Compared to WHO and UKPDS risk assessment
tools , Framingham risk score has a stronger
association with a surrogate marker of athero-
sclerosis

• Suboptimal HDL level is present in nearly one
in six patients with type 2 diabetes treated with
statins.

• Suboptimal HDL is more likely to be prevalent
among patients with diabetic dyslipidemia under
statins with younger age, higher BMI and LDL
levels and female gender.

These observations may enrich our understanding
of higher CVD risk among people with diabetes and
would be helpful in optimizing clinical care and re-
ducing their cardiovascular morbidity and mortality.

References

1. Zhang PY. Cardiovascular disease in diabetes. European review for medical
and pharmacological sciences. 2014; 18: 2205-14.

2. Pinidiyapathirage MJ, Kasturiratne A, Ranawaka UK, et al. The burden of
diabetes mellitus and impaired fasting glucose in an urban population of
Sri Lanka. Diabet Med. 2013; 30: 326-32.

3. Ramachandran A, Snehalatha C and Ma RC. Diabetes in South-East Asia:
an update. Diabetes Res Clin Pract. 2014; 103: 231-7.

4. Jayawardena R, Ranasinghe P, Byrne NM, Soares MJ, Katulanda P and
Hills AP. Prevalence and trends of the diabetes epidemic in South Asia: a
systematic review and meta-analysis. BMC Public Health. 2012; 12: 380.

5. Bellary S, O’Hare JP, Raymond NT, et al. Premature cardiovascular events
and mortality in south Asians with type 2 diabetes in the United Kingdom
Asian Diabetes Study - effect of ethnicity on risk. Curr Med Res Opin.
2010; 26: 1873-9.

6. Al-Lawati JA, Barakat MN, Al-Lawati NA, et al. Cardiovascular risk as-
sessment in diabetes mellitus: comparison of the general Framingham
risk profile versus the World Health Organization/International Society of
Hypertension risk prediction charts in Arabs--clinical implications. Angi-
ology. 2013; 64: 336-42.

7. Ewang-Emukowhate M, Perera D and Wierzbicki AS. Dyslipidaemia Re-
lated to Insulin Resistance and Cardiovascular Disease in South Asian and
West African Populations. Curr Pharm Des. 2014.

8. Goldstein KM, Melnyk SD, Zullig LL, et al. Heart matters: Gender and
racial differences cardiovascular disease risk factor control among veter-
ans. Women’s health issues : official publication of the Jacobs Institute
of Women’s Health. 2014; 24: 477-83.

Cardio Diabetes Medicine

136 Cardio Diabetes Medicine 2017

Effect of Stroke on Heart,
Diabetes & Hypertension

Prof. Dr. Lakshminarasimhan Ranganathan,

MBBS MD(Int. Med)., DNB (Int.Med) DM (Neuro)., DNB(Neuro)., Director and Professor,
Institute of Neurology Madras Medical College, Chennai

Dr. Lenin Sankar P, Dr.Thamil pavai N & Dr. Guhan R

Abstract: Figure 1. Relationship of Stroke With Heart, Diabetes
And Hypertension
Stroke is the second most common cause of death.
The most common diseases associated in the patho- The scope of this chapter is to highlight the ways
physiology of stroke are diabetes, hypertension, and by which stroke can affect heart, diabetes and hy-
heart disease. Stroke in turn affects these diseas- pertension.
es adversely. Stroke can affect heart by producing
arrhythmias, left ventricular dysfunction, or isolated Effects of stroke on heart: These are broadly
cardiac enzyme elevation through myocytolysis. The classified into
severity of cardiac involvement is proportional to the
neurological injury. Post–stroke hyperglycemia is a 1. Electrical,
commonly encountered entity, seen especially with 2. Structural and
ischemic stroke and with involvement of insula in 3. Biochemical. (fig.2)
specific. The post –stroke hyperglycemia is due to
the action of inflammatory cytokines released from BRAIN
the infarct which in turn increase glucose production
or decrease utilization. Impaired glucose tolerance HEART
and overt diabetes mellitus are also seen weeks af-
ter stroke onset in a significant number of patients. ELECTRICAL BIOCHEMICAL MECHANICAL
Stroke results in acute hypertensive response com-
monly and hypotension rarely. The acute hyperten- 1. BRADARRYTHMIAS 1. CARDIA 1. LV
sive response is stroke sub-type specific and it is 2. TACHYARRHYTHMIAS ENZYME DYSFUNCTION
secondary to disturbed vasomotor tone. The central 3. REPOLARISATION ELEVATION 2. STRESS
key to the pathogenesis of stroke related effects on CARDIOMYOPATHY
heart, diabetes and hypertension is disturbed auto- ABNORMALITES
nomic function.
Figure2. EFFECTS OF STROKE ON HEART
KEY WORDS: myocytolysis, neurogenic cardiac in-
jury, post-stroke hyperglycemia, acute hypertensive
response in stroke.

Introduction: Stroke is the second most common
cause of death worldwide and the first being isch-
emic heart disease. Both these vascular diseases
share most of the risk, diabetes and hypertension
being the top two. Both hypertension and diabetes
have a definite role in deciding the outcome and
morbidity associated with ischemic heart disease and
cerebrovascular disease. Heart and brain also affect
each other’s function in a vice-versa manner (fig.1).

GCDC 2017

Effect of Stroke on Heart, Diabetes and Hypertension 137

1.The various ECG changes seen in patients with patients with stroke. The pattern of myocardial dys-
stroke include: function in SAH patients is quite different from that
of a coronary artery disease because apical myocar-
Prolongation of the QT interval, repolarisation ab- dium is typically spared in patients with SAH. The
normalities like-ST segment depression or elevation, proposed mechanism for myocardial dysfunction is
inverted or flat T waves, new Q waves, bradyarrhyth- stroke related increase in myocardial catecholamine
mias, tachyarrhythmias levels especially in the subendocardium resulting in
‘myocytolysis’ through a cascade of mechanisms.
These electrical changes can be further These myocardial necroses are concentrated around
classified into: the cardiac nerve endings and not in the vascular
territory as seen in coronary artery disease. Adding
1. Life threatening or potentially life strength to this is a study by Banti et.al, in which they
threatening compared echocardiogram, cardiac MIBG scintigrapy
to assess the myocardial sympathetic innervations
Bradyarrythmias and tachyarrhythmia of all kinds can and Technitium Sestabamibi scintigraphy to assess
be seen. The proposed mechanism is disturbed auto- the myocardial perfusion in patients with neurogenic
nomic balance as a result of damage to the specif- myocardial injury. In that study they observed cardi-
ic brain areas. Bradyarrhythmias are more common ac perfusion study to be normal in all the subjects
with right insular lesions and tachyarrhythmias with whereas MIBG scintigraphy abnormality was directly
left sided lesions and animal studies have shown proportional to the myocardial regional wall motion
that right insula has a preferential influence over abnormality scores and cardiac enzyme elevation.
sinuatrial node(fig.5). One could have a speculation The Left ventricular dysfunction observed in such
that arrhythmia might be the cause for the stroke or cases is reversible. Treatment of the primary disease
the stroke has unveiled a subclinical cardiac disease, and its associated complication alone are needed in
but there is ample evidence to say arrhythmias are such cases unless the ventricular dysfunction causes
seen even in patients without any evidence for cardi- hemodynamic instability. An important clinical sce-
ac disease or abnormality. Prompt identification and nario one might anticipate especially in patients with
an appropriate early management are essential for a sub arachnoid haemorrhage is ventricular dysfunc-
favourable outcome.(1) tion which might preclude the use of HHH therapy
which will be counterproductive setting a vicious cy-
2. Innocuous or possibly innocuous cle. When such is the case Intra aortic balloon coun-
terpulsation can be used. Patients with subarachnoid
This includes repolarisation abnormalities like devia- hemorrhage who are brain dead are potential candi-
tion of the ST segment, U wave flattening / inversion dates for organ donation. But transient left ventricular
and prolongation of the QT interval .In few cases new dysfunction might preclude the donation of heart. A
Q waves may be seen. The word “possibly innocu- study has specifically addressed this issue in which
ous” is used because QT prolongation may be a tran- they have observed that in 92% of such cases the
sient finding without causing any hemodynamically heart resumed normal function following transplan-
significant arrhythmias or at times it may be a har- tation. (1)
binger for a life threatening arrhythmia. Most of these
findings are transient and will disappear over a period Takotsubo cardiomyopathy: Named after Japanese
of time without any treatment or causing any impact. octopus trapping pot because the Left ventricular
A point of caution here is, other possible causes of angiogram of such patients resembles the pot. A
such ECG abnormalities like dyskalemia must be special form of stress cardiomyopathy with apical
ruled out before tagging them as stroke related. ballooning seen also in patients with subarachnoid
haemorrhage.
3. Structural abnormalities/ functional:
4. Biochemical:
Left ventricular dysfunction: This may be seen in
pre-existing coronary artery disease which is further Cardiac enzyme abnormalities: Elevation of cardiac
worsened by the current stroke related stressors ( muscle enzymes namely Creatine kinase , Creatine
as both of them share many risk factors) or de novo kinase -MB, Troponin I are seen in both ischemic and
as evidenced in clinical studies wherein left ventric- hemorrhagic stroke and correlates with the devel-
ular dysfunction have been documented in the pres- opment of cardiac arrhythmias, Left ventricular dys-
ence of normal coronary angiogram. Both regional function and severity of neurologic injury. Female
and global l wall motion abnormalities are seen in

Cardio Diabetes Medicine

138 Cardio Diabetes Medicine 2017

gender is observed as risk factor for neurogenic car- carboxykinase(PEPCK) and glycogen phosphory-
diac enzyme elevation. The pattern of enzyme eleva- lase (GPase) thereby resulting in hyperglycemia. In
tion in coronary artery disease and neurogenic myo- skeletal muscles, down regulation of insulin recep-
cardial injury are different, helping us to differentiate tor expression results in decreased translocation of
between the two. In case of neurogenic myocardial glucose transporter (GLUT4) into plasma membrane
damage the rate of enzyme elevation will be slow and hence hyperglycemia, because of impaired glu-
and the peak values will be low but in coronary artery cose utilization by the skeletal muscles
disease related myocardial injury there will be rapid
elevation of cardiac enzymes and the peak values
will be high(1) .

Effects of stroke on diabetes Figure 4. Mechanisms of Post Stroke Hyperglycemia

The effect of diabetes on the pathogenesis and the Altered adipokine kinetics during ischemic stroke
outcome of stroke is a well known entity. But, not has been demonstrated in human and animal stud-
much is known about the effects of stroke on diabe- ies. Among the various adipokines known, four
tes and more research is needed to explore this area. needs special mention namely –TNF-alpha, resistin,
Diabetes and stroke produces detrimental effects on adiponectin and leptin. Expression of diabtogenic ad-
each other, setting a vicious cycle at least during the ipokines Viz., TNF-alpha and resistin are up regulated
acute phase of stroke. Most evidences (animal and in stroke which by downstream pathways increases
human) available for the effects of stroke on diabe- insulin resistance and worsens diabetes. Conversely,
tes are for ischemic strokes. the levels of insulin sensitizing adipokines viz., leptin
Ischemic cascade of stroke produces inflammatory and adiponectin are decreased(2).
cytokines, which acts on the hypothalamo-pitutary-
adrenal axis and increases synthesis of cortisol and Controversies exist whether the size or site of the
catecholamines, which in turn increases gluconeo- lesion determines the development and severity of
genesis and insulin resistance and thereby results in post stroke hyperglycemia. Some studies favours that
hyperglycemia( fig.3) insular involvement is associated with post stroke hy-
perglycemia. Autonomic nervous system acts as a
. messenger between central nervous system and pe-
Figure 3 Effects of Cytokines on Hypothalamo - ripheral tissues for exchanging information regarding
the energy status. Hence insular involvement produc-
Pitutary-Adrenal Axis es post stroke hyperglycemia. Even in the studies
Animal models of middle cerebral artery occlusion which showed a directly proportional relationship be-
(MCAO) have shown 1.increased basal secretion of tween the infarct volume and hyperglycemia , insula
insulin, suggesting impaired sensitivity to insulin 2. was within the infracted volume of tissue(2).
Failure of increase in serum insulin concentration fol-
lowing glucose load, suggesting insufficient insulin All the above mentioned mechanisms explain the
secretion. post stroke hyperglycemia in the acute phase of
Ischemic stroke produces decreased expression of stroke. There are significant proportion of individ-
insulin receptors (InsR) in the peripheral tissues like uals in whom, either diabetes or impaired glucose
liver and skeletal muscles. In liver, decreased expres- tolerance is documented at 3 months and 12 months
sion of insulin receptors results in increased levels of post stroke in the absence of prior history of diabetes
gluconeogenic enzymes like phosphoenolpyruvate and/or normal HbA1c at the time of admission(4). The

GCDC 2017

Effect of Stroke on Heart, Diabetes and Hypertension 139

possible mechanisms for this are not yet very clear
and needs further research.

Effect of stroke on hypertension Figure 5. Differential Influence of The Two
Hemispheres On Vasomotor Centre
Hypertension is one of the modifiable risk factors
for stroke and stroke in turn can affect pre-exist- In most strokes one or the other structures are af-
ing hypertension or produce an acute hypertensive fected because of widespread nature of these control
response due to various factors. Both low and high systems resulting in altered autonomic balance and
blood pressure values are detrimental to the outcome hence the blood pressure. This is the most import-
of stroke as shown in the International stroke trial, ant mechanism underlying blood pressure changes
which suggests a ‘U’-shaped relationship between following stroke. Other less important mechanisms
systolic blood pressure and stroke outcome in terms or causes that might contribute to blood pressure
of both morbidity and mortality. Hence, a detailed un- changes following stroke includes increased serum
derstanding of the pathophysiology of acute hyper- levels of cathecholamine and cortisol secondary to
tensive response is absolutely essential for an appro- release of inflammatory mediators from infracted tis-
priate management. Even though stroke can affect sue, infection, urinary retention(5).
blood pressure in either way, the acute hypertensive
response is more common than the other, seen ap- Few studies have shown that the pattern and course
proximately in 50% of stroke patients according to of blood pressure changes following stroke are sub-
international studies. Acute hypertensive response type specific, with lacunar infarcts showing high-
of stroke is defined as “Elevation of blood pressure er blood pressure at the time of admission and 24
above normal or premorbid values within 24 hours hours later when compared to cardio-embolic and
of stroke onset”(5). large vessel atherothrombotic strokes(5).

In few patients it may be because of undiagnosed Post thrombolysis hypertension is associated with
or undertreated chronic hypertension but in most pa- poor outcome at 90 days which is probably relat-
tients it is because of stroke specific and stroke re- ed to failure of recanalisation,( as recanaliastion is
lated causes as evidenced by normalization of blood associated with early spontaneous decline in blood
pressure over few days and early spontaneous de- pressure )or reperfusion injury resulting in release of
cline in blood pressure following thrombolytic ther- inflammatory cytokines from the infarcted tissue and
apy. thereby resulting in hypertension.

In human brain the parasympathetic system is later-
alised to left cerebral hemisphere with inhibitor inputs
from the prefrontal region and excitatory inputs from
the insular cortex. Similarly the sympathetic system
is lateralized to right cerebral hemisphere with similar
excitatory and inhibitory inputs. These two systems
are further modulated by amygdala, hypothalamus
and cingulate cortex. The final outputs from these
two systems are through the brainstem structures(

On the converse

The pathophysiology of stroke is influenced by (Ta-
ble:1)

Cardio Diabetes Medicine

140 Cardio Diabetes Medicine 2017

Heat Diabetes Hypertension
1. Qualitative or quantitative lschemic
High Risk
change in platelets 1. Large vessel atherothrombotic
1. Atrial fibrillation disease
2. Left atrial or ventricular 2. Qualitative or quantitative
increase in procoagulant 2. Small vessel occlusive disease
thrombus and myxoma activity
3. Dilated cardiomyopathy 3. Hypertensive heart disease
4. Recent anterior wall MI 3. Quantitative or qualitative
5. Mitral stenosis decrease in antithrombotic Hemorrhagic
6. Endoca rditis activity
7. Prosthetic valve 1. Charcot-bouchard aneurysm
Low risk Decreased fibrinolysis
2. Acute hypertensive crisis
1. Congestive cardiac failure 1. Decreased activity of t-PA
2. Dys/akinetic ventricular wall 3. Anurysmal sub-arachnoidl
3. Atrilal septal aneurysm 2. Increased PAI-1 & alpha haemorrhage
4. Mitral-valve prolapsed
5. Patent foramen ovale 2 antiplasmin

Table 1 : Mechanism Of Stroke In Heart Disease, Diabetes And Hypertension

Caveats, controversies and captivating issues in the more randomized clinical trials are required to refute
management of these co-morbidities in the presence or recommend its use.
of stroke:
Conclusion
Management of hyperglycemia with insulin in the
acute phase of stroke is being followed for decades. Hypertension, diabetes and cardiac diseases play a
Recently interest has shifted towards use of oral an- major role in the pathogenesis and in deciding the
ti-diabetic drugs both for diabetic and non-diabetic final outcome of stroke. Stroke in turn affects these
indications. Metformin is shown to improve function- three entities adversely. Even though it appears as
al recovery after stroke if started weeks before stroke an oversimplification of the above discussed com-
or weeks after stroke in experimental animals. But, plex pathophysiological process, autonomic system
metformin in the acute phase is shown to be asso- dysregulation secondary to brain damage plays a key
ciated with increased infarct volume probably related role in the effects of stroke on heart, diabetes and
to neuronal AMPK activation leading on to increased hypertension.
lactate accumulation. Intravenous formulations of
glyburide is shown to reduce the risk of cerebral ede- References:
ma by acting on specific channel proteins involved in
the pathogenesis of cerebral edema. 1. Kopelnik A, Zaroff JG. Neurocardiogenic injury in neurovascular disorders.
Critical care clinics. 2006 Oct 1;22(4):733-52.
In the management of hypertension during acute
phase of stroke the target blood pressure and the 2. Harada S, Fujita-Hamabe W, Tokuyama S. Ischemic stroke and glucose
time to start therapy has to be individualised as it intolerance: a review of the evidence and exploration of novel therapeutic
is determined by multiple factors. In general vaso- targets. Journal of pharmacological sciences. 2012;118(1):1-3.
dilatory antihypertensive agents are to be avoided
as they impair cerebrovascular auto regulation and 3. Johansson Å, Ahren B, Näsman B, Carlström K, Olsson T. Cortisol axis ab-
there by worsen the ischemia. There are few studies normalities early after stroke–relationships to cytokines and leptin. Journal
to support the use of beta-blockers and/or ACE in- of internal medicine. 2000 Feb 1;247(2):179-87.
hibitors for the management of hypertension in pa-
tients with stroke as they are shown to decrease the 4. Dave JA, Engel ME, Freercks R, Peter J, May W, Badri M, Van Niekerk
risk of infections especially pneumonia but further L, Levitt NS. Abnormal glucose metabolism in non-diabetic patients pre-
senting with an acute stroke: prospective study and systematic review.
QJM: An International Journal of Medicine. 2010 Apr 28;103(7):495-503.

5. Qureshi AI. Acute hypertensive response in patients with stroke. Circula-
tion. 2008 Jul 8;118(2):176-87.

GCDC 2017

Cardio Diabetes Medicine 2017 141

Thyroid Dysfunction, Diabetes
and the Cardiac Link

Dr. Muthukumaran Jayapaul, MBBS., MD (UK)., MRCP (UK)., CCT (Int. Med & Endo).,

Arka Center for Hormonal Health Pvt Ltd

Abstract Thyroid dysfunction, Diabetes and the
Cardiac link
Thyroid dysfunction and Diabetes mellitus are two
common disorders encountered in day-to-day endo- Thyroid dysfunction and Diabetes mellitus are two
crine practice. The prevalence of both conditions re- common disorders encountered in day-to-day endo-
mains high and continues to rise as with advancing crine practice. The prevalence of both conditions re-
age. Hypothyroidism and hyperthyroidism has been mains high and continue to rise as with advancing age.
investigated to be associated with diabetes mellitus. Hypothyroidism and thyroid over-activity has been
Common susceptibility genes have been acknowl- investigated to be associated with diabetes mellitus.
edged to confer a risk for development of both au- A recent meta-analysis reported an increased prev-
toimmune thyroid disease and type 1 diabetes mel- alence of around 11 % of thyroid dysfunction in pa-
litus. The association between autoimmune thyroid tients with diabetes[1]. The major etiological factor of
disease and type 1 diabetes has been recognized as concern in these patients is suspected autoimmunity.
a variant of autoimmune polyglandular syndrome Most parts of the world including India have become
referred to as APS3 variant.In hypothyroidism, glu- iodine replete, post-iodisation programmes in their
cose-induced insulin secretion by the β-cells is re- respective countries except for isolated areas. The
duced. The rates of glucose oxidation and glycogen current common etiological factors stand as primary
synthesis are also decreased in hypothyroidism. Ex- atrophic hypothyroidism, Hashimoto’s thyroiditis and
cess thyroid hormone leads to hyperglycaemia via autoimmune hyperthyroidism. The knowledge of this
multiple mechanisms which association is crucial so that appropriate diagnostic
and therapeutic provisions could be made to prevent
include increased glucose absorption in the gastro- worsening of both these conditions. When untreated
intestinal tract, increased hepatic glucose output, hy- both hypothyroidism and diabetes aggravate compli-
perinsulinaemia, increased free fatty acid levels and cations such as increasing cardiovascular morbidity
increased peripheral glucose transport. The increased and mortality, worsening of lipids, fluctuating glycae-
hepatic glucose output leads to hyperinsulinaemia, mia, and declining cognitive function.
progression to glucose intolerance and further de-
velopment of peripheral insulin resistance.Hyperthy- Untreated or sub-optimally managed diabetes both
roidism may complicate or exacerbate pre-existing type1 and type 2 diabetes, may induce a low T3 state
heart disease because of increased myocardial ox- characterized by both low total and free T3 levels but
ygen demand, increased contractility and heart rate. normal TSH and free T4 levels. It is well documented
The prevalence of atrial fibrillation peaks up to 15 % that both thyroid diseases and type 1 diabetes share
in patients older than 70 years. There is evolving ev- a common etiological factor – autoimmunity. In type
idence that early management of sub-clinical hypo- 2 diabetes the core pathological defect is likely to
thyroidism and sub-clinical hyperthyroidism may play be due to inappropriate secretion of insulin – beta
a role, in preventing or worsening heart disease in cell dysfunction. Here the pancreas is unable to com-
individuals less than 65 years. The knowledge of this pensate for the prevailing insulin resistance. This de-
association is crucial so that appropriate diagnostic fective insulin secretion leads to various metabolic
and therapeutic provisions could be made to prevent aberrations in Type 2 diabetes, including decreased
worsening cardiovascular risk.

Cardio Diabetes Medicine

142 Thyroid Dysfunction, Diabetes and the Cardiac Link

insulin stimulated glucose uptake, increase hepatic itive patients. Positive TPO antibodies have been re-
glucose output and impaired lipid homeostasis. ported as high as 38% of diabetic individuals and are
a strong predictor for the development of future hy-
Prevalance of thyroid disease and diabetes pothyroidism. The association between autoimmune
thyroid disease and type 1 diabetes has been rec-
The earliest study on the prevalence of thyroid dys- ognized as a variant of autoimmune poly glandular
function wasfrom the Wickhamsurvey, which showed syndrome referred to as APS3 variant. Common sus-
a prevalence of thyroid dysfunction in male adults ceptibility genes have been acknowledged to confer
in England to be 6.6%. The mean annual incidence a risk for development of both autoimmune thyroid
of spontaneous hypothyroidism during a 20-year fol- disease and type 1 diabetes mellitus.
low-up period was 3.5 per 1000 and 0.6 per 1000 in
surviving females and males, respectively. A raised Peripheral Effects of Thyroid Hormones on
TSH or positive antibodies alone or in combination Insulin Secretion and Sensitivity
were associated with an increased risk of future hy-
pothyroidism[2]. The annual risk of developing hy- Thyroid hormone actions on peripheral tissues fur-
pothyroidism was 4 percent when they had a higher ther explain the global effects of thyroid function on
TSH than 2 and raised antibodies. The risk impart- insulin secretion, action and glucose uptake. Insulin
ed by TSH and antibodies were additive and inde- secretion is under direct control of thyroid axis. In
pendent of each factor.In the Colorado prevalence hypothyroidism, glucose-induced insulin secretion
study, 9.5 percent had an elevated thyroid-stimu- by the β-cells is reduced. Experimental hypothyroid-
lating hormone, while another 2.2% had a low TSH. ism in healthy subjects affect glucose uptake. The
Recent Indian data suggest that 3.9% of the study rates of glucose oxidation and glycogen synthesis
population was found to have overt hypothyroidism are decreased in hypothyroidism (Figure 1). Insulin
and a further 9.4% have subclinical thyroid disease. sensitivity further improves in parallel with increasing
The prevalence of thyroid dysfunction increases with thyroxine concentrations across the normal range.
advancing age and is higher in women at 11.4% com- Hypothyroidism is also associated with reduced re-
pared to 6.2% in men. nal clearance of insulin leading to reduced require-
ments of further insulin secretion[4]. Clinically, insu-
The co-existence of diabetes mellitus and hypothy- lin requirements are decreased in diabetic patients
roidism is very common in day-to-day clinical prac- in untreated hypothyroidism increasing the risk of
tice. There is evolving data that patients with dia- hypoglycemia. Correction of hypothyroidism will im-
betes are more prone to thyroid dysfunction when prove insulin doses to basal requirements. Recurrent
compared to the general population. Patients with hypoglycemia despite correction of hypothyroidism
organ-specific autoimmune disease are at a risk of would need exclusion of associated pituitary or ad-
developing other autoimmune disorders. Women renal failure.
with type 1 diabetes show a very high prevalence of
hypothyroidism at 31% with an overall prevalence of Gene array studies of human skeletal muscle in hy-
thyroid disease with diabetes at 13.4 %[3]. The prev- pothyroid and euthyroid subjects suggest a marked
alence of thyroid dysfunction in type 2 diabetes from impact on glucose transporter expression with down
Greece and Saudi Arabia are 12.3 and 16 % respective- regulation of GLUT5 in hypothyroidism. In these stud-
ly. One recent report from India suggested that up to ies, GLUT4 expression was not significantly altered.
30 % of patients with type 2 diabetes had some form Animal models indicate impaired GLUT4 transloca-
of thyroid dysfunction. In this particular cohort, 16% tion to the plasma membrane and negative regula-
had sub-clinical hypothyroidism, 11% had overt hypo- tion of enzymatic breakdown of intracellular glucose
thyroidism, 2% sub-clinical hyperthyroidism and 1.5% in both hyperthyroidism and hypothyroidism. This
had frank hyperthyroidism.The prevalence of thyroid appears to depend critically on the intracellular gen-
disorder in the diabetic population is higher at 13.4 % eration of free T3 as polymorphisms of DIO2 with de-
and women tend to show an even higher prevalence creased T3 generation are associated with some de-
at 31.4% compared to male type 2 diabetic subjects. gree of insulin resistance.Insulin resistance has been
also reported in subclinical hypothyroidism, adding
Thyroid autoimmunity remains the most frequent au- one more possible mechanism to the association of
toimmune disorder associated with type 1 diabetes. sub-clinical hypothyroidism and cardiovascular risk.
This was shown in a cross-sectional study involving In subclinical hypothyroidism, there is diminished
1419 children with type 1 diabetes mellitus, where 3.5% rate of insulin stimulated glucose transport caused
had Hashimoto’s thyroiditis. A 3.5-fold increased risk by altered expression of glucose transporter GLUT
of autoimmune thyroiditis was noticed in GADA pos-

GCDC 2017

Cardio Diabetes Medicine 2017 143

Figure 1 .The interface between thyroid and diabetes mellitus

2 leading to insulin resistance[4]. Both in euthyroid, They include adverse effects on systolic and dia-
non-diabetic and diabetic adults, those small varia- stolic function, endothelial dysfunction, lipid levels
tions in TSH at different levels of insulin sensitivity and have been shown to affect cardiovascular risk
might exert a marked effect on lipid levels. The inter- independently. It is well documented that thyroid
action between insulin resistance and lower thyroid dysfunction at both hyper and hypo function wors-
function might be a key determinant for a more ath- ens heart failure events. It is now established that
erogenic lipid profile in these populations. in patients with heart failure both hypothyroidism
and sub-clinical hypothyroidism increased the risk
Thyroid dysfunction, diabetes and heart of death[5]. In another study both higher TSH > 10
disease mIU/L and TSH < 0.10 mIU/L was associated with
increased heart failure events[6]. It is well known that
It is well known that excess thyroid hormone leads heart failure is a final common pathway affecting the
to hyperglycaemia via multiple mechanisms which cardiovascular system due to poorly treated diabe-
include increased glucose absorption in the gastro- tes, dyslipidaemia or hypertension. Hypothyroidism
intestinal tract, increased hepatic glucose output, hy- and diabetes has been considered as independent
perinsulinaemia, increased free fatty acid levels and factors for increasing cardiovascular risk. It has been
increased peripheral glucose transport. The most im- well proven that hypothyroidism affects cardiovascu-
portant mechanism seems to be increased hepatic lar dynamics is several ways including increased sys-
glucose output leading to hyperinsulinaemia, further temic vascular resistance, diastolic dysfunction, re-
progression to glucose intolerance and development duced systolic function and reduced cardiac preload.
of peripheral insulin resistance. This development Treatment with appropriate thyroxine dosage revers-
may even proceed to extremes such as ketoacidosis es these abnormalities. The increased cardiovascular
both in type 1 and type 2 diabetes. Severe hyperthy- risk can be attributed to dyslipidaemia predominantly
roidism has significant anti-lipolytic effects and in- increased LDL, diastolic dysfunction, increased arte-
creased β-oxidation of thyrotoxicosis. The increased rial stiffness, altered coagulability and raised hs-CRP.
insulin requirements will subside when thyrotoxicosis These abnormalities are also present in diabetes,
is treated. In patients with unexplained diabetic ke- which aggravates risk. Lipoprotein a is also found
toacidosis, thyrotoxicosis has to be excluded as a to be increased individuals with hypothyroidism and
precipitating factor. diabetes in independent studies which has been a
good surrogate marker of predicting cardiovascular
Hypothyroidism and diabetes are well known to disease. In a large meta-analysis evaluating subclin-
affect the cardiovascular system in multiple ways.

Cardio Diabetes Medicine

144 Thyroid Dysfunction, Diabetes and the Cardiac Link

ical hypothyroidism and coronary heart disease there In the NHANES III the prevalence was around 3.2%
was a modest elevation of risk particularly in individ- with a TSH cut of 0.4 mIU/L. Excessive thyroid hor-
uals younger than 65 years (Figure 2). Two observa- mone has important effects on the cardiac muscle,
tional studies provide us with good insight such as peripheral circulation and the sympathetic system.
United Kingdom General Practitioner database where The main changes are increased heart rate, cardiac
50% of individualsaged 40-70 years old treated with contractility, mean pulmonary artery pressure, car-
L-thyroxine, with TSH between 4.5-10 mIU/L hazard diac output and myocardial oxygen consumption. It
ratio of cardiac events reduced (0.67, CI 0.49 – 0.92). also reduces systemic vascular resistance and dia-
The Cleveland clinic looked at high risk patients with stolic pressure.
a TSH between 6.1-10 and >10 mIU/L who were under
65 years old and patients not treated with thyroxine Metformin and thyroid function
had higher all-cause mortality.
Metformin, an oral anti-diabetic compound, is regard-
Walsh et al. (ref 38) ed as a first-line drug for treatment of type 2 diabe-
tes. It reduces mortality among overweight patients
Hak et al. (ref 193) with diabetes and also used for prevention of diabe-
tes in high-risk individuals.
Imaizumi et al. (ref 194)
Metformin acts primarily by suppressing hepatic glu-
Kvetny et al. (ref 196) coneogenesis via activation of AMPK, a prerequisite
for the drug’s inhibitory effect at the hepatic level.
Parle et al. (ref 229)
Metformin is not metabolized but is transported by
Rodondi et al. (ref 231) the organic cation transporters, OCT1 and OCT2. Met-
formin has opposite effects on hypothalamic AMPK,
Cappola et al. (ref 230) inhibiting activity of the enzyme. These metformin ef-
RISK fects on hypothalamic AMPK activity will counteract
50 60 70 80 90 years T3 effects at the hypothalamic level. AMPK therefore
represents a direct target for dual regulation involved
Gussekloo et al. (ref 92) in the hypothalamic partitioning of energy homeo-
stasis[4].
Figure 2;Sub-clinical Hypothyroidism and the risk of
heart disease In rats, metformin has recently been shown to cross
the blood–brain barrier and its concentrations in the
Hyperthyroidism may complicate or exacerbate hypothalamus match the levels in plasma. Inter-
pre-existing heart disease because of increased estingly, metformin levels in the pituitary gland are
myocardial oxygen demand, increased contractility substantially increased it is supposed to suppress-
and heart rate. Many patients experience exercise es pituitary TSH secretion. In a small retrospective
intolerance and dyspnea on exertion due to inability study, metformin suppressed TSH to subnormal lev-
of the heart to increase heart rate or lower vascular els, without signs of hyperthyroidism or changes in
resistance. About 6 % of thyrotoxic patients develop FT4 and FT3.In prospective studies of patients with
heart failure and < 1 % develop dilated cardiomyopa- diabetes and hypothyroidism on stable thyroxine
thy with impaired LV systolic function due to tachy- treatment, metformin administration for 3 months
cardia-mediated mechanisms. All these potential lowered serum TSH concentrations with opposite ef-
mechanisms are likely to aggravate an ailing diabetic fects on metformin withdrawal. This effect was not
heart. The most common ECG abnormality is sinus reproduced in non-diabetic controls. In another study,
tachycardia, shortened PR interval and intra-atrial 1 year of metformin administration, significant TSH
prolongation of conduction leading to increase in P decrease was observed in diabetic subjects withhy-
wave duration. The prevalence of atrial fibrillation in pothyroidism who were treated (2.37 ± 1.17 to 1.41 ± 1.21
overt hyperthyroidism was 13.8 % peaking up to 15 mIU/l) with thyroxine. No significant change in free
% in patients older than 70 years in one particular T4 was observed in any group[7]. Questions remain
study. In subjects with atrial fibrillation maintenance regarding the interaction between metformin and
of sinus rhythm is not possible until euthyroid status thyroid status despite its convincing suppression of
is restored, hence it is advisable to defer cardio-ver- TSH.
sion until the same is achieved.
Monitoring of thyroid function in Diabetes
Sub-clinical Hyperthyroidism is defined by low or un-
detectable serum TSH and normal free T4 and free T3
concentrations. This became simpler to identify due
to the availability of third generation assays that have
a functional sensitivity of 0.01- 0.2 mIU/L, discrimi-
nate between complete and incomplete suppression.

GCDC 2017

Cardio Diabetes Medicine 2017 145

Close monitoring of thyroid function particularly in Hyperthyroidism leads to hyperglycaemia affecting
patients with type 1 diabetes has long been advocat- carbohydrate metabolism through multiple mecha-
ed. An initial TSH 0and ATPO antibody testing will nisms.
help to predict the development of hypothyroidism
in patients with type 1 diabetes. The British Thyroid Hyperthyroidism and Hypothyroidism may compli-
Association supports ATPO testing at baseline and cate or exacerbate pre-existing heart disease.
TSH monitoring at yearly intervals in type 1 diabetes.
Guidelines remain unclear on testing for thyroid dys- Early intervention of sub-clinical hypothyroidism and
function in newly diagnosed type 2 diabetes. There sub-clinical hyperthyroidism may prevent heart dis-
are large variations in the different guidelines, rang- ease in individuals less than 65 years.
ing from ignoring thyroid function to yearly testing.
Various studies have been undertaken to understand References
the role, importance, and need of determination of
thyroid dysfunction in the patients with type 2 diabe- 1. Wu P. Thyroid disorders and diabetes. It is common for a person to be
tes[8]. Regular screening for thyroid abnormalities in affected by both thyroid disease and diabetes. Diabetes self-management.
all diabetic patients may allow early treatment of sub- 2007 Sep-Oct;24(5):80-2, 5-7.
clinical thyroid dysfunction. It has also been proposed
that in type 2 diabetic patients, a TSH test should be 2. Vanderpump MP, Tunbridge WM, French JM, Appleton D, Bates D, Clark
performed at diagnosis and then repeated at least F, et al. The incidence of thyroid disorders in the community: a twen-
every 5 years. A sensitive serum TSH assay is the ty-year follow-up of the Whickham Survey. Clinical endocrinology. 1995
screening test of choice and treatment interference Jul;43(1):55-68.
needs to be taken into account. Some guidelines
suggest thyroid function testing only when there is 3. Perros P, McCrimmon RJ, Shaw G, Frier BM. Frequency of thyroid dysfunc-
a clinical suspicion of autoimmune disease.Recent tion in diabetic patients: value of annual screening. Diabet Med. 1995
recommendations suggest more frequent testing, Jul;12(7):622-7.
on an annual basis in patients over 50 with goiter,
suspicious symptoms or raised antibody titres or with 4. Duntas LH, Orgiazzi J, Brabant G. The interface between thyroid and
dyslipidaemia. diabetes mellitus. Clinical endocrinology. Jul;75(1):1-9.

Conclusion 5. Rhee CM, Curhan GC, Alexander EK, Bhan I, Brunelli SM. Subclinical hy-
pothyroidism and survival: the effects of heart failure and race. The Journal
A complex pattern of interactions between thyroid of clinical endocrinology and metabolism. Jun;98(6):2326-36.
metabolism and diabetes is well established and a
multifaceted cardiac link is evolving. Treating both 6. Gencer B, Collet TH, Virgini V, Bauer DC, Gussekloo J, Cappola AR, et
thyroid function and diabetes early and aggressively al. Subclinical thyroid dysfunction and the risk of heart failure events: an
may offer cardiovascular risk reduction. Basal mech- individual participant data analysis from 6 prospective cohorts. Circulation.
anisms controlling appetite and energy expenditure Aug 28;126(9):1040-9.
is evolving. Increasing evidence suggests that insulin
sensitivity or drugs used to modulate it, will also af- 7. Cappelli C, Rotondi M, Pirola I, Agosti B, Gandossi E, Valentini U, et al.
fect thyroid function. Better definition of interactions TSH-lowering effect of metformin in type 2 diabetic patients: differences
between glucose metabolism and thyroid hormones between euthyroid, untreated hypothyroid, and euthyroid on L-T4 therapy
is necessary to optimize treatment of patients with patients. Diabetes care. 2009 Sep;32(9):1589-90.
diabetes mellitus reduce heart disease risk.
8. Wang C. The Relationship between Type 2 Diabetes Mellitus and Related
Thyroid Diseases. Journal of diabetes research.2013:390534.

Highlights

The prevalence of diabetes and thyroid dysfunction
remains high in the general population.

Common susceptibility genes confer risk for develop-
ment of both autoimmune thyroid disease and type
1 diabetes mellitus.

In hypothyroidism, insulin secretion is reduced; glu-
cose oxidation and glycogen synthesis are also de-
creased.

Cardio Diabetes Medicine

146 Cardio Diabetes Medicine 2017

Mechanism, Clinical Presentation and
Treatment of Diabetic Kidney Diseases

Prof. Soundarajan, MD., DM., Phd., FRCP (Glasg).,

HOD Nephrology Saveetha Medical College, Chennai.

Abstract most common reason for progressing to end stage
renal disease in the US and in many parts of the
Diabetic kidney disease develops in approximately world [3–5]. The number of people initiating treatment
40% of patients who are diabetic and is the lead- for ESRD related to diabetes was 48,374 people in
ing cause of CKD worldwide. Although ESRD may 2008, more than 18- fold what it was in 1980. DKD
be the most recognizable consequence of diabetic was previously known as diabetic nephropathy and
kidney disease, the majority of patients actually die is defined as diabetes with albuminuria (ratio of urine
from cardiovascular diseases and infections before albumin to creatinine ≥ 30 mg/g), impaired glomerular
needing kidney replacement therapy. The natural filtration rate (<60ml/min/1.73m2) or both and is the
history of diabetic kidney disease includes glomeru- single strongest predictor of mortality in patients with
lar hyperfiltration, progressive albuminuria, declining diabetes . Today, DKD encompasses not only diabet-
GFR, and ultimately, ESRD. Metabolic changes asso- ic nephropathy but also atheroembolic disease, isch-
ciated with diabetes lead to glomerular hypertrophy, emic nephropathy, and interstitial fibrosis that occurs
glomerulosclerosis, and tubulointerstitial inflamma- as a direct result of diabetes.
tion and fibrosis. Despite current therapies, there is
large residual risk of diabetic kidney disease onset Previously, histopathological changes seen in dia-
and progression. Therefore, widespread innovation betic kidney disease , were attributed primarily to
is urgently needed to improve health outcomes for metabolic and hemodynamic derangements seen
patients with diabetic kidney disease. Achieving this in diabetes, the latter referring to the hyperfiltration
goal will require characterization of new biomarkers, which occurs as a result of efferent arteriolar vaso-
designing clinical trials that evaluate clinically per- constriction due to an activated renin-angiotensin-al-
tinent end points, and development of therapeutic dosterone system (RAAS). However, it has become
agents targeting kidney - specific disease mecha- increasingly evident over the years that hyperglyce-
nisms (e.g., glomerular hyperfiltration, inflammation, mia in and of itself is not the sole cause of DKD,
and fibrosis) although inarguably, it plays a major role. Several
pathophysiologic pathways are involved in the de-
Diabetes has long been a growing epidemic in the velopment of DKD.
United States (US) and around the world. In 2011,
there were 20.8 million people aged 18 years and Mechanism of DKD
older who carried a diagnosis of diabetes in the US
alone [1].The number of adults aged 18–79 in the US Hemodynamic Pathways of DKD
that were newly diagnosed with diabetes has more
than tripled from 493,000 in 1980 to over 1.5 million Activation of the RAS leads to increased angiotensin
in 2011 [2]. The increased prevalence of diabetes has II levels which subsequently cause efferent arteriolar
also led to an increase in the number of macro- and vasoconstriction. Elevated levels of angiotensin II are
microvascular complications of diabetes such as associated with increased albuminuria and nephrop-
coronary heart disease, stroke, visual impairment, athy in both humans and mice [8,9,10]. ACEIs and
diabetic kidney disease (DKD), and end stage renal ARBs have a long track record in reducing the dou-
disease (ESRD). Additionally, diabetes remains the bling rate of creatinine, albuminuria, and progression
to nephropathy, ESRD, and death. Another potent va-

GCDC 2017

Mechanism, Clinical Presentation and 147
Treatment of Diabetic Kidney Diseases

soconstrictor of the efferent arteriole is endothelin-1 Glycolysis is the biochemical pathway in which glu-
(ET-1). ET-1 has various physiologic functions in the cose is broken down by cells to make energy. In
kidney that mimic RAS including mediating vasocon- a normoglycemic environment, that is, in patients
striction and hence playing a role in hypertension, without diabetes, glycolysis proceeds down its well
endothelial dysfunction, inflammation, and fibrosis. described path without shunting into the polyol path-
Additionally, increased ET-1 expression activates a way, hexosamine pathway, or pathways that would
signaling cascade which leads to mesangial cell hy- lead to AGE production or PKC activation. (b) In a
pertrophy and proliferation as well as extracellular hyperglycemic environment, as would be seen in
matrix (ECM) production. patients with either type 1 or type 2 diabetes, high
glucose conditions lead to activation of excess su-
Metabolic Pathways of DKD peroxide which then inhibits the enzyme GADPH.
This prevents glycolysis from proceeding down its
This pathway was first detailed by Brownlee in Na- natural course and creates a backlog of glycolysis
ture in 2001 [16]. He helped clarify that hyperglycemia precursors. Increased levels of glucose upregulate
leads to increased glycolysis which then upregulates the polyol pathway whereas increased levels of fruc-
four distinct entities: the polyol pathway, hexosamine tose-6-phosphate upregulate the hexosamine path-
pathway, production of advanced glycation end prod- way. Increased levels of glyceraldehyde-3-phosphate
ucts (AGEs), and activation of protein kinase C (PKC). upregulate both AGE precursors and DAG, the latter
Before going into the details of each of the above being a cofactor for PKC activation.
pathways, a review of glycolysis is worthwhile. Gly-
colysis is the biochemical pathway in which glucose Inflammatory Pathways of DKD
is broken down by cells to make energy. Intracellu-
lar glucose is first broken down into glucose-6-phos- The inflammatory pathway supports the idea that
phate and then fructose-6-phosphate. One step later DKD is not solely a result of uncontrolled hemody-
glyceraldehyde- 3-phosphate becomes 1,3-diphos- namics and hyperglycemia but is also a consequence
phoglycerate with the help of glyceraldehyde-3-phos- of a chronically activated innate immune system and
phate dehydrogenase (GADPH) . This is important be- a low-grade inflammatory state in patients with dia-
cause GADPH is inhibited by excess superoxide pro- betes. NF-κB is a transcription factor that regulates
duced by the electron-transport chain which occurs the expression of multiple genes related to inflam-
in the setting of hyperglycemia. Inhibition of GADPH mation, immunity, apoptosis, and chemoattractant
prevents glycolysis from taking place and causes an protein-1. In DKD, NF-κB activation correlates with
upregulation of upstream component of glycolysis, proteinuria and interstitial cell infiltration. Proteinuria
specifically glucose, glucose-6-phosphate, and fruc- is known to further stimulate NF-κB and contributes
tose-6-phosphate to persistent proteinuria in a cyclic fashion. The Ja-
nus kinase/signal transducers and activators of tran-
scription (JAK/STAT) signaling pathway is a way for
chemical signals outside of a cell to be relayed to
gene promoters at the DNA level. JAK2 is present
in renal and vascular tissue. It is activated by ROS
caused by hyperglycemic states and is associated
with hypertrophy of mesangial cells. Inflammatory
cytokines such as TNF-κ and interleukins 1, 6, and
18 (IL-1, IL-6, and IL-18, resp.) are expressed in greater
proportions in the kidneys of diabetic models when
compared to nondiabetic controls.

Alternative Pathways of DKD

Autophagy is a highly conserved protective mech-

anism that allows cells and organisms to maintain

homeostasis during periods of cell starvation or

oxidative stress. Decreased autophagic activity has

. been demonstrated in both obesity and diabetes [29-
31] suggesting that autophagy is hampered in the

setting of hypernutrition Another conserved evolu-

Cardio Diabetes Medicine

148 Cardio Diabetes Medicine 2017

tionary mechanism is linked to the sodium-glucose Despite current approaches to management of dia-
transporter 2 (SLGT2) in the proximal tubule. SLGT2 betes and hypertension and use of ACE inhibitors
is a low-affinity and high-capacity transporter and is and ARB, there is still large residual risk in DKD. Nov-
responsible for >90% of glucose reabsorption in the el agents targeting mechanisms, such as glomerular
proximal tubule. Animals with a genetic deficiency hyperfiltration, inflammation, and fibrosis, have been
of SLGT2 lose approximately 60% of their filtered a major focus for development of new treatments.
glucose into the urine. In settings of hyperglycemia, Agents that have shown promise include ruboxistau-
there is upregulation of SLGT2 expression which is rin, a protein kinase C-b inhibitor; baricitinib, a se-
believed to be of evolutionary benefit as it allows for lective Janus kinase 1 and Janus kinase 2 inhibitor;
glucose reabsorption and hence energy conservation pentoxifylline, an anti-inflammatory and antifibrotic
for both the body and brain. agent ; atrasentan, a selective endothelin A receptor
antagonist; and finerenone, a highly selective non-
Clinical manifestations and natural history steroidal mineralocorticoid receptor antagonist. How-
ever, thus far, there are no available phase 3 clinical
Clinical stages of type 1 diabetes mellitus renal in- trial data for these agents, and none are approved
volvement is summarized in Table-1. These stages are for use in DKD.
also accepted for type 2 diabetic patients however
they might not always follow these steps . ESRD is References
not the only major consequence of diabetic nephrop-
athy but patients have increased risk of cardiovas- 1. Centers for Disease Control and Prevention. Number (in Millions)
cular disease , morbidity and mortality even in the of Civilian, Noninstitutionalized Adults Diagnosed with Diabetes, United
early stages of nephropathy. Microalbuminuria (30- States, 1980–2014. 2015..
300 mg/day albuminuria) is the first clinical sign
of diabetic nephropathy and this situation is highly 2. Centers forDiseaseControl and Prevention,AnnualNumber (inThousands)
associated with other complications of diabetes like of New Cases of Diagnosed Diabetes Among AdultsAged 18–79 Years,
cardiovascular disease and retinopathy. 24 hour urine United States, 1980–2011,
or spot urine albumin / creatinine ratios should be
used for microalbuminuria follow-up. Overt protein- 3. “Salahudeen AK. Obesity and survival on dialysis. American journal of
uria is defined as >300 mg/day albuminuria and at kidney diseases. 2003 May 31;41(5):925-32.
this stage total protein loss in urine might exceed 1g/
day. 5-7 years after development of overt proteinuria 4. Ritz E, Rychlík I, Locatelli F, Halimi S. End-stage renal failure in type 2
these patients usually develop ESRD. diabetes: a medical catastrophe of worldwide dimensions. American journal
of kidney diseases. 1999 Nov 30;34(5):795-808.
Treatment of DKD
5. A. T. Reutens, “Epidemiology of Diabetic Kidney Disease,” Medical Clinics
Prevention of diabetic complications, particularly ofNorth America, 2013vol. 97, no. 1, pp. 1–18, .
DKD, by long-term intensive glycemic control from
early in the course of diabetes is well established
for DM1 and DM2. However, intensive glucose con-
trol after onset of complications or in longstanding
diabetes has not been shown to reduce risk of DKD
progression or improve overall clinical outcomes. Tar-
geting low HbA1C (6%–6.9%) compared with standard
therapy in this population did not reduce risk of car-
diovascular (CV) or microvascular complications but
increased the risk of severe hypoglycemia. The Amer-
ican Diabetes Association recommends that targets
for glycemia should be tailored to age, comorbidities,
and life expectancy of individual patients.

The KDIGO guidelines recommend use of an ACE or
an ARB and a BP goal ,130/80 mmHg in all patients
with CKD and albuminuria irrespective of diabetes
status (Table 1)

GCDC 2017

Cardio Diabetes Medicine 2017 149

DKD is Coronary Equivalent
(Evidence and Remedy)

Dr.T. Dhinakaran, M.D., MNAMS., D.M.,(Neph)

Director and Chief Nephrologist, Madurai Kidney Centre & Transplantation Research Institute,
6/6 B-2 Sivagangai Road, Madurai.

INTRODUCTION vated plasma creatinine concentration or RRT had an
annual death rate of 19.2% (95% confidence interval,
Cardiovascular disease (CVD) is the leading cause of CI, 14.0–24.4%). There was a trend towards an increas-
death in people with diabetes, especially accounting ing risk of cardiovascular death associated with in-
for approximately 80% of mortality in type 2 diabetic creasing severity of nephropathy (P < 0.0001), with
(T2DM) patients.1,2 The Framingham Heart Study has an annual death rate of 0.7% for subjects with no
shown a 2–10 fold excess risk of CAD, stroke, heart nephropathy, a rate of 2.0% for those with microal-
failure, and CVD death among subjects with diabetes buminuria, a rate of 3.5% for those with macroalbu-
compared with non-diabetic subjects.3 minuria, and a rate of 12.1% for those with an elevated
plasma creatinine concentration or RRT.
The mortality and cumulative incidence of CVD are
much higher in T1DM patients with DN than in those The mechanism through which the relationship be-
without nephropathy.4 The relative risk for T1DM with tween albuminuria and GFR mediate cardiovascular
DN compared with those without DN was 10.3 fold and renal outcomes is an area of great interest. It
higher for coronary heart disease, 10.9 fold higher for has been suggested that albuminuria and reduced
stroke, and 10 fold higher for any CVD, with similar GFR may simply represent the renal manifestations
rates in men and women.4 of systemic endothelial dysfunction6,7 and systemic
atherosclerosis,8,9 respectively. Indeed, it is likely that
PROTEINURIA : GLOMERULAR albuminuria and reduced GFR may be markers of dif-
FILTERATION RATE AND CARDIAC RISK ferent pathologic processes.

The irony is that cardiac risk overtakes the renal HYPERGLYCEMIA
risk at all stages of DN. As renal involvement pro-
gresses, the CV risk also progresses, but at a faster The role of glycemic control in preventing the mac-
pace.5 This intriguing and unexpected deviation in the rovascular complications of diabetes is somewhat
course of renocardiac race is explicitly brought about controversial, although epidemiologic studies have
by an analysis of United Kingdom Diabetes Prospec- shown an association between hyperglycemia and
tive Study (UKPDS) data by Adler et al. macrovascular complications.10-12 For example, in
the UKPDS observational study, each 1% reduction
The progression to microalbuminuria occurred at a in HbA1c was associated with 18% fewer MIs and
rate of 2.0% per year, the progression from microal- 21% fewer diabetes related deaths. But the Action to
buminuria to macroalbuminuria occurred at a rate of Control Cardiovascular Risk in Diabetes (ACCORD)
2.8% per year, and the progression from macroalbu- trial suggests that very aggressive glucose control in
minuria to elevated plasma creatinine (178 µmoL) or patients with established diabetes and either CVD or
renal replacement therapy (RRT) occurred at a rate additional cardiovascular risk factors may result in
of 2.3% per year. Ten years following the diagnosis increased mortality without a reduction in major car-
of diabetes, the prevalence of microalbuminuria was diovascular events.13,14
24.9%, the prevalence of macroalbuminuria was 5.3%,
and the prevalence of an elevated plasma creatinine
concentration or RRT was 0.8%. Patients with an ele-

Cardio Diabetes Medicine

150 DKD is Coronary Equivalent (Evidence And Remedy)

OTHER RISK FACTORS been shown to improve vascular reactivity and re-
duce markers of fibrinolysis and inflammation, and
they may reduce thickening of the carotid artery
wall.22,23 They also reduce BP and may favorably af-
fect the lipid profile.

Table 1 : Risk factors for cardiovascular disease (CVD) in HYPERTENSION AND DYSLIPIDEMIA
T2 DM
Adding further fuel to fire are the two major risk fac-
Traditional risk factors for T2DM, including hypergly- tors: namely hypertension and dyslipidemia which
cemia, hypertension, and dyslipidemia, do not fully includes hypertriglyceridemia ; low levels of high
account for the increased mortality from CVD in pa- density lipoprotein (HDL) cholesterol, and elevated
tients with T2DM.15,16 Insulin resistance and a group levels of low density lipoprotein (LDL) cholesterol.
of associated abnormalities, so-called non traditional Blood pressure control has been shown to reduce the
risk factors, have been identified as probable me- risk of CVD and microvascular complications by one
diators and additional targets for treatment in these third or more in patients with diabetes.In the UKP.
patients (Table 1).17,18 each 10 mm Hg reduction in systolic blood pressure
(SBP) was associated with a reduction of 15% in di-
Role of Insulin Sensitizers abetes-related deaths, 11% in MIs, and 13% in macro-
vascular complications.
Dandona and Aljada et al. have demonstrated that
insulin has anti- inflammatory and reactive oxygen Role of Lipid Management: The characteristic pattern
species (ROS) suppressive effects.19 In vitro studies of dyslipidemia associated with T2DM is one of el-
showed that insulin suppresses several inflammato- evated triglyceride levels, low levels of HDL-C, and
ry mediators; adhesion molecules, chemokines and elevated LDL-C consisting mostly of highly athero-
NFκB binding in human aortic endothelial cells.24 genic small dense LDL particles. Oxidative stress
Metformin is a weak insulin sensitizer that works resulting from hyperglycemia further increases
by reducing hepatic glucose output and increasing the risk of cardiovascular events in these patients.
insulin action in muscle and fat. It was the first insu- For young patients (age ≤ 40 years) without overt
lin sensitizer observed to reduce MIs and mortality CVD, the primary goal is an LDL-C level less than
in patients with diabetes. This effect was found to 100 mg/dL. More aggressive therapy is recommend-
be greater in patients treated with metformin than ed for patients more than 40 years of age, those with
in those who achieved a similar degree of glyce- additional cardiovascular risk factors, and those with
mic control with noninsulin sensitizing agents.20 established CVD. In these high-risk groups, pharma-
In a recent follow-up analysis of the UKPDS, patients cotherapy is recommended, with the goal of achiev-
receiving metformin were found to have significant ing an LDL-C reduction of 30–40%, regardless of the
reductions in the incidence of MI (33%; P < 0.01) and baseline level. In patients at high risk, including those
death from any cause (27%; P < 0.01), even 10 years with acute coronary syndromes or a previous stroke
after the trial ended.21 or MI, a lower target of less than 70 mg/dL may be
appropriate, consistent with the NCEP ATP IIIoptional
Thiazolidinediones (TZDs) are more potent insulin target for high-risk patients.
sensitizers that work primarily by lowering insulin re-
sistance in peripheral tissues. These agents appear NON­TRADITIONAL RISK FACTORS
to have a number of beneficial effects on non-tra-
ditional cardiovascular risk factors associated with However, traditional risk factors for CVD do not fully
insulin resistance. For example, these agents have account for the high prevalence of CVD and CVD
death in patients with CKD, especially DN. Recently,
several non-traditional risk factors have been identi-
fied. There are a number of novel risk factors for CVD
in patients with DN or CKD. These novel risk factors
may participate in inflammation and oxidative stress
in patients with diabetes or CKD.

Homocysteine: Elevations of plasma homocysteine
concentrations occur when the kidneys fail to excrete
homocysteine into the urine.Furthermore, defects of
any enzymes or cofactors involved in homocysteine

GCDC 2017

Cardio Diabetes Medicine 2017 151

metabolism (folate, vitamin B6 or B12) are known to a mortality multiplier; that is, at every decrease in the
cause elevation of the plasma homocysteine concen- hemoglobin concentrations below 12 g/dL, mortality
tration. Several investigators have demonstrated that increases in patients with either CKD or CVD, and
in patients with T2DM, the presence of DN is a ma- those with both. Treatment of anemia with exoge-
jor determinant of elevated plasma total homocys- nous erythropoietin in patients with cardiorenal dis-
teine concentrations because of the reduced renal ease has shown promise in reducing morbidity and
clearance of homocysteine. Several studies suggest in improving survival and quality of life. However, he-
that homocysteine may induce thrombus formation moglobin concentrations more than 12.0 g/dL are not
by disturbing the balance between coagulation and recommended for patients with overt nephropathy.
fibrinolysis. Homocysteine can downregulate the ex-
pression of thrombomodulin (TM) in endothelial cells, Newer Drugs for Diabetes and their CV effects: In the
resulting in inactivation of protein C, a natural an- year 2008, the US FDA issued guidance for industry
ticoagulant. Homocysteine also can upregulate the insisting on evaluating CV risk in new antihypergly-
expression of tissue factor, an initiator of the coag- cemic therapies seeking approval for the treatment
ulation cascade. Thus, homocysteine is associated of T2DM.Based on this data from several Cardio
with the increased generation of thrombin, resulting Vascular Outcome Trials (CVOT) involving DPP-4
in hypercoagulation. inhibitors have been reported. The Trial Evaluating
Cardiovascular Outcomes with Sitagliptin (TECOS )46
Two large-scale prospective studies, which tested showed that sitagliptin was noninferior to placebo
whether treatment with folate and vitamin B6 and for the primary composite CV outcome of CV death,
B12 supplementation improves vascular outcomes, nonfatal myocardial infarction, nonfatal stroke, or
have reported that treatment with B vitamins did not hospitalization for unstable angina. Likewise, the
reduce the risk of major cardiovascular events in Saxagliptin Assessment of Vascular Outcomes Re-
patients with vascular disease, although B vitamins corded in Patients with Diabetes Mellitus–Throm-
supplementation was associated with a reduction bolysis in Myocardial Infarction (SAVOR-TIMI ) Trial
in plasma homocysteine Taken together, although showed noninferiority for saxagliptin when compared
it has been demonstrated that moderate elevation with placebo on the primary composite outcome.
of plasma homocysteine is associated with an in- This trial was done to determine whether alogliptin is
creased risk for CVD, hyperhomocysteinemia may noninferior to placebo with respect to major cardio-
be a marker, rather than a cause, of CVD. vascular events in patients with type 2 diabetes who
are at very high cardiovascular risk — those with recent
Asymmetric Dimethylarginine: Asymmetric dimethy- acute coronary syndromes. In conclusion, among pa-
larginine (ADMA) is an endogenous inhibitor of NO tients with type 2 diabetes and a recent acute coro-
synthase (NOS). In addition to inhibition of NO pro- nary syndrome, treatment with alogliptin resulted in
duction, ADMA may promote uncoupling of eNOS rates of death from cardiovascular causes, nonfatal
and lead to the generation of superoxide, resulting myocardial infarction, and nonfatal stroke that were
in increased oxidative stress. Elevated plasma ADMA similar to those with placebo.
concentrations have been reported in patients with
chronic renal failure, hypercholesterolemia, diabetes,, GLP-1 ANALOGS: Two of the GLP-1 analogs, namely,
and coronoary artery disease. Since renal function is liraglutide and lixisenatide, currently have CVOT data
a main determinant of serum ADMA concentrations available. In the LIRAGLUTIDE Effect and and Action
in humans, circulating ADMA accumulates in pa- in Diabetes: Evaluation of Cardiovascular Outcome
tients with chronic kidney disease. Elevated plasma Results (LEADER) Study, fewer patients experienced
ADMA concentrations are associated not only with the primary composite CV outcome in the liraglutide
endothelial dysfunction but also predict mortality and group when compared with those receiving place-
CVD events in CKD and ESRD. Like CKD, elevated bo. Studies in patients with DKD have additionally
plasma ADMA is associated with the morbidity of shown that liraglutide lowered albuminuria levels in
CVD in early diabetic nephropathy in T1DM patients. patients with normal kidney function or early-stage
Thus, elevated circulating ADMA concentrations may CKD and that liraglutide treatment did not adversely
contribute to endothelial dysfunction, resulting in a affect eGFR and showed improved glycemic control
high incidence of CVD in the setting of DN or CKD. in patients with T2DM and CKD stage 3. Recently re-
leased data from the LEADER Study as well as clini-
Anemia is common in patients with DN as well as cal trials of semaglutide and dulaglutide consistently
CKD, and has been shown to have an independent show reduced risk of albuminuria onset and progres-
role in the genesis of left ventricular hypertrophy sion. The consistency of these data across GLP-1 RA
(LVH) and subsequent CVD.Anemia seems to act as

Cardio Diabetes Medicine

152 DKD is Coronary Equivalent (Evidence And Remedy)

class strongly suggests a class effect toward protec- lar disease in Type 1 (insulin-dependent) diabetic subjects with and with-
tion against DKD. The mechanisms of action may be out diabetic nephropathy in Finland. Diabetelogia. 1998;41(7):784-90.
multifactorial from lower levels of glycemia and body
weight to direct effects on the kidney.This has abear- 5. Charles.T, The Risk of Cardiovascular Disease Mortality Associated with
ing on CV outcomes also. Microalbuminuria and Gross Proteinuria in Persons with older onset DM.
Arch.of Int.Med 2000 : 160 (8) 1093-1100
SGLT 2 inhibitors and Cardio Renoprotection: The
available SGLT2 inhibitors are Canagliflozin, Dapagli- 6. Stehouwer CD, Smulders YM. Microalbuminuria and risk for cardio-
flozin and Empagliflozin.The Empaglifozin Cardio- vascular disease: analysis of potential mechanisms. J Am Soc Nephrol.
vascular Outcomes, and Mortality in Type 2 Diabe- 2006;17(8):2106-111.
tes Clinical Trial (EMPA REG Study)48 recently showed
that empaglifozin significantly lowered rates of death 7. Jefferson JA, Shankland SJ, Pichler RH. Proteinuria in diabetic kidney dis-
from CV causes (38% relative risk reduction), hospi- ease: a mechanistic viewpoint. Kidney Int. 2008;74(1):22-36.
talization for heart failure (35% relative risk reduction),
and death from any cause (32% relative risk reduc- 8. Bigazzi R, Bianchi S, Nenci R, et al. Increased thickness of the carotid
tion) in patients with T2DM and CV already receiving artery in patients with essential hypertension and microalbuminuria. J
standard of care for treatment of BP and lipids. CVOT Hum Hypertens.1995;9(10):827-33.
data with canagliflozin as reported in CANVAS study
has also shown similar CV outcome benefits. 9. Diamond JR. Analogous pathobiologic mechanisms in glomerulosclerosis
and atherosclerosis. Kidney Int. 1991;31 (Suppl):S29-34.
In a nutshell:
10. American Diabetes Association. Standards of medical care in diabe-
• A very high cardiac risk exists in patients with di- tes—2008. Diabetes Care. 2008;31(Suppl 1): S12–S54.
abetic nephropathy (DN). This risk starts very early
in the course of DN 11. Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with
diabetes: Part I: recent advances in prevention and noninvasive manage-
• Albuminuria and reduced eGFR are continuous risk ment. J Am Coll Cardiol. 2007;49(6):631-42.
factors for cardiovascular and kidney outcomes in
patients with T2DM that are independent of each 12. Stratton IM, Adler AI, Neil HA, et al. Association of glycemia with macro-
other and of other known risk factors vascular and microvascular complications of type 2 diabetes (UKPDS 35):
prospective observational study. BMJ. 2000;321(7258):405-12.
• The non-traditional and DKD related risk factors
like insulin resistance, endothelial dysfunction, 13. American Diabetes Association. Standards of medical care in diabe-
plasminogen activator inhibitor, C-reactive protein, tes-2008. Diabetes Care. 2008;31(Suppl 1):S12-54.
adhesion molecules, hyperhomocysteinemia and
vascular wall abnormalities also play a contribu- 14. Action to Control Cardiovascular Risk in Diabetes Study Group. Ef-
tory role fects of intensive glucose lowering in type 2 diabetes. N Engl J Med.
2008;358(24):2545-59.
• Metformin and Pioglitazone have been more wide-
ly investigated with regard to cardiovascular end 15. Berry C, Tardif JC, Bourassa MG. Coronary heart disease in patients with
points, with several large randomized trails show- diabetes: Part I: recent advances in prevention and noninvasive manage-
ing beneficial effects on cardiovascular outcomes ment. J Am Coll Cardiol. 2007;49(6):631-42.

• Blood pressure control use of statins and other life 16. Stratton IM, Adler AI, Neil HA, et al. Association of glycemia with macro-
style changes have shown definite CV outcome vascular and microvascular complications of type 2 diabetes (UKPDS 35):
benefits. prospective observational study. BMJ. 2000;321(7258):405-12.

• Newer drugs for diabetes offer promise towards 17. Fonseca VA. Rationale for the use of insulin sensitizers to prevent cardio-
cardio Renal protection and long term studies and vascular events in type 2 diabetes mellitus. Am J Med. 2007;120(Suppl
experience should help us to improve the outcome. 2):S18-25.

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Cardio Diabetes Medicine 2017 153

Stroke in Cardiodiabetic Syndrome:
How different is it?

Dr. K. Mugundhan MD.,DM (Neuro)

Senior Assistant Professor, Dept. of Neurology,
Govt. Mohan Kumaramangalam Medical College Hospital, Salem.Tamilnadu

Introduction ma. Minor sources of cardioembolism are patent fora-
men ovale, atrial septal aneurysm, atrial or ventricular
Stroke is the leading cause of disability and the sec- septal defects, calcific aortic stenosis, and mitral an-
ond most common cause of death worldwide 1,2 It nular calcification. Although the vast majority of the
is defined as an abrupt onset of focal neurological above causes are already known, the exact mecha-
deficit that is attributable to a vascular cause. There nisms require attention.4 The dynamics that play an
are 2 mechanisms by which stroke occurs- Isch- important role in cardiac patients that develop stroke
emic and hemorrhagic. Ischemic strokes are due to include increased thrombus formation, increased co-
inadequate perfusion of a vascular bed leading to agulation, reduced fibrinolysis, and increased throm-
ischemia, tissue necrosis and cell death. Ischemic bocyte aggregation, endothelial dysfunction. Factors
stroke can occur due to either 1. Embolism from the that increase thrombus formation in cardiac patients
heart, proximal arteries 2. Thrombosis of large and are due to prevalence of left ventricular hypokinesia,
small intra and extracranial arteries and 3. Systemic reduced ejection fraction, prevalence of atrial fibril-
hypoperfusion. Hemorrhagic strokes usually are due lation and increased blood viscosity. Factors that
to various cause most common being uncontrolled promote coagulation in cardiac disease includes
hypertension and reperfusion of the previously in- increased D-dimer concentration, increased Throm-
farcted area. bin-antithrombin complex level, fibrin degradation
products, thrombin concentration and increased lev-
Cardio-diabetic syndrome els of tissue plasminogen activator which activates
the coagulation cascade. It has also been observed
The entity of Cardio-diabetic syndrome is relatively that reduced fibrinolysis has been observed in car-
new. The factors that play a vital role in the dynamics diac patients due to increased levels of circulating
of circulation are entirely different for patients with plasminogen activator inhibitor-1. Factors that pro-
cardiac disease and patients with diabetic disease. mote thrombocyte aggregation includes raised levels
Though each one have their own effects in promoting of P-selectin and β-Thromboglobulin concentration.
the nature of progression in stroke, the effects of In cardiac disease endothelial dysfunction is due to
cardiac disease and diabetes together has a marked increased von Willebrand factor concentration, sol-
role together. But before attributing the combined ef- uble thrombomodulin concentration and E-selectin
fects of cardiac disease and diabetes it is essential level. The prevalence of hypertension and diabetes
to know what really precipitates or promotes stroke can both enhance these effects.4 (Pic 1)
in each entity.
Mechanism of Stroke in Diabetes Mellitus
Mechanism of Stroke in Cardiac disease4
Diabetes causes various microvascular and macro-
The common causes of cardiac conditions precipi- vascular changes often culminating in major clinical
tating stroke includes atrial fibrillation, recent myo- complications, 1 of which, is stroke. Of the several
cardial infarction, mechanical prosthetic valve, dilated mechanisms implicated in stroke evolution, individ-
myocardiopathy, and mitral rheumatic stenosis. Oth- uals with diabetes are the most vulnerable to the
er major sources of cardioembolism include infective consequences of cerebral small vessel diseases.5
endocarditis, marantic endocarditis, and atrial myxo-

Cardio Diabetes Medicine

154 Stroke in Cardiodiabetic SyndromeHow different is it?

Pic 1 : Mechanism of Stroke in Cardiac disease4

Hyperglycemia deliberates greater risk of stroke oc- having normal glucose level. Type I diabetes is more
currence. This increased risk is often observed in frequently concomitant with an early structural im-
patients with diabetes and is associated with worse pairment of the common carotid artery, commonly
clinical outcomes (including higher mortality), which diagnosed as increased intima-medial thickness,
especially occurs following an ischemic stroke.5 and is reflected to be an early sign of atherosclero-
These include vascular endothelial dysfunction, in- sis. Both acute hyperglycemia and hyperinsulinemia
creased early-age stiffness of the arterial walls, sys- have been shown to increase plasminogen activator
temic inflammation and thickening of the capillary inhibitor type 1 and decrease free tissue plasmino-
basal membrane. Derangements in early left ventric- gen activator (tPA) activities by decreasing plasma
ular diastolic filling are commonly seen in T2DM. The fibrinolytic activity. Acute hyperglycemia increases
anticipated mechanisms of congestive heart failure brain lactate production, reduces salvage of pen-
in T2DM include microvascular changes, metabolic umbral tissue and causes greater final infarct size.
derangements, interstitial fibrosis, hypertension and The influence of hyperglycemia to patients with ICH
autonomic dysfunction . The function of the vascular is similar to that of ischemic stroke. The effect of
endothelial is imperative for maintaining the struc- hyperglycemia on patients with ICH leading to poor
tural and functional integrity of the vessel walls as outcomes may be related to exacerbation of hema-
well as the vasomotor control. Nitric oxide (NO) ar- toma expansion and perihematoma edema. An exag-
bitrates vasodilation, and its reduced availability can gerated inflammatory response is commonly seen in
cause endothelial dysfunction and initiate a cascade individuals with diabetes, inflammation plays an vital
of atherosclerosis. For example, NO-mediated vaso- role in the progression of the atherosclerotic plaque.
dilation is defective in patients with diabetes, most The C-reactive protein, cytokines and adiponectin are
commonly due to increased inactivation of NO or the main serum markers of inflammation. The C-re-
decreased reactivity of the smooth muscle to NO. active protein and the plasma levels of these cyto-
Patients with type II diabetes have tauter arterial kines including interleukin-1, interleukin-6 and tumor
walls and reduced elasticity compared with subjects necrosis factor-α are independent prognosticators of

GCDC 2017

Cardio Diabetes Medicine 2017 155

cardiovascular risk. Adiponectin seems to be a mod- References
ulator of lipid metabolism and systemic inflamma-
tion. A low level of adiponectin itself has also been 1. Ferro JM. Brain embolism. Answers to practical questions. J Neurol.
associated with CVD.5 2003;250:139–47.

2. Weir NU. An update on cardioembolic stroke. Postgrad Med J.
2008;84:133–42.

3. Di Tullio MR, Homma S. Mechanisms of cardioembolic stroke. Curr Car-
diol Rep. 2002;4:141–8

4. Haeusler KG, Laufs U, Endres M (2011) Chronic heart failure and ischemic
stroke. Stroke 42:2977– 2982

5. Chen R, Ovbiagele B, Feng W. Diabetes and Stroke: Epidemiology,
Pathophysiology, Pharmaceuticals and Outcomes. The American jour-
nal of the medical sciences. 2016;351(4):380-386.doi:10.1016/j.am-
jms.2016.01.011.



Effects of Cardiac disease and diabetes in the pro-
gression of stroke

Although, not directly implicated, the effects of car-
diac disease and diabetes go hand in hand in pro-
mulgating the end point of stroke. Amongst the two
entities , diabetes seems to have a bigger role in
the evolution of either entities and stroke. The main
mechanisms that can be attributed to the develop-
ment of stroke in a patient with both cardiac disease
and diabetes include 1. Increased endothelial damage
and dysfunction which promotes atherosclerosis 2.
Autonomic dysregulation which precipitates arrhyth-
mias in a pre existing cardiac disease and thereby
causing reduced blood flow and increased stasis pro-
moting clot formation 3. Increased systemic inflam-
mation 4. Increased coagulation, reduced fibrinolysis,
increased platelet activation which promotes aggre-
gation and therefore a thrombotic event 5. Increased
stiffness of vessel walls thereby causing increased
systemic resistance in a pre-existing damaged heart
,subsequently worsening the cardiac functions and
beginning a cascade of events that ends in a chain
reaction till the cessation of blood flow occurs to ei-
ther the heart or the brain.

Conclusion

Although significant gains have been undertaken
to reduce the burden of stroke in the community
the recent rise in rates of diabetes and cardiac dis-
ease threatens to reverse these advances. Improving
stroke outcomes in individuals with diabetes and car-
diac disease requires prompt and persistent imple-
mentation of evidence-based medical therapies as
well as adoption of beneficial lifestyle practices.

Cardio Diabetes Medicine

156 Cardio Diabetes Medicine 2017

Management of Cardioembolic Stroke

Dr. N. Thamilpavai

MD - General Medicine, DM - Neurology
Assistant Professor of Neurology, Madras Institute of Neurology

&

Dr. R.Lakshminarasimhan

MBBS MD(Int. Med)., DNB (Int.Med) DM (Neuro)., DNB(Neuro)., Director and Professor,
Institute of Neurology Madras Medical College, Chennai

Abstract boembolic risk individuals after risk assessment and
investigations. Aspirin is used during this period of
Stroke is the commonest cause of mortality and increased thromboembolic risk, if decompressive
morbidity after coronary artery disease. According surgery is not done.
to the India stroke factsheet updated in 2012, the
estimated age-adjusted prevalence rate for stroke Figure 1. Cause of Cardioembolic Stroke
ranges between 84/100,000 and 262/100,000 in
rural and between 334/100,000 and 424/100,000
in urban areas. Ischemic stroke is the commonest
followed by cardioembolic which is 20% which may
be higher in developing countries because of illiter-
acy and lower socioeconomic status Cardioembolic
strokes are usually severe in presentation and prone
for early recurrence. The risk of long term recurrence
and mortality are also high. Hemorrhagic transfor-
mation occurs in up to 71% of cardioembolic strokes.
Atrium, ventricle and valves are the high-risk origins.
This article highlights the importance of balancing
between thromboembolism and bleeding risks while
making therapeutic decisions. Anticoagulation is in-
dicated both for primary and secondary stroke pre-
vention. The role of Novel oral anticoagulant versus
warfarin and they edge over and they don’t need INR
monitoring Thrombogenic atrial substrate even in the
absence of atrial fibrillation can predispose to atri-
al thromboembolism.TEE allows better visualization
(aortic atheromas, patent foramen ovale, atrial septal
aneurysms) of earlier crytogenic lesions elucidating
a cause and thereby reducing the embolic risk. Be-
cause of varied etiology and presentation, a tailored
individual approach is needed.

ANTICOAGULATION AFTER ACUTE Fig 2. High Risk Sources of Cardioemboli
STROKE :

Anterior circulation stroke candidates with contrain-
dications to intravenous r-tPA, endovascular therapy
completed within 6 hours of stroke onset is reason-
able ( IIa; C). In large hemispheric infarcts oral anti-
coagulation is reinitiated 2–4 weeks in high throm-

GCDC 2017

Management of Cardioembolic Stroke 157

Fig 3. Anticoagulation in Elderly.

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158 Cardio Diabetes Medicine 2017

Fig 4. ANTIPLATELET VERSUS ANTICOAGULANT THERAPY:

GCDC 2017

Management of Cardioembolic Stroke 159

ANTICOAGULATION IN ELDERLY: NOVEL ORAL ANTICOAGULANTS (NOAC S) : They
are the oral direct thrombin inhibitors dabigatran ,
WASPO and BAFTA trials have shown that OAC is oral direct factorXa inhibitors rivaroxaban, apxiaban.
safe even in octagenerians. Algorithm for anticoag- INR should be than 2 when switching from VKA to
ulation in elderly (Fig 3) NOAC because of rapid onset of action. Renal func-
tion should be normal on changing from NOAC to
ANTICOAGULATION IN STROKE VKA with an 2-3 day overlap.
PREVENTION
150 mg b.i.d of dabigatran is preferred to110 mg b.i.d.,
RHYTHM ABNORMALITIES : Atrial fibrillation is the with the latter dose given in:
commonest significant cause with its incidence in-
creasing with age, and tends to produce severe dis- • elderly patients, age ≥80
abiling strokes. It is associated with 5 fold increase
risk of stroke and a 3 fold increase of congestive • concomitant use of interacting drugs (e.g. ver-
cardiac failure with frequent hospitalizations . It can apamil)
be valvular or non valvular, paroxysmal ,.persistent
or permanent. Its pertinent to decide assiduously • high bleeding risk (HAS-BLED score 3)
thromboprophylatic therapy as it needs to balance
the risk of stroke against the risk of major bleeding, • moderate renal impairment (CrCl 30-49 mL/min).
ICH,which is the most dreaded complication of anti-
coagulation therapy. (Fig 4) Rivaroxaban in a dose of 20 mg o.d. is preferenced
to15 mg o.d., with the latter dose given in:
Thromboembolic risk stratification is based on
CHA2DS2VASc score and has been validated in mul- • high bleeding risk (HAS-BLED score ≥3)
tiple trials . Prediction accuracy of it in stratifying truly
low risk patients with non valvular atrial fibrillation • moderate renal impairment (CrCl 30-49 mL/min)
is valuable in evaluating those who are unlikely to
benefit from oral anticoagulant therapy. HAS BLED is Choice of anticoagulant should be discussed with the
a simple bleeding assessment score than the more patient and care giver and documented
complicated scores like HEMORR2HAGES score or
ATRIA score and allows the physician to decide the Mitral Stenosis, Mitral Regurgitation, Mitral
correctable risk factors for bleeding. Prolapse, Mitral Annular Calcification, and
Aortic Valve Disease Recommendations :
AHA /ASA /ESC GUIDELINES : Nonvalvular AF pa-
tients with prior stroke, or transient ischemic attack , The risk of cardioembolism is multifactorial and de-
or a CHA2 DS2 -VASc score of 2 or greater in males, pends on location of the valve , severity of the dis-
CHA2 DS2 -VASc score of 3 or greater in females ease and underlying pathology. Long-term VKA ther-
oral anticoagulants are recommended. Options in- apy ( target INR of 2.5 range, 2.0– 3.0) is recommend-
clude warfarin (INR 2.0 to 3.0)( 1 A), or NOACs (1 B). ed in rheumatic mitral valvular disease and AF who
develop ischemic stroke or TIA, (1A). Patients with
INR is checked weekly and later monthly time in rheumatic mitral valve disease without AF ,develop
therapeutic range TTR should be kept as high as pos- ischemic stroke or TIA due to other causes long-
sible at the start of antithrombotic therapy. (1 A) . Non- term VKA therapy (INR target of 2.5 , range 2.0–3.0)
valvular AF patients unable to maintain a therapeutic may be considered instead of antiplatelet therapy (
INR level with warfarin, use of NOAC is recommend- IIb; C). Rheumatic mitral valve disease patients who
ed. ( I C) . Periodic monitoring type of antithrombot- are on VKA therapy after an ischemic stroke or TIA,
ic therapy is recommended to reassess stroke and antiplatelets should not be prescribed as a routine
bleeding risks. (1C). .(III; C). Patients with rheumatic mitral valve disease
while on adequate VKA therapy develop an ischemic
Baseline renal function and annual reevaluatuion stroke or TIA, aspirin may be added.( IIb; C). Native
should be done in patients on NOAC . (1 B). In atrial aortic or nonrheumatic mitral valve disease patients
flutter, antithrombotic therapy is recommended as without AF or an indication for anticoagulation, de-
for AF. (1C). No antithrombotic therapy for patients velop an ischemic stroke or TIA antiplatelet therapy
with nonvalvular AF patients with a CHA2 DS2 -VASc is recommended ( I C).
score of 0. (11a, B). Combination of oral anticoagu-
lants and antiplatelets is avoided in AF patients due PROSTHETIC MECHANICAL AND
to bleeding risk unless there is an indication for BIOPROSTHETIC VALVES
platelet inhibition (111 B).
Anticoagulation with a VKA and (INR) monitoring is
recommended .Aspirin 75-100 mg/d is recommend-

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160 Cardio Diabetes Medicine 2017

ed in addition.(1A) Anticoagulation with a VKA to or ischemic stroke patients.
achieve an INR of 2.5 is recommended in patients
with a mechanical aortic valve replacement (AVR) and Patients with ischemic stroke or TIA with acute MI
no risk factors, an INR of 3.0 in patients with risk with left ventricular mural thrombus or anterior or
factors (atrial fibrillation, previous thromboembolism, apical wall-motion abnormalities with a left ventricu-
left ventricular dysfunction, or hypercoagulable con- lar ejection fraction <40% who are intolerant to VKA
ditions) or an older-generation mechanical AVR (such therapy because of nonhemorrhagic adverse events,
as ball-in-cage)or with a mechanical mitral valve re- treatment with an LMWH, NOAC s for 3 months may
placement (1B).Aspirin 75-100 mg/d is recommend- be considered as an alternative to VKA therapy for
ed in all patients with a bioprosthetic aortic or mitral prevention of recurrent stroke or TIA ( IIb , C).
valve. (11a, B). Anticoagulation with a VKA is done
for the first 3 months after bioprosthetic mitral valve Heart Failure and Sinus Rhythm: Anticoagulation is
replacement or repair to achieve an INR of 2.5. (11A , not well established in patients with HF in stable
C). Anticoagulation with a VKA to achieve an INR of rhythm or a previous thromboembolic event( IIb).
2.5 is given for the first 3 months after bioprosthet-
ic AVR. (11b, B). Clopidogrel 75 mg/d may be given Heart Failure (NYHA Class II – IV) and Atrial Fibrilla-
for the first 6 months after transcatheter aortic valve tion: An oral anticoagulant is recommended for all
replacement in addition to lifelong aspirin 75 -100 patients with a CHA2 DS2 -VASc score ≥1, and irre-
mg/d. (11b,C). NOACs should not be used in patients spective of whether a rate- or rhythm-management
with mechanical valve prostheses. (111 B) strategy is used including after successful cardiover-
sion ( 1A).
INFECTIVE ENDOCARDITIS :
Patients with AF of ≥48 h duration, or unknown du-
Neurological complications occurs in 15–30% of pa- ration , an oral anticoagulant is recommended at a
tients and occur either before or at the event but therapeutic dose for ≥3 weeks prior to electrical or
recurrent or new events can also occur . Emergen- pharmacological cardioversion ( 1C). When urgent
cy cardiac surgery is done after a transient ischemic electrical or pharmacological cardioversion is needed
attack or silent embolism after recovery from coma and not on prior anticoagulants intravenous heparin
and excluding intracerebralhaemorrhage. (1B) For or LMWH is recommended(1C).
ruptured or very large enlarging aneurysms neuro-
surgery or endovascular therapy is recommended. Based on a CHA2DS2-VASc score, NOACs are pre-
Intracranial infectious aneurysms should be ruled by ferred as they are associated with a lower risk of
imaging. (1B) stroke, intracranial haemorrhage and mortality, which
outweigh the increased risk of gastrointestinal haem-
PATENT FORAMEN OVALE orrhage( 11a , B). Combination of an oral anticoagulant
and an antiplatelet agent is not recommended in pa-
Exclusion of other causes of stroke before attrib- tients with chronic (>12 months after an acute event)
uting PFO as the cause. Recurrent strokes despite coronary or other arterial disease, because of a high
adequate medical therapy with no other mechanism risk of serious bleeding. Single therapy with an oral
identified, clinicians may offer the AMPLATZER anticoagulant is preferred after 12 months.
PFO Occluder if it is available (Level C). Antiplatelet
medications are given instead of anticoagulation to Heart Failure and LV Thrombus: OAC for 6 months .
patients with cryptogenic stroke and PFO in the ab- OAC can be stopped after 3 months if the repeat im-
sence of an indication for anticoagulation (Level C). aging is normal ansd there is recovery of wall motion.
Recurrent strokes which occurs while a patient is on
antiplatelet therapy, for cryptogenic stroke and PFO HYPERTROPHIC CARDIOMYOPATHY: Anticoagula-
anticoagulation is preferred. (Level C). tion is indicated in patients with HCM with AF inde-
pendent of the CHA2 DS2 -VAScscore(1 B).No data
ACUTE MYOCARDIAL INFARCTION AND on NOACS.
LEFT VENTRICULAR THROMBUS :
AORTIC ARCH ATHEROSCLEROSIS : It is associated
Patients with acute anterior STEMI with no left ven- with 3-4 fold increase in the risk of cerebral embolism
tricular mural thrombus formation but with anterior if the plaque is more than 4mm. Antiplatelet ther-
apical akinesis or dyskinesis identified by echocardi- apy is recommended for patients with an ischemic
ography or other imaging modality (IIb; C), 3 months stroke or TIA and evidence of aortic arch atheroma
of VKA therapy is given targeting an INR of 2.5 in TIA (1A). Statin therapy is also recommended (1 B). Effec-
tiveness of anticoagulation with warfarin, compared
with antiplatelet therapy, is unknown ( IIb; C). Surgical

GCDC 2017

Management of Cardioembolic Stroke 161

endarterectomy of aortic arch plaque forsecondary CONCLUSION :
stroke prevention is not recommended (III; C).
The choice of an anticoagulant may be influenced by
ARTERIAL DISSECTION : Patients with extracranial clinical features , patterns of risk factors, and comor-
carotid or vertebral arterial dissection with ischemic bidities. Newer anticoagulants have revolutionized
stroke or TIA , 3- 6 months of either antiplatelet or the anticoagulation management.
anticoagulant therapy is reasonable. (11A, b).In pa-
tients with recurrent cerebral ischemic events despite Stroke burden to be reduced by detection and treat-
medical therapy, endovascular therapy is considered. ment of cardiac risk factors addressing knowledge
Surgical management in those who fail.(11b,C) gaps about thrombogenic atrial substrate , treatment
of occult AF and optimal antithrombotic strategies.
PACEMAKERS: Sick sinus syndrome patients who
convert to atrial fibrillation or who have a ventric- REFERENCES
ular-demand pacemaker might represent high-risk
groups for stroke.Stroke in sick sinus syndrome after 1. Kernan WN, Ovbiagele B, Black HR, Bravata DM, Chimowitz MI, Ezekow-
pacemaker insertion is not rare, and pacing does not itz MD, Fang MC, Fisher M, Furie KL, Heck DV, Johnston SC. Guidelines
appear to be protective. for the prevention of stroke in patients with stroke and transient ischemic
attack. Stroke. 2014 Jan 1:STR-0000000000000024.
CARDIAC PROCEDURES : In high-risk populations
the safest approach to be followed during coronary 2. Font M, Krupinski J, Arboix A. Antithrombotic medication for cardioembolic
angiography to prevent peri-interventional stroke stroke prevention. Stroke research and treatment. 2011 Jun 22;2011.
.Recommendation are based on expert opinions and
case series. Intra-arterial thrombolysis and mechani- 3. Werner N, Zahn R, Zeymer U. Stroke in patients undergoing coronary
cal embolectomy in patients are emerging therapeu- angiography and percutaneous coronary intervention: incidence, predictors,
tic options, but needs further research by randomized outcome and therapeutic options. Expert review of cardiovascular therapy.
clinical trials to validate their safety and efficacy pro- 2012 Oct 1;10(10):1297-305.
file in this special setting. Treatment is individualized .
4. Culebras A, Messé SR, Chaturvedi S, Kase CS, Gronseth G. Summary of
ANTICOAGULATION IN PREGNANCY evidence-based guideline update: Prevention of stroke in nonvalvular atrial
WITH MECHANICAL PROSTHETIC HEART fibrillation Report of the Guideline Development Subcommittee of the
VALVES American Academy of Neurology. Neurology. 2014 Feb 25;82(8):716-24.

Warfarin is recommended to achieve a target (INR) in 5. Camm AJ, Lip GY, De Caterina R, Savelieva I, Atar D, Hohnloser SH,
the second and third trimesters (1B). Hindricks G, Kirchhof P, Bax J, Baumgartner H, Ceconi C. 2012 Focused
Update of the ESC Guidelines for the Management of Atrial Fibrillation.
Discontinuation of warfarin with initiation of intrave- Revista Espanola de Cardiologia. 2013 Jan;66(1):54-.
nous UFH (aPTT) >2 times control) is recommended
before planned vaginal delivery (1 C). Continuation of 6. Messe SR, Silverman IE, Kizer JR, Homma S, Zahn C, Gronseth G, Kasner
warfarin during the first trimester is reasonable if the SE. Practice parameter: recurrent stroke with patent foramen ovale and
dose of warfarin is 5 mg/day or less to achieve a atrial septal aneurysm report of the Quality Standards Subcommittee of
target INR after discussing the risks and benefits ( the American Academy of Neurology. Neurology. 2004 Apr 13;62(7):1042-
IIa, B). Dose-adjusted LMWH bid (with a target anti-Xa 50.
level of 0.8–1.2 U/mL, 4–6 h postdose) during the first
trimester is reasonable if the dose of warfarin is >5
mg/day (11a: B),(I1b,B ) if the dose of warfarin is 5 mg/
day or less to achieve a therapeutic INR.

Dose-adjusted continuous intravenous UFH (with an
aPTT atleast two times control) during the first tri-
mester if the dose of warfarin is >5 mg/day (11a: B),
(11b: B) if the dose of warfarin is 5 mg/day or less to
achieve a therapeutic INR

TIMING OF RESTARTING OF ANTICOAGULATION:
By 1-3-6-12 rule OAC may be restarted on the 3rd day
in mild stroke, 5-7 days in moderate stroke , after 12-
14 days in severe stroke after ruling out haemorrhagic
transformation.

Cardio Diabetes Medicine

162 Cardio Diabetes Medicine 2017

STEMI in Young

Dr. Joy M Thomas,

MD, MD, DM ( Cardiology), FRCP (G), FACC, FHRS, FCSI.
Chief Cardiologist (Adult Cardiology) & Chief Electrophysiologist.

Dr. M Anand,

MD., DM (Cardiology), Junior Consultant.
Frontier Lifeline Hospital, R-130-C, Ambattur Industrial Estate Road, Chennai 600101.

Introduction constraints and thus greater mortality.5,6

Acute myocardial infarction (AMI) is a major cause Definition of STEMI in young
of death worldwide. The incidence of AMI in adults
younger than 45 years of age is less when compared There is no universal definition for who constitutes
to elderly age group people. The Framingham study young people. Studies in western countries consider
reported a ten-year incidence rate of myocardial in- ACS occurring in people less than 55 years of age
farction (MI) of 12.9 % in men 30 - 34 years old and 5.2 as young. Indian studies have taken age less than 45
% in women of 35 to 44 years old1. AMI among young years or 40 years as young. Most of the studies use
patients aged 40 years or younger is rare, accounting the age cut off of 45 years to define young patients.
for approximately 2% to 6% of all cases1,2. However
in recent times the incidence of AMI in young is in- Clinical presentation
creasing as shown by various studies.
The spectrum of CAD in India is different from west-
AMI in young is more important in clinical and soci- ern countries. In India, 60% of ACS (Acute coronary
etal interest because of the potential of premature syndrome) patients present with STEMI when com-
death and long-term disability with the resultant loss pared to less than 40% of ACS patients in developed
to family and society. Moreover, they are an import- countries presenting with STEMI.
ant group to examine with regard to risk factor mod-
ification and secondary prevention. A cross-sectional study from tertiary care centre from
Kerala show that male patients present at a younger
The mechanism and disease course of AMI in the age than females7. 64% of males present with STEMI
young are likely to be different from those in the older while 38% of females present with NSTEMI or UA
population. The lifestyles of young people, character- (Unstable angina). The major risk factors in STEMI in
ized by high work stress, overwork, physical inactivi- young are smoking, dyslipidemia and family history
ty,unhealthy diet, smoking and drinking alcohol likely of CAD. In one study from Christian Medical College,
cause coronary atherosclerosis, which increases the Vellore, STEMI in young was seen in 8%. Most com-
incidenceof AMI 3. Hence, a better understanding of mon territory involved is AWMI (61%) followed by IWMI
the causes and mechanisms in these young patients (38%)8. Coronary Angiogram revealed single vessel
helps in the management and prevention of AMI. disease in 51% of males and 30% of females7. Triple
vessel disease was seen in 21% of males and 38% of
CAD in India females. Young patients do not experience anginal
pain antecedent to the MI (less than 12%). Presence
Global Burden of Diseases (GBD) Study has reported of antecedent angina improves ischemic precondi-
that from year 1990 to 2013, CAD (Coronary artery tioning and this major advantage is lost in the young
disease) in India increased to become the number MI patients.
one cause of death4. This study also reported that
number of patients with IHD increased from less than Most of the young patients seek medical attention
a million to 2 million. IHD in India is characterized very late due to ignorance on the part of the patient
byincreasing numbers, regional variations, premature and also the attending physician. Appropriate treat-
onset, poor management aggravated by resource ment received by the young STEMI patients in the

GCDC 2017

STEMI in Young 163

form of primary PCI (percutaneous intervention) or vessel disease and predominantly involvement of left
thrombolysis is also less. In a study only 10.7% re- anterior descending artery.
ceived PCI and 4% received thrombolysis. National
registry data from 89 cities suggest that Indian pa- Coronary involvement other than atherosclerosis
tients with STEMI fail to receive an adequate reperfu- can occur but infrequent. It includes coronary vaso-
sion therapy9. Thrombolysis is received by less than spasm (Printzmetal angina), drug abuse like cocaine
60% of Indian patients. The important reasons for not use, amphetamine, alcohol and tobacco, congenital
receiving reperfusion therapy was late presentation, coronary artery anomalies like anomalous origin with
consequent to delayed diagnosis and referral, poor intramural course, ALCAPA (Anomalous origin of left
transport facilities and lack of awareness in the gen- coronary artery from pulmonary artery), coronary AV
eral population. fistula, coronary ectasia, coronary artery aneurysm
occurring as a sequalae to childhood Kawasaki dis-
RISK FACTORS ease, coronary arteritis occurring with connective
tissue diseases like rheumatoid arthritis, SLE (Sys-
In most of the studies conducted all around the world temic lupus erythematosus), ankylosing spondylitis,
on myocardial infarction in the young, the most com- psoriatic arthritis and Takayasu arteritis. Connective
monly observed risk factors were smoking, sedentary tissue diseases leads to premature atherosclerosis.
lifestyle with obesity and family history of coronary Hypercoagulant states also predisposes to coronary
artery disease. In India according to the CAD regis- thrombosis. Some of the hypercoagulant states are
try, moderate to high psychosocial stress level was APLA (Antiphospholipid antibody syndrome), ne-
found in 56% of young CAD10. Males had a higher phrotic syndrome, protein S and protein C deficien-
incidence of family history of CAD when compared cy, Factor V leiden mutation.
to females (72% vs 28%). Significant proportion of
participants had modifiable risk factors: hypertension Smoking adversely affects all phases of athero-
49.3%, diabetes 44.2%, dyslipidemia 11.4%, smoking sclerosis given that it hastens thrombotic process,
and/or tobacco use 38.6%, overweight/obesity in instigates endothelial dysfunction, augments proin-
56.3% and sedentary habits in 19.5%. Women,as com- flammatory effects, and induces coronary vasocon-
pared to men, had greater prevalence of diabetes striction even in patients with normal coronary vas-
(62.1%vs37.1%, p<0.001), hypertension (72.1%vs 40.3%, culature.
p<0.0001) and overweight/obesity (60.1 vs 35.2%,
p<0.0001), whereas men had greater prevalence of STEMI with angiographically normal
smoking/tobacco use (52.7 vs 3.2%, p<0.0001).In an coronary arteries
analysis of risk factors of STEMI in young patients in
Chinese population showed that levels of HbA1c and This scenario is more common in STEMI in young
Fib were independent risk factors for STEMI in young and exact pathophysiology is unclear. Possible
patients and they proposed that these can be used mechanisms put forward are – coronary vasospasm,
as risk markers of CAD in the young. recanalised thrombus with mild residual atheroma,
embolization or a combination of these.

Angiographic Findings In-hospital course and short term outcome

Angiography in young patients with STEMI reveal one Fibrinolytic therapy in young adults has compara-
of the following pictures ble effects to that of adults with STEMI. In-hospital
incidence of heart failure, death, repeat revasculari-
1. Normal coronaries sation, stroke and major bleeding were lower when
compared to older patients11. However the readmis-
2. Coronary artery disease of various etiologies sion rates were higher in those who continued to
smoke and it is not related to severity of coronary
Coronary Artery disease artery disease but due to low left ventricular ejection
fraction. This finding underscores the need for inten-
Atherosclerosis is the most common cause for sive efforts to reduce smoking.
STEMI in young. However the atheroma in the young
is different from older people with more thrombus Collateral vessels in young patients
containing lesion which are usually discrete and sin-
gle vessel involvement. On the other hand, the older Rentrop had described in 1987 that Chronic myocar-
people have diffuse disease with multivessel involve- dial ischemia is a stimulus for the formation of col-
ment. The young patients have a prothrombotic state lateral vessels in patients. Diabetes has been found
attributable to smoking. The various studies have
shown that most of the young patients have single

Cardio Diabetes Medicine

164 Cardio Diabetes Medicine 2017

to be an impediment in this arteriogenesis. This ex- Conclusion
plains the propensity for Diabetic young patients who
suffer an acute myocardial infarction to land up with Thus the conventional risk factors continue to be the
severe left ventricular dysfunction compared to the major cause of CAD in the young. There is an urgent
older patient who has been having ischemia over a need to focus on these risk factors in primary and
period of time. secondary prevention. It should not be difficult to cor-
rect under use of life style modification and drugs.
Management There is a greater scope for preventive practice in the
female population, given the delayed onset of CAD
Treatment of STEMI in young is same as in older and higher rate of comorbidities, offering more time
patients. However, many young patients with STEMI and more opportunities.
present late due to atypical symptoms especially
women. When the door to balloon time is more than References:-
90 minutes thrombolysis is given and elective PCI
if it is done within 48 hours, MACEs were found to 1. Zimmerman, F.H., Cameron, A., Fisher, L.D. and Ng, G. (1995) Myo-
be lower. In STEMI, patient’s radial access reduces cardial Infarction in Young Adults: Angiographic Characterization, Risk
the primary cardiovascular outcomes compared with Factors and Prognosis (Coronary Artery Surgery Study Registry). Jour-
femoral access. Major bleeding after PCI is associ- nal of the American College of Cardiology, 26, 654-661. http://dx.doi.
ated with three fold increase in mortality and major org/10.1016/0735-1097(95)00254-2
adverse cardiac events.
2. Imazio, M., Bobbio, M., Bergerone, S., Barlera, S. and Maggioni, A.P.
There is clearly a need to improve the utilization of (1998) Clinical and Epidemiological Characteristics of Juvenile Myocar-
evidence based drug therapy in patients with CAD, dial Infarction in Italy: The GISSI Experience. GiornaleItaliano di Car-
especially premature CAD in India. The CADY registry diologia, 28, 505-512.
showed that in patients with ACS, the prescription
of antiplatelets, statins, betablockers and ACE-Inhibi- 3. Wang, Y.Y., Li, T., Liu, Y.W., Liu, B.J., Wang, Y., Hu, X.M., et al. (2014)
tors/ARB were 80%, 80%, 55% and 36% respectively10. Analysis of Risk Factors of ST-Segment Elevation Myocardial Infarction
The usage of evidence based medication is subopti- in Young Patients. BMC Cardiovascular Disorders, 14, 179. http://dx.doi.
mal and needs to be improved. org/10.1186/1471-2261-14-179

Framingham studyhas shown that aggressive life 4. Global, regional, and national age-sex specific all-cause and cause-specific-
style measures reduce events in stable IHD12. Hence mortality for 240 causes of death, 1990-2013: a systematic analysis for
we have to aggressively promote healthy lifestyle in the Global Burden of Disease Study 2013. GBD 2013 Mortality and
young to prevent CAD and STEMI. What we know Causes of Death Collaborators. Lancet. 2015;385:117–170.
from clinical studies is that aspirin, beta blockers,
statins, ACE inhibitors and therapeutic life style 5. Reddy KS, Yusuf S. Emerging epidemic of cardiovascular disease in de-
changes reduce mortality in stable IHD and so do veloping countries. Circulation. 1998;97:596–601.
the appropriately instituted revascularization proce-
dures. Before these measures were widely applied, 6. Gupta R, Guptha S, Sharma KK, et al. Regional variations in cardio-
the annual mortality rate in patients with stable IHD vascular risk factors in India: India Heart Watch. World J Cardiol.
was 4.5%, and now it is 1–3%13. Awareness among the 2012;4:112–120
physicians should be heightened about STEMI in
the young and appropriate implantation of evidence 7. Alappatt, et al.: Acute coronary syndrome in young adults,Journal of
based medicine. Medical Sciences and Health/Jan-Apr 2016/Volume 2/Issue 1
: 5-10
Cardiological Society of India has come up with po-
sition statement for the management of ST eleva- 8. Brajesh Kumar Kunwar, Amit Hooda, George Joseph. Recent trends in
tion myocardial infarction in India in supplementary reperfusion STEMI in a South Indian tier-3 city. Indian Heart journal
issue in Indian Heart Journal in April 201715. According 2012;64; 368-73
to this policy document, if patient arrives at a PCI
capable centre with a diagnosis STEMI, primary PCI 9. Chopra HK, Challenges of STEMI care in India and the real world. Indian
should be done within 60minutes. If the patient ar- Heart Journal 2015;67;5-17
rives in a non-PCI centre, and PCI is possible within
120 minutes, transfer the patient for PCI otherwise 10. SS Iyengar et al Premature coronary artery disease in India: coronary
immediate thrombolysis. artery disease in the young (CADY) registryIndian Heart Journal 69
(2017) 211–216

11. Clinical Outcomes and Risk Factor inPatients with STEMI Treated with-
ercutaneous Coronary Intervention - Ashraf SafiyaManzil, VenkateshRad-
hakrishnan, Jithu Sam RajanInternational Journal of Clinical Medicine,
2015, 6, 753-758

12. Lloyd-Jones DM, Leip EP, Larson MG, et al. Prediction of lifetime risk
forcardiovascular disease by risk factor burden at 50 years of age. Cir-
culation.2006;113:791–798.

13. Braunwald’s heart disease,10th Edition. Stable ischemic heart disease,
chapter54, page 1190, Elsevier Saunders Philadelphia

14. STEMI- Cardiology Update – HK Chopra, Sameer Mehta . Chapter 106
– Page 795-799

15. Cardiological Society of India:Position statement for the managementof
ST elevation myocardial infarction in IndiaS. Guha et al. / Indian Heart
Journal 69 (2017) S63–S97

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Cardio Diabetes Medicine 2017 165

Cardiomegaly
in Diabetes Mellitus

Dr. T. Geetha, MD.,

Associate Professor of Medicine
Government Medical College and ESI Hospital, Coimbatore

INTRODUCTION : CARDIOMEGALY IN DIABETES

Diabetes is now regarded as the strongest risk factor Cardiomegaly is a well recognized condition in di-
for heart disease. The heart disease is not solely due abetes. The metabolic changes induce hypertrophy
to blood glucose levels. The blood vessels in these of the cardiac cells. This, combined with other risk
patients are more susceptible to well established fac- factors like obesity, hypertension, increasing age,
tors like smoking, high cholesterol levels and high lipid dysfunction and the use of thiazolidinediones
blood pressure. All these lead to accelerated athero- can accentuate the process of cardiomegaly. This
sclerosis. This in turn causes increase in cardiovas- results in the well recognized entity called Diabetic
cular mortality and heart failure. Epidemiological and Cardiomyopathy.
clinical data now indicate that diabetes increases the
risk for cardiac dysfunction by structural, functional Female gender has a special predilection for cardio-
and metabolic changes. Left ventricular hypertrophy megaly. Thiazolidinediones can cause adipose tissue
is an ongoing process which may not be recognised accumulation and myocardial hypertrophy.
early.
A lesser known entity is the role of erythrocyte rhe-
THE HEART IN DIABETES MELLITUS : ology in the development of cardiac hypertrophy. Re-
search using animal models has tried to explore this
Heart failure is a very common presentation in the relationship. Rheological changes include reduced
diabetic. Early progression to heart failure after an red cell filtration and increased red cell aggregation.
acute myocardial infarction is more frequent in di- Decreased coronary reserve in diabetes mellitus can
abetics than in non diabetics. While atherosclerosis result in rheological changes leading to left ventric-
and ular hypertrophy.

ischaemic injury are important contributing factors to Increased intracellular magnesium is also attributed
the high incidence of heart failure, another important to the development of cardiac hypertrophy.
factor is diabetes induced changes within the heart
itself. A prominent change which occurs is a switch DIABETES, CARDIOMEGALY AND FEMALE
in the cardiac energy metabolism. Increase in fatty GENDER
acid oxidation accompanied by decrease in glucose
metabolism1 , can result in the myocardium becoming Cardiovascular disease is the leading cause of death
entirely reliant on fatty acid oxidation as a source of in women, globally. Women with Type 2 diabetes are
energy. The change in energy metabolism and the re- at even more higher risk than non diabetic women
sultant increase in advanced glycosylation products and diabetic men2. There are considerable sex differ-
increases the susceptibility of the heart to both isch- ences in the occurrence of various manifestations of
aemic injury and contractile dysfunction, both systol- cardiovascular disease.
ic and diastolic. Evidence also reveals that patients
with diabetes have increased levels of low grade in- Diabetic women have higher levels of endothelial
flammation in their arterial lining, which becomes a dysfunction, higher prevalence of abdominal obesi-
forerunner for cardiac disease. ty, abnormalities in fibrinolysis and thrombosis path-
ways and abnormalities in lipids (low HDL and high

Cardio Diabetes Medicine

166 Cardiomegaly in Diabetes Mellitus

triglycerides). These predispose to more chances of CLINICAL FEATURES
cardiac hypertrophy and thereby to heart failure and
stroke. Women are also easily predisposed to hypo- Prominent ‘a’ wave in JVP or a sustained cardi-
glycaemic events. ac apical impulse is an early clinical finding. After
the development of systolic dysfunction in the later
Women have some unique risk profiles such as hy- stages, associated with left ventricular dilatation and
pooestrogenemia and protracted dysmetabolic state symptomatic heart failure, JVP may become elevated
which may promote an inflammatory milieu. Inflam- and apical impulse would become displaced down
matory factors disturb insulin action and interact with and left. Systolic murmur might be heard in the mitral
female sex hormones. area. ECG changes occur in 60% of the patients and
QT prolongation occurring in later stages is indicative
Insulin resistance which is higher in women, stimu- of fibrosis.
lates increase in left ventricular mass3. Framingham
study shows insulin resistance to be significantly CARDIOMEGALY IN INFANTS OF DIABETIC
more related to left ventricular mass in women than MOTHERS
in men. Trophic stimulating effect of insulin resis-
tance, causes increase in wall thickness and thereby Congenital cardiac defects predominate in infants
the ventricular dimension. born to diabetic mothers. They include cardiovascular
maladaptation to extrauterine life, congenital heart
Obesity is commoner in women with diabetes, mak- defects and hypertrophic septal cardiomyopathy.
ing their left ventricles prone for concentric hypertro- The incidence of foetal cardiac malformations is the
phy. This explains the higher incidence of diastolic highest in mothers who are on insulin at the time of
dysfunction, which is comparatively more severe in conception.
women.
Symptomatic hypertrophic cardiomyopathy6 occurs
Moreover, women are relatively undertreated com- in12.1% of these infants, but when routinely searched
pared to men. with ECHO , it is found to be 30%. The left ventricular
mass and contractility are increased and there is left
According to Framingham study, cardiovascular risk ventricular outlet tract obstruction. Cardiac output is
develops in a female at least 15 years before a clinical significantly reduced secondary to decreased stroke
diagnosis of diabetes4. volume and is directly related to the degree of septal
hypertrophy.
DIABETIC CARDIOMYOPATHY (DCM)
Foetal hyperinsulinaemia triggered by maternal hy-
The incidence of diabetic cardiomyopathy is being perglycaemia during the third trimester causes the
recognized as not only due to the metabolic and asymmetric septal hypertrophy. Foetal cardiac septal
functional changes, but to the structural changes hypertrophy correlates with maternal HbA1c levels.
also.
The severity of cardiomyopathy in these infants, can
Leading causes of heart failure in diabetes are due vary from an incidental finding on ECHO (30%cases),
to coronary artery disease (CAD) and diabetic car- to congestive cardiac failure (1.2)% cases.
diomyopathy. But the cardiomyopathy is recognised
only in the absence of CAD. This cardiomyopathy is usually benign, producing
a systolic murmur and transitory cardiomegaly. All
DCM is characterised by enlargement of cardiac symptoms usually regress spontaneously within a
cells, ventricular enlargement, prominent interstitial few weeks. Rarely, overt congestive cardiac failure
fibrosis and decreased or preserved systolic function, may develop with tachypnoea, tachycardia, gallop
in the presence of diastolic dysfunction. rhythm and hepatomegaly. Hence, supportive care
with fluid restriction, diuretics and oxygen are all that
One peculiarity of DCM is the long latent phase, is necessary.
during which the disease progresses, but is com-
pletely asymptomatic5. The natural history of hypertrophic cardiomyopathy
in the infants is benign and the symptoms resolve in
One of the earliest signs is mild left ventricular di- 2 to 4 weeks and septal hypertrophy resolves in the
astolic dysfunction, with little effect on ventricular first 2 to 12 months of life, irrespective of treatment.
filling.
Hence a detailed ECHO needs to be done in all dia-
betic women with pregnancy.

GCDC 2017

Cardio Diabetes Medicine 2017 167

PREVENTION PET Scan is used to establish an association be-
tween myocardial metabolic derangement and early
Careful diabetic management of the mother may re- manifestation of diastolic dysfunction.
duce severity of hypertrophic cardiomyopathy in the
infant7. However a routine use of these methods is imprac-
tical.
EVALUATION OF CARDIOMEGALY IN A
DIABETIC PATIENT PREVENTION OF CARDIOMEGALY ,
CARDIOMYOPATHY AND HEART FAILURE
There are three main interlinked characteristics of IN DIABETES
diabetes mellitus.
There is no totally certain way to avoid heart disease
1. Patients with diabetes develop more severe cor- in diabetes. The best way is to prevent diabetes itself.
onary artery disease at a younger age and more
micro angiopathy than in individuals without di- People with increased risk of diabetes can be iden-
abetes. tified and the following recommendations can be
made on the basis of The Diabetes Prevention Pro-
2. Increased frequency of heart failure (diastolic gram, which is an NIH (National Institutes of Health)
dysfunction in earlier stages and systolic dys- sponsored study.
funtion, later on) in general, is the second main
manifestation of diabetic cardiomyopathy. 1. Modest weight reduction by a 30 min. exercise,
5 days a week can reduce the development of
3. The third, often unappreciated, but important fea- diabetes by 50% over a 3 year period.
ture of diabetic heart disease is a disproportion-
ate increase in LV mass. 2. Abnormalities in BP and lipid levels in prediabet-
ics should be corrected, to prevent cardiovascu-
Framingham study showed LV mass, was on an av- lar disease. The goal for LDL cholesterol is less
erage, 22% higher in females with diabetes and hy- than 100mg% in diabetics and less than 70mg%
pertension increases the risk of left ventricular hy- in diabetics with heart disease. This is the recom-
pertrophy (LVH). mendation of the American Heart Association.

Diabetes with LVH causes LV dysfunction and coro- 3. Smoking cessation
nary artery disease. Long standing LVH with left ven-
tricular dysfunction will lead on to LV fibrosis. 4. Blood sugar control with a HbA1c of less than 7,
along with a low dose aspirin.
However, in the initial stages, diabetic cardiomyopa-
thy is an asymptomatic disease. So far, there are no CONCLUSION
diagnostic biochemical or imaging methods to detect
subclinical manifestations of the disease. Diabetic cardiomegaly and cardiomyopathy progress
slowly and silently, and is diagnosed with current de-
There is current evidence to propose circulating mi- tection procedures like ECHO only when the heart
croRNA8 as promising biomarkers for early detection manifests a certain degree of dysfunction. So before
of diabetic cardiomyopathy. this subclinical state of the illness becomes critical
following an ischaemic episode, adequate preventive
Micro RNAs are small non coding RNA molecules, measures need to be taken. In the present scenario,
which down regulate gene expression by a post tran- there is no other option to rescue the heart.
scriptional mechanism.
REFERENCES
Cardiac hypertrophy measured by Tissue Doppler,
ECHO ( in the absence of coronary artery disease 1. Fonarrow GC, Srikanthan P Diabetic Cardiomyopathy; Endocrinol Metab
and hypertension ), have been considered as the 2 Clin North Am sep 2006,: 35 (3); 575 -99;
principal hallmarks, to propose a diagnosis of DCM
in asymptomatic diabetic patients. 2. Peter Sa, Huxley RR, Sattar N, Woodwart M, Sex differences in the excess
risk of cardiovascular diseases associated with Type 2 diabetes. Potential
Imaging diagnostic techniques used for explanations and clinical implications. Curr CV Risk Rep; 2015; 9 (7):36.
detecting myocardial metabolic changes in
diabetic patients 3. Ballotari P Ranieri SC, Luberto F, Caroli S, Greci M, Giorgi Rossi P, Mani-
cardi V, Sex differences in CV mortality in diabetic and nondiabetic
Protein magnetic Resonance Spectroscopy : detects subjects : A population based study (Italy) Int J Endocrinol; 2015; 2015:
excessive storage of lipid in the myocardium of pa- 914057.
tients in a prediabetic stage,
4. Recarti C, Stehower CDA, Unger T. Excess CV riskin diabetes mellitus in
female : A case for intensive treatment; Current HT Rep;2015 June:17
(6):554.

Cardio Diabetes Medicine

168 Cardio Diabetes Medicine 2017

Clinical Presentation and
Management of Acute Heart Failure

Dr. Prayaag Kini

Consultant, Dept of Cardiology, Sri Sathya Sai Institute of Higher Medical
Sciences Whitefield , Bangalore ,India

ABSTRACT patient with AHF at each stage of in-hospital man-
agement is fundamental to adjust therapy to actual
Acute decompensated heart failure (ADHF) is a com- clinical conditions.
mon and potentially fatal clinical syndrome charac-
terized by the development of dyspnea, generally Clinical Diagnosis of Acute Heart Failure
associated with rapid accumulation of fluid within
the lung’s interstitial and alveolar spaces, most com- Acute heart failure (AHF) is essentially a pump failure
monly due to left ventricular systolic or diastolic dys- causing downstream hypoperfusion and upstream
function, with or without additional cardiac patholo- congestion. The initial diagnosis of AHF is based on
gy, such as coronary artery disease or valve abnor- the presence of clinical symptoms and signs and is
malities Clinical profiling is essential for determining further confirmed by appropriate additional investi-
the underlying cause and pathophysiology involved gations such as ECG, chest X-ray, laboratory assess-
in an individual patient for tailoring therapy. The mul- ment (with specific biomarkers), and echocardiogra-
titude of newer therapies on the horizon for AHF only phy. Typically, the clinical picture results from symp-
serves to remind us that the ideal “magic bullet” for toms and signs resulting from overt or covert fluid
AHF treatment is still elusive, keeping the manage- retention (pulmonary congestion and/or peripheral
ment of AHF, in real clinical sense, a ”moving target”. edema) and is less often related to reduced cardiac
output with peripheral hypoperfusion.
Introduction
Symptoms of AHF are manifestation of conges-
Despite major achievements in the treatment of tion, reflecting elevated ventricular filling pressures;
chronic heart failure (HF) over the last decades, left-sided HF may be characterized by orthopnea,
which led to marked improvement in long-term sur- paroxysmal nocturnal dyspnea, and breathlessness
vival, outcomes of AHF remain poor with 90-day at rest or with minimal exertion, whereas right-sided
re-hospitalisation and 1-year mortality rates reach- HF can be characterized by peripheral edema, as-
ing 10–30%. Despite lacking evidence of beneficial cites, and symptoms of gut congestion. Systematic
effects on outcome, acute treatment of AHF still physical examination is essential in the diagnostic
mainly consists of non-invasive ventilation in case process of AHF and should always contain an eval-
of pulmonary oedema, intravenous diuretics and/or uation of the following:
vasodilators, generally tailored according to the initial
haemodynamic status without specific regard to the -Peripheral perfusion, for which low systolic blood
underlying pathophysiological irregularities. pressure and cold skin temperature are the most ac-
cessible measures of hypoperfusion; additionally, the
During the last two decades a more complex net- patient may show confusion, dizziness, and anuria/
work of interactions has been added to the simplis- oliguria.
tic haemodynamic model for explaining the patho-
physiology and dynamic nature of AHF. It is not an -The presence of signs associated with elevated
understatement to say that multiple clinical presen- filling-pressures (left-sided: bi-basal rales, an audi-
tations are a typical feature of acute heart failure. ble third heart sound, an abnormal blood pressure
Thus, careful and comprehensive evaluation of each response to the Valsalva maneuver, or right-sided:

GCDC 2017

Clinical Presentation and Management 169
of Acute Heart Failure

elevated jugular venous distention, hepatojugular re- severe peripheral hypoperfusion with subsequent
flux, hepatomegaly, ascites, and peripheral edema; end-organs damage; typically it is associated with
pleural effusions are often seen in patients with a low blood pressure (systolic BP < 90 mmHg) and low
previous history of chronic HF). urine output (< 0.5 mL/kg/min).

The sensitivity and specificity of symptoms and signs Acute Coronary Syndrome Complicated by Heart
to predict both clinical scenarios, i.e., elevated filling Failure: Up to 15% to 20% of patients admitted with
pressures or low cardiac output is often unsatisfac- ACS have signs and symptoms of heart failure and
tory, which leaves a relatively large margin of uncer- an additional 10% develop HF during hospital stay;
tainty to confirm the final diagnosis of AHF as well the incidence is even higher in reports focusing on
as need for additional investigations , which may patients with a diagnosis of AHF, where up to 40%
objectively also add to costs incurred. may have ACS as a precipitating factor ; interesting-
ly, ACS complicated by AHF is now often viewed as
Clinical Classifications: What the guidelines a separate clinical entity, characterized by complex
say about patient presentation structural, hemodynamic and neurohormonal inter-
actions, the need for urgent referral for coronary
According to the ESC guidelines,a patient with AHF intervention,confusing troponin positivity and poor
may present with one of the following clinical cate- outcome.
gories:
The updated AHA/ACC guidelines tend to indicate
Decompensated Chronic Heart Failure: When a pa- a lack of widely accepted nomenclature for HF syn-
tient with chronic HF develops progressive deterio- dromes requiring hospitalization and instead of ‘‘the
ration and worsening in signs and symptoms; periph- AHF patient’’ propose ‘‘the hospitalized HF patient’’
eral edema and/or pulmonary congestion are charac- with the following subgroup classification: a) patients
teristic for this clinical category; these patients may with acute coronary ischemia; b) patients with accel-
appear with low blood pressure which is often associ- erated hypertension with acutely decompensated
ated with impaired LVEF and predicts poor prognosis. HF; c) patients with shock; d) patients with acutely
worsening right HF; and e) patients with decompen-
Pulmonary Edema: For many physicians, pulmo- sation after surgical procedures.
nary edema is the real clinical presentation of AHF;
typically, signs and symptoms develop rapidly and Clinical Profiling: Key for Therapeutic
patients demonstrate severe respiratory distress with Decisions in Acute Heart Failure
tachypnea, orthopnea, and pulmonary congestion.
-- AHF comprises a wide spectrum of clinical condi-
Hypertensive Heart Failure: Hypertensive heart fail- tions ranging from gradual worsening of chronic
ure is associated with elevated blood pressure with conditions (ie, peripheral edema and dyspnea) to
accompanying dyspnea and signs of pulmonary con- pulmonary edema or cardiogenic shock. For clin-
gestion, often in patients with relatively preserved ical purposes, characterizing the patient’s clinical
LVEF. profile at each phase of AHF management consti-
tutes a key element for therapeutic decision-mak-
Isolated Right Heart Failure: Isolated right heart fail- ing. In this context, the following clinical profiles
ure is characterized by low output syndrome in the may be present:
absence of pulmonary congestion, with low left ven-
tricle filling pressures; importantly, a clear differenti- -- Respiratory failure with inadequate ventilation and
ation is needed here between patients with chronic peripheral oxygenation; in such cases, oxygen
HF who gradually develop signs and symptoms of should be administered; in more severe cases,
right HF (elevated jugular venous pressure, peripher- there may be a need for endotracheal intubation
al edema, hepatomegaly, gut congestion), which at and invasive ventilation.
some stage dominate the clinical picture vs patients
with new-onset isolated right heart failure, often -- Presence of life-threatening tachy- or bradyar-
secondary to either acute coronary syndrome (ACS) rhythmias with a need for urgent electrical cardio-
or pulmonary embolism; although the former does version or temporary pacing.
not fulfil the diagnostic criteria often with some pul-
monary congestion and elevated LV filling pressure -- Peripheral hypoperfusion (typically with low systol-
many physicians tend to put such patients into this ic blood pressure, sometimes with a clinical picture
category. of cardiogenic shock); often there is a need for
inotropic agents, vasopressors or, in most severe
Cardiogenic Shock: Cardiogenic shock characterizes

Cardio Diabetes Medicine

170 Cardio Diabetes Medicine 2017

cases, mechanical circulatory support. ;some of these patients may also present low systolic
blood pressure.
-- Hemodynamic deterioration due to acute mechan-
ical cause (eg, acute interventricular septal or mi- ‘‘Vascular’’ Profile: This profile is characterized as
tral valve papillary rupture in ACS, acute valvular rapid clinical deterioration (typically within hours),
incompetence due to endocarditis). with severe dyspnea, evidence of pulmonary conges-
tion (in the most severe cases in a form of pulmonary
-- Acute coronary syndrome as an underlying cause edema), with no (or only minimal) weight gain, where
for decompensation with urgent transfer for expe- fluid redistribution to the lungs is essential for symp-
diting coronary reperfusion. toms and vasoconstriction plays a major role; these
patients often have preserved LVEF and present with
As the AHF pathophysiology is a consequence of normal or elevated systolic blood pressure.
elevated ventricular filling pressure and reduced car-
diac output, hemodynamic profiling of a patient is This explains the background for different treatment
often used in clinical practice.Typically, it is based strategies often applied for these clinical profiles:
on bedside evaluation of congestion and perfusion, diuretics for those with the ‘‘cardiac’’ profile and a
which allows differentiation of 4 different ‘‘hemody- combination of vasoactive agents with diuretics for
namic’’ profiles: those with the ‘‘vascular’’ profile.

-- ‘‘Wet and warm’’. Most commonly present with pa- In-hospital Heart Failure Worsening: A
tients demonstrating congestion (wet profile) and Newly Recognized Clinical Profile
still adequate peripheral perfusion (warm profile).
The natural course of AHF can comprise a clinical
-- ‘‘Wet and cold’’. With congestion and inadequate scenario characterized by initial stabilization with
peripheral perfusion (cold profile). symptomatic improvement, followed by often sudden
and unexpected deterioration, worsening of symp-
-- ‘‘Dry and cold’’. With impaired perfusion and lack toms and signs of AHF, requiring re-intensification
of congestion. of therapy. This clinical profile has only recently been
recognized as worsening heart failure (WHF), which
-- ‘‘Dry and warm’’. Often with symptoms of AHF, is associated with adverse outcomes. Between 10%
but compromised hemodynamics. and 30% of AHF patients may develop WHF during
hospital stay. WHF represents a meaningful change
Hemodynamic profiles are associated with outcome in clinical status, with variable clinical manifestations
(patients with ‘‘wet and cold’’ characteristic having (from only symptomatic deterioration to severe he-
the worst prognosis) but more importantly they may modynamic collapse) and should always be consid-
also have important therapeutic and prognostic im- ered in patients with changing hemodynamics.In the
plications. RELAX-AHF study, treatment with serelaxin was as-
sociated with a 30% reduction in WHF at day 1442
Clinical signs in Acute Heart Failure Patient whereas rolophylline, which enhances diuresis, failed
With Congestion: Fluid Accumulation or to prevent WHF in the PROTECT study, thus high-
Redistribution? lighting that the clinical profile of WHF needs to be
recognized pertinently.
Signs and symptoms of fluid overload are present
in most patients hospitalized due to HF decompen- Clinical Profile and Comorbidities
sation, whereas only a minority demonstrate signifi-
cantly impaired peripheral perfusion and hypoten- The clinical presentation of an individual patient ad-
sion. This explains why the ‘‘wet and warm’’ pro- mitted with AHF is often influenced by cardiovascular
file (depicting congestion with adequate peripheral and non-cardiovascular comorbidities. Recent data
perfusion) is most commonly seen in these clinical from the ESC HF Registry demonstrate that atrial
settings. However, the ‘‘warm and wet’’ profile may fibrillation is present in 44% of AHF patients, diabetes
comprise 2 groups of patients with different clinical mellitus in 39%, chronic obstructive pulmonary dis-
characteristics and pathophysiological profiles: ease in 20%, and renal dysfunction in 26%. One study
showed that only 25% admitted with AHF tended to
‘‘Cardiac’’ Profile: This profile typically occurs in pa- have preserved iron status indicating surrogately
tients with a history of chronic HF, impaired LVEF, that iron deficiency (irrespectively of the presence of
slow symptomatic deterioration, gradual (over sever- anaemia) often coincides with HF decompensation.
al days-weeks) fluid accumulation with concomitant
weight gain and dominating signs of peripheral ede-
ma, jugular venous distension, and hepatomegaly

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Clinical Presentation and Management 171
of Acute Heart Failure

The unsatisfactory results of most recently com- apy.Venous thromboembolism prophylaxis is indicat-
pleted large clinical trials in patients with acute HF ed in patients hospitalized with acute HF. Sodium re-
clearly suggest a need for change in the traditional striction is suggested in all patients with HF.
paradigm of diagnosis and treatment in this complex
clinical syndrome, and a need to segregate patient Vasopressin receptor antagonists (aquaretics )are a
profiles for triaging treatment modalities rarely required option for patients with volume over-
load with severe hyponatremia (ie, serum sodium ≤120
TREATMENT OF ACUTE HEART FAILURE – meq/L) despite fluid restriction.It is suggested gen-
FROM PATHOPHYSIOLOGY TO BEDSIDE erally to avoid opiate therapy in patients with ADHF.
Supplemental oxygen therapy and assisted ventila-
INITIAL THERAPY tion should be provided as needed to treat hypoxemia
(SpO2 <90 percent). Oxygen is not recommended as
Approach to general management — Patients present- routine therapy in patients without hypoxemia, as it
ing with acute dyspnea from acute decompensated may cause vasoconstriction and reduction in cardiac
heart failure (ADHF) should be rapidly assessed and output.
stabilized. The initial approach is similar in patients
with ADHF whether caused by systolic or diastolic For patients requiring supplemental oxygen,initial
dysfunction. Initial measures include: therapies are usually in the following order:

• Airway assessment and continuous pulse oxim- • Non-rebreather facemask delivering high-flow
etry to assure adequate oxygenation and venti- percent oxygen
lation
• If respiratory distress, respiratory acidosis,
• Supplemental oxygen and ventilatory support and/or hypoxia persist on oxygen therapy, we
(noninvasive ventilation [NIV] or intubation) as recommend a trial of noninvasive ventilation
indicated (NIV) if emergent intubation is not indicated,
no contraindications to NIV exist , and person-
• Vital signs assessment with attention to hypo- nel with experience in NIV are available.This
tension or hypertension approach is supported by evidence from me-
ta-analyses and randomized trials in patients
• Continuous cardiac monitoring , securing intrave- with cardiogenic pulmonary edema, indicating
nous access ,head-up position that NIV decreases the need for intubation
and improves respiratory parameters, such as
• Diuretic therapy and / or early vasodilator thera- dyspnea, hypercapnia, acidosis, and heart rate.
py (for severe hypertension, acute mitral regurgi- NIV may be particularly beneficial in patients
tation, or acute aortic regurgitation); later vasodi- with hypercapnia.
lator use for refractory cases is discussed below.
• Patients with respiratory failure who fail to im-
• Urine output monitoring (perhaps with urethral prove with NIV (within one-half to two hours)
catheter placement) or do not tolerate or have contraindications
to NIV should be electively intubated for con-
Following airway and oxygenation assessment and ventional mechanical ventilation with positive
management, initial therapy includes the initiation of end-expiratory pressure being often useful to
treatments aimed at rapidly correcting hemodynam- improve oxygenation.
ic and intravascular volume abnormalities. The main-
stay of therapy in the acute setting is diuretics for • Once initial therapy has begun, oxygen sup-
volume overload. Early intravenous vasodilator thera- plementation can be titrated in order to keep
py is suggested in selected patients with ADHF who the patient comfortable and arterial oxygen
require a decrease in systemic vascular resistance saturation consistently above 90 percent.
and left ventricular afterload (eg, those with severe
hypertension, acute mitral regurgitation, or acute Diuretics — Patients with ADHF and evidence of vol-
aortic regurgitation). The aggressiveness of diuretic ume overload, regardless of etiology, should be treat-
and vasodilator therapy depends on the patient’s he- ed with intravenous diuretics as part of their initial
modynamic and volume status. Patients with flash therapy . As noted in the 2013 ACC/AHA HF guide-
pulmonary edema due to hypertension, for instance, lines, patients admitted with significant fluid overload
require aggressive vasodilatory therapy. Patients with should receive diuretic therapy without delay in the
normotension and volume overload may be treated emergency department or outpatient clinic, as early
with diuretic therapy with or without vasodilator ther- intervention may produce better outcomes . Rare ex-

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172 Cardio Diabetes Medicine 2017

ceptions include patients with severe hypotension or necessary. A continuous intravenous infusion is an
cardiogenic shock.Patients with aortic stenosis with alternative to intravenous bolus therapy, although
volume overload should be diuresed with caution. data are limited in its favour. Use of a continuous
intravenous infusion requires that the patient be re-
Even in the less common situation in which cardio- sponsive to intravenous bolus therapy. Adding a thia-
genic pulmonary edema develops without significant zide diuretic may potentiate the effect, but hypokale-
volume overload (eg, with hypertensive emergency, mia may occur.The onset of diuresis typically occurs
acute aortic or mitral valvular insufficiency), fluid re- within 30 minutes with peak diuresis usually at one
moval with intravenous diuretics can relieve symp- to two hours after intravenous diuretic administra-
toms and improve oxygenation. Intravenous rather tion. Switching from an effective intravenous dose
than oral administration is recommended because to an oral regimen is done once the patient’s acute
of greater and more consistent drug bioavailability.. symptoms have been stabilized with careful attention
to HF status, supine and upright hypotension, renal
Diuretic administration function, and electrolytes.

Individualized dosing — Diuretic dosing should be in- Monitoring — Volume status to prevent hypovolemia,
dividualized and titrated according to patient status evidence of congestion, oxygenation, daily weight,
and response. The approach to initial diuretic therapy fluid intake, and output as well as dyselectrolyte-
in patients with ADHF and fluid overload varies ac- mia esp potassium , magnesium and sodium levels,
cording to whether or not the patient has received worsening renal parameters and hypotension should
prior loop diuretic therapy: be continually reassessed. Reductions in right and
left heart filling pressures with diuresis are frequently
For patients who have not previously received loop associated with augmented forward stroke volume
diuretic therapy, the following are common initial and cardiac output, due to reduction in right ventric-
intravenous doses of loop diuretics in patients with ular volume with relief of interdependent LV com-
normal renal function: pression and improved LV distensibility .However.
patients with HF with preserved LVEF or restrictive
•Furosemide – 20 to 40 mg intravenously physiology and those on angiotensin converting en-
zyme (ACE) inhibitor or angiotensin receptor blocker
•Bumetanide – 1 mg intravenously (ARB) therapy may be more sensitive to diuresis-in-
duced hypotension.
•Torsemide – 10 to 20 mg intravenously
Renal function
If there is little or no response to the initial dose,
the dose should be doubled at two-hour intervals as Patterns of change — The blood urea nitrogen (BUN)
needed up to the maximum recommended doses. and serum creatinine often rise during diuretic treat-
While patients with a relatively normal glomerular fil- ment of ADHF and in the absence of other causes
tration rate can usually be diuresed with intravenous for an elevated BUN, a disproportionate rise in BUN
doses of 40 to 80 mg of furosemide, 20 to 40 mg of relative to serum creatinine (BUN/serum creatinine
torsemide, or 1 to 2 mg of bumetanide, patients with ratio >20:1) suggests a prerenal state with increased
renal insufficiency or severe HF may require higher passive reabsorption of urea. An initial rise in BUN
maximum bolus doses of up to 160 to 200 mg of may be accompanied by a stable serum creatinine,
furosemide, 100 to 200 mg of torsemide, or 4 to 8 reflecting preserved GFR. An otherwise unexplained
mg of bumetanide . rise thereon in serum creatinine alone reflects a re-
duction in GFR and is a marker of reduced perfusion
Patients treated with loop diuretics chronically may to the kidney and other organs. Among patients with
need a higher dose in the acute setting with initial an elevated central venous pressure, the associat-
intravenous dose equal to or greater than (eg, 2.5 ed increase in renal venous pressure can reduce the
times) their maintenance total daily oral dose and GFR, while lowering venous pressure with diuretics
then adjusted depending upon the response (eg, an and other therapies might therefore increase the
initial intravenous furosemide dose of 40 to 100 mg GFR. Nevertheless, fluid removal may still be required
for a patient who had been taking 40 mg orally per to treat signs and symptoms of congestion, partic-
day). In the DOSE trial of intravenous furosemide ularly pulmonary edema. On the other hand, a sta-
in patients with ADHF, there was an almost signif- ble serum creatinine suggests that perfusion to the
icant trend toward greater improvement in patients’ kidneys (and therefore to other organs) is being well
global assessment of symptoms in the high-dose
(2.5 times the patients’ prior total daily diuretic dose)
group compared to the low-dose group.Bolus diuretic
administration two or more times per day may be

GCDC 2017

Clinical Presentation and Management 173
of Acute Heart Failure

maintained and that the diuresis can be continued if creased rates of hypotension, and did not alter rates
the patient is still edematous. of death, rehospitalisation at 30 days, or worsening
renal function .
Management of worsening renal function- General
principles for management of patients with ADHF Nitroglycerin: Nitrates,probably the most commonly
with elevated or rising BUN and/or serum creatinine used vasodilators in ADHF, cause greater venous
include the following : than arterial vasodilation,thus reducing LV filling
pressure. At higher doses, nitrates variably lower sys-
• Other potential causes of kidney injury (eg, use temic vascular resistance and LV afterload, and may
of nephrotoxic medications, urinary obstruction) thereby increase stroke volume and cardiac output.
should be evaluated and addressed. In patients with ADHF receiving nitrate therapy, an
intravenous route is used for greater speed and reli-
• Patients with severe symptoms or signs of con- ability of delivery and ease of titration. An initial dose
gestion, particularly pulmonary edema, require of 5 to 10 mcg/min of intravenous nitroglycerin is
continued fluid removal independent of changes recommended with the dose increased in increments
in GFR. In the presence of elevated central venous of 5 to 10 mcg/min every three to five minutes as re-
pressure, renal function may improve with diuresis. quired and tolerated (dose range 10 to 200 mcg/min).
The longer half-life of isosorbide dinitrate compared
• If the BUN rises and the serum creatinine is sta- to intravenous nitroglycerin (four hours versus three
ble or increases minimally, and the patient is still to five minutes) is a major disadvantage in setting of
fluid overloaded, the diuresis can be continued to hypotension with these agents.
achieve the goal of eliminating clinical evidence
of fluid retention with careful monitoring of renal Tachyphylaxis, hypotension and headache are major
function. limiting side effects of this class of drugs and it is
avoided in right ventricular infarction or aortic steno-
• If increases in serum creatinine appear to reflect sis and concomitant sildenafil therapy.
intravascular volume depletion, then reduction in
or temporary discontinuation of diuretic and/or Nitroprusside: In contrast to nitroglycerin, nitroprus-
ACE inhibitor/ARB therapy should be considered. side causes balanced arterial and venous dilation
Adjunctive inotropic therapy may be required thus lowering left ventricular filling pressures and sys-
temic vascular resistance, thereby increasing stroke
• If substantial congestion still persists,then ultrafil- volume without lowering blood pressure; whereas
tration or( renal replacement therapy)dialysis may if systemic vascular resistance is not elevated, ni-
be considered. troprusside may cause hypotension. These proper-
ties are of value in patients with depressed stroke
Vasodilator therapy :Vasodilators are required to cor- volume due to elevated LV afterload such as acute
rect elevated filling pressures and/or left ventricular aortic regurgitation, acute mitral regurgitation, acute
afterload in patients with ADHF. ventricular septal rupture, or hypertensive emergen-
cy. Because of its very potent hemodynamic effects,
Indications for vasodilator therapy in the setting of the use of nitroprusside requires close hemodynam-
ADHF include the following: early vasodilator therapy ic monitoring, typically with an intra-arterial catheter.
(eg, nitroprusside) being recommended for patients The initial dose of 5 to 10 mcg/min is titrated up every
with urgent need for afterload reduction (eg, severe five minutes as tolerated to a dose range of 5 to 400
hypertension); vasodilator therapy (eg, nitroglycerin) mcg/min.
is suggested as an adjunct to diuretic therapy for pa-
tients without adequate response to diuretics; and The major limitations to the use of nitroprusside is
vasodilator therapy is a component of therapy for thiocyanate, toxicity, which may be fatal esp with
patients with refractory HF and low cardiac output. It doses above 400 mcg/min and rebound vasocon-
is suggested that early vasodilator therapy (typically, striction upon discontinuation. Thus, the use of nitro-
nitroprusside) in patients with severe hypertension, prusside is limited to selected patients for durations
acute mitral regurgitation, or acute aortic regurgita- of less than 24 to 48 hours.
tion be initiated. Reliable blood pressure monitoring
is required, with careful patient monitoring( prefera- Nesiritide: Nesiritide, like nitroprusside, is a balanced
bly with intra arterial line) for drug tolerance . arterial and venous dilator. In carefully selected pa-
tients with appropriate hemodynamics (absence of
Routine use of vasodilators does not improve out- hypotension or cardiogenic shock) who remain symp-
comes, and should be avoided, as exemplified in tomatic despite routine therapy, a trial of nesiritide
ASCEND-HF, where nesiritide showed a borderline
significant trend toward reducing dyspnea, but in-

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174 Cardio Diabetes Medicine 2017

may be helpful as an alternative to other vasodilator recommendation .
therapy (nitroglycerin or nitroprusside).
For patients with HF with volume overload with per-
Nesiritide is typically given as an initial intravenous sistent severe hyponatremia (ie, serum sodium ≤120
bolus of 2 mcg/kg, followed by a continuous infusion meq/L) despite water restriction and maintenance of
of 0.01 mcg/kg per minute, with subsequent dose guideline-directed medical therapy, short-term use of
adjustment as necessary. Close monitoring of hemo- a vasopressin receptor antagonist (either a V2 recep-
dynamics, urine output, and renal function are nec- tor selective or nonselective vasopressin antagonist)
essary for effective clinical use and safety. Nesiritide is an option to improve serum sodium concentration.
is less potent than nitroprusside, and both the onset Cautions include hepatotoxicity and overly rapid cor-
and offset of action are slower. Because nesiritide rection of hyponatremia, which can lead to irrevers-
has a longer effective half-life than nitroglycerin or ible neurologic injury.
nitroprusside, side effects such as hypotension may
persist longer. Opiates: Data is limited but morphine does reduce
patient anxiety and decreases the work of breathing.
Sodium and fluid restriction These effects diminish central sympathetic outflow,
leading to arteriolar and venous dilatation with a re-
Hyponatremia is common among HF patients and sultant fall in cardiac filling pressures . The largest
the degree of reduction in serum sodium parallels of the studies found that morphine administration
the severity of the HF and is an adverse prognos- for ADHF was associated with increased frequency
tic indicator. Given the available evidence, sodium of mechanical ventilation, admission to an intensive
restriction (eg, <2 g/d) in patients with symptomatic care unit, and in-hospital mortality; hence their use
HF is suggested. The 2013 ACC/AHA guidelines sug- is not recommended
gest some degree (eg, <3 g/d) of sodium restriction
in patients with symptomatic HF, while the 2012 ESC MANAGEMENT OF INADEQUATE
guidelines note that the safety and efficacy of salt RESPONSE TO DIURETIC THERAPY
restriction require further study .
In patients with ADHF who fail to adequately respond
Fluid restriction — Fluid restriction (eg, 1.5 to 2 L/d) to diuretic therapy ,the following measures are sug-
may be helpful in patients with refractory HF and gested:
hyponatremia, as suggested by the 2013 ACC/AHA
guidelines. Stricter fluid restriction is indicated in • Doubling the diuretic dose until diuresis ensues
patients with severe (serum sodium <125 meq/L) or or the maximum recommended dose is reached.
worsening hyponatremia.
• Addition of a second diuretic to potentiate the ef-
Venous thromboembolism prophylaxis fects of the loop diuretic. For patients in whom the
diuretic response is inadequate, intravenous chlo-
Prophylaxis against venous thromboembolism (deep rothiazide or oral metolazone or spironolactone are
vein thrombosis and pulmonary embolism) with low- reasonable choices for a second diuretic.
dose unfractionated heparin or low molecular weight
heparin, or fondaparinux, is indicated in patients ad- Chlorothiazide is the only thiazide diuretic that can
mitted with ADHF who are not already anticoagulated be given intravenously (500 to 1000 mg/day). An
and have no contraindication to anticoagulation. In oral thiazide, such as hydrochlorothiazide (25 to 50
patients admitted with ADHF who have a contraindi- mg twice daily) or metolazone (which has the ad-
cation to anticoagulation, venous thromboembolism vantage of once daily dosing), is an alternative for
prophylaxis with a mechanical device (eg, intermit- acute therapy and can be given chronically. Although
tent pneumatic compression device) is suggested . it has been suggested that metolazone is the thia-
zide of choice in refractory patients with advanced
Vasopressin receptor antagonists (VRA) renal failure (glomerular filtration rate below 20 mL/
min), there is at present no convincing evidence that
VRA have been investigated as an adjunct to di- metolazone has unique efficacy among the thiazides
uretics and other standard therapies in patients with when comparable doses are given.
ADHF as a means of countering arterial vasocon-
striction, hyponatremia, and water retention. Tolvap- Addition of a mineralocorticoid receptor antagonist
tan is the most studied agent in this setting. The 2012 (spironolactone or eplerenone) is recommended in
ESC guidelines suggest consideration of tolvaptan selected patients with HF with reduced ejection frac-
for HF patients with hyponatremia in an ungraded tion to improve survival. In addition, the associated re-
duction in collecting tubule sodium reabsorption and

GCDC 2017

Clinical Presentation and Management 175
of Acute Heart Failure

potassium secretion can both enhance the diuresis assigned to either stepped pharmacology therapy or
and minimize the degree of potassium wasting, esp ultrafiltration . The stepped pharmacologic care algo-
with a low or low-normal serum potassium on loop rithm included bolus plus high doses of continuous
diuretic therapy alone. When given for diuresis or po- infusion loop diuretic, the addition of metolazone,
tassium-sparing effects, a higher dose (up to 100 mg and selective use of inotrope or vasodilator therapy.
daily) than the usual HF dose may be needed. The primary end point of change in the serum cre-
atinine level and body weight from baseline to 96
• In patients with refractory volume overload, the hours after enrollment was worse in the Ultrafiltra-
addition of a vasodilator (eg, nitroglycerin, nitro- tion arm due to increase in serum creatinine in that
prusside, or nesiritide) as a temporizing measure group in contrast to a fall in mean serum creatinine in
to relieve congestion. the pharmacologic therapy group,with no significant
difference in weight loss at 96 hours A higher per-
Ultrafiltration centage of patients in the ultrafiltration group had se-
rious adverse events (eg, HF, renal failure, anemia or
Ultrafiltration is an effective method of fluid removal thrombocytopenia, electrolyte disorder, hemorrhage,
that provides adjustable fluid removal volumes and pneumonia, sepsis; 72 versus 57 percent).
rates and no effect on serum electrolytes,but is re-
served for patients with fluid overload who do not TREATMENT OF REFRACTORY ACUTE
achieve an adequate response to an aggressive di- HEART FAILURE AND HYPOTENSION
uretic regimen. This recommendation is consistent
with the 2013 ACC/ AHA HF guidelines. Consulta- Approach to refractory acute heart failure and hypo-
tion with a kidney specialist may be appropriate prior tension — The approach to refractory acute heart fail-
to opting for a mechanical strategy of fluid removal. ure (HF) and hypotension differs for HF with reduced
Most studies have used a peripherally inserted ultra- ejection fraction (HFrEF) and HF with preserved ejec-
filtration device that does not require central access, tion fraction (HFpEF).
specialized nursing, or intensive care unit admission ,
however the risk of device thrombosis in recent trials Treatment of patients with HFrEF and refractory vol-
have raised questions about its use, in the wake of ume overload unresponsive to diuretic therapy is
no clear clinical benefit. guided by hemodynamics, clinical findings or by right
heart catheterization performed selectively. Intrave-
The efficacy of ultrafiltration in patients with ADHF nous vasodilator therapy is suggested for patients
has been evaluated in several randomized trials : with refractory HF without symptomatic hypotension.
Selected patients with hypotension may benefit from
In the UNLOAD trial, 200 patients hospitalized for vasodilator therapy guided by invasive monitoring,
ADHF were randomly assigned to ultrafiltration or to including pulmonary artery catheter. If the systolic
standard care, including intravenous diuretics found blood pressure is <85 mmHg or there is evidence
that: of shock , an inotrope is added . In patients with
persistent shock, a vasopressor may be added as
• At 48 hours, patients assigned to ultrafiltration had a temporizing measure to support perfusion to vital
a significantly greater fluid loss (4.6 versus 3.3 li- organs, though this is at the expense of increased
ters with standard care) and at 90 days, patients left ventricular afterload. For selected patients with
assigned to ultrafiltration had significantly fewer severe HFrEF (generally with left ventricular ejection
HF rehospitalizations than patients assigned to fraction <25 percent) with acute, severe hemody-
standard care (0.22 versus 0.46 admissions per namic compromise, nondurable mechanical support
patient) and fewer unscheduled clinic visits (21 (eg, intraaortic balloon pump [IABP], extracorporeal
versus 44 percent with standard care). circulatory membrane oxygenator [ECMO], or extra-
corporeal ventricular assist devices) is an option as
• The rates of adverse events were similar in the two a “bridge to decision” or “bridge to recovery” , espe-
groups, although there was a higher incidence of cially common in the current era of complex PCI in
bleeding in the standard care arm. There was no ACS patients.
difference in serum creatinine, as was also found
in a smaller trial with detailed assessment of renal Patients with HFpEF presenting with hypotension
hemodynamics . should not receive inotropes and may require a va-
sopressor in addition to diuretic therapy. Patients
In CARRESS-HF, 188 patients with ADHF, worsened who develop hypotension with dynamic LV outflow
renal function (defined as an increase in the serum obstruction are treated with beta blocker therapy, a
creatinine level of at least 0.3 mg/dL [26.5 micro-
mol/L]), and persistent congestion were randomly

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176 Cardio Diabetes Medicine 2017

vasopressor (eg, phenylephrine or norepinephrine), • Milrinone: – Milrinone is a phosphodiesterase inhib-
and gentle hydration if pulmonary edema is not itor that increases myocardial inotropy by inhibiting
present. Ultrafiltration is an option for patients with degradation of cyclic adenosine monophosphate.
HFrEF or HFpEF with refractory volume overload not Other direct effects of milrinone include reducing
responding to diuretic strategies. systemic and pulmonary vascular resistance (via
inhibition of peripheral phosphodiesterase) and
Vasodilator therapy — Intravenous vasodilator therapy improving left ventricular diastolic compliance .
is suggested in patients with refractory HF who re- These changes lead to an increase in cardiac index
quire reduction in preload, afterload, or both. Nitrates and decrease in left ventricular afterload and filling
reduce LV filling pressure primarily via venodilation pressures. Patients should receive a loading dose
and at higher doses, lower SVR and LV afterload. of 50 mcg/kg over 10 minutes, followed by a main-
Nitroprusside and nesiritide both provide balanced tenance dose of 0.375 to a maximum of 0.750
arterial and venous dilation. The use of these agents mcg/kg per min. Dose adjustment is required in
should be reserved for patients in whom improved the presence of renal insufficiency, hypotension,
hemodynamic function is likely to lead to clinically or arrhythmias.
useful improvements in oxygenation and/or organ
perfusion, but monitored with utmost caution in in- Since milrinone does not act via beta receptors, its
tensive care setting. effects are not as diminished as those of dobutamine
or dopamine by concomitant beta blocker therapy.
Inotropic agents
• Dobutamine: Dobutamine acts primarily on beta-1
Indications — Intravenous inotropic agents such as adrenergic receptors, with minimal effects on beta-
dobutamine and/or milrinone may be required as 2 and alpha-1 receptors. The hemodynamic effects
a temporizing measure in patients with severe left of dobutamine include increases in stroke volume
ventricular systolic dysfunction and low output syn- and cardiac output, and modest decreases in sys-
drome until definitive therapy (eg, coronary revascu- temic vascular resistance and pulmonary capillary
larization, mechanical circulatory support, or heart wedge pressure . It should be started at 2.5 mcg/
transplantation) is instituted or resolution of the kg per min and, if tolerated and needed, can be
acute precipitating problem has occurred. Continu- gradually increased to 20 mcg/kg per min.
ous intravenous inotropic support has been felt to be
reasonable as “bridge therapy” in patients with stage • Dopamine : Although it has been proposed that
D HF refractory to guideline-directed medical therapy dopamine might improve renal function in patients
and device therapy who are eligible for and awaiting with severe HF by increasing renal blood flow and
mechanical circulatory support or cardiac transplan- possibly by reducing renal venous pressure, data
tation. In addition, the 2013 ACC/ AHA guidelines supporting such a potential benefit are limited.
note that inotropic therapy “may be reasonable” (a Inotropic agents may adversely impact outcomes
very weak recommendation) in the following settings: by increasing heart rate and myocardial oxygen
short-term, continuous intravenous inotropic support consumption and thus mask underlying ischemia
in hospitalized patients presenting with document- and even lead to atrial and ventricular arrhythmias.
ed severe systolic dysfunction who present with low Routine use of inotropes in patients hospitalized
blood pressure and significantly depressed cardiac for HF was found to be harmful in the OPTIME-CHF
output to maintain systemic perfusion and preserve trial,where milrinone therapy was associated with
end-organ performance; and long-term continuous significant increases in hypotension requiring in-
intravenous inotropic support as palliative therapy tervention and atrial arrhythmias, and with nonsig-
for symptom control in select patients with stage D nificant increases in mortality in-hospital
HF despite optimal guideline-directed medical ther-
apy and device therapy who are not eligible for ei- • Vasopressor therapy- In patients with ADHF and
ther mechanical circulatory support or cardiac trans- marked hypotension, vasopressor therapy can be
plantation. If symptomatic hypotension or worsening used as a temporizing measure to preserve sys-
tachyarrhythmias develop during inotrope adminis- temic blood pressure and end-organ perfusion, al-
tration, dose reduction or discontinuation is suggest- though at the cost of increasing afterload and de-
ed.Similar recommendations are echoed in the 2010 creasing cardiac output. Vasopressor use should
Heart Failure Society of America and 2012 European be limited to patients with persistent hypotension
Society of Guidelines .Inotropes are not indicated for with symptoms or evidence of consequent end-or-
treatment of ADHF in the setting of preserved sys- gan hypoperfusion despite optimization of filling
tolic function. pressures and use of inotropic agents. With inva-

GCDC 2017

Clinical Presentation and Management 177
of Acute Heart Failure

sive monitoring.Vasopressors used in this setting lengths of hospital stay (6.8 and 6.9 days) were sim-
include norepinephrine, high-dose dopamine (>5 ilar in the two treatment groups.
micrograms/kg/min), and vasopressin, and these
should be carefully titrated to achieve adequate Ularitide - Ularitide is a synthetic analogue of the re-
perfusion of vital organs. nal vasodilatory natriuretic peptide urodilatin. A ran-
domized trial found that ularitide caused short-term
• Mechanical cardiac support: Mechanical modali- hemodynamic effects but did not improve clinical
ties used in AHF setting include IABP, ECMO, or outcomes . The TRUE-AHF trial found no significant
short-term left ventricular assist devices.For se- difference in clinical outcomes at 48 hours based
lected patients with severe HFrEF (generally with upon a hierarchical composite end point. Cardiovas-
left ventricular ejection fraction <25 percent) with cular mortality rates were similar in the ularitide and
acute, severe hemodynamic compromise (cardio- placebo groups at a median follow-up of 15 months.
genic pulmonary edema with cardiogenic shock), Patients in the ularitide group had higher rates of hy-
nondurable mechanical support is an option as a potension and had slightly higher transient increases
“bridge to decision” or “bridge to recovery” . These in serum creatinine levels with greater reductions in
patients usually have a cardiac index less than 2.0 SBP and N-terminal pro-BNP levels.
L/min per m2, a systolic arterial pressure below
90 mmHg, and a PCWP above 18 mmHg, despite Hypertonic saline plus furosemide - The rationale for
adequate pharmacologic therapy. using hypertonic saline solution includes an osmotic
effect that might help optimize refilling of the intra-
INVESTIGATIONAL THERAPY FOR ACUTE vascular compartment during intravenous diuretic
HEART FAILURE therapy and increases in renal blood flow that might
promote diuretic action .A meta-analysis included
The following investigational therapies have shown nine randomized controlled trials comparing intra-
some promise but are not considered appropriate for venous hypertonic saline solution plus intravenous
routine treatment. furosemide to intravenous furosemide alone with the
following results:
Investigational vasodilators
• Analysis for all-cause mortality included five trials
Serelaxin - Relaxin is a naturally occurring human and found a survival benefit with combined hyper-
peptide vasodilator. Although an international ran- tonic saline solution plus furosemide compared to
domized controlled trial comparing 48-hour inter- furosemide alone (risk ratio [RR] = 0.57, 95% con-
venous infusion of serelaxin (recombinant human fidence interval [CI] 0.44-0.74). However, there was
relaxin-2) with placebo in patients with ADHF (with substantial heterogeneity among the studies (I2 =
any left ventricular ejection fraction)found improve- 66 percent) and no significant benefit remained if
ments in some clinical outcomes (including reduc- either of two trials was excluded.
tions in cardiovascular and all-cause mortality at six
months), a subsequent larger trial failed to confirm • Based upon pooled results from four trials, com-
a clinical benefit.The RELAX-AHF trial enrolled 1161 bined hypertonic saline solution plus furosemide
patients with ADHF and systolic blood pressure >125 decreased heart failure-related hospital readmis-
mmHg . Serelaxin improved one measure of dyspnea sion compared to furosemide alone (RR = 0.51; 95%
through day five and reduced average length of in- CI 0.35-0.75). However, there was moderate het-
dex hospital stay but did not improve the proportion erogeneity among studies (I2 = 58 percent) and no
of patients with moderate or marked improvement in significant benefit remained if either of two trials
dyspnea measured by Likert scale during the first 24 was excluded.
hours or readmission to the hospital within 60 days.
The serelaxin group experienced a significantly lower • Analyses of length of hospital stay (seven trials),
rate of cardiovascular death (hazard ratio [HR] 0.63; weight loss (eight trials), and preservation of renal
95% CI 0.41-0.96) and all-cause mortality (HR 0.83, function (serum creatinine) all favored therapy with
95% CI 0.43-0.93) at six months . combined hypertonic saline solution plus furose-
mide versus furosemide alone, although there was
The RELAX-AHF-2 trial enrolled 6545 patients with marked heterogeneity among studies for each of
ADHF and systolic blood pressure >125 mmHg . these outcomes.
Cardiovascular mortality (8.7 and 8.9 percent) and
all-cause mortality (11.2 and 11.9 percent) rates at six Continuous aortic flow augmentation - Continuous
months were similar for serelaxin and placebo. Rates aortic flow augmentation (CAFA) provides continu-
of worsening heart failure (6.9 and 7.7 percent) and ous flow through the aorta that augments pulsatile
cardiac output. CAFA does not increase cardiac out-

Cardio Diabetes Medicine