Cardio Diabetes_2017 book

78 Cardio Diabetes Medicine 2017

with ACE inhibitors. In the EPHESUS randomized trial ies consistently demonstrating a substantial gap be-
in post-MI patients, superior efficacy of eplerenone tween the accumulated evidence and its application
was observed in the diabetes subset of 2122 pa- in patients with diabetes. Second, continued investi-
tients, similar to that in the overall trial. On the basis gation into specific therapies and strategies targeting
of these results, eplerenone is recommended for all the unique risks for CVD associated with diabetes
patients with diabetes and acute MI with decreased remains a critical global public health imperative.
ejection fraction, except in the presence of contra-
indications. Beta blockers and diuretic medications References :
significantly reduce incident HF among patients with
diabetes. Carvedilol may offer advantages in diabetic 1. American Diabetes Association: Standards of medical care in diabe-
patients because of its favorable effects on insulin tes-2013. Diabetes Care 36(Suppl 1):S11, 2013.17. Buse JB, Ginsberg
sensitivity and plasma lipid profiles, but the clinical HN, Bakris
relevance of these observations remains uncertain.
Poor glycemic control is associated with risk of HF 2. Heart Outcomes Prevention Evaluation Study Investigators: Effects of
in diabetes, with the association stronger in women ramipril on cardiovascular and microvascular outcomes in people with
than in men.Drugs with a propensity to precipitate diabetes mellitus: Results of the hope study and micro-hope substudy.
hypoglycemia, especially sulfonylureas and exog- Lancet 355:253, 2000
enous insulin administration, should be used with
some caution, as the stress response to hypoglyce- 3. Braunwald’ Heart Disease,Chapter 61,Diabetes and the Cardiovascular
mia stimulates the neurohormonal axis implicated System ,Darren K. McGuire
in the clinical complications of HF. Thiazolidinedione
medications have a propensity to increase plasma 4. Hurst’s Heart, Chapter 91,Diabetes and Cardiovascular Disease ,Michael
volume and to precipitate incident or worsening HF; E. Farkouh, Elliot J. Rayfield, and Valentin Fuster
their use requires caution in patients with any degree
of HF, and they are contraindicated in patients with
NYHA class III or IV HF.

Cardiomyopathy:

The Framingham Heart Study showed that men with
diabetes are twice as likely to develop congestive
heart failure compared with their nondiabetic coun-
terparts and females with diabetes had a five-fold
increase in the rate of congestive heart failure. The
spectrum of heart failure ranges from asymptomatic
to overt systolic failure. Diabetes complicated by hy-
pertension represents a particularly high-risk group
for the development of congestive heart failure.27
Diastolic dysfunction is exceedingly common (>50%
prevalence in some studies) and may be linked to
diabetes without the presence of concomitant hyper-
tension. The etiology of impaired left ventricular func-
tion may involve any of the following mechanisms: (1)
coronary atherosclerotic disease, (2) hypertension, (3)
left ventricular hypertrophy, (4) obesity, (5) endothe-
lial dysfunction, (6) coronary microvasculature dis-
ease, (7) autonomic dysfunction, and (8) metabolic
abnormalities.

Overall, diabetes increases risk for virtually all CVD
complications and, most notably, atherosclerotic vas-
cular disease and HF. Further progress requires con-
tinued efforts in two domains: First, increased and
optimal application of the existing evidence for CVD
risk reduction is of paramount importance, with stud-

GCDC 2017

Cardio Diabetes Medicine 2017 79

Gestational Diabetes Mellitus
and Cardiovascular Disease

Prof. Dr. Sidhartha Das, MD,FRCP(Glasg),FRCP(Edin),FRCP(London)

Senior Consultant in Medicine & Diabetes, Dean and Principal,
S.C.B.Medical College and Hospital, Cuttack-753007, Odisha

Dr. Mrs. Sujata Misra, MD., FICOG.,

Senior Consultant in Obst. & Gyn.
Associate Prof. P.G.Department of Obst. & Gyn. S.C.B.Medical College and Hospital,

Cuttack-753007, Odisha

Abstract a higher prevalence of CVD was noted 29.9 years
after the index pregnancy in332 women with a his-
Women with gestational diabetes mellitus (GDM) tory of GDM ( adjusted OR: 1.85; 95% CI: 1.21.2.82),
are at a greater risk of type 2 diabetes mellitus and irrespective of associated type II diabetes (OR: 1.56;
cardiovascular disease in later life. With the growing 95% CI: 1.002-2.43).. In comparison to pregnant wom-
prevalence of GDM , it is inevitable that the inci- en with normal glucose tolerance, women with GDM
dence of women with cardiovascular disease (CVD) were seen to have an adjusted hazard ratio of 1.66
will be on the rise. Hence , it is imperative that screen- ( 95% CI: 1.30-2.13)for CVD ( acute myocardial infarc-
ing, follow up , and treatment strategies should be in tion, coronary bypass, coronary angioplasty, stroke,
place to control the disorders created by the triad of carotid end arterectomy.). In pregnant women with an
pregnancy, obesity and GDM. This will help to contain abnormal glucose test same was 1.19(955 CI:1.02-1.39).
the increased incidence of CVD in women in future. Even women with mild hyperglycemia in pregnancy,
not amount in to GDM are at an increased risk for
Introduction CVS. But, the highest incidence of CVD in women
with a history of GDM is seen in those subsequently
Pregnancy, per se, is a hyperinsulinemic state . De- developed type II diabetes mellitus. 3
creasing insulin sensitivity (increasing insulin resis-
tance ) with increasing gestational age is a physio- Common CVD Risk factors
logical process designed to provide glucose to the
fetus. This is a prerequisite for fetal growth and de- The potential new markers for of CVD in women with
velopment. 1The increased insulin resistance is due to GDM include hypertension, Dyslipidemia and Meta-
the placental hormones such as human placental lac- bolic syndrome.
togen, human placental growth hormone, estrogen,
progesterone and cortiosol which are antagonize Hypertension: Women with a history of GDM are at a
the action of insulin. Most women can combat this greater risk of developing hypertension as compared
physiological insulin resistance and remain euglyce- to women without a history of GDm (46.8% vs37% ;
mic. The few who cannot cope up with this increasing p<0.001). In addition , hypertension is diagnosed at
insulin resistance manifest as cases of Gestational an earlier age in the former as compared to the latter
diabetes Mellitus (GDM). Hence, GDM is defined as grpoup (40+/- 1.0 vs 47.8 +- 0.9 years;p<0.001). 4
of glucose intolerance developing or first recognised
during pregnancy with values of blood sugar which Goueslard et al have studied 62,958 women with
are not clearly indicative of overt diabetes.2 GDM and 1,452,429 women without a history of GDM
with a follow uo for seven years . They have reported
Women with a history of GDM are at a higher risk of that GDM was associated with a higher risk of hy-
overt cardiovascular disease in later life. GDM alone pertension with an adjusted OR of 2.92 (2.77-3.08).5
contributes to this risk ; independent of subsequent
type II diabetes mellitus. In a cross sectional study, Dyslipidemia: Carr et al have reported that women

Cardio Diabetes Medicine

80 Gestational Diabetes Mellitus
and Cardiovascular Disease

who developed GDM were also more likely to report history of GDM itself can be considered a risk factor
a history of dyslipidemia(33.9% vs 26.9 %; p<0.05); for atherosclerosis even before the onset of diabetes
increased history of intake of medicines for dyslipid- or metabolic syndrome. The flow-mediated dilation
emia (18.4%vs13.7%; p<0.05) and were diagnosed with (FMD) of the brachial artery is an indicator of endo-
dyslipidemia at an younger age (47.6 vs 51.9; p= 0.01) thelial dysfunction and is one of the earliest signs of
3. Another study analysed cases who had GDM and atherosclerosis 12,13. Anastasiou et al. measured FMD
those who were euglycemic in their index pregnancy,- 3–6 months postnatally in women with a history of
from two to four months after their pregnancy. They GDM, and found it to be significantly lower in both
reported that women with history of GDM had a high- nonobese and obese GDM women than in control
er total cholesterol (5.06 vs 4.56 mmol/Lp=0.001),, women14. It was seen that FMD correlated inversely
LDL cholesterol(3.17 vs 2.57mmmol/L;p=0.001) and with BMI, serum total cholesterol, and basal insulin
triglyceride levels (1.02 vs 0.86mmol/L).The HDL cho- resistance (assessed with a homeostasis model). But
lesterolwas lower (1.53 vs 1.73 mmol/L; p =0.001) . 6 Hannemann et al. And Brewster have found no differ-
ences in FMD between women who had experienced
Retnakaran et al too have concluded that GDM is an GDM five years earlier and control women matched
independent predictor of total cholesterol, LDL-cho- for age, BMI, and smoking habits .15,16 Therefore, there
lesterol, and triglyceride levels measured 3 months is no sureity of impairment of FMD in later years in
after delivery. The authors have demonstrated a women with history of GDM. Impairment of FMD may
stronger correlation between the area under the be an early vascular function abnormality influenced
curve on the antepartum oral glucose tolerance test by hyperglycemia, which normalises once the wom-
and postpartum lipid profile. 7 en is normoglycemic .hence, it may work as a mark-
er in tests donein the early years following delivery.
Metabolic Syndrome The authors of a multivariate analysis have found
an independent association between the coronary
Metabolic syndrome (abdominal obesity, hyperten- flow velocity reserve (CFVR); which reflects coronary
sion, dyslipidemia, and abnormal glucose tolerance microvascular function,and GDM 17
)carries a six- to eightfold higher risk of CVD and a
two- to threefold higher CVD-related mortality rate New Markers:
by comparison with healthy controls 8. Women who
have had GDM are at high risk of developing meta- Apelin,produced by the adipose tissue, is a recently
bolic syndrome discovered adipocytokine . It is an endogenous li-
gand of the G protein-coupled receptor APJ and is
A recent hospital-based cohort study reported that expressed in various tissues (brain, lung, heart, pan-
the risk of metabolic syndrome 2–6 years after deliv- creas, kidney, and endothelial cells).It is postulated
ery was 2.4 times higher in women with a history of to have a role in the cardiovascular system18. Sup-
GDM as compared to those who had normal glucose pressed apelin levels are therefore associated with
tolerance in pregnancy. In a multivariate analysis it a higher cardiovascular risk in women with a history
was seen that a history of GDM predicted the onset of GDM. Osteoprotegerin (OPG), a soluble member
of metabolic syndrome with an OR of 2.83 9 of the tumor necrosis factor (TNF) receptor super-
family, inhibits osteoclast maturation and protects
4. Early Structural and Functional the Changes in bone from normal osteoclast remodeling OPG has
Vascular Structure in Women with history of prior an important role in lymphocyte production, apopto-
GDM Women with a history of GDM , without any sis, and its levels have been associated with CVD19.
cardiovascular risk factors are at a greater risk of In a cross-sectional case-control study, wommen
CVD than those with normal glucose tolerance in who were confirmed to have metabolic syndrome
pregnancy. The effect of GDM on the endothelial had higher OPG levels than those who were not, or
function and structure acts as a trigger for initiation healthy controls; and serum OPG levels were found
of atherosclerosis.It is well documented that carotid to be associated with obesity, insulin resistance, and
artery intima-media thickness (cIMT) is a measure cIMT 20.Pentraxin 3 (PTX3) is produced by endo-
of early atherosclerosis and strongly predicts heart thelial cell macrophages and granulocytes at sites
disease and stroke, especially in women 10. Bo et al. of inflammation. Raised levels in patients with CVD
measured cIMT six and a half years after delivery in denotes a beneficial response in terms of reduced
82 women withGDM and 113 who were euglycemic immune activation21. Low plasma concentrations of
in pregnancy .[25] They reported a significantly higher PTX3 in early pregnancy are therefore associated
cIMT in those with a history of GDM.these values with the subsequent onset of GDM and a higher risk
were independant of their BMI levels 11. Infact, a

GCDC 2017

Cardio Diabetes Medicine 2017 81

of CVD later on22. Subclinical inflammation is a major 10. S. H. Johnsen, E. B. Mathiesen, O. Joakimsen et al., “Carotid atherosclero-
risk factor of CVD future in the general population, sis is a stronger predictor of myocardial infarction in women than in men:
and the higher risk of CVD later in life for women with a 6-year follow-up study of 6226 persons: the Tromsø study,” Stroke, vol.
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are identifiable before the onset of diabetes, meta- tection of endothelial dysfunction in children and adults at risk of athero-
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Cardio Diabetes Medicine

82 Cardio Diabetes Medicine 2017

Diabetes Retina Screening
Project in Sudan

Dr. Dina Nagodra,

MBBS., MSc Public and Tropical Health UMST., Sudan
Certified in Regenerative Medicine, Utrecht University, Netherlands

Certified in Diabetes, IDF, Belgium

Introduction: and detection of diabetic retinopathy.30 ophthalmol-
ogists will have undergone training to conduct la-
This project will build upon the continuum of the on- ser treatment.300,000 people will be reached with
going and previous World Diabetic Federation proj- awareness activities for diabetes eye disease.
ects in Sudan to prevent blindness due to diabetes in
Sudan. Developing organized diabetes care has be- Reference: Eltom M. A. Secretary, Sudan Diabetes
come a priority in Federal Ministry of Health (FMOH) Federation
five year strategic plan. FMOH is a major partner
in this project with other three states ministries of
health (MOH).

Goal:

The project goal is to prevent blindness due to dia-
betes in Sudan by establishing screening program of
diabetic retinopathy through increasing capacity of
health professionals, early detection of retinopathy
and increasing access of laser treatment.

Implementation:

Instead of randomized effort, it is going to be syn-
chronized effort in harmony with strong referral sys-
tem from primary care to tertiary care in coordina-
tion with MOH and Diabetes Programs Promotion
Organisation (DPPO). Central software system would
be connecting grading stations at different locations.
Academic teaching institutes will provide medical
training and education.

Outcome:  

Motivated ophthalmologists will be assisted to
establish laser treatment units in their facilities with
application of a user fee with the exception of those
with low income.10,000 patients with diabetes to be
screened for diabetic retinopathy.1,000 patients with
diabetic retinopathy will have undergone laser treat-
ment.120 family care physicians will have attended
special education sessions on diabetes management

GCDC 2017 & Cardio Diabetes Medicine

Cardio Diabetes Medicine 2017 83

Pre Diabetes- Beyond
The Tip of The Iceberg

Dr. Arulprakash

MD., MRCP(UK)., MCA., FRCP(London)
Indra Diabetes and Endocrine Centre,Tuticorin

Introduction was large variation in state-specific diabetes preva-
lence. The differences in the prevalence of diabetes
Prevalence of impaired fasting glucoseand IGT gen- between states might be explained by factors such
erally considered as prediabetic state. It stands at 3% as differences in SES, physical activity, dietary pat-
of the total adult population as per latest estimates terns, obesity prevalence, and possibly genetic varia-
by the IDF and the phenomenon is commonto all tion. The overall prevalence of diabetes was higher in
geographical regions. The prevalence of pre diabetes the mainland than in the northeast states. Diabetes
is increasing world wide and by 2035 projected 471 prevalence was higher in the more economically de-
million people will have this condition. It has attained veloped states, and even within states diabetes was
clinical significance because of epidemiological as- more common in individuals of medium or high SES
sociation with macro-vascular disease and neurop- than in individuals of low SES, which agrees with
athy. Compounding this problem, Indians show a results from earlier studies in India. However, the
high conversion rate from pre- diabetes to diabetes prevalence of diabetes was higher in individuals of
(approximately 18%) as seen in the Indian Diabetes low SES in the urban areas of seven states, most of
Prevention Programme-1 (IDPP-1) , a 3 year prospec- which are also ranked among the more economically
tive study. Such high conversion may even slow in- advanced states of India. Conversely, in rural areas,
creased prevalence of overt diabetes at the expense the prevalence of diabetes was higher in individuals
of (declining) population with prediabetes. The prev- of higher SES in all the states studied. This find-
alence rate of IGT amongst two North Indian cohorts ing suggests that the urban areas of more affluent
were comparable with the National Urban Diabetes states have transitioned further along the diabetes
Survey(1001) reporting 8.6% in Delhi, and Zargar AH et epidemic, such that less affluent individuals have a
all(200) in their study reporting 8.1% in Kashmir, An- higher prevalence of diabetes than their more afflu-
jana RM et all(2011) in ICMR-INDIAB found somewhat ent counterparts. However, in rural areas throughout
higher pre diabetes prevalence amongst pre domi- India, diabetes continues to be a disease of more af-
nantly south indian (14.5%) and rural (14.7%) areas. A fluent sections of society, suggesting that the epide-
much higher crude prevalence of 37% was described miological transition is less advanced in these areas.
in a cross-sectional survey (2009) among employees This finding is all the more important because Asian
aged 20-59 years of a large industry near Delhi. Indians have been shown to progress faster through
the prediabetes stage than do people of other eth-
The ICMR–INDIAB study is the largest nationally rep- nic groups. Declines have previously been noted in
resentative study of diabetes in India. The cumulative the prevalence of prediabetes in Chennai and other
data from 15 states represent a total adult population south Asian populations. The prevalence of impaired
of 363·7 million people (51% of India’s adult popula- fasting glucose was substantially higher than that of
tion). The estimated overall prevalence of diabetes in impaired glucose tolerance.The main factors driving
India to be 7·3% and the prevalence of prediabetes the diabetes epidemic in both urban and rural areas
to be 10·3% (WHO criteria) or 24·7% (ADA criteria), of India are obesity, age, and family history of diabe-
depending on which definition was used. However, tes. Results from an earlier study have shown similar
these estimates are based on data from 15 states prevalence of impaired fasting glucose and impaired
out of a total of 31 to be studied, and cannot be con- glucose tolerance in the urban population of south
sidered as final. Among the 15 states studied, there

GCDC 2017 & Cardio Diabetes Medicine

84 Pre Diabetes- Beyond The Tip of The Iceberg

India, attributing a greater role to insulin secretory de-
fects in the pathogenesis of type 2 diabetes in Asian
Indians compared with people of other ethnic groups.

The Indian study was conducted on children and
adolescents attending the urban endocrine clinic for
obesity. Robust biochemical evaluation including gly-
cose tolerance tests and HOMA-IR was carried out in
224 obese patients. This cross- sectional data sowed
as increase in the prevalence of IFG (8-10%) IGT (10
to 15%), and diabetes (1.3to 1.8%) from childhood to
adolescent stage, respectively. The increase can also
be attributed to the pubertal spurt of counter reg-
ulatory hormones. Their data also showed positive
association of both systolic and diastolic blood pres-
sure readings with insulin resistance.Studies have re-
corded prediabetes in >10% of Sri Lankan and 20%
in Bangaladeshi adult population. These data raise
questions regarding ethnicity and beta cell reserve.
Parity also has been raised as a possible risk factor
leading to obesity and diabetes in women. The other
observation is that high prevalence of hypertension
and obesity among prediabetics. Studies from the
sub Saharan countries have consistently reported a
higher prevalence of hypertension with rates rang-
ing from 19% in rural Tanzania, 20% in rural Kenya,
21% in rural Nigeria and 32% in urban Namibia. The
situation in the Indian subcontinent is equally worse.
Likewise the prevalence of obesity is high in children
of Africa and India. The associated dyslipidemia and
microalbuminuria in the pre diabetic stage warrant
intervention strategies from care providers.

The good news is that there is an accumulated evi-
dence that this intermediate disorder can be slowed
down or prevented from deteriorating to diabetes
and related pathological consequences. The success-
ful intervention tested were diet and exercise, met-
formin, tolbutamide, orlistat and acarbose. Improved
awareness and diagnosis is possibly the results of
concerted efforts by the Government (through pro-
grammes such as the National Programme for Con-
trol and Prevention of Cancer, Diabetes, Cardiovas-
cular Disease and Strokes) and nongovernmental
organisations. The coordinated effort of Government,
NGOs, Privatesector health care providers with the
focus on the preventable strategies at appropriate
level will be helpful to decelerate this ongoing dys-
glycemic epidemic.

GCDC 2017 & Cardio Diabetes Medicine

Cardio Diabetes Medicine 2017 85

03. Clinical Presentation

1. Peripheral Vascular Disease - Dr. J. Ezhilan
2. Stress Hyperglycaemia or Diabetes – Which is Bad in ICU? - ? Dr. M. Jayapaul
3. Resistant Hypertension in Clinical Practice - Dr Virendra Kumar Goyal
4. Diabetic Cardiovascular Autonomic Neuropathy - Dr. Ulhas M. Pandurangi
5. Erectile Dysfunction: Endothelial Dysfunction; Emotional Disturbance - Prof Dr Deepak K

Jumani
6. Regression of Atherosclerosis- In Diabetics - Dr Joy M Thomas
7. Triglyceride and Cardiovascular Risk-Whats New??? - Dr.Aarathy Kannan
8. Impaired Glucose Tolerance and Coronary Artery Disease and Peripheral Artery Disease -

Dr D. Selvaraj
9. Atypical Presentation of Acute Coronary Syndrome in Diabetics - Dr. T. Neelambujan
10. Cardiovascular Risk in Diabetes: Known vs Unknown - Dr. T.P. Weerarathna
11. Effect of Stroke on Heart, Diabetes and Hypertension - Prof. Dr. Lakshminarasimhan
12. Thyroid dysfunction, Diabetes and the Cardiac Link - Dr. Muthukumaran Jayapaul
13. Mechanism , Clinical Presentation and Treatment of Diabetic Kidney Diseases - Prof.

Soundarajan
14. DKD is Coronary Equivalent (Evidence And Remedy) - Dr. T. Dhinakaran
15. Stroke in Cardiodiabetic Syndrome – How Different is it? - Dr. K. Mugundhan
16. Management of Cardioembolic Stroke - Dr. N. Thamilpavai
17. Stemi in Young - Dr. Joy M Thomas
18. Cardiomegaly in Diabetes Mellitus - Dr. T. Geetha
19. Clinical Presentation and Management of Acute Heart Failure - Dr. Prayaag Kini
20. Non-Infarct Related Artery Intenvention in ST-Elevation Myocardial Infarction with Multives-

sel Disease - Dr. Shirish Hiremath
21. Obstructive Sleep Apnoea (OSA): Cardiodiabetic issues - Professor. Dr. Ram Dhillon
22. Diabetes and Systemic Complications in Immune Deficiency Syndrome - Prof. Kutikuppala

Surya Rao
23. Low Body Weight T2DM and Macro Vascular Disease - Prof. Dr .Sidhartha Das
24. Alcohol – Heart, Diabetes and Lipids - Dr.Meenakshi Sundaram
25. Anxiety and Diabetes - Dr. Avinash De Sousa
26. Diabetes Melitus and Tuberculosis –Double Jeopardy - Dr. Prof. Preetam Arthur
27. Eating Disorders in Diabetes Mellitus - Dr. Davis Prabhakar
28. Obstructive Sleep Apnoea Syndrome and Cardio Metabolic Risk - Dr. Solaiman Juman
29. Pre Diabetes as Risk Factor for Coronary Artery Disease and Peripheral Vascular Disease -

Dr. Arulprakash
30. Bradyarrhythmias - Dr. Kader Sahib

Cardio Diabetes Medicine

86 Peripheral Vascular Disease

31. Congestive Heart Failure in Diabetic ....! How It is Different? - Dr. Dhanushkodi
32. Remnant Lipo Proteins –Residual Vascular Risk - Dr. R. Sarvanan
33. Treatment of Acute Ischemic Stroke - Dr B. Kannan
34. Hypoglycemic Heart- Cardiologist Perspective - Dr. Senthil Kumar
35. Listening to our Gut: Microbiomes and NCD /CVD - Dr. Rajesh Upadhyay
36. Diabetic Dysrhythmias - Dr. Ulhas Pandurangi
37. Cardiac Complications in Diabetic Ketoacidosis - Dr. Sankar
38. Role of Oxygen Insufficiency in the Onset and Development of Vascular Complications of

Diabetes - Dr. V.N. Rajasekaran
39. Heart Rate Variability in Ischemic Heart Disease and Diabetes - Dr. R. Hari Hara Krishnan
40. Hypoglycemia How Critical It is? - Prof. Dr. S. Arulrhaj
41. Diabetes and Genitalia - Dr. M. Balasubramanian
42. Diabetic Kidney Disease: When to Refer to a Nephrologist & Why? - Dr. Pritam Gupta
43. Role of Nerve Conduction Study in Diabetic Patients - Dr. B. Kannan
44. South Asians with PCOS – Metabolic Risk in Future Generation - Dr. Aarathy Kannan
45. Hypertension in Elderly Population - Prof. Dr. Jyotirmoy Pal
46. CVD in Diabetes – Is it only Macrovascular? - Dr.Arulprakash
47. Double Trouble - Diabetes And Heart Disease - Dr Preetam Arthur
48. Diabetic Cardiomyopathy: Mechanisms, Diagnosis and Treatment - Dr. A. K. Das
49. International Lipid Guidelines : What is Needed for Indians ? - Dr. S. N. Narasingan
50. Maternal obesity & Pregnancy outcomes - Dr. Archana Ambujan

GCDC 2017

Cardio Diabetes Medicine 2017 87

Peripheral Vascular Disease

Dr. J. Ezhilan, MD, DM, DNB, FNB, FSCAI.

Senior Consultant Interventional Cardiologist
Madras Medical Mission- Chennai

ABSTRACT EPIDEMIOLOGY

Peripheral arterial disease (PAD) affects 12% of adult Peripheral arterial disease (PAD) of the lower limbs
population and both male and female are equally af- affects approximately 12% of the adult population.
fected. PAD is always associated with Coronary ar- At younger age, PAD is more prevalent in men than
tery disease and cerebral vascular disease hence it women; however, with advancing age, gender distri-
leads to increase risk of myocardial infarction, stroke bution is equal1. PAD is always associated with cor-
and death. Through history taking and physical ex- onary artery disease and cerebrovascular disease
amination complimented by a array of non invasive in 38% of the population. Patients with PAD have a
testing can lead to early diagnosis of PAD which is higher rate of all cause mortality and are at increased
usually diagnosed late or missed. Medical manage- risk of cardio vascular events, including myocardial
ment of PAD is primary risk factor optimization like infarction, stroke and cardiovascular death. In India,
smoking cessation, good control of diabetes mellitus, around 10 million people are affected with PAD of the
optimum blood pressure levels in systemic hyperten- lower limbs. The 5-year rate of non-fatal cardiovascu-
sion and satin therapy. For atypical symptoms and lar events among patients with symptomatic PAD is
mild to moderate claudication exercise therapy and 20% and the mortality ranges from 15 to 30%. Major
pharmaco therapy is sufficient. For severe claudica- risk factors for PAD are increasing age, current or
tion, chronic limb ischemia and acute limb ischemia, past tobacco use, and the presence of diabetes, dys-
endovascular interventions and surgical bypass are lipidemia, hypertension and chronic kidney disease.
done. The field of interventional cardiology in PAD Of these risk factors, smoking and diabetes pose the
has been rapidly expanding in the last decade with greatest risk for the development and progression
a wide array of new devices that has made endo- of PAD.
vascular interventions much safer and is now slowly
replacing surgical Bypass. CLINICAL FEATURES OF PAD

The peripheral arterial system includes all non-cardiac arteries: the A thorough history taking and physical examination
thoracic and abdominal aorta and their branches extending to vis- is the first step in diagnosing PAD. Majority of the
ceral organs and both upper and lower extremities as well as the patients (30 to 50%) with PAD are asymptomatic and
extra cranial vessels Fig.1. although patients do not have symptoms with their
activities of daily living, they may have functional
impairment of formal testing. Atypical symptoms of
PAD include lower extremity discomfort or fatigue
that begins during exertion but is not reproducible
with the same level of exertion and may require a
longer period of time to resolve. Claudication, the
classical symptom of PAD includes pain, discom-
fort and heaviness, tiredness, cramping and burning
sensation in the muscles of the calf, hip, thigh or
buttocks, which is reproducible with a similar level of

Cardio Diabetes Medicine

88 Peripheral Vascular Disease

activity such as walking and disappears after several Grade Classification of PVD
minutes of rest 0 Category Clinical Discription
i 0 Asymptomatic
Fig.2. Based on the site of claudication one can fairly local- ii 1 Mild claudication
ize the level of obstruction the lower extremities iii 2 Mod-Severe claudication
iv 3 Sev claudication
4 Ulceration or gangrene

Fig.4. The Rose angina and claudication questionnaire and
the Edinburgh claudication questionnaire can be used to as-
sist clinicians with screening patients for PAD2&3.

Physical examination includes measurement of blood
pressure in both arms, cardiac auscultation for heart
rate and rhythm, auscultation for carotid, subclavi-
an, abdominal and femoral artery bruits, abdominal
palpation for signs of aortic aneurysm, palpation of
peripheral pulses in all four extremities and inspec-
tion of the four extremities to assess for any signs
of PAD. Peripheral pulses should be described as
bounding (3+), normal (2+), diminished (1+), or absent.
Careful inspection of the extremities should include
observations for ulcerations, calluses, tenia pedia,
trophic skin changes, infection, pallor on elevation
or temperature changes relative to the proximal or
contralateral limb. A thorough history taking and
physical examination should always be supported
by noninvasive diagnostic testing to confirm the di-
agnosis of PAD.

Figure 3 Localization of PAD lesion in lower extremity DIAGNOSIS OF PAD

Critical limb ischemia includes symptoms of rest pain ANKLE BRACHIAL INDEX
or tissue loss. Rest pain is characterized by pain in
the toes or distal forefoot with elevation which is re- The ankle brachial index(ABI) is the single best initial
lieved when the limb is dependent. Tissue loss in- screening test in patients with suspected PAD. It is
cludes the presence of ischemic ulceration or frank the ratio of the systolic blood pressure measurement
gangrene. PAD can be clinically staged by Fontaine of the ankle to that of the brachial artery. The ABI
and Rutherfords classification as follows Fig.4. correlates well with the severity of the obstruction ;
however, it is poorly correlated with functional impair-
Grade Rutherfords classification ment because of PAD. The ABI is easy to perform bed
0 Category Clinical Discription side test with a hand held continuous wave Doppler
i 0 Asymptomatic and manual blood pressure cuff. An ABI of between
ii 1 Mild claudication 0.91 and 1.3 is considered normal. An ABI of 0.71 to
iii 2 Moderate claudication 0.90 indicates mild obstruction , 0.41 to 0.70 is con-
iv 3 Sev claudication sistent with moderate obstruction , 0.00 to 0.40 de-
v 4 Rest Pain notes severe obstruction. A low ABI consistent with
vi 5 Minor tissue loss arterial occlusive disease, is an independent predic-
6 Major tissue loss tor of increased mortality. In patients with ABI great-
er than 1.3 and suspected medial calcinosis, the toe
brachial index is a better assessment of underlying
vascular disease. The ABI however does not provide
information about the level of obstruction

TOE PRESSURE MEASURMENTS

GCDC 2017

Cardio Diabetes Medicine 2017 89

Toe pressure measurement is a useful clinical meth- CT ANGIOGRAPHY
od especially in diabetics because digital vessels are
usually spared from medial sclerosis. It is useful in CT Angiography has revolutionized the evaluation
detecting individual at high risk of gangrene ulcer- and management of PAD. Current multidetector CTA
ation and infection associated with PAD. Arterial BP scanners can generate high-resolution arterial imag-
at toe is approximately 60% systolic BP at ankle. Toe es which allows superb delineation of small vessels
systolic pressure index > 0.6 is a good screening test in the foot. The volumetric acquisition of axial im-
next to ABI. ages and software-based reformatting allows one
to visualize the anatomy from multiple angles and
SEGMENTAL ARTERIAL PRESSURE in multiple planes after a single acquisition. It has
a sensitivity and specificity of greater than 95% for
Segmental limb pressure evaluation can help to identifying lesions greater than 50%, however limita-
identify the anatomic location and severity of lower tions are exposure to radiation and usage of 100 to
extremity PAD by comparing systolic blood pressure 150 ml of iodinated contrast. Extensive calcification
measurements at the upper and lower thigh, calf and can obscure the lumen and overestimate the degree
ankles. The difference in pressures between two ad- of stenosis
jacent leg segments, and between the two extremi-
ties at the same level is typically less than 20 mm/ Magnetic resonance angiography
hg. A pressure drop greater than 20 mm/hg implies
the presence of an obstructive lesion between two Magnetic Resonance angiography (MRA) provides
measured segments. excellent-quality image of the peripheral vascular
system. Gadolinium-enhanced 3D MRA affords the
PULSE VOLUME RECORDING opportunity to acquire angiography like images. Con-
trast enhanced 3D MRA has a sensitivity of 95% and
The Pulse volume recording (PVR) is a form of air specificity of 97% for identifying PAD. Limitations of
plethysmography. A blood pressure cuff is placed on MRI are claustrophobia and inability to perform the
the lower extremity and inflated to a baseline pressure test in patients with intracranial artrial aneurysmal
of appropriately 65 mm/hg. Placement of the cuffs clips, and implantable devices like pacemakers, de-
is similar to those used for segmental pressures and fibrillators and pumps. Exposure to gadolinium-based
the cuff is attached to plethysmograph. The lower ex- contrast agent in the setting of renal failure has been
tremity pulsatile flow causes small changes in limb associated with nephrogenic systemic fibrosis, a rare
volume, which are recorded as arterial contours and dermopathy that involves fibrosis of the joints eyes,
correspond to direct arterial pressure waves record- and internal organs. Hence GFR < 30 ml/mt/1.73 me-
ed at that level. The normal PVR tracing has a sharp ter square is a contraindication for gadolinium en-
upstroke a distinct pulse peak, and a rapid decline. hanced MRA.
With increasing arterial obstruction the PVR tracing
becomes progressively flattened and prolonged. In MANAGEMENT OF PAD
patients with noncompressible vessels, the PVR is
more reliable than segmental pressure or ABI. The overall treatment approach in the PAD patient
focuses on 1) reducing cardiovascular events through
DUPLEX ULTRASONOGRAPHY risk factor optimization, 2) preventing progression
of PAD and limb loss, and 3) improving symptoms
Duplex Ultrasonography combines B-mode imaging and well-being through exercise regimen programes,
and pulse wave Doppler imaging. It is an accurate, pharmacotherapy and surgical / endovascular inter-
cost-effective non-invasive method to localize ste- ventions when required. Table.1.
nosis and differentiate stenosis from occlusion. Gray
scale B-mode imaging creates a 2-dimensional im- MEDICAL MANAGEMENT OF PAD
age of the arterial wall and lumen, which allows the
operator to identify morphological changes in the ar- PAD is associated with a high prevalence of cardio-
tery. Pulsed wave Doppler allows an estimation of the vascular morbidity and mortality and is thus consid-
degree of stenosis based on the blood flow velocity. ered as a CHD risk equivalent by cholesterol guide-
In peripheral arteries a peak systolic velocity greater lines. Hence all patients require aggressive manage-
than 200 cm/sec correlates with an obstruction of ment to optimize their CHD risk factors.
more than 50%. This test however is time consuming
and operator dependent.

Cardio Diabetes Medicine

90 Peripheral Vascular Disease

Table 1: Medical Management

RISK FACTOR OPTIMIZATION DIABETES MELLITUS

SMOKING CESSATION Diabetes mellitus is a strong risk factor for athero-
sclerosis of both coronary and peripheral vessels.
Smoking is the most potent modifiable risk factor for Patients with diabetes and PAD have an amputation
the development of PAD. Observational studies have risk of 20% and 5 year mortality of 50%. Major factors
shown that the risk for MI, deaths and amputation is contributing to amputation in diabetic patients is lack
less in patients who quit smoking. It is recommend- of diabetes education and neuropathic symptoms.
ed that every physician emphasize the importance Though a aggressive HbA1c control reduces micro-
of smoking cessation in patients with PAD. Phar- vascular complications like neuropathy, retinopathy
macological interventions with nicotine replacement and nephropathy, macrovascular complications are
therapy such as nicotine transdermal patch, nicotine not affected. Hence a target HbA1c of < 7% is rea-
gum, nicotine spray or nicotine inhalers have cessa- sonable.
tion rates of 15% to 30%. Bupropion an antidepressant
has approximately 25% efficacy in cessation. Vareni- SYSTEMIC HYPERTENSION
cline, a partial nicotine agonist used to improve crav-
ings and withdrawal symptoms, is the most effective Systemic hypertension is also a strong risk factor for
agent for smoking cessation at this time. PAD. Antihypertensives should be given to lower BP
at least to less than 140/90 mm/hg. The TASC II and
JNC VII recommend for a more aggressive BP goal of

GCDC 2017

Cardio Diabetes Medicine 2017 91

lower than 130/80 mm/hg. Among the antihyperten- EXERCISE PROGRAMS
sive agents ACEI should be a preferred agent.
A supervised exercise program has confirmed im-
STATINS provement in symptoms of claudication. Meta anal-
ysis of RCTs showed that a supervised exercise
As per the NCEP ATP III guidelines PAD is considered causes an increase in walking time by 6.5 minutes.
as a CAD risk equivalent. The TASC II and AHA/ACC This applies even to asymptomatic PAD patients. An
recommends statins to all patients with PAD irrespec- exercise rehabilitation program includes the use of
tive of their LDL levels and the LDL target level is < a motorized treadmill to allow monitoring of patients
100 mg/dl. However the more aggressive target level claudication. The patient attends 3 sessions per week
of < 70 mg/dl is recommended only for patients with of 45-60 minutes for more than 3 months under the
lower extremity PAD at high risk of ischemic events supervision of an exercise physiologist, nurse, or
including those with concomitant CAD. physical therapist, who monitors the patients claudi-
cation threshold and cardiovascular limitation.
ANTIPLATELET THERAPY
PHARMACOLOGY THERAPY FOR
Official guidelines have continued to recommend an- INTERMITTENT CLAUDICATION
tiplatelet therapy to decrease the risk of MI, stroke
or vascular death in patients of lower extremity PAD. CILASTAZOL: Cilastazol a phosphodiesterase-3 in-
Doses of 75 to 325 mg/day are generally recom- hibitor is the most effective medication to improve
mended. Clopidogrel 75 mg/day is an effective al- claudication and should be the first line-medical ther-
ternative therapy and compared with aspirin in PAD apy for treatment of lower extremity PAD. It has vaso-
subgroup of CAPRIE trial showed a relative risk re- dilator effects, antiplatelet effect and ant proliferative
duction of 24% for MACE, compared to aspirin. There activity. Cilastazol therapy gives a 50.7% improvement
is no role for dual antiplatelet therapy aspirin and in maximal walking distance versus placebo in 20
clopidogrel for PAD. However based on new studies weeks. Though it improves walking distance it does
there is insufficient evidence to firmly recommend not reduce all cause mortality. AHA/ACC and TASC
use of aspirin or clopidogrel in all patients with PAD. II supports the use of 100 mg Cilastazole twice a day
as the first line treatment to improve symptoms. Side

Fig.5: (A) Trans-Atlantic inter -society Consensus II Classifications for (A) Aortaliac and (B) Femoro-
popliteal peripheral Arterial Disease

Cardio Diabetes Medicine

92 Peripheral Vascular Disease

effects of cilastazol are headache diarrhea, dizziness Bypass grafting is done with prosthetic grafts or au-
and palpitation. It should be taken 30 minutes before togenous vein grafts. The various Bypass surgeries
or 2 hours after a meal. Cilastazole is contraindicat- done are aorto-femoral Bypass, Fem-Pop Bypass
ed in systolic dysfunction and heart failure of any and fem-fem cross over Bypass. The Bypass grafts
severity4. have a patency rate of 70 to 80% at 5 years.

PENTOXIFYLLINE: a methylxanthine derivative is ap- References
proved by FDA for treatment of claudication however
it is less effective than Cilastazol. The possible mech- 1. Hiatt WR. Sealove BA, Peripheral artery disease and claudication. N Engl
anism of action include antiplatelet effects, lowering J Med 2001:344(21):1068-21.
of plasma fibrinogen and improving the deformity of
red blood cells and white blood cells. It gives a 12% 2. Leng GC, Fowkers FG. The Edinburgh Claudication Questionnaire: an im-
improvement n maximal treadmill walking distance. proved version of the WHO/Rose Questionnaire for use in epidemiological
ACC/AHA guidelines recommend its usage as a survey. J Clin Epidemio1 1992;45(0):1101-9.
second line agent after cilastazol if it fails or is not
tolerated. 3. Rose G, McCartney P, Reid DD. Self-administration of a question-
naire on chest pain and intermittent claudication. Br. J Prev Soc Med
NAFTIDROFURYL: is a 5-hydroxytryptamine-2 recep- 1977;31(1):42-8.
tor agonist that may act by improving muscle me-
tabolism, glucose uptake, and increasing ATP levels 4. Pande RL, Hiatt WR, Zhang P, et al. A pooled analysis of the durability and
in skeletal muscle. TASC II recommends the use of predictors of treatment response of cilostazol in patients with intermittent
Naftidrofuryl at a dose of 600 mg/day for treatment respond of claudication. Vasc Med 2010;15(3):181-8.
of claudication.
5. Sanjay Rajagopalan, Michael H. Crawford . Cardiol Clin 29(2011) 319-
ENDOVASCULAR INTERVENTIONS 329.

Clear indications for PAD patients who need revascu-
larization are 1) Chronic limb ischemia as evidenced
by rest pain, non healing ulcers or gangrene. 2) Acute
limb ischemia with threat to limb. 3) severe claudica-
tion that interferes with lifestyle and a trial of exercise
and pharmacotherapy has failed. TASC II has classi-
fied Aorto-illiac and Femoro-popliteal lesions into 4
types Type A,B,C and D : Fig.5

Endovascular interventions is the preferred mode of
treatment for Type A and B lesions, where as Type C
and D lesions are best sent for surgical revasculariza-
tion. The last decade has seen an unprecedent role
of new device development for the treatment of PAD
like cryoplasty, excimer laser, excisional atherecto-
my, sub-intimal reentry,

crosser catheters, front runner, drug eluting stents,
covered stents, cutting balloons and embolic protec-
tion devices have given us the albeit to treat a vast
array of lesions5.

SURGICAL INTERVENTIONS

Surgical Intervention is done only for acute limb isch-
emia, chronic limb ischemia and very rarely, patients
with claudication. The two choices for surgical revas-
cularization are Endarterectomy and Bypass grafting
Fig.6

GCDC 2017

Cardio Diabetes Medicine 2017 93

Stress Hyperglycemia or Diabetes -
Which is bad in ICU?

Dr. M. Jayapaul

MBBS, MD (UK) MRCP (UK) CCT (Int Med & Endo)
5/2 First Avenue, Sastri Nagar, Adyar,Chennai

Abstract Stress hyperglycemia or Diabetes – Which is
bad in ICU?
Hyperglycemia has been recognized as a common
complication in critically ill patients with or without Hyperglycemia has been recognized as a common
diabetes. It was considered to be an adaptive re- complication in critically ill patients with or without
sponse to stress and believed to be beneficial. But, diabetes. Stress hyperglycemia is very common in
further observations noted that poorly controlled a hospital setting and a significant proportion of
glucose levels are associated with higher in-hospi- these patients have no history of previous impaired
tal mortality, prolonged hospital stay and increased glucose tolerance or diabetes. It was earlier believed
healthcare costs. Treatment with insulin therapy us- to be due to body’s adaptive response to stress
ing differing regimes and protocols had noted that or injury and hence considered to be beneficial to
glycemic control in acutely ill patients might improve the system. But further observations felt that poorly
morbidity and mortality. The main role of metabolic controlled glucose levels are associated with high-
response to stress is to maintain influx of substrates er in-hospital mortality, prolonged hospital stay and
to vital tissues. Brain is the major user of glucose in excess healthcare costs. Stress hyperglycaemia is
the fasting state and is independent of insulin. Tissue defined as a fasting blood glucose level ≥ 126 mg/
damage contributes to hyperglycemia and the most dl or random blood glucose ≥ 200 mg/dl without a
important factor is known history of diabetes. The threshold for hospital
related hyperglycemia in a patient with diabetes re-
the release of stress hormones such as adrena- mains to be established. But for a patient with good
line,noradrenaline, cortisol, growth hormone, inter- glycemic control with HbA1c of 7 % any high glucose
leukin-1 and tumor necrosis factor alpha. Sepsis levels more than the expected range would be con-
and other factors also aggravate pre-existing insulin sidered as hyperglycemia. Recent studies have sug-
resistance, which worsens,hyperglycemia. Evolving gested that new-onset hyperglycemia carried an 18
data suggest that stress hyperglycaemia may be fold increased risk of mortality when compared to
more dangerous than hyperglycemia in a patient with patients with normoglycemia(1). Evidence suggests
pre-existing diabetes. There is good evidence that that insulin therapy to control stress hyperglycemia
aggressive management of glycemia during man- can reduce mortality and improve patient outcomes.
agement of myocardial infarction, acute coronary
syndromes and stroke is beneficial. Other studies Normal glucose homeostasis
examining the benefits of intensive glucose control
in sepsis failed to improve morbidity or mortality. Glucose is the primary energy source for most cells in
Glucose control in an intensive care setting is chal- the body. Glucose is absorbed in the small intestine
lenging in an ill patient with multiple co-morbidities via a sodium dependent active transporter – SGLT1.
and multi-organ dysfunction but may be needed with Following absorption into enterocytes, glucose enters
meticulous care to avoid hypoglycemia. the portal circulation and is transported to the liver.
The main processes of glucose metabolism such as
glycolysis, glycogenesis, glycogenolysis and gluco-
neogenesis all happen in the liver. These metabolic

Cardio Diabetes Medicine

94 Stress Hyperglycemia or Diabetes - Which is bad in ICU?

pathways are under the direct control of insulin and Management of stress induced
glucagon. Insulin is primarily secreted after meals or hyperglycemia
when blood glucose levels rise, it is also secreted at
basal levels in between meal times. Glucagon se- New data suggests that new onset stress hypergly-
cretion happens mostly in between meals or when cemia in hospital may be more dangerous than hy-
blood glucose levels get too low to maintain glycog- perglycemia in a patient with pre-existing diabetes(1,
enolysis and gluconeogenesis. Both these hormones 4). The treatment of stress hyperglycemia depends
maintain blood glucose levels within a close normal on the primary condition being treated, need for in-
range. After a meal, glucose enters the liver and the creased substrate or in conditions where there is no
muscle, adipose tissue and other tissues take the increase in calorie need. In patients with severe hy-
rest. Glucose utilizes a carrier mediated transport sys- povolemic or hypotensive states such as severe cere-
tem entry to cells and the most important isoform is brovascular or low cardiac output states maintenance
GLUT4, which is predominantly present in skeletal, of glucose levels at a higher level may be needed. In
cardiac muscle and adipocytes. Under physiological conditions such as burns or severe trauma increas-
conditions, when blood glucose rises after a meal, ing glucose turnover by infusing glucose and insulin
insulin is secreted from the beta-cells initiates a mul- may improve glucose utilization by glucose sensitive
titude of signaling pathways leading to recruitment tissues.
of GLUT4 to translocate to the cell membrane. This
leads to uptake of glucose leading to maintenance The number of patients admitted to hospital with hy-
of normal blood glucose. perglycemia is increasing. There is a large group of
patients with high glucose levels ,during hospitaliza-
Stress and Metabolism tion due to disease related stress and reverts to nor-
mal glucose tolerance post-discharge. There is evolv-
The main role of metabolic response to stress is to ing evidence that poorly controlled glucose levels are
maintain influx of substrates to vital tissues. Brain associated with increased hospital related mortality,
is the major user of glucose in the fasting state and increased length of stay and excessive health care
is independent of insulin. Hence maintenance of costs. Data from one particular study showed that
glucose delivery to central nervous system is de- patients with new onset hyperglycemia had an 18
pendent on plasma glucose concentration and ce- fold increased in-hospital mortality, 2.7 fold risk in
rebral blood flow. In situations of prolonged fasting patients with pre-existing diabetes when compared
with normal blood flow, the central nervous system with normo-glycemic patients(1). There are guidelines
is programmed to utilize ketone bodies from the liver suggesting that hyperglycemia is very common prob-
and reduce up to 50 % of the obligatory carbohydrate lem in an inpatient setting and early identification
need .Tissue damage contributes to hyperglycemia and aggressive management approach is needed to
in a variety of ways. The important contributor is the improve patient outcomes.
release of stress hormones such as adrenaline, nor-
adrenaline, cortisol, growth hormone, interleukin-1 The initial data originated from the DIGAMI trial where
and tumor necrosis factor-alpha. Sepsis and other insulin-glucose infusion was used to treat hypergly-
factors also aggravate pre-existing insulin resistance, cemia in acute ST-segment elevation myocardial in-
which worsens hyperglycemia. It is also postulated farction. This showed a significant reduction of mor-
that stress hyperglycemia is regulated by central tality of 27 % at the end of the first year. Unfortu-
mechanisms. Afferent inputs to the central nervous nately DIGAMI 2 couldn’t replicate the previous study
system can signal the need for increased carbo- results, which was disappointing. The early evidence
hydrate flux to the brain. These afferent inputs are in critical care originated from the study done by Van
from chemoreceptors in the carotid bodies, pressure den Berghe et al in post-operative patients. Intensive
sensors in the carotid sinus & aortic arch, tempera- post-operative insulin therapy in surgical ICU setting
ture receptors and glucose receptors in the liver and reduced mortality and morbidity(5, 6). This same
the brain. These signals are integrated in the high- study group failed to replicate reduction in mortality
er centers including the hypothalamus, which then by insulin infusion in a medical ITU setting. A large
integrates the efferent responses leading to stress multicenter, international trial was designed to con-
hyperglycemia. Upto 25 % of patients with an acute firm these findings. In NICE-SUGAR trial (The Normo-
MI or stroke when being admitted to hospital fulfill glycemia in Intensive Care Evaluation – Survival using
the criteria for diabetes (2, 3). Glucose Algorithm Regulation), over 6000 patients
were randomized to receive either strict glycemic
control (glucose target 81-108 mg/dl) or conventional
treatment (glucose target < 180 mmol/l) comparing

GCDC 2017

Cardio Diabetes Medicine 2017 95

2 insulin based glucose control strategies. No differ- covering function was significantly less. In one par-
ence in survival, length of mechanical ventilation or ticular review of observational studies examining the
length of hospital stay was observed. A meta-anal- prognostic significance of hyperglycemia in stroke,
ysis of 26 trials investigating the use of intensive the unadjusted relative risk of in-hospital or 30 day
insulin therapy in patients admitted to an intensive mortality was 3.07 95 % CI 2.5-3.79 in patients with
care unit did not show a beneficial effect(7). Another stress hyperglycemia with admission glucose levels
meta analysis of nine randomized studies and ten greater than 108-144 mg/dl. The risk was compara-
observational studies also failed to show any advan- tively lower with subjects with known diabetes at 1.3
tage for intensive insulin therapy, except for a small fold (95% CI 0.49-3.43). The relative risk of poor func-
reduction on the occurrence of infections. tional outcome in patients with stress hyperglycemia
was worse at 1.41(95% CI 1.16- 1.73)(10). It seems from
Management of glucose levels in ACS and available data that patients with sudden increase in
stroke glucose levels fair poorer compared to patients with
known diabetes.
There is good evidence that aggressive manage-
ment of glycemia during management of myocardi- Sepsis
al infarction, acute coronary syndromes and stroke
is beneficial. The incidence of stress hyperglycemia The Surviving Sepsis Campaign guidelines recom-
at presentation of acute myocardial infarction ranges mend starting insulin therapy after two consecutive
from 10-16%. The estimated prevalence of diabetes blood glucose measurements greater than 180 mg/
at presentation of acute myocardial infarction is 25- dl. Several studies have examined the relationship
32%. It would be prudent to measure plasma glucose between glycemic control and severity of sepsis. One
levels on admission to hospital with suspected acute such study which looked at a cohort of 191 patients
coronary syndrome and rapid correction of hypergly- treated with intensive glucose control with a target of
cemia initiated. The MINAP project (Myocardial Isch- between 80-140mg/dl found that rates of both hy-
aemia National project) demonstrated that patients perglycemia and hypoglycemia to be higher. In the
with troponin positive acute coronary syndrome VISEP study (The Efficacy of Volume substitution and
presenting with blood glucose greater than 170 mg/ Insulin therapy in Severe Sepsis), conventional insu-
dl had a higher 30 day mortality compared to 3.3 % lin was compared to intensive insulin therapy and
in patients with lower glucose levels. Of the 38,864 also differing fluids for resuscitation were assessed.
individuals in the MINAP database 10% had blood There were high rates of hypoglycemia in severe sep-
glucose levels greater than 250mg/dl suggestive of sis and the trial was topped early. These results were
stress hyperglycaemia or undetected diabetes. Pa- also replicated in the NICE-SUGAR trial, which failed
tients who did not receive insulin had a relative risk to show any mortality benefits in patients with se-
of death of 56 % and 51% at 30 days(8). In patients vere sepsis. But, there is emerging data that patients
with myocardial infarction form the New York munic- receiving parenteral nutrition may benefit from good
ipal hospital cohort the 3-year mortality was 52 %in glucose control.
stress hyperglycemia, 42% in pre-existing diabetes
and 24% in normal individuals. A meta-analysis of 15 Summary
studies showed a blood glucose levels greater that
120 mg/dl with or without diabetes was associated Glucose control in an intensive care setting is chal-
with increased risk of mortality and heart failure. Re- lenging in an ill patient with multiple co-morbidities
sults from one of the largest observational data from and multi-organ dysfunction. Some studies have
the Portland Diabetic project suggests that treatment shown intensive glucose control to be beneficial but
of hyperglycemia post-cardiac surgery with intrave- many studies have failed to replicate promising re-
nous insulin for 3 days improved mortality, reduction sults from earlier studies. These contradictory results
in sternal wound infections and favorably reducing can be argued to be due to differing patient profiles,
hospital stay. nature of their illness and different intensive care pro-
tocols. But treatment areas such as acute coronary
Glucose levels at presentation during acute stroke re- syndrome have shown better results with strict glu-
mains an important prognostic factor. A single series cose control and improvement in mortality. In acute
suggested that patients with acute stroke with blood stroke glucose levels at presentation remains a great
glucose levels less than 144 mg/dl had full functional prognostic marker.
recovery at 4 weeks(9). Patients with higher glucose
levels faired badly and the proportion of patients re-

Cardio Diabetes Medicine

96 Stress Hyperglycemia or Diabetes - Which is bad in ICU?

Highlights

1. Hyperglycaemia is a common barrier in critically
ill patients with or without diabetes.

2. Increased glucose levels are associated with
higher in-hospital mortality and excess health-
care costs.

3. Stress hyperglycemia may be more dangerous
than hyperglycemia in a diabetic patient.

4. Acute coronary syndromes and strokes are areas
were good glycemic control is essential and has
mortality benefits.

Treatment in an intensive care setting remains con-
troversial and a more relaxed conventional approach
is used with an aim to avoid hypoglycemia.

KEYWORDS

Stress hyperglycaemia, Type 1 Diabetes, Type 2 di-
abetes, Intensive care, Acute coronary syndrome,
Stroke.

References

1. Umpierrez GE, Isaacs SD, Bazargan N, You X, Thaler LM, Kitabchi
AE. Hyperglycemia: an independent marker of in-hospital mortal-
ity in patients with undiagnosed diabetes. J Clin Endocrinol Metab.
2002;87(3):978-82.

2. Norhammar A, Tenerz A, Nilsson G, Hamsten A, Efendic S, Ryden L, et
al. Glucose metabolism in patients with acute myocardial infarction and
no previous diagnosis of diabetes mellitus: a prospective study. Lancet.
2002;359(9324):2140-4.

3. Matz K, Keresztes K, Tatschl C, Nowotny M, Dachenhausen A, Brainin
M, et al. Disorders of glucose metabolism in acute stroke patients: an
underrecognized problem. Diabetes Care. 2006;29(4):792-7.

4. Krinsley JS. Association between hyperglycemia and increased hospital
mortality in a heterogeneous population of critically ill patients. Mayo
Clin Proc. 2003;78(12):1471-8.

5. van den Berghe G, Wouters P, Weekers F, Verwaest C, Bruyninckx F,
Schetz M, et al. Intensive insulin therapy in critically ill patients. N
Engl J Med. 2001;345(19):1359-67.

6. Investigators N-SS, Finfer S, Chittock DR, Su SY, Blair D, Foster D, et
al. Intensive versus conventional glucose control in critically ill patients.
N Engl J Med. 2009;360(13):1283-97.

7. Griesdale DE, de Souza RJ, van Dam RM, Heyland DK, Cook DJ, Mal-
hotra A, et al. Intensive insulin therapy and mortality among critically
ill patients: a meta-analysis including NICE-SUGAR study data. CMAJ.
2009;180(8):821-7.

8. Weston C, Walker L, Birkhead J, National Audit of Myocardial Infarc-
tion Project NIfCOR. Early impact of insulin treatment on mortality for
hyperglycaemic patients without known diabetes who present with an
acute coronary syndrome. Heart. 2007;93(12):1542-6.

9. Weir CJ, Murray GD, Dyker AG, Lees KR. Is hyperglycaemia an inde-
pendent predictor of poor outcome after acute stroke? Results of a
long-term follow up study. BMJ. 1997;314(7090):1303-6.

10. Capes SE, Hunt D, Malmberg K, Pathak P, Gerstein HC. Stress hyper-
glycemia and prognosis of stroke in nondiabetic and diabetic patients:
a systematic overview. Stroke. 2001;32(10):2426-32.

GCDC 2017

Cardio Diabetes Medicine 2017 97

Resistant Hypertension
in Clinical Practice

Dr Virendra Kumar Goyal, DM., FICP., FACP., FIACM.,

HOD-Internal Medicine, G. B. H.
American International Institute of Medical Sciences

ABSTRACT: their associated medical therapies, which confound
interpretation of study results; and the difficulty in
Resistant hypertension is a common clinical prob- enrolling large numbers of study participants. Ex-
lem faced by primary care clinicians and specialists. panding our understanding of the causes of resis-
It is not rare, involving perhaps 20% to 30% of study tant hypertension and thereby potentially allowing for
participants. The prognosis of resistant hyperten- more effective prevention and/or treatment will be
sion is unknown, but cardiovascular risk is undoubt- essential to improve the long-term clinical manage-
edly increased as patients often have a history of ment of this disorder.
long-standing, severe hypertension complicated by
multiple other CV risk factors such as obesity, sleep INTRODUCTION
apnoea, diabetes, and CKD. The diagnosis of resis-
tant hypertension requires use of good blood pres- Resistant hypertension is defined as blood pressure
sure technique to confirm persistently elevated blood that remains above goal in spite of the concurrent
pressure levels. Pseudo resistance, including lack of use of 3 antihypertensive agents of different classes
blood pressure control secondary to poor medica- at optimal dose amounts, out of which one should
tion adherence or white coat hypertension, must be be a diuretic. Arbitrary, resistant hypertension is de-
excluded. Resistant hypertension is almost always fined in order to identify patients who are at high
multifactorial in etiology. Successful treatment re- risk of having reversible causes of hypertension and/
quires identification and reversal of lifestyle factors or patients who, because of persistently high blood
contributing to treatment resistance; diagnosis and pressure levels, may benefit from special diagnos-
appropriate treatment of secondary causes of hy- tic and therapeutic considerations. Patients whose
pertension; and use of effective multidrug regimens. blood pressure is controlled but require 4 or more
Observational assessments have allowed for identi- medications to do so should be considered resistant
fication of demographic and lifestyle characteristics to treatment.
associated with resistant hypertension, and the role
of secondary causes of hypertension in promoting PREVALENCE
treatment resistance is well documented; however,
identification of broader mechanisms of treatment The prevalence of resistant hypertension is unknown;
resistance is lacking. In particular, attempts to eluci- however, it is not uncommon.
date potential genetic causes of resistant hyperten-
sion have been limited. Recommendations for the Uncontrolled hypertension is not synonymous with
pharmacological treatment of resistant hypertension resistant hypertension. The former includes patients
remain largely empiric due to the lack of systematic who lack blood pressure control secondary to poor
assessments of 3 or 4 drug combinations. Studies adherence and/or an inadequate treatment regimen,
of resistant hypertension are limited by the high CV as well as those with true treatment resistance.
risk of patients within this subgroup, which gener-
ally precludes safe withdrawal of medications; the African-American participants had more treatment
presence of multiple disease processes (e.g., sleep resistance & black women had the lowest control rate
apnoea, diabetes, CKD, atherosclerotic disease) and (59%) and non-black men the highest (70%).

Cardio Diabetes Medicine

98 Resistant Hypertension in Clinical Practice

Prognosis 40% of patients may persist with their prescribed an-
tihypertensive treatment.
The prognosis of patients with resistant hypertension
is impaired as such patients typically present with a White-Coat Effect: White-coat effect is as common in
long-standing history of poorly controlled hyperten- patients with resistant hypertension as in the more
sion and commonly have associated CV risk factors general hypertensive population (prevalence = 20%
such as diabetes, obstructive sleep apnea, left ven- to 30%). Also, as with more general hypertensive
tricular hypertrophy (LVH), and/or CKD. patients, patients with resistant hypertension on
the basis of a “white coat” phenomenon manifest
Patient Characteristics less severe target organ damage and appear to be
at less cardiovascular risk compared with those pa-
Strong predictor of lack of blood pressure control tients with persistent hypertension during ambulatory
was older age, with participants >75 years being monitoring.
less than one fourth as likely to have systolic blood
pressure controlled compared with participants ≤60 Lifestyle Factors
years of age. The next strongest predictors of lack
of systolic blood pressure control were the presence Obesity: Obesity is a common feature of patients
of LVH and obesity (body mass index [BMI] >30 kg/ with resistant hypertension. Mechanisms of obesi-
m2) . In terms of diastolic blood pressure control, the ty-induced hypertension are complex and not fully
strongest negative predictor was obesity, with blood elucidated but include -
pressure being controlled less often compared with
lean participants (BMI <25 kg/m2). -- impaired sodium excretion,

Older age, higher baseline systolic blood pressure, -- increased sympathetic nervous system activity,
LVH, and obesity all predicted treatment resistance, and
needing 2 or more antihypertensive medications.
Overall, the strongest predictor of treatment resis- -- Activation of the renin-angiotensin-aldosterone
tance was having CKD as defined by a serum cre- system.
atinine of ≥1.5 mg/dL. Other predictors of the need
for multiple medications included having diabetes Dietary Salt: Excessive dietary sodium intake con-
mellitus. tributes to the development of resistant hypertension
both through directly increasing blood pressure and
Genetics/Pharmacokinetics by blunting the blood pressure–lowering effect of
most classes of antihypertensive agents.
Compared with normotensive controls, 2 β ENaC
and γ ENaC gene variants were significantly more Alcohol: Heavy alcohol intake is associated with
prevalent in the patients with resistant hypertension. both an increased risk of hypertension, as well as
It was associated with increased urinary potassium treatment-resistant hypertension. Cessation of heavy
excretion relative to plasma renin levels but was not alcohol ingestion reduces 24-hour ambulatory systol-
related to baseline plasma aldosterone or plasma ic and diastolic blood pressure, while dropping the
rennin activity. prevalence of hypertension from 42% to 12%.

The CYP3A5 enzyme (11β-hydroxysteroid dehydroge- Drug-Related Causes
nase type 2) plays an important role in the metabo-
lism of cortisol and corticosterone, particularly in the Several classes of pharmacological agents can in-
kidney. crease blood pressure and contribute to treatment
resistance. The effects of these agents, however, can
Pseudo resistance be highly individualized, with most persons manifest-
ing little or no effect, while other individuals may ex-
Poor Blood Pressure Technique: Inaccurate measure- perience severe elevations in blood pressure.
ment of blood pressure can result in the appearance
of treatment resistance. Two of the most common Given their widespread use, nonnarcotic analgesics,
mistakes—measuring the blood pressure before let- including nonsteroidal anti-inflammatory agents
ting the patient sit quietly and use of too small a cuff. (NSAIDs), aspirin, and acetaminophen, are the most
common offending agents in terms of worsening
Poor Adherence: Poor adherence to antihypertensive blood pressure control. NSAIDs & selective cycloo-
therapy is a major cause of lack of blood pressure xygenase-2 (COX-2) inhibitors can blunt the blood
control. During 5 to 10 years of follow-up, less than pressure–lowering effect of several antihypertensive
medication classes, including diuretics, ACE inhib-

GCDC 2017

Cardio Diabetes Medicine 2017 99

itors, angiotensin receptor blockers (ARBs), and and peripheral resistance as well as by increased flu-
β-blockers. id retention.

Although NSAIDs have an overall modest effect on Primary Aldosteronism
blood pressure levels, in susceptible individuals sig-
nificant fluid retention, increases in blood pressure, Primary aldosteronism is common in patients with
and/or acute kidney disease may occur. These ef- resistant hypertension with a prevalence of approxi-
fects occur secondary to inhibition of renal prosta- mately 20%, based on suppressed renin activity and
glandin production, especially prostaglandin E2 and a high 24-hour urinary aldosterone excretion in the
prostaglandin I2, with subsequent sodium and fluid course of a high dietary sodium intake.
retention. Elderly patients, diabetics, and patients
with CKD are at increased risk of manifesting these Generalized activation of the renin-angiotensin-al-
adverse effects. dosterone system has been described with obesity,
while other studies suggest that adipocytes may re-
Other medications are sympathomimetic compounds lease secretagogues that stimulate aldosterone re-
such as decongestants and certain diet pills, amphet- lease independent of angiotensin-II.
amine-like stimulants, modafinil39, and oral contra-
ceptives. Glucocorticoids, such as prednisone, induce Pheochromocytoma
sodium and fluid retention and can result in signifi-
cant increases in blood pressure. Corticosteroids with Pheochromocytoma represents a small but important
the greatest mineralocorticoid effect (eg, cortisone, fraction of secondary causes of resistant hyperten-
hydrocortisone) produce the greatest amount of fluid sion. The prevalence of pheochromocytoma is 0.1% to
retention, but even agents without mineralocorticoid 0.6% of hypertensives in a general ambulatory pop-
activity (eg, dexamethasone, triamcinolone, beta- ulation. The occurrence of a sustained increase and
methasone) produce some fluid retention. Herbal the degree of blood pressure variability are related to
preparations containing ephedra (or ma huang) have the level of norepinephrine secretion by the tumor.
been associated with worsening blood pressure. Lic-
orice, a common ingredient in oral tobacco products, Thediagnosis of pheochromocytoma should be en-
can raise blood pressure by suppressing the metab- tertained in a hypertensive patient with a combina-
olism of cortisol, resulting in increased stimulation tion of headaches, palpitations, and sweating, typi-
of the mineralocorticoid receptor. In anemic patients cally occurring in an episodic fashion.
with CKD, erythropoietic agents may increase blood
pressure in both normotensive and hypertensive pa- The best screening test for pheochromocytoma is
tients. plasma free metanephrines (normetanephrine and
metanephrine), which carries a 99% sensitivity and
Secondary Causes an 89% specificity.

Secondary causes of hypertension in patients with Cushing ’s syndrome
resistant hypertension, are older patients with great-
er prevalence of sleep apnea, renal parenchymal Hypertension is present in 70% to 90% of patients
disease, renal artery stenosis, and possibly primary with Cushing’s syndrome. Although the main mech-
aldosteronism.Others, include pheochromocytoma, anism of hypertension in Cushing’s syndrome is
Cushing’s syndrome, hyperparathyroidism, aortic overstimulation of the nonselective mineralocorticoid
coarctation, and intracranial tumors. receptor by cortisol, other factors such as sleep ap-
nea and the insulin resistance syndrome are major
Obstructive Sleep Apnea contributors to hypertension in this disease.

There was a significant gender difference, with sleep Although the exact prevalence of resistant hyper-
apnea being more common and more severe in the tension in patients with Cushing’s syndrome is un-
men compared with women patients. known, the overall CV risk in Cushing’s syndrome is
substantial because the disorder is associated with
A well-described effect is that the intermittent hy- other major risk factors such as diabetes mellitus,
poxemia, and/or increased upper airway resistance the metabolic syndrome, sleep apnea, obesity, and
associated with sleep apnea, induces a sustained in- dyslipidemia, in addition to hypertension.
crease in sympathetic nervous system (SNS) activity.
Increases in SNS output would be expected to raise Surgical excision of an adrenocorticotropic hormone
blood pressure through increases in cardiac output (ACTH) or cortisol-producing tumor effectively lowers
blood pressure. The most effective antihypertensive
pharmacological agent in Cushing’s syndrome is a

Cardio Diabetes Medicine

100 Resistant Hypertension in Clinical Practice

mineralocorticoid receptor antagonist (spironolac- al in etiology with obesity, excessive dietary sodium
tone or eplerenone). intake, obstructive sleep apnea, and CKD being par-
ticularly common factors. Target-organ damage such
Renal Parenchymal Disease as retinopathy, CKD, and LVH supports a diagnosis
of poorly controlled hypertension and in the case of
CKD is both a common cause and complication of CKD will influence treatment in terms of classes of
poorly controlled hypertension. Most of this popu- agents selected as well as establishing a blood pres-
lation was receiving antihypertensive drug therapy , sure goal of <130/80 mm Hg.
but achievement of current goal levels (<130/85 mm
Hg) was uncommon. Treatment resistance in patients Medical History
with CKD is related in large part to increased sodium
and fluid retention and consequential intravascular The medical history should document duration, se-
volume expansion. verity, and progression of the hypertension; treat-
ment adherence; response to prior medications,
Renal Artery Stenosis including adverse events; current medication use,
including herbal and over-the-counter medications;
Renovascular disease is a common finding in hyper- and symptoms of possible secondary causes of hy-
tensive patients undergoing cardiac catheterization, pertension. Daytime sleepiness, loud snoring, and
with more than 20% of patients having unilateral or witnessed apnea are suspicious for sleep apnea. A
bilateral stenosis (with a degree of obstruction ≥70%). history of peripheral or coronary atherosclerotic dis-
Studies of treatment-resistant hypertension com- ease increases the likelihood of renal artery stenosis.
monly reveal a high prevalence of previously unrec- Labile hypertension, in association with palpitations
ognized renovascular disease, particularly in older and/or diaphoresis, suggests the possibility of pheo-
patient groups. chromocytoma.

More than 90% of renal artery stenosis are athero- Assessment of Adherence
sclerotic in origin. The likelihood of atherosclerotic
renal artery stenosis is increased in older patients; Ultimately, adherence can only be known by patient
in smokers; in patients with known atherosclerotic self-report. Patients should be specifically asked, in
disease, especially peripheral arterial disease; and in a nonjudgmental fashion, how successful they are
patients with unexplained renal insufficiency. Bilater- in taking all of their prescribed doses, including dis-
al renal artery stenosis should be suspected in pa- cussion of adverse effects, out-of-pocket costs, and
tients with a history of “flash” or episodic pulmonary dosing inconvenience, all of which can limit adher-
edema, especially when echocardiography indicates ence. Family members will often provide more objec-
preserved systolic heart function. tive assessments of a patient’s adherence, but such
input should generally be solicited in the presence
Diabetes of the patient.

Diabetes and hypertension are commonly associ- Blood Pressure Measurement
ated, particularly in patients with difficult-to-control
hypertension. Pathophysiologic effects attributed to Use of good blood pressure measurement tech-
insulin resistance that may contribute to worsening nique is essential to the accurate diagnosis of re-
hypertension include increased sympathetic nervous sistant hypertension, including having the patient sit
activity, vascular smooth muscle cell proliferation, quietly in a chair with his or her back supported for
and increased sodium retention. 5 minutes before taking the measurement; use of
the correct cuff size with the air bladder encircling
Evaluation at least 80% of the arm (the adult large cuff for the
majority of patients); and supporting the arm at heart
The evaluation of patients with resistant hyperten- level during the cuff measurement. A minimum of
sion should be directed toward confirming true treat- 2 readings should be taken at intervals of at least
ment resistance; identification of causes contributing 1 minute and the average of those readings should
to treatment resistance, including secondary causes be taken to represent the patient’s blood pressure.
of hypertension; and documentation of target-organ The blood pressure should be measured carefully
damage. Accurate assessment of treatment adher- in both arms and the arm with the higher pressures
ence and use of good blood pressure measurement generally should be used to make future measure-
technique is required to exclude pseudoresistance. ments. Supine and upright blood pressures should
In most cases, treatment resistance is multifactori-

GCDC 2017

Cardio Diabetes Medicine 2017 101

be measured during follow-up to detect orthostatic tion. Measurement of 24-hour urinary metanephrines
complications with treatment. or plasma metanephrines is an effective screen when
pheochomocytoma is suspected.
Physical Examination
Noninvasive Imaging
A fundoscopic examination should document the
presence and severity of retinopathy. The presence Imaging for renal artery stenosis should be reserved
of carotid, abdominal, or femoral bruits increases the for patients in whom there is an increased level of
possibility that renal artery stenosis exists. Dimin- suspicion. This would include young patients, particu-
ished femoral pulses and/or a discrepancy between larly women, whose presentation suggests the pres-
arm and thigh blood pressures suggest aortic coarc- ence of fibromuscular dysplasia and older patients
tation or significant aortoiliac disease. Cushing’s dis- at increased risk of atherosclerotic disease. Due to
ease is suggested by abdominal striae, particularly if poor specificity, abdominal CT imaging is not rec-
pigmented; moon facies; or prominent interscapular ommended to screen for adrenal adenomas in the
fat deposition. absence of biochemical confirmation of hormonally
active tumors (hyperaldosteronism,pheochromocyto-
Ambulatory Blood Pressure Monitoring ma , Cushing’s syndrome).

Documentation of a significant white-coat effect Treatment Recommendations
requires reliable assessment of out-of-office blood
pressure values. This is accomplished most objec- Resistant hypertension is almost always multifactori-
tively with the use of 24-hour ambulatory blood pres- al in etiology. Treatment is predicated on identification
sure monitoring. and reversal of lifestyle factors contributing to treat-
ment resistance; accurate diagnosis and appropriate
A significant white-coat effect should be suspected treatment of secondary causes of hypertension; and
in patients with resistant hypertension in whom clinic use of effective multi-drug regimens.Lifestyle chang-
blood pressure measurements are consistently high- es, including weight loss; regular exercise; ingestion
er than out-of-office measurements; in patients who of a high-fiber, low-fat, low-salt diet; and moderation
repetitively show signs of overtreatment, particularly of alcohol intake.
orthostatic symptoms; and in patients with chronical-
ly high office blood pressure values but an absence Potentially interfering substances should be with-
of target organ damage (LVH, retinopathy, CKD). In drawn or down-titrated as clinically allowable. Ob-
such cases, 24-hour ABPM is recommended. A mean structive sleep apnea should be treated if present.
ambulatory daytime blood pressure of >135/85 mm
Hg is considered elevated. If a significant white-coat Maximize Adherence
effect is confirmed, out-of-office measurements
should be relied on to adjust treatment. Prescribed regimens should be simplified as much as
possible, including the use of a long-acting combina-
Biochemical Evaluation tion of products to reduce the number of prescribed
pills and to allow for once-daily dosing. Adherence
Biochemical evaluation of the treatment-resistant hy- is also enhanced by more frequent clinic visits and
pertensive should include a routine metabolic profile by having patients record home blood pressure mea-
(sodium, potassium, chloride, bicarbonate, glucose, surements. Involving the patient by having him or
blood urea nitrogen, and creatinine); urinalysis; and her maintain a diary of home blood pressure values
a paired, morning plasma aldosterone and plasma should improve follow-up and enhance medication
renin or plasma renin activity to screen for primary adherence, while involvement of family members will
aldosteronism. Even in the setting of ongoing antihy- likely enhance persistence with recommended life-
pertensive treatment (excluding potassium-sparing style changes.
diuretics, particularly aldosterone antagonists), the
aldosterone/renin ratio is an effective screening test Nonpharmacological Recommendations
for primary aldosteronism, having a high negative
predictive value. Weight Loss: Weight loss, has a clear benefit in terms
of reducing blood pressure and often allows for re-
A 24-hour urine collected during ingestion of the duction in the number of prescribed medications.
patient’s normal diet can be helpful in estimating di- While difficult to achieve and even more difficult to
etary sodium and potassium intake, calculating cre- maintain, weight loss should be encouraged in any
atinine clearance, and measuring aldosterone excre- patient with resistant hypertension who is either
overweight or obese.

Cardio Diabetes Medicine

102 Resistant Hypertension in Clinical Practice

Dietary Salt Restriction: The benefit of dietary salt re- excess of 20% of patients after 1 year.Endovascular
duction is well documented in general hypertensive angioplasty, with or without stenting, should be con-
patients with observed reductions in systolic and di- sidered when drug therapy alone is unsuccessful.
astolic blood pressure. However, in an evaluation of However, if the blood pressure remains poorly con-
patients whose blood pressure was uncontrolled on trolled in spite of optimal medical therapy, revascu-
a combination of an ACE inhibitor and hydrochloro- larization is recommended.
thiazide, a reduced-salt diet lowered systolic and dia-
stolic blood pressure.A dietary salt restriction, ideally Pharmacological Treatment
to less than 100 mEq of sodium/24-hour, should be
recommended for all patients with resistant hyper- Withdrawal of Interfering Medications
tension.
Medications that may interfere with blood pressure
Moderation of Alcohol Intake: Cessation of heavy al- control, particularly NSAIDs, should be avoided or
cohol ingestion can significantly improve hyperten- withdrawn in patients with resistant hypertension
sion control. Daily intake of alcohol should be limited or lowest effective dose should be used with sub-
to no more than 2 drinks (1 ounce of ethanol) per sequent down titration whenever possible. When ini-
day (eg, 24 ounces of beer, 10 ounces of wine, or 3 tiating treatment with these agents, blood pressure
ounces of 80 proof liquor) for most men and 1 drink should be monitored closely while recognizing that
per day for women or lighter-weight persons. adjustments to the antihypertensive regimen may
become necessary.
Increased Physical Activity: Aerobic exercise regimen
(stationary cycling 3 times a week) lowers both di- Therefore, if analgesics are necessary, acetamino-
astolic & systolic BP. Reductions in diastolic blood phen may be preferable to NSAIDs in subjects with
pressure are maintained after 32 weeks of exercise, resistant hypertension, recognizing, however, that
even with withdrawal of some antihypertensive med- acetaminophen will provide little if any antiinflam-
ications. Based on these observed benefits, patients matory benefit.
should be encouraged to exercise for a minimum of
30 minutes on most days of the week. Diuretic Therapy

Ingestion of a High-Fiber, Low-Fat Diet: Ingestion of Evaluation of patients with resistant hypertension
a diet rich in fruits and vegetables; high in low-fat have been consistent that treatment resistance was
dairy products, potassium, magnesium, and calci- a lack of, or underuse of, diuretic therapy. Blood
um; and low in total saturated fats (i.e., the Dietary pressure control was improved primarily through the
Approaches to Stop Hypertension or DASH diet) re- use of increased doses of diuretics. Lack of blood
duced systolic and diastolic blood pressure. pressure control was attributed most often to the use
of a suboptimal medical regimen, which was modi-
Treatment of Secondary Causes of fied most frequently by adding a diuretic, increas-
Hypertension: ing the dose of the diuretic, or changing the class
of prescribed diuretic based on the underlying renal
When primary aldosteronism, pheochromocytoma, or function.
Cushing’s disease is suspected or confirmed, treat-
ment will be specific for that particular disorder. Ef- In most patients, use of a long-acting thiazide diuret-
fective management of these diseases may require ic will be most effective. Chlorthalidone 25 mg daily
referral to an appropriate specialist. provided greater 24-hour ambulatory blood pres-
sure reduction. Given the outcome benefit demon-
Treatment of Obstructive Sleep Apnea strated with chlorthalidone and its superior efficacy
compared with hydrochlorothiazide, chlorthalidone
Treatment of sleep apnea with continuous positive should be preferentially used in patients with resis-
airway pressure (CPAP) likely improves blood pres- tant hypertension. In patients with underlying CKD
sure control. (creatinine clearance <30 mL/min), loop diuretics
may be necessary for effective volume and blood
Treatment of Renal Artery Stenosis pressure control. Furosemide is relatively short acting
and requires twice-daily dosing. Alternatively, loop
Angioplasty of fibromuscular lesions almost always diuretics with a longer duration of action, such as
benefits, and is often curative, of the associated hy- torsemide, can be used.
pertension and therefore is the recommended treat-
ment of choice. Restenosis, however, may occur in

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Cardio Diabetes Medicine 2017 103

Combination Therapy Amiloride 10 mg daily, spironolactone 25 mg daily, or
a combination of both were used as add-on therapy
This is particularly true of thiazide diuretics, which in patients whose blood pressure was uncontrolled
significantly improve blood pressure control when on a 2-drug regimen. Amiloride was associated with
used in combination with most classes of agents.The significant increases in plasma renin activity while
combinations that included a thiazide diuretic were spironolactone was not.
consistently more effective than combinations that
did not include the diuretic. Spironolactone and amiloride, both agents are gen-
erally safe and well tolerated. The most common ad-
It is appropriate to combine agents of different mech- verse effect of spironolactone is breast tenderness
anisms of action. In that regard, a triple drug regimen with or without breast enlargement, particularly in
of an ACE inhibitor or ARB, calcium channel blocker, men. Hyperkalemia is uncommon with either agent,
and a thiazide diuretic is effective and generally well but it can occur. Risk of hyperkalemia is increased in
tolerated. older patients, patients with diabetes and/or CKD, or
when added to ongoing treatment with ACE inhibi-
Combined α-β-antagonists, because of their dual tors, ARBs, and/or NSAIDs. The mechanism of min-
combination of action, may be more effective anti- eralocorticoid receptor blockade in the treatment of
hypertensives, although head-to-head comparisons resistant hypertension likely involves more effective
of maximal doses are lacking. An add-on antihyper- diuresis than is provided with thiazide diuretics alone.
tensive benefit is achieved with aldosterone antago-
nists in patients uncontrolled on multidrug regimens. Dosing
Centrally acting agents are effective antihypertensive
agents but have a higher incidence of adverse ef- The patients taking at least one of their hyperten-
fects. Lastly, potent vasodilators such as hydralazine sive agents at bedtime had better 24-hour mean
or minoxidil can be very effective, at higher doses, blood pressure control and, in particular, lower night
but adverse effects are common. With minoxidil ,re- time systolic and diastolic blood pressure values.
flexive increases in heart rate and fluid retention oc- Nighttime blood pressure levels better predict car-
cur such that concomitant use of a β-blocker and a diovascular risk than do daytime values. It may be
loop diuretic is generally necessary. that twice-daily dosing of nondiuretic blood pressure
medications will improve control rates in patients with
Ultimately, combinations of 3 or more drugs must resistant hypertension.
be tailored on an individual basis taking into con-
sideration prior benefit, history of adverse events, Hypertension Specialist
contributing factors, including concomitant disease
processes such as CKD or diabetes. Patients with resistant hypertension do benefit from
referral to a hypertension specialist, if the blood pres-
A combined use of an ACE inhibitor and ARB or sure remains elevated in spite of 6 months of treat-
a dihydropyridine and non-dihydropyridine calcium ment.If a specific secondary cause of hypertension
channel blocker provides significant additional an- is suspected in a patient with resistant hypertension,
tihypertensive benefit compared with monotherapy referral to the appropriate specialist is recommended
with the different agents. as needed.

Mineralocorticoid Receptor Antagonists Controlled Resistant Hypertension

Consistent with reports of a high prevalence of pri- With the current definition of resistant hypertension,
mary aldosteronism in patients with resistant hyper- patients whose blood pressure is controlled but who
tension have been studies demonstrating that miner- use 4 or more medications should still be considered
alocorticoid receptor antagonists provide significant resistant to treatment. Whether or not to adjust the
antihypertensive benefit when added to existing mul- treatment regimen in this situation should be decid-
tidrug regimens. Spironolactone (12.5 to 50 mg daily), ed on an individual basis with the primary objective
lowers blood pressure significantly. Spironolactone being to maintain blood pressure control but use few-
lowers systolic and diastolic blood pressure, when er medications and/or use a regimen that minimizes
added to the regimen of patients whose blood pres- adverse effects.
sure was uncontrolled with at least 2 medications.
Research Challenges and Needs
Amiloride antagonizes the epithelial sodium channel
in the distal collecting duct of the kidney, thereby Experimental assessment of patients with resistant
functioning as an indirect aldosterone antagonist.

Cardio Diabetes Medicine

104 Resistant Hypertension in Clinical Practice

hypertension is complicated by the associated high • All failure hypertension should not be taken as re-
CV risk, which limits the safe withdrawal of medica- fractory hypertension, as pseudorefractory & sec-
tions and which restricts the types and duration of ondary hypertension may also simulate in one way
experimental interventions that can be used to ex- or other. Even white coat hypertension should be
plore proposed etiologies. Studies are further limited clearly separated before putting a level of resistant
by concomitant disease processes such as diabe- hypertension.
tes, CKD, sleep apnea, and atherosclerotic disease.
These concurrent diseases and their treatments are • Compared with patients with white-coat hyper-
difficult to systematically control for and confound tension, true resistant hypertension is associated
interpretation of study results. Overcoming such a with male gender,longer duration of hypertension,
challenge will likely require a consortium of hyper- smoking, diabetes, target-organ damage (as mea-
tension centres allowing for multicenter participation. sured by presence of LVH, impaired renal function,
microalbuminuria, documented CVD.
Lastly, even among patients with resistant hyperten-
sion, subgroups of patients with different aetiologies • ABPM is desirable for correct diagnosis and man-
undoubtedly exist. As an extreme example, the young agement.
patient with combined systolic and diastolic resistant
hypertension is undoubtedly different in terms of • For true resistant hypertension along with avail-
aetiology, prognosis, and likely effective treatment able drugs (excluding secondary hypertension,and
than the elderly patient with severe, isolated, resis- ensuring normal renal functions), renal denerva-
tant systolic hypertension. Meaningful differentiation tion should be considered when both kidneys are
of these subgroups will likely speed identification of normal in terms of anatomy, vasculature without
respective causes of treatment resistance and devel- stenosis/stenting of both renal arteries.
opment of specific treatment strategies.
References
Much additional knowledge is needed to better iden-
tify and treat patients with resistant hypertension. 1. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Re-
Cross-sectional and outcome studies have identified search Group (2002). Major Outcomes in High-Risk Hypertensive Patients
patient characteristics associated with resistant hy- Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Chan-
pertension, but underlying mechanisms of treatment nel Blocker vs Diuretic: The Antihypertensive and Lipid-Lowering Treat-
resistance, particularly potential genetic mechanisms, ment to Prevent Heart Attack Trial (ALLHAT). JAMA: The Journal of the
have not been widely investigated. Efficacy assess- American Medical Association, 288(23), pp.2981-2997.
ments of specific multidrug regimens are needed to
better guide therapy. 2. Persell, S. (2011). Prevalence of Resistant Hypertension in the United
States, 2003-2008. Hypertension, 57(6), pp.1076-1080.
HIGHLIGHT
3. de la Sierra, A., Segura, J., Banegas, J., Gorostidi, M., de la Cruz, J.,
• Failure to achieve goal BP (<140/90 mmHg) using Armario, P., Oliveras, A. and Ruilope, L. (2011). Clinical Features of 8295
3 different drugs with pharmacologically comple- Patients With Resistant Hypertension Classified on the Basis of Ambulatory
mentary mechanisms, one of which is an appro- Blood Pressure Monitoring. Hypertension, 57(5), pp.898-902.
priately dosed diuretic.
4. Bangalore, S., Kamalakkannan, G., Parkar, S. and Messerli, F. (2007).
• All three drugs given in maximally tolerated dos- Fixed-Dose Combinations Improve Medication Compliance: A Meta-Anal-
es .Failure to control blood pressure (BP) inevita- ysis. The American Journal of Medicine, 120(8), pp.713-719.
bly heralds renal deterioration as well as accom-
panying increases in cardiovascular morbidity and 5. Myers, M., Valdivieso, M. and Kiss, A. (2009). Use of automated office
mortality. blood pressure measurement to reduce the white coat response. Journal
of Hypertension, 27(2), pp.280-286.
• CKD itself is a predictor of cardiovascular events
as a result of failure to achieve adequate BP con- 6. Pickering, T. and White, W. (2008). When and how to use self (home)
trol. and ambulatory blood pressure monitoring. Journal of the American Society
of Hypertension, 2(3), pp.119-124.
• BP control should be a role in management of CKD
& diabetes mellitus.

• A resistant hypertension in CKD & DM, results
poor prognosis, high mortality, more prone to ter-
minal cardiovascular events.

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Cardio Diabetes Medicine 2017 105

Diabetic Cardiovascular
Autonomic Neuropathy

Dr. Ulhas M. Pandurangi, MD., DM (Cardio).,

Chief. Cardiac Electrophysiology & Pacing
The Madras Medical Mission

Introduction with PNP have asymptomatic CAN, whereas 100%
of those with symptomatic DCAN present classical
Diabetic cardiovascular autonomic neuropathy PNP1,2.
(DCAN) is a neuro-humoral regulation disturbance
due to malfunction of autonomic nervous system Pathogenesis
(ANS).DCAN represents a significant cause of mor-
bidity and mortality in patients with diabetes melli- DCAN is widely believed and largely proven to be to
tus (DM)and is associated with a high risk of car- be the result of complex interactions among degree
diac arrhythmias and sudden death.It is one of the of glycemic control, disease duration, age-related
most insidious complications of DM especially if it is neuronal attrition, and systolic and diastolic blood
long standing and poorly controlled. DCAN is often pressure1,7. Hyperglycemia plays the key role in the
overlooked both in terms of diagnosis and treatment activation of various biochemical pathways related to
simply because there is no widely accepted single the metabolic and/or redox state of the cell, which,
approach to its diagnosis and management1,2,3.This in concert with impaired nerve perfusion, contribute
review covers the epidemiology, pathophysiology, to the development and progression of diabetic neu-
clinical presentation, and diagnosis of DCAN and ropathies.
discusses current evidence on approaches to pre-
vention and treatment. Pathophysiology:

Epidemiology: It has been shown that chronic hyperglycemia pro-
motes progressive autonomic neural dysfunction
Diabetic neuropathies, including DCAN, are a com- (Fig.1) in a manner that parallels the development of
mon chronic complication of type 1 and type 2 DM peripheral neuropathy, e.g., beginning distally and
and confer high morbidity and mortality. The reported progressing proximally. The vagus nerve, the lon-
prevalence varies greatly depending on the criteria gest autonomic nerve, mediates 75% of all parasym-
used to identify DCAN and the population studied. pathetic activity (Fig.2). Because neuropathy is seen
DCAN prevalence ranges from as low as 2.5% of the first in the longest fibers, the earliest manifestations
primary prevention cohort in the Diabetes Control of autonomic neuropathy in diabetes tend to be as-
and Complications Trial (DCCT)4to as high as 90% of sociated with parasympathetic denervation. As such,
patients with long-standing type 1 diabetes who were the initial development of DCAN is characterized by
potential candidates for a pancreas transplantation5. early augmentation of sympathetic tone2,7.The initial
In a large cohort of patients with type 1 and type 2 augmentation in cardiac sympathetic activity with
diabetes, Ziegler et al.2,6, using predefined heart rate subsequent abnormal norepinephrine signalling and
variability (HRV) tests and spectral analysis of the metabolism, increased mitochondrial oxidative stress,
R-R intervals, found that 25.3% of patients with type and calcium- dependent apoptosis may contribute to
1 diabetes and 34.3% of patients with type 2 diabetes myocardial injury and may explain the high risk of
had abnormal findings. Age, sex, and other risk fac- cardiac events and sudden death in these patients.
tors may also influence DCAN development. DCAN The sympathetic imbalance associated with DCAN
is more often seen in patients with polyneuropathy may critically influence myocardial substrate utili-
(PNP). Approximately 50% of the diabetic patients

Cardio Diabetes Medicine

106 Diabetic Cardiovascular Autonomic Neuropathy

Fig1: Mechanisms that relate hyperglycemia to neuropathy

zation and contribute to mitochondrial uncoupling, gression of DCAN and correlation with clinical signs
regional ventricular motion abnormalities, functional and symptoms.
deficits, and cardiomyopathy7,8. (Fig 1 & 2)
Impaired HRV: In a normal individual, the heart rate
Clinical Signs and Symptoms: has a high degree of beat- to-beat variability and HRV
fluctuates with respiration increasing with inspiration
Great majority of diabetic patients with DCAN remain and decreasing with expiration. The earliest clinical
asymptomatic for decades. Since clinical history and indicator of DCAN is a decrease in HRV.
physical examination are ineffective for its early de-
tection, it is of crucial importance to perform quan- Resting tachycardia: Resting heart rates of 100 bpm
titative tests in order to diagnose DCAN in its initial with occasional increments up to 130 bpm usually
and still reversible stages2,4.Subclinical DCAN, mani- occur later in the course of the disease and reflect
fested as changes in Heart rate variability (HRV), may a relative increase in the sympathetic tone associat-
be detected within 1 year of diagnosis in type 2 DM ed with vagal impairment. A fixed heart rate that is
and within 2 years of diagnosis in type 1 DM9. DCAN unresponsive to moderate exercise, stress, or sleep
is also accompanied very often by ANS malfunction indicates almost complete cardiac denervation and is
seen in other organs-gastroparesis, constipation indicative of severe DCAN1.
and diarrhoea (gastro-intestinal) and urinary inconti-
nence, neurogenic bladder and erectile dysfunction Exercise intolerance: Autonomic dysfunction may im-
(genitourinary system). Fig.3 illustrates natural pro- pair exercise tolerance and has been shown to re-

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Cardio Diabetes Medicine 2017 107

Fig2: Cardiac Innervation

duce heart rate, blood pressure, and cardiac output thetic vasomotor denervation, causing reduced va-
responses to exercise. It is generally recommended soconstriction of the splanchnic and other peripheral
that patients suspected to have DCAN be tested with vascular beds. Symptoms associated with orthostatic
a cardiac stress test before undertaking an exercise hypotension include: light-headedness, weakness,
program. faintness, dizziness, visual impairment, and, in most
severe cases, syncope on standing. These symptoms
Abnormal blood pressure regulation: At night, non- can be aggravated by several drugs including: vaso-
diabetic subjects exhibit a predominance of vagal dilators, diuretics, phenothiazines, insulin (through
tone and decreased sympathetic tone, associated endothelium-dependent vasodilatation), and tricyclic
with reduction in nocturnal blood pressure. In DCAN antidepressants, a class of drugs commonly used for
this pattern is altered, resulting in sympathetic pre- symptomatic relief of pain associated with painful di-
dominance during sleep and subsequent nocturnal abetic neuropathy11. (Fig 3)
hypertension. These are associated with a higher fre-
quency of left ventricular (LV) hypertrophy and both Clinical Evaluation and Diagnosis Criteria:
fatal and severe nonfatal cardiovascular events in
diabetic CAN subjects10. There is no widely accepted single approach to the
diagnosis of DCAN. Assessment of HRV, orthostatic
Orthostatic hypotension: Orthostatic hypotension hypotension, and 24-hr blood pressure profiles pro-
occurs largely as a consequence of efferent sympa-

Cardio Diabetes Medicine

108 Diabetic Cardiovascular Autonomic Neuropathy

Fig.3: Natural progression of DCAN and correlation with clinical signs and symptoms.

vide indexes of both parasympathetic and sympa- parasympathetic limb. Spectral analysis of HRV is
thetic autonomic function and can be used in clinical another tool to evaluate DCAN. It decomposes the
settings. Other methods such as cardiac sympathetic R-R signal into a set of sine and cosine waves and
imaging, microneurography, occlusion plethysmog- estimates the magnitude of variability as a function
raphy, and baroreflex sensitivity are currently used of frequency.
predominantly in research settings but may find a
place in the clinical assessment of DCAN in the fu- Orthostatic hypotension: Orthostatic hypotension
ture. is documented by a fall 30 mmHg in systolic or 10
mmHg in diastolic blood pressure in response to a
HRV: Simple bedside tests12 to detect HRV using ECG postural change from supine to standing11.
in DCAN are:
The rapid postural changes that are part of head-
1. Changes in R-R intervals with deep breathing, up-tilt-table testing, with or without pharmacological
which measures sinus arrhythmia during quiet provocation, can be used for the investigation of
respiration which primarily reflects parasympa- DCAN or of predisposition to neurally mediated (va-
thetic function sovagal) syncope due to the wide range of changes
in the autonomic input to the heart and in the R-R
2. R-R response to standing, which induces reflex intervals.
tachycardia followed by bradycardia and is jointly
vagal and baroreflex mediated Imaging techniques for DCAN: Quantitative scinti-
graphic assessment of sympathetic innervation of
3. Valsalva ratio, which evaluates vagal function in the human heart is possible with positron emission
response to increase in intrathoracic pressure tomography (PET) and either [123I] metaiodobenzyl-
during Valsalva manoeuvre guanidine (MIBG) or [11C]-meta-hydroxy-ephedrine
([11C] HED). Quantitative regional measurements of
HRV can also be evaluated using statistical indexes myocardial-adreno receptor density can also be as-
in the time and frequency domains. 24 hour R-R re- sessed using PET and the high-affinity–adrenorecep-
cordings allow calculation of more complex statistical tor radioligand [11C] CGP-12177
time domain measures, such as standard deviation
(SD) of all normal R-R intervals (SDNN), SD of 5-min Baroreflex sensitivity: Baroreflex sensitivity (BRS) is
average of normal R-R intervals (SDANN), root-mean a technique that evaluates the capability to reflexive-
square of the difference of successive R-R intervals ly increase vagal activity and decrease sympathetic
(rMSSD), and the number of instances per hour in activity in response to a sudden increase in blood
which two consecutive R-R intervals differ by 50 ms pressure. It is calculated from the measurement of
over 24 h (pNN50). SDNN is thought to represent the heart rate– blood pressure relation after an intra-
joint sympathetic and parasympathetic modulation venous bolus of phenylephrine.
of HRV, and rMSSD and pNN50 are specific for the

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Cardio Diabetes Medicine 2017 109

Microneurography: This technique is based on re- Intraoperative and perioperative cardiovascular in-
cording electrical activity emitted by peroneal, tibial, stability: Observations in diabetic patients under-
or radial muscle sympathetic nerves and identifica- going general anaesthesia reported that individuals
tion of sympathetic bursts. Bursts have a characteris- with DCAN required vasopressor support more of-
tic shape consisting of a gradual rise and fall that is ten than those without CAN. Individuals with DCAN
usually constrained by the cardiac cycle and at least may experience a greater decline in heart rate and
twice the amplitude of random fluctuations. Recent- blood pressure during induction of anaesthesia and
ly available fully automated sympathetic neurogram more severe intraoperative hypothermia resulting in
techniques provide a rapid and objective method that decreased drug metabolism and impaired wound
is minimally affected by signal quality and preserves healing1.
beat-by-beat sympathetic neurograms.
Stroke: A recent study in 1,458 patients with type 2
Clinical Implications diabetes reported that presence of DCAN, assessed
by standard HRV testing, was one of the strongest
Mortality risk: DCAN is associated with a high risk predictors of ischemic stroke in this cohort together
of cardiac arrhythmias and with sudden death. Lon- with age and hypertension. Earlier reports showed
gitudinal studies of subjects with DCAN have shown similar associations1.
5-year mortality rates 16–50% in type 1 and type 2 DM,
with a high proportion attributed to sudden cardiac Therapeutic Approaches
death18. In the EURODIAB Prospective Cohort Study
of 2,787 type 1 DM patients, DCAN was the strongest Glycaemic control: The DCCT demonstrated that in-
predictor for mortality during a 7-year follow-up, ex- tensive insulin therapy for type 1 DM reduced the inci-
ceeding the effect of traditional cardiovascular risk dence of DCAN by 53% compared with conventional
factors. The mechanisms proposed to account for therapy. The Epidemiology of Diabetes Interventions
this increased mortality are: difficulty in recogniz- and Complications (EDIC) study, the prospective ob-
ing angina (atypical manifestations such as nausea, servational study of the DCCT cohort, has shown
shortness of breath and tiredness are common), as- persistent beneficial effects of past glucose control
ymptomatic ischemia or MI, dysfunction of the cor- on microvascular complications despite the loss of
onary flow autoregulation, increased heart rate, LV glycaemic separation24. In type 2 DM, the effects of
systolic and diastolic dysfunction, increased risk of glycaemic control are less conclusive. The VA Coop-
arrhythmias (prolonged QT interval), decreased noc- erative Study demonstrated no difference in the prev-
turnal protection against MI, changes in BP circadian alence of autonomic neuropathy in type 2 DM after 2
cycle, increased cardiac mass, increased risk of mi- years of tight glycaemic control compared with those
croalbuminuria and, lastly, apnea1,2. The death in bed without tight control. On the other hand, the Steno-2
syndrome, in which the triad CAN + sympathetic-ad- Trial reported that a targeted, intensive intervention
renergic discharge + nocturnal hypoglycemia plays a involving glucose control and multiple cardiovascular
key role, is also well-known1,2. risk factors reduced the prevalence of DCAN among
patients with type 2 DM and microalbuminuria.
Silent myocardial ischemia and diabetic cardiomy-
opathy: In a meta-analysis of 12 published studies, Other therapies: Data regarding the impact of lifestyle
Vinik et al1. reported a consistent association be- interventions in preventing progression of DCAN
tween DCAN and the presence of silent myocardial are emerging. Strictly supervised endurance training
ischemia, measured by exercise stress testing, with combined with dietary changes was associated with
point estimates for the prevalence rate ratios from weight loss and improved HRV in patients with min-
0.85 to 15.53. In the Detection of Ischemia in Asymp- imal abnormalities. In the Diabetes Prevention Pro-
tomatic Diabetics (DIAD) study of 1,123 patients with gram, indexes of DCAN improved most in the life-
type 2 diabetes, DCAN was a strong predictor of si- style modification arm compared with the metformin
lent ischemia and subsequent cardiovascular events. or placebo arm. ACE inhibitors, angiotensin receptor
The presence of DCAN was also linked to the de- blockers, or aldose reductase inhibitors appear prom-
velopment of diabetic cardiomyopathy in type 1DM ising but are yet to be validated1.
because in these patients ventricular dysfunction of-
ten precedes or occurs in the absence of significant Orthostatic hypotension: The treatment of orthostat-
coronary artery disease or hypertension21. Further ic hypotension is challenging. Nonpharmacological
studies are needed to clarify the complex interac- treatments include avoidance of sudden changes in
tions between CAN, silent myocardial ischemia, and body posture to the head-up position; avoiding med-
cardiomyopathy in diabetes. ications that aggravate hypotension, such as tricyclic

Cardio Diabetes Medicine

110 Diabetic Cardiovascular Autonomic Neuropathy

antidepressants and phenothiazines; eating small, mechanism of action of these agents is the blockade
frequent meals to avoid postprandial hypotension; of vasodilating beta-2 receptors allowing unopposed
and avoiding activities that involve straining, since in- alpha-adrenoceptor–mediated vasoconstriction. To
creased intra-abdominal and intra-thoracic pressure date there is no clear efficacy evidence in diabetic
decrease venous return. Several physical counter DCAN.
manoeuvres, such as leg crossing, squatting, and
muscle pumping can help maintain blood pressure Clonidine: Clonidine, an alpha-2 antagonist, produces
during daily activities by inducing increased cardiac a central sympatholytic effect and a consequent de-
filling pressures and stroke volume. crease in blood pressure. Patients with severe DCAN
have little central sympathetic efferent activity, and
Pharmacological Treatment the use of clonidine (0.1– 0.6 mg/day) could result
in an increase in venous return without a significant
Midodrine: Midodrine, a peripheral-selective alpha increase in peripheral vascular resistance. Its use is
1- adrenoceptor agonist is widelytested agent for limited by the inconsistent hypertensive effect and
the treatment of orthostatic hypotension in doses serious side effects.
of 2.5–10 mg three times/day. It does not cross the
blood-brain barrier, resulting in fewer central side Somatostatin analogs: Somatostatin analogs (25–
effects. The main adverse effects are piloerection, 200 g/day) may attenuate orthostatic hypotension
pruritis, paraesthesia, urinary retention, and supine in patients with DCAN by inhibiting the release of
hypertension. vasoactive gastrointestinal peptides, enhancing car-
diac output, and increasing forearm and splanchnic
Fludrocortisone acetate: Fludrocortisone acetate, a vascular resistance. However, severe cases of hyper-
synthetic mineralocorticoid with a long duration of tension were reported with their use in patients with
action, induces plasma expansion and may enhance DCAN29.
the sensitivity of blood vessels to circulating cate-
cholamines. The effects usually occur over a 1- to Conclusions
2-week period. Supine hypertension, hypokalaemia,
and hypomagnesemia may occur. Caution must be DCAN is one of the most clinically significant compli-
used, particularly in patients with congestive heart cations of diabetes mellitus (DM), but one of the least
failure, to avoid fluid overload. Treatment with fludro- frequently diagnosed. It also is one of the most ob-
cortisone should begin with 0.05 mg at bedtime and scure and controversial topics in current diabetology.
may be titrated gradually to a maximum of 0.2 mg/ DCAN is an independent predictor of cardiovascular
day. Doses up to 0.3– 0.4 mg used in refractory cases disease mortality. It is associated with a poor prog-
are associated with high risk for hypokalaemia, ex- nosis and poor quality of life. Conclusive clinical ev-
cessive fluid retention, hypertension, and congestive idence from randomized prospective trials supports
heart failure. a central role for hyperglycaemia in the pathogene-
sis of DCAN, although other metabolic and vascular
Erythropoietin: Erythropoietin may improve ortho- factors contribute to the disease state. The clinical
static hypotension, but the mechanism of action for presentation of DCAN comprises a broad constella-
this pressor effect is still unresolved. Possibilities in- tion of symptoms and deficits. Assessment of HRV
clude the increase in red cell mass and central blood is an easily available tool to document the presence
volume, correction of the normochromic normocytic of DCAN. Cardiac scintigraphic imaging with sympa-
anaemia that frequently accompanies severe CAN, thetic analogs offers more sensitive diagnostic al-
and direct or indirect neuro- humoral effects on the ternatives for research use. The treatment of DCAN
vascular wall and vascular tone regulation mediated is challenging. Recent clinical evidence continues to
by the interaction between haemoglobin and the va- prove the benefits of glycemic control, while the ben-
sodilator nitric oxide. Erythropoietin is administered efits of lifestyle and pharmacologic interventions are
subcutaneously or intravenously at doses of 25–75 emerging.
units/kg three times a week until the haematocrit lev-
el approaches normal followed by lower maintenance
doses (25 units/kg three times/week).

Non-selective Beta-blockers: Nonselective be-
ta-blockers, particularly those with intrinsic sym-
pathomimetic activity, may have a limited role in the
treatment of orthostatic hypotension. The suggested

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Cardio Diabetes Medicine 2017 111

References:

1. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Cir-
culation 2007;115:387–97.

2. Ziegler D. Cardiovascular autonomic neuropathy: clinical manifestations
and measurement. Diabetes Rev. 1999; 7: 300-15.

3. Tesfaye S, Boulton AJM, Dyck PJ. Diabetic neuropathies: update on
definitions, diagnostic criteria, estimation of severity, and treatments.
Diabetes Care 2010;33(10):2285–93.

4. The Diabetes Control and Complications Trial Research Group. The effect
of intensive diabetes therapy on measures of autonomic nervous system
function in the Diabetes Control and Complications Trial (DCCT). Dia-
betologia. 1998; 41: 416-23.

5. Kennedy WR, Navarro X, Sutherland DE. Neuropathy profile of dia-
betic patients in a pancreas transplantation program. Neurology
1995;45:773–780

6. Ziegler D, Dannehl. Prevalence of cardiovascular autonomic dysfunction
assessed by spectral analysis, vector analysis, and standard tests of
heart rate variation and blood pressure responses at various stages of
diabetic neuropathy. Diabet Med 1992;9: 806 – 814

7. Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy:
mechanisms to management. PharmacolTher2008;120:1–34

8. Paulson DJ, Light KE. Elevation of serum and ventricular norepineph-
rine content in the diabetic rat. Res CommunChemPatholPharma-
col1981;33:559 –562

9. Pfeifer MA, Weinberg CR, Cook DL, Reenan A, Halter JB, Ensinck JW,
Porte D Jr. Autonomic neural dysfunction in recently diagnosed diabetic
subjects Diabetes Care 1984;7:447– 453

10. Spallone V, Bernardi L, Ricordi L, Solda` P, Maiello MR, Calciati A, Gam-
bardella S, Fratino P, Menzinger G. Relationship between the circadian
rhythms of blood pressure and sympathovagal balance in diabetic au-
tonomic neuropathy. Diabetes 1993;42:1745–1752

11. Consensus Committee of the American Autonomic Society and the Amer-
ican Academy of Neurology. Consensus statement on the definition of
orthostatic hypotension, pure autonomic failure, and multiple system
atrophy. Neurology 1996;46:1470

12. Boulton AJ, Vinik AI, Arezzo JC, Bril V, Feldman EL, Freeman R, Malik
RA, Maser RE, Sosenko JM, Ziegler D, American Diabetes Association.
Diabetic neuropathies: a statement by the American Diabetes Associ-
ation. Diabetes Care 2005;28:956 –962

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112 Cardio Diabetes Medicine 2017

Erectile Dysfunction: Endothelial Dysfunction;
Emotional Disturbance

Prof. Dr. Deepak K Jumani

Senior Sexual health Physician & Counselor, Mumbai, INDIA,
Asst. Prof of Medicine Sir JJ Govt Group of Hospitals & Grant Medical College,, Hon. Sexologist:

Mumbai Police Hospital & Apollo Sugar Clinic, Mumbai.

India is the oldest civilization in the world, where sex- spent in each phase varies from person to person.
uality is illustrated in literature, sculptures, scriptures,
and religion and dressing attires.  India played a sig- As per DSM V Classification2 include:
nificant role in the history of sex, from writing the first
literature that treated sexual intercourse as a science 1. Male Hypoactive Sexual Desire Disorders
“The Kama sutra by Rishi Vatsayana “ which even in
modern times has been instrumental as the guide for 2. Erectile Disorders (Erectile Dysfunction)
the philosophical focus for new-age groups towards
the understanding and attitudes on sex. India also 3. Premature ( Early) Ejaculation
pioneered the use of sex education through art and
literature. 4. Male Orgasmic Disorder: Delayed Ejaculation

There have been not enough or relevant surveys or In today’s modern world the most common sexual
studies related to sexual functions and dysfunctions dysfunction in males is Erectile Dysfunction.
in India. While human sexuality has long been the
subject of intense interest, it’s only since last 5 to 6 Its highly prevalent across the globe to the extent of
decades this has become an area of legitimate sci- 20 to 60 percent and less talked about and hence
entific interest. undertreated .

One of the most important and exciting work has It is Persistent or recurrent inability of a male to attain
been the four stage model of sexual response, which or maintain adequate erection until complete sexual
they described as the human sexual response cycle . activity. Penile erection is the most valid indicator of
The human sexual response cycle set the foundation male sexual arousal.
for studying and categorizing sexual dysfunctions in
men and women Penile erection is a complex neurovascular phenom-
enon that depends upon neural integrity, a functional
This human sexual response cycle1 is characterized vascular system, and healthy cavernosal tissues.
by
Normal erectile function involves 3 synergistic and
• Excitement phase (initial arousal) simultaneous processes:

• Plateau phase (at full arousal, but not yet at or- • neurologically mediated increase in penile - arterial
gasm) inflow

• Orgasm • relaxation of cavernosal smooth muscle

• Resolution phase (after orgasm) • restriction of venous outflow from the penis

Both men and women experience these phases, al- The incidence of Erectile Dysfunction almost doubles
though the timing usually is different. It is unlikely and triples with co morbid conditions such as Diabe-
that both partners will reach orgasm at the same tes, Hypertension, obesity and dyslipidaemia.
time. The intensity of the response and the time
Besides Ageing other vascular causes which include
venous leak, Peyronies disease, smooking and con-
sumption of excess of alcohol.

The hormonal causes of Erectile Dysfunction are Hy-

GCDC 2017

Erectile Dysfunction: Endothelial Dysfunction; 113
Emotional Disturbance

pogonadism, Hyerprolactinaemia, Diabetes, Thyroid metabolic, synthetic, anti-inflammatory, and anti-
disease, Androgen deficiency, Excess of Estrogen, thrombogenic processes.
Adrenal, Pitutary or hypothalamic diseases.
To understand the management of erectile dysfunc-
The Neurological Causes of erectile dysfunction in- tion one must understand that a normal vascular and
clude Multiple Sclerosis, Spinal cord injury, Diabetic neuronal endothelium produces endothelial Nitric
Neuropathy. oxide Synthase and neuronal nitric oxide synthase.
eNOS and nNos initate the NO to enter in the corpo-
Drugs which cause erectile dysfunction are Antian- ra cavernosa spongy tissue and converts Guanosine
drogens , Antihypertensives Diuretics, H2 Receptor Monophosphate to Cyclic Guanosine Monophos-
antagonists, Anticholinergics like atropine, proban- phate with the help of an enzyme Gyanylate Cyclase.
thine, dicyclomine, Antidepressants like Tricyclics, This Cyclic GMP is the main chemical which relaxes
MAO inhibitors, Antipsychotics, Antiepileptics and the smooth muscle cell of the Corpora and allows the
Certain Substance of Abuse like Heroin, Marijauna, blood to flow in the penile vasculature
etc.

Certain stresses and psychological factors which This cGMP also decreases the Calcium influx through
cause erectile dysfunction include fatigue, guilt, low specific protein kinases and allows the smooth mus-
self esteem, body image issues, certain mental dis- cle relaxation and erections.
orders, and religious restrictions, negative feelings
towards the partner, resentment, hostility and lack But soon cGMP gets hydrolysed to 5 Guanosine mo-
of trust. nophosphate with the help of a enzyme Phospho-
diastrase 5.
Chronic Kidney disease, Prostatectomy can also
lead to erectile dysfunction. So for a good enough erection one has to see that
the endothelium has to be normal & functional, Ade-
Other common causes include watching too much of quate Nitric Oxide, Guanylate Cyclase Activators and
pornography, infertility and stresses of modern life. Stimulators, cGMP to be present in more bioavaila-
bale form to maintain tumusence and lastly some-
In India Diabetes is the biggest health tsunami of our thing to block the PDE5 enzyme.
century. There are 417 million diabetics3 across the
globe and of these one-third are in India either at So in Erectile dysfunction the main cause is endo-
diabetic or pre-diabetic stage. India and China are two thelial dysfunction as we are aware that a normal
countries in the world where diabetes is an explosive healthy endothelium produces homeostasis by var-
epidemic1. In fact India and China, let us call it Chin- ious mechanisms.
dia, are the diabetes capital of the worlds. Men and
Women with diabetes have sexual problems. The Endothelium is an endocrine organ5 and plays a
commonest complication of diabetes seen in Indian central role in regulating the vasomotor tone and lo-
men is Erectile Dysfunction, cal homeostasis and also controls the coagulation
process. Endothelial cells have sensors and release
The last 20 years have established 4that the vascu- mediators and these mediators are the functional
lar endothelium, rather than being a mere barrier be- molecules on the cell surgace. The mediators include
tween intravascular and interstitial compartments, is Nitric Oxide, cyclooxygenase, endothelin -1, endothe-
a widely spread organ responsible for the regulation lium dependent factor, prosetenoids, angiotensin,
of hemodynamics, angiogenic vascular remodeling,

Cardio Diabetes Medicine

114 Cardio Diabetes Medicine 2017

Rho/Rhokinase, prostaglandin-E and proteocyclin. Initiation or erection Sexual Stimulation

Cavernosal smooth muscle cells in the penis are Maintenance of
predominately found in the contracted state with erection Central and
minimal blood flowing through the cavernous si- Peripheral
nuses. The balance between known contractile sys- Activation of nNOS-
tems (RhoA/Rho-kinase, α-adrenergic, endothelin, Derived NO
angiotensin, thromboxane A2) and vasodilatory sec-
ond-messenger systems (adenylate cyclase-cyclic 
AMP and guanylate cyclase-cyclic GMP) determines Cavernosal smooth
the overall tone of corpora cavernosa smooth muscle Muscle Relaxation
of the penis This balance is controlled by both central
and peripheral mechanisms and involves a plethora Blood Flow -
of neurotransmitters acting through various signal Mediated Shear
transduction pathways.
Stress
Of all the mediators of the endothelium the most im- 
portant is Nitric oxide6. Nitric oxide is the main chem-
ical currency which initiates the erectogenic process. Cavernosal P13
It’s the only free radical which is anti thrombogenic Kinase / Akt
and anti atherogenic and the only biological mole- Activation
cule which out completes superoxide dismutase for 
superoxide. Its protective action includes Smooth
muscle relaxation and vasodilatation, Essential for Phophorylation of
regulation of blood pressure, eNOS

Reduces proliferation of vascular smooth muscle
and Protects blood vessel intima from injurious con- Endothelial - Derived
sequences of platelet aggregation. Thus in endothe- NO
lial dysfunction we see reduction in NO and this NO 
deficiency promotes Inflammation, Oxidation of lipo-
proteins, Smooth muscle proliferation, Accumulation Maximal Erection
of lipid rich material, Platelet activation and thrombus
formation

In patients with Metabolic syndrome, ageing and
neurological disorders which are the organic causes
of Erectile dysfunction the main chemical currency
Nitric oxide is reduced which is the prime molecule
to initiate the erectogenic mechanism and also di-
minished cyclic GMP bio availability.

Pic: An “Airport hub” model of endothelial functions. In this mod-

el, all functions are intrinsically interconnected, and any impair-
ment of one would be affect the others. Some essecntial mediators
fo these functions are shown in brackerts. Pathophysiological con-
sequences of endothelial dysfunction are depicted at the primeter,
HTN, hypertension, EDHF, endothelium - derived hyperpolarizing
factor; EDF, endohtelium - derived relaxign factor, NO, nitric oxide;
VSM vascular smothe muscle; PAI-1, plasminogen activator inhibi-
tor-1; TF, tissue factor, PA, plasminogen actovator; MCP, monocyte
chemotactic protein; prot protein

Adapted from Hurt et al 20029

GCDC 2017

Erectile Dysfunction: Endothelial Dysfunction; 115
Emotional Disturbance

Research today has proved that Penis is the barome- and what you do to your body is the crux of our re-
ter of Endothelial function and Erectile dysfunction7 maining healthy.
is the earliest marker of Myocardial ischaemia. The
onset of Coronary artery disease is at least 2 to 3 Rishi Vatsayana in Kamasutra says sex is to be used
years after the onset of erectile dysfunction. So, if and not abuse. Sex wasn’t God’s mistake, judging
we detect erectile dysfunction as early as possible we against it is humanity’s biggest mistake. So, by ad-
can retard the onset of critical events like Myocardi- dressing the physical, psychological and couple fac-
al infarction or stroke in an individual, by changing tors we physicians can play a major role in helping
his life style and reducing the risk factors, like con- our sex starved patients enjoy by improving their
trolling hyperglycaemia, dyslipidemia hypertension, sexual functions, increase their self-esteem and
and smoking. give them good quality of sex life. Sensitivity of the
physician in approaching the problem by just asking
The endothelium plays a vital role in maintaining their patients about their sex life shall make a great
vascular homeostasis in the penis. Endothelial-de- difference. Sympathetic approach along with relevant
rived NO8 plays an integral role in the physiology of treatment to all patients with erectile dysfunction will
erection both in normal and in pathological disease go a long way in improving their sex starved life.
states. The earliest detectable changes in vascular
disease states associated with ED are abnormalities References:
of the endothelium, causing a loss in its normal ho-
meostatic mechanisms that conventionally protect 1. Masters and Johnson Male Sexual response
against disease-related processes. Given the central
importance of the endothelium, it is not surprising 2. DSM 1V American Psychiatric Association
that conditions that cause endothelial dysfunction,
such as aging, diabetes, cardiovascular disease, and 3. International Disabtes Federation Atlas 2016
hypercholesterolemia, are closely associated with ED.
Indeed, normal penile erection requires coordinated 4. Michael S. Goligorsky: Division of Nephrology and Renal Research In-
arterial endothelium-dependent vasodilation and si- stitute, Departments of Medicine and Pharmacology, New York Medical
nusoidal endothelium-dependent corporal smooth College,
muscle relaxation.
5. Bonetti P, Lerman L, and Lerman A. Endothelial dysfunction. A marker of
Another important aspect of Erectile dysfunction is atherosclerotic risk. Arterioscler Thromb Vasc Biol 2009, 23: 168– 175,
that it does affect the individual by imbibing in him
a feeling of inadequacy, reduces self-esteem, frus- 6. Maas R., Schwedhelm E., Albsmeier J., Boger RH. The pathophysiology
trates a man and makes him anxious and depressed of erectile dysfunction related to endothelial dysfunction and mediators
and not to confront the failure in performance in the of vascular function. Vasc Med. 2002;7: 213–225. 
bed room, he avoids having sex and feels guilty or
tries to blame the partner. Also, the partner gets frus- 7. Taddei S., Virdis A., Ghiadoni L., Salvetti G., Bernini G., Magagna A., Sal-
trated and angry and has low self-esteem and even vetti A.. Age-related reduction of NO availability and oxidative stress in
tries to suspect the husband as he is avoiding having humans. Hypertension. 2001;38: 274–279.
sex. All these take a heavy toll on the relationships
as there is unhappiness, no communication at times 8. Sullivan ME, Thompson CS, Dashwood MR, Khan MA, Jeremy JY, Mor-
they quarrel or become violent because of comparing gan RY, Mikhailidis DP. Nitric oxide and penile erection: is erectile
themselves with other colleagues etc. out of jealou- dysfunction another manifestation of vascular disease?  Cardiovasc
sy. Eventually there have been incidence of marital Res. 1999;43: 658–665.
breakdown and divorces. If this couple is married and
have some children they become poor role models 9. Hurt KJ, Musicki B., Palese MA, Crone JK, Becker RE, Moriarity JL, Sny-
for their children. All this leads to a mental turmoil der SH, Burnett AL. Proc Natl Acad Sci U S A. 2002;99: 4061–4066
and a disturbed family environment and in fact Emo-
tional disturbance sets in.

Erectile dysfunction is not an option, not for anyone
with metabolic syndrome or any other cause of erec-
tile dysfunction. It is how gracefully we handle the
process and how lucky we are as the process han-
dles us. I believe that to be sexually fit is a choice
and a lifestyle decision. It’s what you put in your body

Cardio Diabetes Medicine

116 Cardio Diabetes Medicine 2017

Regression of Atherosclerosis
- In Diabetics

Dr Joy M Thomas, MD, DM ( Cardiology), FRCP (G), FACC, FHRS, FCSI

Chief Cardiologist ( Adult Cardiology) & Chief Electrophysiologist

Dr H. Nagaraja Rao, DCH, DNB (Pediatrics),

Senior registrar, Cardiology

INTRODUCTION: Plaque burden in a two-dimensional IVUS frame is
expressed by the ratio of plaque plus media area
Atherosclerosis is a chronic disease of the vessel divided by vessel area. Volumetric (three-dimension-
wall that progresses over time by accumulation of al) measures of disease burden include total ather-
atheromatous plaque. This follows a course of arte- oma volume (TAV), i.e., the sum of atheroma area
rial injury associated with coexistent systemic risk measured in sequential cross-sectional frames and
factors. Understanding the complex pathophysiology percent atheroma volume (PAV), i.e., the percent of
of atherosclerosis led to the development of inter- the vessel volume occupied by atheroma.PAV is con-
ventions that effectively reduce the clinical manifes- sidered the primary endpoint in the majority of serial
tations of coronary atherosclerotic disease including IVUS studies [5-6].
angina or acute coronary thrombosis [1,2]. Introduc-
tion of medications including lipid-lowering drugs [3- Intracoronary imaging technologies for in
4], antihypertensive medications and investigational vivo assessment of plaque morphology and
anti-inflammatory agents have shown to favorably composition
affect the development and progression of coronary
plaque including reduction of plaque size and favor- Imaging modalities to characterize composition of
able changes in plaque morphology and composi- coronary atheroma in vivo
tion.Novel in vivo intracoronary imaging modalities
help in providing knowledge of the natural history of • IVUS-virtual histology (VH),
coronary atherosclerosis and assessment of plaque
stabilization and regression in response to potent • Optical coherence tomography (OCT)
anti-atherosclerotic medications.
• Near-infrared spectroscopy (NIRS).
Coronary imaging for in vivo plaque
quantification and characterization: IVUS-VH : This investigatory modality uses radiof-
requency range ultrasound signals to derive plaque
Intravascular ultrasound for quantification components, which are defined as necrotic core, fi-
of coronary atheroma: brofatty tissue, fibrous tissue, or dense calcium. Le-
sions are classified as pathologic intimal thickening,
Intravascular ultrasound (IVUS) is based on acous- fibrotic plaques, fibrocalcific plaques, thin- or thick-
tic sound wave backscattering. Reflected ultrasound cap fibroatheromas [7]. Studies have reported good
wave creates a gray-scale image resulting in a axi- correlation of IVUS-VH against human plaque his-
al resolution of 80–120 μm and a penetration depth tology. However, it is an imperfect surrogate of true
of 4–8 mm.IVUS Enables acquisition of tomographic histology and is limited by inter-observer variability
images of the entire coronary vessel wall and allows and differences in definitions .
for accurate, reproducible quantification of athero-
ma burden.This imaging modality, when performed OCT: This imaging technique has an axial resolution
serially at consecutive time points,helps for assess- 10-fold higher compared with IVUS with limited axial
ment of plaque progression or regression over time. penetration depth (1–4 mm). So, the assessment of
plaque burden is nearly impossible in the presence
of a lipid-rich plaque. OCT is well validated in the

GCDC 2017

Regression of Atherosclerosis- In Diabetics 117

accurate measurement of fibrous cap thickness and FIG -1 : Matched images of grayscale-IVUS (1); IVUS-VS (2), and
tissue composition, and also for detection of macro- OCT (3) showing two different plaque types as defined byintracor-
phages that appear as signal-rich bands with a sharp onary imaging.
shadow [8].
The upper row shows a fibrous plaque characterized
NIRS: This imaging technique shows a high correla- by predominantly green color (fibrous tissue) by
tion with histopathology for lipid detection with a IVUS-VH (A2) and a homogenous high-intensity sig-
sensitivity and specificity of 90% [9]. “Chemogram” nal area with low attenuation by OCT (A3). The lower
derived from NIRS provides compositional and no row depicts a calcified thin-capped fibro-atheroma.
structural information. It also provides automated IVUS-VH shows an extensive red area (confluent
lipid-core detection, thereby facilitating its real-time necrotic core) partly abutting the lumen(B2); consis-
use for detection of lipid-rich lesions during cardiac tently, OCT shows from 12 to 6 o’clock a signal-poor
catheterization. Overall, these modalities each fea- region with diffuse borders and a high light attenu-
ture certain advantages and limitations (Table 1) and ation,suggesting the presence of lipid pool/necrotic
reveal only partial aspects of plaque morphology and core, covered by a fibrous cap of minimally 50 nm
composition thickness (B3). In the same lesion, a hyper-dense
area by grayscale-IVUS (arrowheads; B1) localizes
TABLE 1- Comparison of IVUS/IVUS-VH, OCT, and with a white-color area (i.e., calcium) by IVUS-VH(B2)
NIRS for assessment of indices of plaque morphol- and a small rim of calcium, as indicated by a sig-
ogy and composition nal-poor area with low attenuation and clear border
lines, by OCT (B3); note that the calcium rim is not
Spatial resolution (mm) IVUS / NIRS OCT thick enough to cause shadowing in B1. Images were
IVUS-VH/ obtained from the IBIS-4 study database.
Measurement of athero- N/A 10
ma volume IB-IVUS - - Major serial IVUS studies reporting statin-
80-120 - +++ mediated plaque regression.
Measurement of cap - -
thickness +++ - ++ REVERSAL, ASTEROID, SATURN, IBIS 4 are the four
++ ++ studies reporting statin-mediated plaque regression
Assessment of arterial - - ++ and the results are summarized below (Table 2)
remodeling - +
+++ - ++ Factors associated with coronary plaque regression:
Assessment of plaque
calcification +++ - ++ • LDL-C

Assessment of lipid pool/ ++ • Diabetes mellitus,
necrotic core
- • Higher systolic blood pressure
Assessment of macro-
phage accumulation - • Baseline PAV

Assessment of neoves- + • C-reactive protein
sels
+
Assessment of luminal
integrity (erosion, rupture,

&tears)

Assessment of in-stent
neoatherosclerosis

Combined use of intracoronary imaging tools can
provide substantial incremental information for in
vivo characterization of coronary lesions compared
with the information obtained by each modality alone.
Fig. 1 shows a representative example of different le-
sion types imaged with IVUS, IVUS-VH, and OCT

LDL-C:

Serial IVUS studies have shown a significant rela-
tionship between LDL-C levels and the occurrence

Cardio Diabetes Medicine

118 Cardio Diabetes Medicine 2017

Study Study Population Sample Months Drug & On Treatment Median Change of Pav
Size Dose LDL-C

REVERSAL Stable CAD 654 18 mon 2.05 +0.2% (_0.3% to 0.5%),
Atorvastatin 80 p = 0.18 vs. baseline

ASTEROID Stable CAD 349 24 mon Rosuvas- 1.57 -0.79% (-1.21% to 0.53%),
tatin40 p <0.001 vs. baseline

SATURN Stable CAD 1039 24 mon 1.82 -0.99% (_1.19 to _0.63),
Atorvastatin 80 1.62 p <0.001 vs. baseline
Rosuvastatin40 1.22% (_1.52 to _0.90),
p < 0.001 vs. baseline

IBIS 4 STEMI 103 13 mon Rosuvasta- 1.90 0.90% (_1.56% to - 0.25%),
tin 40 p 1/4 0.007 vs. baseline

Table 2: REVERSAL, ASTEROID, SATURN, IBIS 4 are the four studies reporting statin-mediated plaque
regression and the results are summarized.

of plaque progression or regression In SATURN, diabetics achieved lower LDL-C levels
and showed similar PAV regression as did non-dia-
LDL-C levels were independent predictors of plaque betic patients overall (0.83 7 0.13% vs. 1.15 7 0.13%),
regression in both ASTEROID and SATURN [10]. as well as in the setting of on-treatment LDL-C < 70
mg/dl (1.09 +/- 0.16% vs. 1.24 +/- 0.16%); PAV reduction
Diabetes mellitus and Higher systolic blood was lower in diabetics only when on-treatment LDL-C
pressure : was >70 mg/dl [12].

Continued plaque growth despite LDL-C levels below In ASTEROID : Atheroma regression was compara-
the recommended thresholds was associated with ble in patients with vs. without diabetes [0.9% (2.8
the presence of diabetes mellitus, higher systolic to 0.9) vs. 0.8% (3.0 to 0.8)] [4]. These findings are
blood pressure, and smaller increase in HDL-C [11]. in contrast with earlier observations obtained from a
pooled analysis of IVUS studies where diabetics had
Baseline PAV: Strongest multivariable predictor of an on-treatment LDL-C of 80mg/dl and displayed
PAV regression in SATURN was increased baseline PAV increase of 0.6% as compared with LDL-C levels
PAV. of 84 mg/dl and no significant progression of PAV
in non-diabetics [13].
CRP:
Very high-intensity statins produce plaque regression
• Pivotal role of inflammation in atherosclerosis [1] among diabetics and reduce the differences in the
has also been reflected in serial IVUS studies. natural history of coronary atherosclerotic disease
between patients with or without diabetes when very
• In REVERSAL, reduction of C-reactive protein low LDL-C levels (<70 mg/dl) are achieved.
(CRP) was identified as an independent predictor
of a reduction in plaque progression . Association between plaque regression and clinical
outcomes:
• In SATURN non-increasing levels of CRP after
24 months of intensive statin therapy were inde- Coronary imaging studies have improved the under-
pendently associated with greater PAV regression standingof the natural history of atherosclerosis and
of the efficacy of anti-atherosclerotic medications on
These insights not only signify inter individual varia- coronary plaque. Plaque stabilization or regression
tion, but also highlight the multifactorial nature and as defined by imaging end points translates into im-
complex pathobiology of atherosclerosis and rein- proved clinical outcomes. Plaque burden measured
force the need for intensive modification of global risk by IVUS correlates with established clinical risk fac-
beyond reduction of LDL-C in patients with coronary tors and may predict subsequent clinical events .FiG2
artery disease.

Plaque regression in Diabetic patient
populations

Diabetic patients are at high risk of accelerated
plaque growth and ischemic events.

GCDC 2017

Regression of Atherosclerosis- In Diabetics 119

Fig. 2: Representative example of a lesion showing regres- change of plaque burden (progression or regression)
sion (left panel) and progression (right panel). The left cross on outcomes could not be assessed in the absence
sections indicate the grayscale-IVUS findings and the col- of serial intravascular imaging.
ored cross sections on the right indicate radiofrequency
IVUS analysis. In SATURN, each standard deviation increase of
baseline PAV was associated with a 28% increase in
In PROSPECT , high plaque burden (>70%) at base- major adverse cardiovascular events—despite the fact
line was associated with major adverse cardiovascu- that LDL-C levels did not differ between patients with
lar events over a 3-year follow-up; however, clinical lower vs. higher baseline PAV.(14)
event rates were overall low, and the impact of the
Von Birgelen et al. [15] reported in an observation-
al study that plaque progression detected by IVUS
was associated with more frequent adverse clinical
events.

In the CAMELOT study, the reduced event rate in pa-
tients treated with amlodipine vs. enalapril or placebo
was associated with absence of plaque progression
in response to amlodipine in patients who under-
went serial IVUS, thus indirectly linking plaque vol-
ume stabilization and prevention of adverse clinical
outcomes .

Moreover, comparison of the same regimens of in-
tensive vs. moderate statin treatment (atorvastatin 80
mg vs. pravastatin 40 mg) in different study popula-

Study/Author Population No. of Study dura- Drug Imaging Endpoint Outcome
patients tion modality
Rosuvastatin IVUS-VH
SATURN Stable CAD 71 24 months 40mg Change of necrotic 0.09 (-12 to
IVUS-VH core volume (mm) 1.9) p=0.84
IBIS-4 STEMI 103 13 months Rosuvastatin, IB -IVUS Change of fibro-fat-
Stable CAD 51 6 months 40 mg ty tissue volume -0.05 (-1.05 to
Kawasaki Pravastatin IB-IVUS (mm) 0.96), p =0.93
et al. 42 9months 20 mg OCT Change of percent -2.6 +/- 5.5, p
70 12 months Atorvastatin necrotic core (%) <0.05
Hattori et al. Stable CAD 20 mg NIRS Change of percent -6.6 +/- 5.3, p
Pitavastatin, lipid volume (%) < 0.01
EASYFIT Unstable 4mg -6.8 +/- 8, p
angina Change of percent <0.020
Atorvastatin lipid volume index
YELLOW Stable CAD 87 7 20 mg (%) +73 (28–131),
Atorvastatin Change of fibrous p < 0.001
5 mg cap thickness (mm) Atorvastatin,
5mg +19 (-1 to
Rosuvastatin Change of lipid-core 48), p < 0.002
40 mg burden index -146 (-210.9 to
-42.9),
p < 0.01

Table 3: Summary of studies that assessed changes of plaque composition or characteristics of
vulnerability in response to statin treatment using various imaging modalities.

Cardio Diabetes Medicine

120 Cardio Diabetes Medicine 2017

tions resulted in fewer adverse events in PROVE IT the discordance between only modest regression
[16] and also in the absence of plaque progression of plaque size on the one hand vs. profound clinical
in REVERSAL in atorvastatin-treated patients, sug- improvement on the other hand and, even more in-
gesting parallel favorable effects of intensive statin triguingly, the minor or absent improvement of pre-
therapy on coronary atheroma burden and patient sumed high-risk plaque morphology in response to
outcomes. intensive statin treatment. While the use of in vivo
intracoronary imaging has revolutionized our under-
In a post hoc pooled analysisof six serial IVUS stud- standing of serial changes of coronary plaque in re-
ies, Nicholls et al. found that PAV progression was an sponse to risk factors and pharmacologic interven-
independent predictor of major adverse cardiovascu- tions, it is possible that our current armamentarium
lar events over a mean 21-month follow-up; the vast may capture only in part the complex pathobiology of
majority of events included repeat revascularization, plaque progression, stabilization, or regression. Given
and no impact of plaque progression on mortality the complementary information provided by different
was reported. modalities separately, efforts should continue to fo-
cus on both the combined use of these techniques
In summary, the association between serial reduction and more robust validation.
of atheroma burden (which has been consistently
quantified around only 1%) and major cardiovascular REFERENCES :
events (which are reduced annually by over one-fifth
per 40 mg/dl LDL-C reduction) appears to be modest 1. Libby P. Mechanisms of acute coronary syndromes and their implications
and remains mostly inferential; direct prospective ev- for therapy. N Engl J Med 2013;368:
idence from randomized trials to address the impact
of plaque regression on the rate of adverse cardiac 2. Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et
events is currently missing. al. Efficacy and safety of more intensive lowering of LDL cholesterol: a
meta-analysis of data from 170,000 participants in 26 randomised trials.
Changes of morphologic plaque Lancet 2010;376: 1670–81.
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al. Effect of very high-intensity statin therapy on regression of coronary
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comes relate to favorable changes of plaque com- et al. Effect of two intensive statin regimens on progression of coronary
position beyond the reduction of plaque size. disease. N Engl J Med 2011;365:2078–87

Recent findings point to an association between in 5. Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, et al.
vivo features of plaque composition and the clinical Comparison of pioglitazone vs glimepiride on progression of coronary ath-
manifestations of coronary lesions and indicate a erosclerosis in patients with type 2 diabetes: the PERISCOPE randomized
beneficial effect of anti-atherosclerotic drugs on cer- controlled trial. J Am Med Assoc 2008;299:1561–73.
tain aspects of high-risk plaque morphology that has
been described as the vulnerable plaque. (Table 3) 6. Nissen SE, Tuzcu EM, Brewer HB, Sipahi I, Nicholls SJ,Ganz P, et al. Effect
of ACAT inhibition on the progression of coronary atherosclerosis. N Engl
Imaging tools that we currently use, focus on specif- J Med 2006;354:1253–63.
ic structural and morphological aspects of coronary
plaques and inherently ignore functional aspects of 7. Stone GW, Maehara A, Lansky AJ, de Bruyne B, Cristea E, Mintz GS, et
plaque biology (including the extent and phenotype al. A prospective natural-history study of coronary atherosclerosis. N Engl
of inflammatory cell infiltration, phagocytic activi- J Med 2011;364:226–35.
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trix-degrading enzymes), which are considered im- 8. Tearney GJ, Regar E, Akasaka T, Adriaenssens T, Barlis P, Bezerra HG,
portant mediators of improved clinical outcomes in et al. Consensus standards for acquisition, measurement, and reporting
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CONCULSION raphy Standardization and Validation. J Am CollCardiol 2012;59:1058–72.

Anti-atherosclerotic medications can halt or even 9. Moreno PR, Lodder RA, Purushothaman KR, Charash WE, O’Connor WN,
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Circulation 2002;105: 923–7.

10. Puri R, Nissen SE, Ballantyne CM, Barter PJ, Chapman MJ, Erbel R, et
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11. Bayturan O, Kapadia S, Nicholls SJ, Tuzcu EM, Shao M, Uno K, et al. Clin-
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GCDC 2017

Cardio Diabetes Medicine 2017 121

Triglyceride And Cardiovascular
Risk Whats New???

Dr. Aarathy Kannan, MD., Dip in Diab.,

Director, Physician & Diabetologist,
Sundaram Arulrhaj Hospitals,Tuticorin

Dr. Bhubaneshwar, & Dr. Kiran Palsania,

DNB (Gen Med).,

Triglycerides Introduction: tissue. Hypertriglyceridemia is a risk factor for the
developmentof atherosclerosis.1
• A Triglycerides (TG Triacylglycerol, TAG or Tri-
glycerides) is an ester derived from glycerol and • Normal- less than 150mg/dL(1.7mmol/L)
three fatty acids
• Borderline high -150-199mg/dL(1.7-2.2 mmol/L)
• Triglycerides (TG) are an important barometer of
metabolic health. • High-200-499-mg/dL(2.3-5.6mmol/L)

• Triglycerides are the main constituents of body fat There is increasing evidence that hypertriglyceridemia
in humans and other animals, as well as vegetable is an independent risk factor for coronary artery
fat. disease. A study from international Atherosclerosis
society suggested that Framingham risk score un-
• Main division between saturated and unsaturated derestimates the cardiovascular (CV) risk associated
types. with metabolic syndrome because high triglycerides
are undervalued as a risk factor.6
• Elevated levels of plasma triglyceride have long
been associated with an increased risk of car-
dio-vascular disease.

• TG has an inverse relationship with HDL-C and the
adjustment for HDL attenuates the relationship
between TG and CAD.

HYPERTRIGLYCERIDEMIA:

Definition: PREVALENCE OF HYPERTRIGLYCERI-
DEMIA INDIAN PERSPECTIVE:
“The current NCEP Adult Treatment panel III(ATPIII)
has defined Hypertriglyceridemia as fasting serum In the recently published Indian council of medical
triglycerides level>150mg/dl[>1.7 mmol/L].” research- India Diabetes study (ICMR- INDIAB) study
in which 16,607 persons (age >20years) from Tam-
• Dyslipidemia is defined as total cholesterol low il Nadu, Maharashtra,Chandigarh, and Jharkhand
density lipolrotein - cholesterol (LDL-C), triglycer- were evaluated for lipid and glycemic profile, it was
ide apolipoprotein (apo)- B, or lipoprotein (a) levels observed that 29.5% population had hypertriglycer-
above the 90th percentile or high density lipo- idemia, While 20.2% had isolated hypertriglyceri-
protein - cholesterol (HDL-C) or apo-A-I levels demia.7
below the 10th percentile for the general popu-
lation.[National Health and Nutrition Examination
Survey (NHANES) III triglycerides exist in the core
of chylomicrons and very low density lipoproteins
(VLDL). They undergo Hydrolysis by an enzyme
lipoprotein lipase be deposited as fat in adipose

Cardio Diabetes Medicine

122 Triglyceride And Cardiovascular Risk Whats New???

The pattern of Indian dyslipidemia is different from 3. Chylomicronemia Syndrome
western dyslipidemia.
4. Type III hyperlipidemia or Dysbetalipoproteinemia
In a study comparing lipid profiles of Indians,A-
sians,and American Whites,it was found that Indians Secondary causes of Hypertriglyceridemia
had higher triglycerides, lower HDL-C and higher li-
poprotein(a) while LDL-C and total cholesterol were 1. Metabolic Syndrome
similar in the two populations.8 In IACMR-INDIAB
study 11.8% had high LDL-C levels while 20.2% had 2. Endocrine Disorder– type 2 diabetes mellitus,Poly-
isolated hypertriglyceridemia These observations cystic Ovary Syndrome,
reinforce the fact that Indians need different guide-
lines,consensus and targets for the management of 3. Others-acromegly, and pregnancy
dyslipidemia as compared to the Western population
Where guidelines are mainly focused in reduction of 4. Drugs
LDL-C alone.
a) Oral estrogen treatment
TRIGLYCERIDES AND ATHEROSCLEROSIS:
b) Tamoxifen therapy (less pronounced with ral-
Earlier the association between hypertriglyceridemia oxifene)
and atherosclerosis was debated, but now it is
recognized that hypertriglyceridemia is associated c) Antihypertensive drugs with a potential to in-
with coronary CV risk. Triglycerides are found only in crease triglyceride levels are thiazide and Fu-
minor quantities in atherosclerotic plaques with cho- rosemide diuretics and β- adrenergic blocking
lesterol forming a major part.In 1972,Stockholm pro- agents and.
spective study suggested that hypertriglyceridemia
was an independent risk factor for heart disease.10 d) Retinoids (e.g isotretinoin and bexarotene) are
Again in 1977, a Finnish study correlated increased associated with increased triglyceride levels
cardiac mortality with triglycerides levels more than ,and Mechanisms may involve both increased
150mg/dL.12Hypertriglyceridemia is also associated hepatic VLDLand apoC-III production and de-
with increased mortality in patients with Known CHD, creased LpL, Hypertriglyceridemia can be seen
and both increased mortality and reduced event-free with certain Antipsychotic medications are as-
survival after coronary artery bypass graft surgery sociated with weight gain,insulin resistance
(CABG).13 and worsening of the metabolic Syndrome

Endogenous pathway of Lipid Metabolism Atherogenic potential of triglycerides:

Nascent VLDL particles containing apolipoproteins B 1. Accumulation of Chylomicron remnants
100 and E are synthesized in the liver.Cholesteryl es-
ters and other lipoproteins derived from breakdown 2. Accumulation of VLDL remnants
of HDL are added to form VLDL particle The en-
zyme Lipoprotein lipase (LPL)lyses VLDL into smaller 3. Generation of small,dense LDL
VLDL remnants.these remants are enriched in apo
B-100 and E.These VLDL remnents are cleared in the 4. Associationn with low HDL-C
liver by LDL receptors, or subjected to the action of
hepatic lipase to form LDL particles containing apoB- 5. Increased coagulability
100(Fig.1)
a) Increased plasminogen activator inhibitor(PAI-1)
HYPERTRIGLYCERIDEMIA- Causes:
B) Increased, factor VIIc6 .Activation of Prothrom-
Hypertriglyceridemia can result from increased pro- bin to thrombin
duction, reduced catabolism,or a combination there-
of. FASTING VS NON FASTING LIPID PROFILE:

Genetic causes of Hypertriglyceridemia Traditionally a blood sample for Lipid profile is taken
in the Fasting state.Severaal Recent studies have not
1. Familial Combined Hyperlipidemia (FCHL) shown any advantage of Performing a Fasting Lipid
profile testing. Rather ,there is an advantage of Non-
2. Familial Hypertriglyceridemia (FHTG) fasting Lipid profile measurements in that the blood
sampling process is simplified for patients,general
practitioners,and hospitals,and therefore probably
increases compliance to Lipid Lowering Therapy
and Monitoring. Also it is Important to note that
most people eat Regularly throughout the day and

GCDC 2017

Cardio Diabetes Medicine 2017 123

are therefore usually fasting(defined as at least 8h triglyceride levels.
since the last meal) only for few hours. For all these
reasons,non- Fasting Lipid concentrations might be In another study, a readuced fructose intake signifi-
a better indicator of average lipid concentrations in cantly lowered triglyceride levels.30, Thus nonpharma-
the blood rather than fasting concentrations. cologic interventions,such as weight loss in obese
optients,aerobic exercise avoidance of concentrated
Hypertriglyceridemia and serum cholesterol sugars and medications that raise serum triglyceride
levels, and strict glycemic control in diabetics should
A combination of hypertriglyceridemia with hypercho- be first-line therapy.31 other risk factors for CV dis-
lesterolemia carries greater tendency to atherosclero- ease,such as hypertension and smoking should also
sis when compared to hypercholesterolemia alone. be addressed.
Small VLDL, IDL,and β-VLDL are more inherently
atherogenic22,23 The presence of hypertriglyceridemia Alcohol abuse must be avoided in patients with ser-
suggests that increase in serum total cholesterol is vere hypertriglyceridemia as it can cause large in-
partially due to increased very low density lipopro- crease in triglyceride levels precipitate pancreatitis. 32
tein- cholesterol(VLDL-C).This relationship also has it is preferable for patients with mild – to- moderate
therapeutic implications Treatment to reduce serum hypertriglycerdemia to limit their alcohol consump-
triglyceride with nicotinic acid or fibrates will also re- tion to less than two drinks per day in men and one
duce total cholesterol. Statins have a smaller effect drink per day in women.
on VLDL compared to LDL compared to LDL,and
therefore, are weak in reducing total serum choles- Pharmacotherapy for hypertriglycerdemia:
terol. (PIC 1)
1. Statins
MANAGEMENT:
2. Fibrates
Mild–to-moderate Hypertriglyceridemia(Triglycerides
150-500mg/dL) 3. Niacin

In any form of hypertriglyceridemia the main indi- 4. Omega-3 fatty acids
cation for therapy is reduction of CV risk Lifestyle
modification is the cornerstone in the management. 5. Dual perxisome proliferator- activated receptors
(PPAR) agonist saroglitazar
It is important to emphasize the role of physical ex-
ercise and dietary modification as effective tools in Statins: Pharmacologictherapy for Cv risk reduction
controlling hypertriglyceridemia to patients. In study,- has been proven with stain therapy.statins are weak
jogging 10milles/week led to 20% reduction in fasting in their effect to reduce triglycerides. They may re-
duce triglycerides by10-15%.However,they are very
effective in reducing CV risk They are therefore fir-

Cardio Diabetes Medicine

124 Triglyceride And Cardiovascular Risk Whats New???

si-linetherapy in patients with mild –to-moderate hy- by 20-50% administration of 3 to 4 g/d of EPA plus
pertriglycerdemia.side effects of stains are reported DHA is required.
in about 10% of patients. They include muscle cramps,
weakness, and muscle aches. Rhabdomyolysis is Newer Hypolipidaemic Drugs:
very rare.33Howeverstatins should be used with cau-
tion in elderly renal failure , and in the presence of Classification – Newer Drugs
acute illness.
Proprotein convertase subtilisin / kexintype 9 (pcsk9)
Fibrates: Fibrates are PPAR-α agonists fibrates re- inhibitors Evolocumab,bococizumab, Alirocumab
duce triglyceride levels by 50%.Various trials with
fibrates have shown reduction of Cv risk in patients Apolipoprotein B synthesis inhibitor – Mipomersen
with dyslipidemia.
Microsomal triglyceride transfer protein (MTTP)inhib-
Fibrates reduces triglyceride levels through several itor- Lopitamide
mechanisms
Thyromimetic- Eprotirome
Increased fatty acid oxidation
Cholestryl ester transfer protein (CETP) Ainhibitors-
Increased LPL synthesis Torcetrapib, dalcetrapib

Reduced apo C-III expression Dual peroxisome proliferator- activated Receptors
Alpha /Gamma Agonist Saroglitazar: Saroglitazar(Li-
The net effect is a decrease in VLDL triglyceride pro- paglyn)
duction and an increase in catabolism of triglycer-
ide-rich lipoproteins in moderate and severe hyper- In clinical studies,saroglitazar has demonstrated re-
triglyceridemia fibrates generally decrease triglycer- duction of triglycerides (TG) LDL cholesterol,VLDL
ide levels by 30-50% and sometimes increase HDL cholesterol,non –HDL cholesterol a characteristic
cholesterol. hallmark of atherogenic diabetic dyslipidemia(ADD)

Common adverse effects with fibrates are gastroin- Saroglitazar is the only drug approved by Drug con-
testinal disturbances, rash, headache, pancreatitis, troller general of india (DCGI).It is approved for the
myalgia, and myotoxicity, combining fibrates with treatment of diadetic dyslipidemia and hupertriglycer-
stains increases the myopathies 5.5%40. Preexisting idemia with T2DM not controlled on statin therapy.48
severe renal dysfunctions, severe liver sysfunction,
and gall bladder disease are contraindications to ad- Other Measures:
ministration to fibrates.
In patients with refractory hypertriglycerdemia com-
Niacin: Niacin lowers triglyceride levels and increases binations of statins,fibrates,nicotinic,acid and fish oil
HDL cholesterol levels. may be used. Patients with marked symptoms with
acute pancreatitis and hypertriglycerdemia have been
At doses of 500 to 2000 mg/d, niacin lowers tri- treated with plasma exchange/plasmapheresis.49
glyceride by 10-30%, increases HDL cholesterol by
10-40%,and lowers LDL cholesterol by 5-20%. In patients with type V hyperlipoproteinemia and
very high triglyceride levels refractory to therapies,
Also has Lp(a)- lowering effect. a study on five patients suggested benefit from orli-
stat. Orlistat is minimally adsorption of approximately
Complications of niacin therapy- hepatotoxicity im- 30% of ingested fat,and reduces intestinal chylomi-
paired glucose tolerance or hyperuricemia requiring corn synthesis.50
laboratory monitoring
Monitoring Response to Pharmacological
N-3 Fatty Acids: Many studies have demonstrated a management:
dose – dependent triglyceride- lowering effect of long
chain marine Omega-3 fatty acids(eicosapentaenoic Pharmacological therapies vary in time taken to re-
acid or EPA and docosahexaenoic acid or DHA).How- duce triglyceride levels.Effects with nicotinic acid is
ever, no studies using high –dose n-3 fatty acids in seen in 6 weeks, with fish oil in 2 weeks and a re-
hypertriglycerdemic patients have demonstrated any sponse to fibrates is seen as early as 2 weeks into
beneficial cardiovascular outcomes to date. therapy with a maximal effect in 6-8 weeks.51

Omega-3 fatty acids may be considered for treatment
of severe and very sever hupertriglyceridemia(>1,000
mg/dl), and to achieve a reductions of triglyceridemia

GCDC 2017

Cardio Diabetes Medicine 2017 125

CONCLUSION:

-- Epidemiological evidence indicates that plasma TG
levels predict CVD

-- The independent relationship between TG and CHD
is more consistently observed in the general popu-
lation. Avoidance of Nicotinic acid ,Smoking,alco-
hol and low fat diet, exercise daily is mandatory.

-- Current Hypolipidemic drugs Statin,BAS,fibrates
fish oil.Statin are standard of care for virtutually
all high-risk patients.

-- Newer agents-PCSK 9 inhibitor ,MTTP inhibitor,a-
po B inhibitor CETP inhibitor Thyromimitics are on
the pipeline

-- Saroglitozar is indicated in RX of hypertriglyceri-
demia.

-- Obese patients aerobic exercise, avoidance of
concentrated sugars and medications that raise
serum triglyceride levels and strict glycemic con-
trol in diabetics should be first-line therapy in pa-
tients with mild-to-moderate hyperlipoproteinemia
.Alcohol consumption can have both favorable and
unfavorable effects on CV risk.It is suggested that
in patients mild-to-moderate hyper lipoprotein-
emia, men limit their alcohol consumption to no
more than two drinks per day. Other risk factors
for CV disease such as hypertension and smoking
should also be addressed. In patients with severe
hyperlipoproteinemia (fasting triglyceride levels
above 1,000mg/dL), a very low fat diet and com-
plete avoidance of alcohol is beneficial.options
for pharmacologic therapy directed at reducing
triglycerides include fibrates,nicotinic acid,and fish
oil.19,52

REFERENCES

1. National Cholesterol Education program (NCEP) Expert Panel on Detec-
tion,Evaluation and Treatment of High Blood Cholesterol in Adults(Adult
Treament panel III)final report.Circulation.2002;106:3143.

2. Global recommendations for the management of dyslipidemia full report.
An international atherosclerosis society position paper;2013.

3. D Kolovou G, P Mikhailidis D, Kovar J, Lairon D, G Nordestgaard B,
Chye Ooi T, Perez-Martinez P, Bilianou H, Anagnostopoulou K, Pano-
topoulos G. Assessment and clinical relevance of non-fasting and post-
prandial triglycerides: an expert panel statement. Current vascular
pharmacology. 2011 May 1;9(3):258-70.

Cardio Diabetes Medicine

126 Cardio Diabetes Medicine 2017

Impaired Glucose Tolerance and Coronary Artery
Disease and Peripheral Artery Disease

Dr. D. Selvaraj, M.D.

SRRA Hospital, Tuticorin.

Coronary Artery Disease (CAD) is the most common Atheroscelorosis in diabetes will cause endothelial
cause of mortality in the developed world. The term damage, platelet aggregation, lipid deposition and
“Coronary Artery Disease” encompasses a range plaque formation with the same risk factor but dis-
of diseases that result from atheromatous changes tribution is different mainly below knee disease and
in coronary vessels. Atherosclerosis is the principal profound femoral artery disease.
cause of death and disability in patients with Type
2 Diabetes Mellitus. In these patients cardiovascular Pathophysiology
disease typically occurs at an early stage with great
severity and different distribution. Macro circulation - Large vessel calcification

More than half of the patients with newly diagnosed Atheroscelerotic plaques
T2 DM have established coronary artery disease,
whereas one third of patients with coronary artery Micro Circulation:
disease have known diabetes mellitus.
-- Thickening of capillary basement membrane
Screening patients with established coronary artery
disease but without pre-existing diabetes will confirm -- Increased microvascular flow (warm foot)
the diagnosis of diabetes mellitus in an additional
15 to 20%. Impaired fasting glucose or impaired glu- -- Oedema secondary to impaired postural vasocon-
cose tolerance will be detected in an additional 30 striction
to 40%. Peripheral vascular disease (PVD) is a major
cause of morbidity and mortality especially affecting -- Increased metabolic requirement
the elderly population. The prevalence of peripheral
vascular disease is multifold higher on patients with -- Impaired ability to respond to trauma
diabetes compared with age and sex matched non-
diabetes subjects. Hence it is very clear that screen- -- Platelet degranulation increased
ing for diabetes mellitus is warranted in patients with
cardiovascular disease or risk factor for other cardio Risk of Cardiovascular Disease is elevated prior to
vascular diseases like peripheral vascular disease. diagnosis of T2DM. Compared with nondiabetics, di-
abetic patients have increased risk of hypertension
The American Diabetes Association and the World 20% and heart diseases 10%. In patients with ACS
Health Organization both recognize l Impaired glu- and diabetes, there is increased risk of in-hospital
cose categories, metabolic stages of glucose inter- mortality nonfatal MI and all cause mortality com-
mediary between normal and diabetes. Impaired Glu- pared with nondiabetes.
cose Tolerance (IGT) is defined by both organizations.
for 2-hour post glucose level >140 but <200 mg/dl. PVD in diabetes has a poor prognosis. PVD is 20
Although not all patients of IGT will progress to overt times more common in diabetics than in nondiabet-
diabetes mellitus, the rate of conversion is particular- ics. Lower limb amputation is 15 times more common
ly high in this group. in diabetes, 10% of diabetics get an ulcer, 10% are
purely ischemic and they are associated with neurop-
athy infection, biochemical abnormalities and charcot
deformity. Increased risk of CAD, CVD, nephropathy,
retinopathy and death. Diabetes and PVD is com-
mon but complications often preventable. Holistic

GCDC 2017

Impaired Glucose Tolerance and Coronary Artery Disease 127
and Peripheral Artery Disease

approach through multidisciplinary team is needed. for secondary cardiovascular prevention, and for pa-
Good community diabetic care and early recognition tients at high risk of first event, could insulin prevent
of symptomatic patients should be done. diabetes? In IFG and IGT, reducing beta cell works by
life style, TZD Metformin Acarbose reduce diabetes.
Many therapeutic approaches delay or prevent the Insulin does not have a major role in patients who do
progression to diabetes; mellitus and are appropriate not have overt diabetes, unless nonpharmacological
for the patient with or without established coronary forms or drugs are contraindicated
artery disease.
References :
Nonpharmocological
1. Glucose tolerance and cardiovascular mortality: comparison of fasting and
Modalities in IGT in CAD and DVD: 2-hour diagnostic criteria.  Arch Intern Med.2001;161:397-405.PubMed

Physical Activity: 2. Haffner SM,Stern MP, Hazuda HP ,Mitchell BD,Patterson JK. Cardiovascu-
lar risk factors in confirmed prediabeticindividuals.  JAMA.1990;263:2893-
Regular aerobic exercise, atleast 150 minutes/week 2998.PubMed
spread over minimum of 3 days should be performed
if cardiovascular health permits. 3. Fuller JH, Shipley MJ, Rose G, Jarrett RJ, Keen H. Coro-
nary-heart-disease risk and impaired glucose tolerance: the Whitehall
Behavioural Modification: Study.  Lancet.1980;1:1373-1376.PubMed

Individuals require support and coping strategies for 4. Tominaga M,Eguchi H,Manaka H, Igarashi K,Kato T,Sekikawa A. Impaired
life style changes including healthy diet, exercise, glucose tolerance is a risk factor for cardiovascular disease, but not
weight reduction. Smoking cessation and treatment impaired fasting glucose: the Funagata Diabetes Study.  Diabetes
compliance and also depression. Care.1999;22:920-924.PubMed

Weight Loss: 5. Temelkova-Kurktschiev TS, Koehler C, Henkel E, Leonhardt W, Fueck-
er K,Hanefeld M. Postchallenge plasma glucose and glycemic spikes are
Weight reduction aimed at 7% weight loss is the COR- more strongly associated with atherosclerosis than fasting glucose or Hb
NER STONE OF treatment For ever weight or obese A1c level.  DiabetesCare.2000;23:1830-1834.PubMed
individual with prediabetes.
6. Bonora E,Kiechl S,Oberhollenzer F.  et al.  Impaired glucose tolerance, type
Along with other life style modifications, Bariatric sur- II diabetes mellitus, and carotid atherosclerosis: prospective results from
gery remains an effective option for obese patients the Bruneck Study.  Diabetologia.2000;43:156-164.PubMed
with Type-2 diabetes.
7. Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M.for
Pharmacological Approach: the STOP-NIDDM trial.   An international study on the efficacy of an
α-glucosidase inhibitor to prevent type 2 diabetes in a population with
For the patients with multiple risk factors of T2DM impaired glucose tolerance: rationale, design, and preliminary screening
progression where the patient is unable to incor- data.  Diabetes Care.1998;21:1720-1725.PubMed
porate life style interventions, Metformin use may
be appropriate, although there is some evidence to
suggest that it is less effective for the older popula-
tion. In high risk patients, with prediabetes, diabetes
prevention, life style modification or Metformin has
been demonstrated to be COST effective and even
cost saving. Metformin should not be prescribed for
patients with lower glomerular fitness rate. Acarbose
and glucosIdase inhibitor that blocks the absorption
of dietary carbohydrate, has also been demonstrated
to reduce the progression from impaired glucose tol-
erance to DM. Further it may have favourable effects
on cardiovasdcular event rates. Although thiazoli-
dinediones may also prevent Type 2 Diabetes Mel-
litus, their use for the prevention of DM is debated,
in part because of weight gain and the controversial
effect in cardiovascular event rates with roziglitazone.
Statins have been associated with incidence of Type
2 diabetes, especially among those with prediabe-
tes. However, their cardiovascular benefits are clear

Cardio Diabetes Medicine