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Published by , 2018-09-22 10:39:45

22sep

22sep

Cardio Diabetes Medicine 2018 148

s.no class Gene name Symbol Location

Diabetes Nephropathy
(susceptible genes)

1. Renin-angiotensin aldo- Angiotensin-converting enzyme 1 ACE 1 17q23
sterone system (RAAS) Angiotensinogen
Angiotensin II receptor, type 1 AGT 1q42-43
Aldose reductase AGTR1 3q21-25
AKR1B

2. Glucose metabolism Glucose transporter-1 SCL2A1 17q35
1p35
Receptor for advanced glycosylation end-prod- RAGE 6p21.3

ucts

3. Growth factors Transforming growth factor β1 TGFB1
Transforming growth factor β receptors I-III TGFBR1/ 2/ 3
Vascular endothelial growth factor 19q13.1
VEGF 9q22, 3p22, 1p33

4. Oxidative stress Superoxide dismutase 1 and 2 Haptoglobin SOD 1/2 21q22, 6p12
Paroxonase HP
Catalase PON 1/2 6q25.3
CAT 16q22

5. Lipid metabolism Glutathione peroxidase 1 GPX 1 7q21–22
Apolipoprotein E APO E 11p13
Adiponectin ADIPOQ 3p21.3
Peroxisome proliferator activated receptor PPARG 19q13.2
gamma

Cardiovascular compli- Adiponectin

cations cyclin-dependent kinase Inhibitor 2A

6. Renin-angiotensin aldo- Phosphatase And Actin Regulator 1 ADIPOQ 3q27
CDKN2A/2B 3p25
sterone system (RAAS) PHACTR1
9p21

7. Lipid metabolism SORT1/CELSR2/PSRC1 CELSR2-PS- 6p24
hepatocyte nuclearfactor 1 homeobox A RC1-SORT1
Proprotein HNF1A 1p21
convertase subtilisin/kexin type PCSK9 1p32
glutamate-ammonia ligase CDKN2A/2B 9p21
GLUL 1q25

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Table 1: List of candidate genes associated with development or
progression of diabetes complication

Conclusion: ered evidence for risk predictions using sus-
ceptible genes.
Diabetes or chronic hyperglycemia leads to • Genome wide association studies are import-
changes in miRNA expression profiles in many ant to enlighten the genetic basis of cardiore-
tissues, such as liver, pancreas, heart and kid- nal complications.
ney. Changes in tissue miRNA levels can pro- • The benefits of identifying novel genetic fac-
mote diabetes at early disease stages or later tors for cariorenal complications could pro-
disease stages (17-18). Furthermore, recent vide novel insights into disease pathogenesis
progress in the development of how to target facilitate early identification of at-risk subjects
miRNAs in vivo. Another major limitation of ge- and might provide novel strategies for inter-
netic studies in diabetic complications relate to vention to reduce the burden of diabetic com-
the different definitions used and the difficulties plications.
relating to case ascertainment. As illustrated
earlier, different definitions of diabetic kidney Reference:
complications have been used, and in addition
to different severity of coronary heart disease, 1. International Diabetes Federation. Diabetes
there is the added difficulty relating to exclusion Atlas, 6th edn. Brussels: The International
of underlying silent coronary disease among Diabetes Federation, 2013.
patients, especially with a long duration of di-
abetes. Given the interrelationship between di- 2. Ramachandran A, Snehalatha C, Ma RC.
abetic cardiovascular and renal complications, Diabetes in South-East Asia: an update. Diabe-
future genetic studies should also consider the tes Res Clin Pract 2014; 103:231–237.
potential overlap between these complications
in terms of their underlying pathogenesis. Nev- 3. Chan JC, Cho NH, Tajima N, et al. Diabe-
ertheless, taking into account the differences tes in the Western Pacific Region–past, present
in study design, case ascertainment and other and future. Diabetes Res Clin Pract 2014; 103:
methodological issues, findings across different 244–255.
ethnic groups for diabetic complications seem
quite consistent. In the meta-analysis of genetic 4. Yeung RO, Zhang Y, Luk A, et al. Meta-
factors for diabetic nephropathy, meta-regres- bolic profiles and treatment gaps in young-onset
sion for variants that have been replicated in type 2 diabetes in Asia (the JADE programme):
multiple ethnic groups (i.e., the ACE rs179975, a cross-sectional study of a prospective cohort.
AKRB1 CA repeat z-2, APOE 2/3/4 variant) and Lancet Diabetes Endocrinol 2014; 2: 1 935–943.
may give novel clues for the treatment of diabe-
tes and its complications in future (19-20).

Highlights: 5. Rask-Madsen C, King GL. Vascular com-
plications of diabetes: mechanisms of injury and
• Early onset of diabetes at a young age is protective factors. Cell Metab 2013; 17: 20–33.
keeping individuals at risk of developing vas-
cular complications due to prolonged expo- 6. Forbes JM, Cooper ME. Mechanisms of
sure to hyperglycemia. diabetic complications. Physiol Rev 2013; 93:
137–188.
• miRNA expression profiles in many tissues,
such as liver, pancreas, heart and kidney 7. Brownlee M. Biochemistry and molecu-
due to hyperglycemia is the major cause for
the cariorenal complications.

• Linkage analysis with a logarithm of odds
(LOD) Score of greater than 3.0 is consid-

Cardio Diabetes Medicine

Cardio Diabetes Medicine 2018 150

lar cell biology of diabetic complications. Nature 15. Chan JC, So WY, Yeung CY, et al. Effects
2001; 414: 813–820. of structured versus usual care on renal endpoint
in type 2 diabetes: the SURE study: a random-
8. Earle K, Walker J, Hill C, et al. Familial ized multicenter translational study. Diabetes
clustering of cardiovascular disease in patients Care 2009; 32: 977–982.
with insulin-dependent diabetes and nephropa-
thy. N Engl J Med 1992; 326: 673– 677. 16. Bakris G, Vassalotti J, Ritz E, et al. Na-
tional Kidney Foundation consensus conference
9. Perkovic V, Verdon C, Ninomiya T, et al. on cardiovascular and kidney diseases and di-
The relationship between proteinuria and coro- abetes risk: an integrated therapeutic approach
nary risk: a systematic review and meta-analy- to reduce events. Kidney Int 2010; 78:726–736.
sis. PLoS Med 2008; 5: e207.
17. Dumortier O, Hinault C, Van Obberghen
10. van der Velde M, Matsushita K, Coresh J, E. MicroRNAs and metabolism crosstalk in ener-
et al. Lower estimated glomerular filtration rate gy homeostasis. Cell Metab 2013; 18: 312–324.
and higher albuminuria are associated with all-
cause and cardiovascular mortality. A collabo- 18. Kantharidis P, Wang B, Carew RM, et al.
rative meta-analysis of high-risk population co- Diabetes complications: the microRNA perspec-
horts. Kidney Int 2011; 79: 1341–1352. tive. Diabetes 2011; 60: 1832–1837.

11. Fox CS, Matsushita K, Woodward M, et 19. Vijay V, YanqingZ, Karthick B ,Stephen
al. Associations of kidney disease measures with D,Chamukuttan S,Ambady R,etal.2001.Associa-
mortality and end-stage renal disease in individ- tion between ACE gene polymorphism and Di-
uals with and without diabetes: a meta-analysis. abetic Nephropathy in South Indian Patients.J
Lancet 2012; 380: 1662–1673. pancreas.,2:83-87.

12. Hsieh MC, Hsiao JY, Tien KJ, et al. Chron- 20. Mooyaart AL, Valk EJ, van Es LA, et al.
ic kidney disease as a risk factor for coronary ar- Genetic associations in diabetic nephropathy: a
tery disease in Chinese with type 2 diabetes. Am meta-analysis. Diabetologia 2011; 54: 544–553.
J Nephrol 2008; 28: 317–323.

13. Chang YT, Wu JL, Hsu CC, et al. Diabe-
tes and end-stage renal disease synergistically
contribute to increased incidence of cardiovas-
cular events: a nationwide follow-up study during
1998–2009. Diabetes Care 2014; 37: 277–285.

14. Luk AO, So WY, Ma RC, et al. Metabolic
syndrome predicts new onset of chronic kidney
disease in 5,829 patients with type 2 diabetes:
a 5-year prospective analysis of the Hong Kong
Diabetes Registry. Diabetes Care 2008; 31:
2357–2361.

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CARDIO RENAL SYNDROME : CARDIO RENAL CROSS TALK

Dr.Kannan baba,DM(Nephro)

Thoothukudi Medical College &Hospital;Tuticorin

introduction : Chronic reno cardiac syndrome (Type 4)
long term abnormalities in kidney function
Various organ systems within the human body
are intimately connected to each other. this so leading to cardiac disease
called "organ crosstalk" refers to complex biolog- Secondary cardio renal syndrome (Type 5)
ical communication and feed back between or-
gan sysytems mediated via various soluble and systemic condiitons causing simutaneous
cellular mediators , normally this crosstalk helps dysfuction of the heart and kidney, like sepsis or
to maintain homeostais and optimal functionong drug toicity.
of human body. during the disease states this
cross talk can carry over the influence of the dis- Epidemiology and risk factors:
eased organ to initiate and perpetuate structural
and functional dysfuction in other organs. acute types 1 and 3
There are number of important interaction pres- CRS type 1 -most common type, has been de-
ent between heart disease and kidney disease. scribed in 27 - 45 % of hospitalized acute heart
the inter action is bidirectional as acute and failure patients and in 9 -54 % of Acute coronary
chronic dysfunction of heart and kidneys can syndrome patients. a significant proportion of
contribute to acute and chronic dysfuction of oth- cases occurs in first 3 - 5 days after admkssion in
er organ. the clinical importance of this relation- AHF and ACS. The increase in serum creatinine
ship is of 0.3 mgs% from baseline or 30 % increase of
1. Mortality is increased in patients with heart serum creatinine from baseline have been used
failure who have a reduced glomerular filtartion to define CRS type 1.
rate
2. Patients with chronic kidney disease have risk factors are divided into non modifiable risk
increased risk of atherosclerotic cardiovascular factors and modifiable risk factors
disease and heart failure Non modifiable risk factors -
3. Acute or chronic systemic disorder can cause
both cardiac and renal dysfuction diabetes, previous history of heart failure or
myocardial infarction or severe myocardial in-
Definition : volvement ( presence of pulmonary edema,
Tachyarrthmias, low ejection fraction and higher
Disorders of heart and kidneys whereby killip class levels)
acute and chronic dysfunction in one organ
may induce acute or chronic dysfunction of the Modifiable risk factors -
others. high dose diuretics, vasodilator and high radio

contrast dose volumes.

Classification of CRS chronic CRS type 2 -
very paucity of data, chronic heart faliure due to
Acute Cardio renal syndrome (Type1) valvular or coronary disease may lead to chronic
acute worsening of cardiac function lead- renal ischemia causing renal dysfunction.

ing to decreased kidney function. CRS type 3 -
very paucity of data regarding the CRS type 3,
Chronic cardio renal syndrome(Type 2) characterized by acute kidney injury leads to AMI,
chronic abnormalities in cardiac function congestive cardiac failure and Arrthymia. The
mortality of AKI patients in the ICU increased
leading to decreased kidney function concomitantly with the number of other organs

Acute renocardaic syndrome (Type 3)
acute worsening of kidney fuction caus-

ing cardiac dysfucntion.

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Cardio Diabetes Medicine 2018 152

failed. Heart diseases was the reported cause of immune mediated process. The presence of sys-
death in 15% of AKI patients. Volume overload tolic dysfunction and decreased cardiac output,
and potassium abnormalities ( Hyperkalemia > kidney arterial underfilling and increased venous
hypokalemia) are important risk factors. congestion leading to decreased glomerular fil-
tration rate. a lower kidney perfusion leads to
Chronic CRS type 4 - increased activity of renin - angiotensin - aldo-
Most common type as like 1 and 3 - uraemic sterone - Axis promoting salt and water retention
cadiomyopathy and coronary artery disease in causinf systemic and glomerular hypeertension
CKD patients as well as Sudden cardiac death leads to endothelial and glomerular injury. Exter-
due to arrthymias and Acute myocardia infarc- nal factors in the form of diuretics used for man-
tion in patients during hemodialysis. aging acute heart failure may cause excessive
intra vascular dehydration and reduces kidney
CRS type 5 - perfusion. diureric resistance may complicate
with systemic disease like sepsis, DM, and the clinical picture of CRS type 1 by acutely or
SLE chronically increasing the fluid retention. ACEIs
ARBs and aldosterone receptor blockers used
Pathophysiology : for the cardiovascular benefits may affects kid-
ney hemodynamics significantly can cause AKI.
CRS type 1 immune mediated mechanisms like increased
The mechanisms that are affecting kideny func- numbers of pro inflammatory cytokines, higher
rate of apoptosis and monocyte reprogramming
tion in acute heart failure includes altered he- have a pathogenic role in AKI.
modynamics, presence of external factors and

Non-hemodynamic network of pathophysiological interactions in CRS type 1. Note the emerging
potential role of macrophages/monocytes as mediator of sodium and fluid retention. Reproduced
with permission from ADQI.

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Cardio Diabetes Medicine 2018 153

CRS type 2 CRS Type 4 -
Example for CRS type 2 is cyanotic nephropa- Chronic reno cardaic syndrome -
thy, occurring in patients with congenital heart  Chronic kidney disease independently acceler-
disease, heart disease clearly precedes kidney ates ischemic heart disease and contributes to
involvement. Neuro hormonal activation, renal pressure and volume overload, leading to left
hypoperfusion and venous congestion, inflam- ventricular hypertrophy. hyperphospahtemia
maton, atherosclerosis and oidative stress re- and secondary hyperparathyroidism can cause
pressent the most improtant pathophysiologi- ossification of vascular smooth muscle of cardi-
cal mechanisms od Type 2 CRS. these above ac vessels and valves contributes to coronary
mechnisms are operative in recurrent episodes and valvular leisons. volume overload of CKD
of acute heart and kidney decompensation. may exacerbates the congestive cardiac failure
along with underllying anaemia. As GFR de-
CRS Type 3 - patho physiology clines gradual accumulation of Toxins leads to
direct AKI effects on heart function by immune chronic inflammation, insulin resistance, hyper-
modualtion ( circulating TNF aplha, Interleukin homocytenemia and malnutiriton - inflammation
1, Interleukin 6 increase immedialtely after renal induced dyslipidemia which accellerates cardio-
ischemia) increased Symphathetic nervous sys- vascular disease.
tem, RAAS activity and activation of coagulation
cascade.

Pathophysiology of sepsis induced organ dysfunction. It has been focused attention on immunologic

pathways leading to toxic damage on target organs since complement and coagulation cascade

activation and endothelial and epitelial damage.
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Cardio Diabetes Medicine 2018 154

CRS type 5 - brane( CRRT) is beneficial.
pathophysiology depends on the underlying dis-
ease. Acute CRS - 5 results systemic process References
ie sepsis, drugs, toinsand connective tissue dis-
orders such as lupus, wegeners granulomatosis 1. Bongartz LG, Cramer MJ, Doevendans PA,
and sarcoidosis. sepsis induced CRS 5 usual- Joles JA, Braam B. The severe cardiorenal
ly have a fulminant course involving heart and syndrome: ’Guyton revisited’. Eur Heart J.
kidney. acute CRS 5 develops into four following 2005;26:11-17.
patterns, Hyper acute phase ( 0 -72 hrs), acute
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) and Chromic phase ( over 30 days ) . Patho- in congestive heart failure. Cardiology.
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between heart and kidney, sepsis associated
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system, Renin - angiotensin- aldosterone axis treatment of acute and chronic heart failure
and Hypotahlamic pitutatory adrenla axis. 2012: The Task Force for the Diagnosis and
Treatment of Acute and Chronic Heart Failure
Management : 2012 of the European Society of Cardiology.
According to pathipysiological pathways cardi- Developed in collaboration with the Heart
ac dysfunction may occur in any stages of AKI Failure Association(HFA) of the ESC. Eur
or CKD. european society of cardiology, AHA ( Heart J. 2012;33:1787-1847.
American Heart Association) and American col-
lege of Cardiology foundation ( ACCF) guide- 4. Cruz D.N., Schmidt-Ott K.M., Vescovo G.
lines for management of ADHF to be followed. Pathophysiology of cardiorenal syndrome type
intra vascular and extra vascular volume control 2 in stable chronic heart failure: workgroup
should be reached with diuretics and extra cor- statements from the eleventh consensus
poreal volume removing methods. conference of the acute dialysis quality initia-
loop diuretics are the gold standard in ADHF and tive (ADQI) Contrib Nephrol. 2013;182:117–
type 1-3 CRS to reduce the fluid overload and 136. [PubMed]
improve symptoms on the other hand inappro-
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injury during AKI. hence diuretics therapy has weiss S. Repeated hospitalizations predict
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AKI patients not showing any benefits in kidney heart failure. Am Heart J. 2007;154(2):260–
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tember (3)):937–946. [PubMed]

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GET showed the benefits of renal and cardio Tarazi F., Sakura N., Paganini E.P. Isolation
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CRS type 5 , maintaining hemodynamic stability ultrafiltrate of heart failure patients with acute
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the hyper acute phase of CRS type 5. inflam- October (5)):M911–915. [PubMed]

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ment is crucial. removal of cytokines and immu- ber (12)):1140–1153. [PubMed]
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9. Levin A., Singer J., Thompson C.R., Ross H., sepsis-induced acute kidney injury: the role
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opportunities for intervention. Am J Kidney 97. [PubMed]
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of CKD-MBD. Nephrol Dial Transplant. 2011  970. [PubMed]

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03.INVESTIGATIONS

1 Risk Stratification in Asymptomatic Patients with Diabetes: Role of Cardiac CT and Nov-
el Biomarkers-Dr.AvijitLahiri

2 Echo in Heart Failure-Dr.T.Neelambujan

3 Styrain Echo-Dr.Amuthan

4 Where do we stand on HbA1C-Prof.Sam Lingam

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Cardio Diabetes Medicine 2018 157

RISK STRATIFICATION IN ASYMPTOMATIC PATIENTS WITH DIABETES:
ROLE OF CARDIAC CT AND NOVEL BIOMARKERS

Avijit Lahiri, MBBS, FACC MSc, MRCP, FESC
Medical Director

British Cardiac Research Trust, London, United Kingdom

Coronary artery disease (CAD) is the leading (Anand et al, Eur Heart J; (2006) 27, 713–721).
cause of death in patients with diabetes. Patients Fig A shows the relation between increasing
often present with advanced and asymptomatic CAC score and cardiac event rate in asymptom-
disease. Proposed strategies that may favour- atic diabetic patients from the Wellington Diabe-
ably affect CAD risk and outcomes in this patient tes Trial. This study formed the basis of the rec-
population include identifying diabetic patients ommendations of the guidelines for early CAC
with subclinical disease at high risk of future car- imaging in asymptomatic diabetic patients (ACC/
diac events such as early onset of myocardial AHA and ESC Guidelines).
infarction (MI) or sudden cardiac death. CAD
is more aggressive in diabetics and has higher Although the risk of coronary heart disease (CHD)
complication rates than in patients without. They mortality has declined substantially in subjects
are also less likely to have chest pain on stress with type 2 diabetes mellitus (T2DM) during the
testing and thus exertional angina. This leads to last two decades, it still remains two-fold higher
delay in presentation to health service and de- than in subjects without diabetes. Indeed, the de-
layed diagnosis. Occult CAD ranges from 20% to cline in CHD mortality has been essentially par-
≥50% in asymptomatic diabetics. Autopsy find- allel in subjects with and without T2DM suggest-
ings reveal that at least 3/4th of diabetic patients ing that current therapies, such as statins, target
without overt clinical CAD will have significant common disease mechanisms while failing to in-
atherosclerosis. Recently, there has been sub- tervene against T2DM-specific disease mecha-
stantial interest in the use of imaging tests such nisms. Factors promoting atherosclerotic-plaque
as myocardial perfusion scintigraphy (MPS) and vulnerability include inflammation, cellular injury
coronary artery calcium (CAC) imaging to detect and extracellular matrix degradation while acti-
subclinical CAD and improve risk stratification in vation of fibrous repair increases plaque stability.
this population Since T2DM is associated with a state of chron-
ic low-grade inflammation it has been assumed
this is a key factor in the development of mac-
rovascular complications. However, recent find-
ings from studies of plaques removed at carotid
surgery have indicated that plaque vulnerability
in subjects with T2DM is associated with a dis-
turbed balance between tissue injury and repair
rather than with increased plaque inflammation.
To increase understanding of the mechanisms
involved in T2DM mediated CHD, we correlated
the degree of coronary calcification with circu-
lating levels of a panel of biomarkers reflecting
inflammation, cell death, apoptosis, extracellular
matrix degradation as well as endothelial and fi-
brous tissue repair in asymptomatic patients with
T2DM.

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Cardio Diabetes Medicine 2018 158

Procedures for patient enrollment, computed to- but could very well be the result of the pleiotropic

mography coronary artery calcium (CAC) scan- effect of statin treatment (76% of study subjects

ning and baseline clinical characteristics of the were on statins) which also is known to reduce

study cohort have previously been reported. plaque inflammation.

Biomarkers were analyzed at the SciLifeLab in The risk factors that correlated most strongly

Uppsala, Sweden using the Proximity Extension with biomarkers reflecting tissue injury and repair

Assay (http://www.olink.com). Of the 262 patients were low HDL and reduced kidney function. It is

recruited, we excluded 45 study subjects due to an interesting possibility that these factors con-

technical issues related to the biomarker analy- tribute to vascular injury in diabetes and explain

ses and categorized the remaining 217 subjects part of the excess CHD mortality in T2DM. One

into those with no (0 Agatston units (Au)), mild of the biomarkers showing the strongest associ-

to moderate (>0-400 Au) and severe (>400 Au) ation with CAC in our study was osteoprotegerin.

coronary artery calcification (Table). Analyses of Osteoprotegerin is a decoy receptor for the death

correlations between CAC and plasma biomark- receptor ligand TRAIL but it has been found to

ers revealed that presence of severe CHD was protect against vascular calcification. It has also

associated with elevated levels of biomarkers been shown to be elevated in patients with kid-

reflecting apoptotic cell death (soluble Fas, sol- ney disease and to correlate with CAC in T2DM.

uble TRAIL receptor-2 and osteoprotegerin), ex- It is not known if decoy receptors for death re-

tracellular matrix degradation (matrix metallopro- ceptor ligands, such as osteoprotegerin, soluble

teinase (MMP)-3 and -12) and growth factors for Fas and soluble TRAILR-2, have any functional

endothelial cells (hepatocyte growth factor and role in the disease process. However, most likely

placental growth factor), but not with biomarkers they, as well as the endothelial mitogens, have

reflecting inflammation and fibrous tissue repair. protective roles and elevated levels function as

Most associations were weakened by adjusting markers of cellular stress and increased apop-

for the UKPDS risk score, but remained signifi- totic activity.

cant for osteoprotegerin. MMP-12 and placental

growth factor (Table). Most biomarkers reflecting References

apoptotic cell death, extracellular matrix degra- 1.Rawshani A, Rawshani A, Franzen S et al. Mor-
dation and endothelial repair correlated inverse- tality and Cardiovascular Disease in Type 1 and
ly with HDL and estimated glomerular filtration Type 2 Diabetes. N Engl J Med 2017;376:1407-
rate (r between -0.2 and -0.4, p<0.001 gener- 1418.
ally), while no or only weak associations were

found with duration of diabetes, HbA1c, LDL, tri- 2.Nilsson J. Atherosclerotic plaque vulnerability
glycerides and systolic blood pressure. in the statin era. Eur Heart J 2017;38:1638-1644.

These findings demonstrate that CHD severity

in T2DM correlates with markers of tissue injury 3.Edsfeldt A, Goncalves I, Grufman H et al. Im-
and remodeling but not with markers of inflam- paired fibrous repair: a possible contributor to
mation. Although it should be kept in mind these atherosclerotic plaque vulnerability in patients
associations cannot be taken as evidence for with type II diabetes. Arterioscler Thromb Vasc
causality they are well in line with observations Biol 2014;34:2143-50.

made in human atherosclerotic plaques suggest- 4.Jeevarethinam A, Venuraju S, Dumo A et al.
Relationship between carotid atherosclerosis
ing that tissue injury and repair responses largely and coronary artery calcification in asymptom-
unrelated to inflammation are involved in diabetic atic diabetic patients: A prospective multicenter
vasculopathy. The lack of association between study. Clin Cardiol 2017;40:752-758.
inflammation and CAC may appear unexpected

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Cardio Diabetes Medicine 2018 159

5.Venuraju SM, Yerramasu A, Corder R, Lahiri
A. Osteoprotegerin as a predictor of coronary
artery disease and cardiovascular mortality and
morbidity. J Am Coll Cardiol 2010;55:2049-61.

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ECHOCARDIOGRAPHY IN HEART FAILURE

DR.T.NEELAMBUJAN MD.,DNB.,FESC.,FCSI.,FIAE.,FSCAI.,

CONSULTANT CARDIOLOGIST & INTERVENTIONALIST,

SUNDARAM ARULRHAJ HOSPITALS,

THOOTHUKUDI.

Heart failure (HF) affects about 26 million people I. CLASSIFICATION OF HEART FAIL-
worldwide. Ageing population, increasing preva- URE:
lence of cardiac risk factors and improved surviv- Ejection Fraction (EF) is an easily measurable
al of patients with acute cardiovascular diseases
have resulted in HF becoming a major public parameter to assess the cardiac function. Heart
health problem. The prevalence of heart failure failure is classified into 3 different categories
in India is estimated to be around 1.3 to 4.6 mil- based on EF.
lion with annual incidence of about 0.4 to 1.8 mil-
lion new cases. Heart failure presents about a 1. Heart Failure with Reduced EF(HFrEF) –
decade earlier in India and most of the burden is LVEF < 40%
in the population below 65 years. The in-hospital
mortality for HF is also higher in Indian patients 2. Heart Failure with Preserved EF(HFpEF)
with 31% all cause mortality at 1 year. The eval- – LVEF > 50%
uation and management of HF poses significant
burden on health care resources. Clinical exam- 3. Heart Failure with Midrange EF(HFmrEF)
ination, ECG and chest X-ray forms initial part of – LVEF 41 - 50%
evaluation of HF patients and is cost effective to
be implemented on a large scale community ba- Echocardiogram play a vital role in assessment
sis. Echocardiogram is the next critical diagnos- of all the three types of heart failure.
tic tool in patients with suspected heart failure.
Echocardiogram is the basic procedure of choice II. CLINICAL UTILITY OF ECHOCAR-
for HF patients. It is easily available and can be DIOGRAM IN HEART FAILURE:
done at relatively cheaper cost when compared
to other modalities of imaging . Another import- Echocardiogram gives the diagnosis and con-
ant advantage with echocardiogram is that it is firms the etiology also. It provides information
portable and can be done in intensive care units regarding the structure and function of myocar-
on critically sick patients. In view of attenuation dium. It can assess the severity of valvular prob-
of clinical skills echocardiogram is an alternative lems when it is involved. It provides important
to clinical examination. information regarding cardiac haemodynamics
which are essential in the management of HF.
It can differentiate a scar or viable myocardium.
Echocardiogram also helps to assess the sever-
ity of heart failure and helps in prognostication.
It also helps in deciding for newer treatment mo-
dalities like cardiac resynchronization therapy-
(CRT)

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III. METHODS FOR ASSESING LV SYS- 2.MAPSE (Mitral Annular Plane) Sys-

TOLIC FUNCTION tolic Excursion:
i. M-MODE:
It estimates the left atrioventricular plane dis-
• EPSS – Mitral septal distance placement. Normal values are > 13 mm in
males and > 11 mm in females. It is easily
• MAPSE – Systolic excursion of mitral obtained even with poor acoustic window as the
annulus mitral annulus is an echogenic structure.
MAPSE derived EF=4.8 x MAPSE (in mm)
• LVFS – Changes of short axis dimension. +5.8.
MAPSE correlates reasonably with biplane
ii. Two dimensional Echocardio- Simpsons method. An average MAPSE < 5 mm
gram
predicted LVEF <30%

• LVFAC – LV Fractional area change 3.LVFAC (LV Fractional Area changes)
• LVEF – LV Volume change
It is the difference of LV short axis dia-
stolic and systolic area.

• Visual – LV area change & wall thicken- LVFAC = LVEDA – LVESA x 100 %
ing. _______________

iii. Doppler : LV EDA

Normal value is > 35%

• MPI- Myocardial performance Index < 15% indicates a severe LV systolic dysfunc-
measures the global function. tion

• Mitral dp/dt – Assesses the Mitral Regur- 4.Visual Eyeballing Method :
gitation pressure gradient rise.
It is done by experienced echocardiographers
and correlates with other quantitative methods

iv. Newer technologies: with inter observer variability of 2-3%. Individual
segment should be assessed for systolic thick-
• Speckle Tracking or strain imaging ening and inward motion.

• 3D Echocardiogram 5.Modified Simpsons Method :
• Myocardial contrast Echocardiogram.
This is the most commonly used method to
calculate the EF using the LV volume measure-

1.EPSS- ‘E’ Point septal separation : ment. Ejection Fraction is the fraction of End

It is an indirect estimation of global systolic diastolic volume (EDV) ejected with each beat.
function. It is a simple and rapid method and EF = LVEDV – LVESV x 100 %
not dependent on image quality. Normal value
should be below 7 mm. _______________

LV EDV

End diastolic volume(EDV) is the volume of

blood remaining in LV just before a contraction.

It is normally about 67 – 155 ml.

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End systolic volume(ESV) is the volume of It depends on a measurable MR jet. The dp/dt
blood remaining in LV at the end of systole and is a measure of LV contactivity in the isovolumic
normal ESV is around 22 – 58 ml. contraction phase. In LV dysfunction the pres-
Ejection Fraction (EF) is dependent on after- sure difference between LV and LA decreases
load, preload, Heart rate and contractility. and hence the rate of MR Jet velocity decreas-
es.
6. Myocardial Performance Index (Tei
index): Normal dp/dt > 1200 mmHg/sec
Mild LV systolic dysfunction : 800 – 1200
It is a Doppler based index. It gives useful in- mmHg/sec
formation about global ventricular systolic and Severe LV systolic dysfunction : <800
diastolic performance. It requires three inter- mmHg/sec
vals of Isovolumic contraction time, Isovolumic
relaxation time and Ejection time for calculation IV.ASSESSMENT OF LV DIASTOLIC
of MPI. The normal value of MPI is 0.39 +0.05. FUNCTION:
MPI maintains an inverse relationship with EF.
An MPI > 0.60 indentifies high risk patients and Assessment of LV diastolic function
is a useful prognostic marker in HF. involves:

7. Mitral Regurgitation dp/dt: i. Pulse wave Doppler sampling between
the tips of Anterior mitral leaflet and pos-
terior mitral leaflet.

ii. Tissue Doppler from septal and lateral
mitral annulus.

iii. Pulse Doppler velocity of pulmonary vein
iv. Left atrial volume measurement
v. Assessment of Pulmonary Hypertension.

Parameter Normal Grade I Grade II Grade III
Mitral E/A > 0.8 < 0.8 >0.8 - < 0.2 > 0.2
Average E/e 1 < 10 < 10 10 – 14 >14
< 2.8 >2.8 >2.8
Peak TR Velocity m/sec < 2.8

LA Volume index < 34 ml/m2 Normal or in- > 34 ml/m2 > 34 ml/m2
creased

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V. ASSESSMENT OF RA PRESSURE GLS above – 16 indicates LV systolic dysfunc-
/ RV FUNCTION & PULMONARY HY- tion.
PERTENSION:
VIII. CONTRAST ECHOCARDIOGRA-
• Pulmonary artery systolic pressure, pul- PHY
monary artery diastolic pressure and
mean PA pressure can be calculated us- It delineates the endocardium and facilitates
ing a tricuspid and pulmonary regurgita- more accurate assessment of LV volume and
tion jet. EF. It is very useful in identification of thrombus,
aneurysm, noncompaction and apical HCM.
• RA pressure can be assessed using IVC
dimension and its change during inspira- IX.STRESS ECHOCARDIOGRAPHY :
tion.
It is useful to identify viable myocardium in pa-
• TAPSE (Tricuspid Annular Plane Sys- tients with LV dysfunction and plan for definitive
tolic Excursion) tells about RV function. revascularization . A biphasic response indicates
TAPSE >15 mm is normal. TAPSE 13 – viable myocardium.
15 mm is mildly abnormal. TAPSE 10 -12
mm is moderately abnormal and TAPSE X . SELECTION OF PATIENT FOR CRT :
< 10 mm indicates severely abnormal RV
function.

VI. ASSESSMENT OF LA VOLUME : Echocardiogram helps in selection of patient for
CRT. A LVEF < 35% is the cutoff for recommend-
Increased LA volume is a marker of long term ing CRT.
increased filling pressures. It is a valuable prog- TDI (Tissue Doppler Imaging) helps to assess
nostic marker of mortality. It also helps to pre- the longitudinal dyssynchrony by measuring the
dict the onset of atrial fibrillation and stroke. It is time delay between peak systolic velocity of sep-
measured by modified Simpsons method. Nor- tal & lateral wall, anterior & inferior wall and an-
mal value is 34 ml/M2. teroseptal & posterior wall.

VII. SPECKLE TRACKING ECHOCAR- KEY POINTS :

DIOGRAPHY :

• Echocardiogram is a readily available modal-

Assessment of global longitudinal strain (GLS) ity of investigation in HF.

by speckle tracking is useful in preclinical as- • Echocardiogram confirm the diagnosis of HF

sessment of HF. Reduced GLS indicates sub- and also gives etiological diagnosis.

clinical LV dysfunction in HFpEF. A decrease of • Haemodynamic parameters guide in the

GLS by 25% indentifies subclinical LV dysfunc- treatment of heart failure.

tion after chemotherapy. It is useful for identifi- • Global longitudinal strain assessment helps

cation of structural abnormalities in patients with in preclinical early diagnosis of HF.

stage A heart failure with multiple risk factor for • Stress Echocardiography helps to indentify

HF thereby helps in early diagnosis of HF. viable myocardium for revascularization.

Normal GLS value : - 18 to – 22% • TDI helps to pick up the responders for cardi-

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REFERENCES

1. Textbook of Echocardiography. An official
publication of Indian Academy of Echocardi-
ography – V.Amuthan – Satish K Parashar.

2. CSI position statement on management of
heart failure in India. Indian Heart Journal.
Volume 70, Supplement 1, July 2018.

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STRAIN ECHOCARDIOGRAPHY IN THE EVALUATION OF
CORONARY

ARTERY DISEASE FOR THE PHYSICIANS

Prof. Dr. V. Amuthan. MD DM FACC FESC FCSI FIAE

President, Indian Academy of Echocardiography
Emeritus Professor of Cardiology

The Tamil Nadu Dr. MGR Medical University,
&

Dr. R.V.A. Ananth MBBS PGDCC
Consultant Cardiologist

Jeyalakshmi Heart Centre,
Madurai

Echocardiography remains one of the marvels ventricular segments should be labelled as ante-
of twenty first Centaury and is one of the most ro septal, infero septal, inferior, inferolateral, an-
important tools in the evaluation of Coronary Ar- terolateral, and anterior. The apex is divided into
tery Disease. The 2011 appropriate use criteria five segments, including septal, inferior, lateral,
for echocardiography classified use of echocar- and anterior segments, as well as the ‘‘apical
diography in the diagnosis of suspected MI as cap,’’ which is defined as the myocardium beyond
appropriate. We shall review the role of Echo- the end of the LV cavity. A Bulls eye plot can be
cardiography in the diagnosis and prognosis of constructed where the outer ring represents the
Coronary artery disease with special reference basal segments, the middle ring represents the
to Strain by speckle tracking Echocardiography. segments at mid papillary muscle level, and the
inner ring represents the distal level. The ante-
Regional wall motion analysis in Coro- rior insertion of the right ventricular wall into the
nary Artery Disease left ventricle defines the border between the an-
tero septal and anterior segments. Starting from
Echocardiographic evidence of regional wall mo- this point, the myocardium is subdivided into six
tion abnormalities occurs prior to ECG changes equal segments of 60o . The apical myocardium
and can occur within seconds of Coronary arteri- in the 17-segment models is divided instead into
al occlusion – as early as 12.5 seconds in studies four equal segments of 90o . In the 17-segment
reported.There are a number of other causes of model an additional segment (apical cap) is add-
RWMAs, including a prior infarction, focal myo- ed in the centre of the bull’s-eye. However, this
carditis, prior surgery, left bundle branch block, methodology depended considerably on the ex-
ventricular preexcitation via an accessory path- pertise of the interpreter and showed relatively
way, and cardiomyopathy. In the Emergency de- low inter observer agreement. For this purpose,
partment, routine eyeballing usually picks up the myocardial strain (i.e., the relative lengthening or
presence of regional wall motion abnormality and shortening of the myocardial segment expressed
the territories involved. The American Society of as a percentage of its initial length) and strain
Echocardiography has recently recommended a rate (i.e., the rate of this lengthening or shorten-
17-segment model for this. (Fig 1 A) In a 17-seg- ing) imaging was introduced.
ment model, beginning at the anterior junction of
the inter ventricular septum and the RV free wall
and continuing counter clockwise, basal and mid

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Strain Imaging in localization and de- Speckle Tracking Echocardiography. Consensus
cision making in Coronary Artery Dis- document published by the EACVI/ASE/ Indus-
ease try Task Force to Standardize Deformation Imag-
ing is the latest one. In patients with acute myo-
Regional strain is a dimensionless measure- cardial infarctions, accuracy for the prediction of
ment of deformation, expressed as a fractional global functional improvement as well as LV re-
or percentage change from an object’s original modelling by 2D STE is comparable with that of
dimension. The LV myocardium consists of cir- late gadolinium enhancement Cardiac Magnetic
cumferential fibres in the sub epicardial layer Resonance imaging. The prediction of segmen-
and longitudinal fibres in the sub endocardial tal functional improvement is non-inferior using
and epicardial layers, and myofibril orientation myocardial deformation analysis by 2D STE
changes continuously from right-handed helix in compared with of late gadolinium enhancement
subendocardium to left-handed helix in subepi- CMR in patients with ST Elevation Myocardial
cardium. LV function is determined by the sum Infarctions(STEMI) . Figures 4 and 5 are from a
of contraction and relaxation in these 3 layers. patient with Anterior wall STEMI before and after
(Fig 2). Speckle-tracking echocardiography percutaneous intervention with deployment of a
(STE) is a novel technique which has emerged Drug Eluting Stent in Left Anterior Descending
as one of the best method that analyses motion Artery. Figure 6 is from a patient with Inferior wall
and strain by tracking natural acoustic reflections STEMI with triple vessel disease and totally cut
and interference patterns within an ultrasonic off right coronary artery. Based on the physiolog-
window. The imageprocessing algorithm tracks ical information from the strain based automated
user-defined regions of interest which are com- functional imaging, intervention was done in right
prised of blocks of approximately 20 to 40 pix- coronary artery only. Prognostication in Myocar-
els containing stable patterns that are described dial Infarction:
as “speckles”, “markers”, “patterns”, “features”,
or “fingerprints”. Figure 3 illustrates an example LV Ejection fraction:
of speckle tracking echocardiography. The 2D
echocardiography derived longitudinal strain is The cornerstone of the prognostication and
analysed using propriety software in Quad view treatment schedule for STEMI Echocardiograph-
and Bull’s eye plot or the Automated Functional ic evaluation starts with evaluation of left ven-
imaging. The ease with which we derive informa- tricular ejection fraction. Despite its limitations,
tion similar to nuclear scans is really amazing. ejection fraction has become part of the lingua
However, this wonderful technique is hampered franca of cardiology.The evidence base for mod-
by inter vender non agreement and the differ- ern cardiology is so heavily based on this simple
ence in reports done on different equipment. measurement that it is unlikely to disappear. The
There are many efforts to correct this by publica problems in calculating EF as the ratio between
tion of definitions for a Common Standard for 2D stroke volume and end-diastolic volume and
their solutions are enumerated in Table 1.

Problem Circumstances of Inaccuracy Potential Solution

Geometry Dependence LBBB Extensive Wall Motion 3D Imaging GLS ( Global Longitudinal
abnormality strain)

Load Dependence Extremes of afterload Mitral Pressure volume loops Pre Ejection
Regurgitation markers

High and low HR Heart blocks, Tachycardias (Es- None
pecially Atrial Fibrillation)

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Fig 1 : Standardized myocardial segmentation and
nomenclature for tomographic imaging of the heart.

A. Showing Apical 3 Chamber, 2 Chamber and 3. Apical 3 chamber view
4 Chamber views and current ASE A1 to A3 Apical Tomographic cuts from the
nomenclature apex towards Mid LV
B. Showing Short Axis at Basal, Mid LV level M1 to M3 Tomographic Mid LV cuts from apex
nomenclature to Basal level
C. Showing Short Axis at Apical level nomen- B1 to B3 Tomographic Basal LV cuts
clature The top and Bottom starting points of the trans-
D. Showing 3D Derived Tomographic slices : verse short axis slices can be
1. Apical 4 Chamber view adjusted
2. Apical 2 Chamber view and

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Fig. 2. A: Strain = % Change in Length

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Fig 3: Quad view and Automated Functional Imaging ( AFI)

A: Tracked apical three chamber loop with col- color and +20 given blue color)
or coding of the 6 myocardial segments. ( BIL D: M mode representation of peak systolic
- Basal Infero lateral, MIL – Mid Infero lateral, AL strain. Myocardial segments are colour cod-
– Apical lateral, AS – Apical Septal, MAS – Mid ed, strain color scale same as in C.
Anterior Septum, BAS – Basal Anterior Septum) E: Automated Functional Imaging ( Polar
B: Average segmental strain graphically dis- Map or Bulls Eye Plot ) From the same pa-
placed. Each color line corresponds to the same tient and a
color coded myocardial segment F: Comparison figure showing all the 17
. C: Color display of peak systolic strain. Color segments recommended by American So-
scale shown on the right corner. ( -20% given red ciety of Echocardiography. Color Scale
shown in C is used

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Fig 4: Bull’s eye map demonstrating infarct localization in a 42 year male with
Anterior wall STEMI.

Peak systolic images recorded from Left Anterior Descending Artery
A. Apical 4 Chamber view
E. 3D Tomographic 12 segmental views cuts
B. Apical 2 Chamber view mentioned in Fig 2, frozen in peak systole
clearly reduced systolic thickness in seg-
C. Apical 3 Chamber view ments supplied by LAD.

D. AFI map showing the area of decreased strain F. Left Coronary angiogram showing Total
in Anterior septum and Anterior wall at basal and cut off of LAD immediately after origin
Mid LV level and the LV apex with strain value
marked in each segment localizing the infarct to G. Normal Right Coronary Angiogram

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Fig 5: Same patient with Anterior wall STEMI after Revascularization

A. In Two Dimensional apical four chamber, two C. Showing the deployment of a drug
chamber and long axis views with Longitudinal eluting stent in LAD with final result
peak systolic Strain derived Automated Func- showing TIMI 3 Flow
tional Imaging clearly showing better strain pa-
rameters.

B. 3D Derived 12 segment Tomographic slices
during peak systole, showing improved systolic
thickening in segment supplied by LAD

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Fig 6: Bull’s eye map demonstrating infarct localization in a 62 year female
with Inferior wall STEMI.

A. Peak systolic images recorded from Apical 4 segments supplied by RCA.
Chamber 2 Chamber and 3 chamber view with
AFI map showing the area of decreased strain C. Right Coronary angiogram showing Total
in Inferior septum and Inferior wall at basal and cut off of RCA immediately after origin. Left
Mid LV level and the LV apex with strain value Coronary Angiogram showing discrete lesions
markedly rin educed in each segment localizing in Left Anterior Descending Artery and Ramus
the infarct in Right Coronary Artery territory

B. 3D Tomographic 12 segmental view with
slices mentioned in Fig 2, frozen in peak systo-
le, clearly showing reduced systolic thickness in

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Prognostication in Myocardial Infarction:

Fig 7: Comparison of 3D Multiplane Echocardiographic recordings in this patient with LAD In
Stent Restenosis (A) with Coronary Angiogram in LAO projection (B) with Longitudinal strainpolar

( AFI) map (C) and Radionuclide perfusion imaging ( D)

Prognostication in Myocardial Infarc- 3D imaging is available with echocardiogra-
tion: LV Ejection fraction: phy, MRI and CT. The main attraction and ad-
vantage of 3D imaging is to avoid geometric
The cornerstone of the prognostication and assumptions when calculations of LV volumes
treatment schedule for STEMI Echocardio- are being obtained, and to avoid errors cre-
graphic evaluation starts with evaluation of left ated by cutting a 3D structure in two dimen-
ventricular ejection fraction. Despite its limita- sions. The current software for 3D evaluation
tions, ejection fraction has become part of the of LVEF is much easier and can be performed
lingua franca of cardiology.The evidence base within minutes in the setting of emergency
for modern cardiology is so heavily based on room. The sphericity index derived from 3D
this simple measurement that it is unlikely to echocardiography (LVEDV divided by the vol-
disappear. The problems in calculating EF as ume of a sphere whose diameter is the LV
the ratio between stroke volume and end-dia- end-diastolic long axis) is an added by product
stolic volume and their solutions are enumerat- and is the best predictor for LV dilatation
ed in Table 2.

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Global Longitudinal strain (GLS): in assessing LV architecture and torsional
dynamics are Heart Failure with Preserved
Global longitudinal strain (GLS) has evolved as Ejection Fraction (HFPEF) and Cardiac Resyn-
one of the most robust parameter, and this has chronisation therapy. So far, only the assess-
been shown to identify subclinical LV dysfunc- ment of global longitudinal strain (GLS) by echo-
tion. GLS is calculated using a variety of propri- cardiography is recommended in the guidelines
etary software (EchoPAC, GE Medical Systems, on hypertrophic cardiomyopathy and patients
Milwaukee, Wisconsin, USA; Syngo velocity assessed for cardiotoxicity of chemotherapy .
vector imaging, Siemens, Mountain View,
California, USA; LV analysis, TomTec GmbH, References
Unterschlessheim, Germany). GLS is well
validated as a marker for the measurement of LV 1. American College of Cardiology Foundation
longitudinal deformation, which has emerged as Appropriate Use Criteria Task Force, American
a sensitive and specific marker to detect early Society of Echocardiography, American Heart
and subtle myocardial dysfunction. In one of the Association, American Society of Nuclear Car-
recent metaanalysis, Kalam et al, have shown diology, Heart Failure Society of America, Heart
the independent prognostic significance of GLS Rhythm Society, Society for Cardiovascular An-
in patients with mild LV global impairment. The giography and Interventions, Society of Critical
prognostic value of this information seems likely Care Medicine, Society of Cardiovascular Com-
to be superior to that provided by LVEF. Left ven- puted Tomography, Society for Cardiovascular
tricular GLS before discharge after ST-segment– Magnetic Resonance, Douglas PS, Garcia MJ,
elevation myocardial Haines DE, Lai WW, Manning WJ, Patel AR,
infarction is independently associated with LV dil- Picard MH, Polk DM, Ragosta M, Ward RP,
atation at follow-up. In another study of five-hun- Weiner RB. J Am Coll Cardiol. 2011;57(9):1126.
dred seventysix patients who underwent echo-
cardiography ≤24 hours after primary 2. Noninvasive evaluation of ischaemic heart
percutaneous coronary intervention for STEMI, disease: myocardial perfusion imaging or stress
GLS and Wall motion score index (WMSI) were echocardiography? A.F.L Schinkel, J.J Bax, M.L
comparable and both superior for early risk Geleijnse, E Boersma, A Elhendy, J.R.T.C Ro-
assessment compared with volume-based left elandt, D Poldermans European Heart Journal
ventricular function indicators such as LVEF and May 2003, 24 (9) 789- 800;
ESVI. Compared with WMSI, the advantage of
GLS is the provision of a semi-automated quan- 3. Regional myocardial dysfunction during coro-
titative measure. nary angioplasty: evaluation by two-dimensional
echocardiography and 12 lead electrocardiogra-
Conclusion: phy. Wohlgelernter D, Cleman M, Highman HA,
Fetterman RC, Duncan JS, Zaret BL, Jaffe CC. J
Significant progress has been achieved with the Am Coll Cardiol. 1986;7(6):1245.
use of this technology, but in terms of user confi-
dence regarding uniformity and its ability to pro- 4. Schiller NB, Shah PM, Crawford M, DeMaria
vide meaningful, consistent results, strain has A, Devereux R, Feigenbaum H, Gutgesell H,
not yet been fully accepted into the clinician’s Reichek N, Sahn D, Schnittger. I. Recommen-
armamentarium. Basic challenges, including dations for quantitation of the left ventricle by
image quality, persist, as do variances between two-dimensional echocardiography. American
the different devices that are currently available . Society of Echocardiography Committee on
3D Speckle tracking has improved the accuracy Standards, Subcommittee on Quantitation of
of Left ventricular deformation imaging and tor- Two-Dimensional Echocardiograms. J Am Soc
sion dynamics. Although to date, no Echocardiogr 1989;2:358-367.
prognostic information exists on the role of
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Avi, Jonathan Afilalo, Anderson Armstrong, Lau- fining left ventricular apex-tobase twist mechan-
ra Ernande, Frank A. Flachskampf, Elyse Foster, ics computed from high-resolution 3D echocar-
et al. Recommendations for Cardiac Chamber diography: validation against sonomicrometry.
Quantification by Echocardiography in Adults: JACC Cardiovasc Imaging 2010;3:227–34.
An Update from the American Society of Echo- 13. Thomas H Marwick. Methods used for the
cardiography and the European Association of assessment of LV systolic function: common cur-
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6. Harvey Feigenbaum. Echocardiographic 14. Mannaerts HF, van der Heide JA, Kamp O,
Chamber Quantification in the Era of Multimo- et al. Early identification of left ventricular remod-
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8. Voigt JU, Pedrizzetti G, Lysyansky P, Marwick
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THE USE OF HBA1C IN CLINICAL MEDICINE

Prof.Sam Lingam, MD(Hons), FRCPCH, FRCP, DCH,DRCOG
Prof. Medical Education, International Board of Medicine & Surgery(IBMS)

Director of the Golbal Medical School Initiative

Health screening (health check) is popular and
are advisable for every one over 40 years or
so. In the UK it is a seven points screening pro-
gramme.

An outcome of the screening is detection of some
medical conditions early. This will allow us to put
measures to prevent it getting worse. In some
cases early detection can help in reversing the
condition or reducing the risks. Health screening
is a secondary prevention programme.
In spite of many criticisms, health screening has
wide support. It is available in the UK in the NHS
(NHS Health Checks) and many private clinics
offer screening packages.

Screening is carried out, among others, to detect
diabetes and heart problems. Most health check
checks offer ECG, BP(various methods), choles-
terol profile, uric acid and thyroid functions, and
tests for kidney functions, anemia and iron lev-
els. And to detect diabetes health screening tra-
ditionally relied on fasting blood glucose. Now
in addition HBA1c test is also included.It is now
well accepted that HBA1c is the most reliable
marker to check for control of diabetes type 1
and type 2.In this presentation I hope to discuss
the role of HBA1c in clinical practice.

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04. THERAPEUTIC OPTIONS

1 Differences in Outcome after Revascularisation between NITDM & ITDM Patients -
Dr.RamasamiNandakumar

2 Improving CV outcomes in diabetes with new antidiabetic medications: Dawn of a new
era-Dr.PCManoria

3 SGLT2: renal cardiovascular pathophysiology-Dr.LuigiGnud

4 Role of Nerve Growth Factor in Diabetic Neuropathy-Dr.DinaNagodra

ARNI: A paradigm shift in diabetics with heart failure-Dr.Neelambujan
5

6 Heart Failure Management in 2018-Prof.Amal Kumar Baneerjee

7 Metabolic Surgery Vs Medical Therapy-Dr. Anil Bhoraskar

8 Heart & Lung Transplant-Dr.T.Sunde

9 New world of NOACs-Prof.Jamshed Dalal

10 Anticoagulant choice in Non valvular AF-Dr.Nihar Mehta

11 Anticoagulant choice in valvular AF-Dr.Amal Kumar Baneerjee

12 What is new treatment for Diabetic Nephropathy-Dr.LuigiGnudi

13 Diabetic Therapy in DKD-Dr.Ram Prasad

14 Aspirin Resistance-Dr.VKGoyal

15 EPS & RF ablation in Diabetic Cardiac Dysrrhythmia-Dr.UlhasPandhurangi

16 Evidence based nutrition priorities in the Mx of NCD-Dr.Jagmeet Madan

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DIFFERENCES IN OUTCOME AFTER REVASCULARISA-
TION BETWEEN INSULIN-TREATED DIABETES MELLITUS
PATIENTS (ITDM) AND NON INSULIN TREATED DIABETES

MELLITUS (NITDM) PATIENTS.

Dr Ramasami Nandakumar,MRCP(UK),FRCP(EDIN),FRCP(London)

Senior interventional cardiologist

The epidemic of cardiovascular disease (11). The atherosclerosis is diffuse and rapidly
and diabetes are both emerging as one of the progressive especially as the smaller EEM di-
main threats to human health in this new century. mensions might exaggerate vascular injury and
Cardiovascular mortality is the leading cause of hence an aggressive proliferative response.
death globally accounting for 31% of all deaths The pro-thrombotic milieu of Diabetes Mellitus
globally ice 17.7 million deaths annually with 7.4 also increases the risk of adverse events with
million due to coronary heart disease and 6.7 increased blood viscosity, decrease in activity
million due to stroke and three-fourths of these of anti-thrombin 2, fibrinogen and factor 8 with
deaths occur in low and middle income coun- enhanced platelet aggregation may also play a
tries. Most cardiovascular disease are caused role. In patients with established CHD, revascu-
by a coalescence of behavioral risk factors and larisation, therefore tends to favor patients with-
increasing prevalence of cardiovascular risk fac- out T2DM.
tors diabetes and hypertension. Several earlier studies have shown that short
Of the many risk factors diabetes has a unique and long term MACEs and mortality were
association with coronary heart disease (CHD). significantly higher in patients with DM compared
We know from 20 years of followup of the Fram- to non-DM patients after PCI(Percutaneous
ingham cohort that those with diabetes have intervention i.e. coronary angioplasty). and even
a two to three fold risk of developing coronary in the contemporary era, DM continues to be
disease than in those without and cardiovascu- a significant predictor of adverse events after
lar mortality was similar between women and PCI. This increase in cardiovascular events
men with diabetes.Stroke, myocardial infarction, predominantly appears to be linked to repeat
sudden death and angina pectoris are twice as revacularisation either of the target lesion or
common as in non-diabetic individuals. and car- target vessel. However, amongst DM patients
diovascular cause is the major cause of mortality both short and long-term adverse outcomes after
(65 to 70%) in diabetic patients. revascularisation (PCI or CABG) are higher in
In short, evidence over time points to diabetes Insulin treated DM(ITDM) patients than in those
behaving as a coronary heart disease equiva- that are not. Berenguer et al have shown that
lent” especially when present for longer than 10 late loss and restenosis with target vessel failure
years. . It appears however that hyperglycaemia were more frequent in the ITDM group after DES
alone is not sufficient to explain the link between implant.
increased prevalence of CHD in diabetes. In fact,
individuals with pre-diabetes already appear to The reasons are multifactorial i.e due to more
have a higher risk of CHD and diabetes duration underlying aggressive disease in ITDM patients,
is also associated with coronary disease pro- more insulin resistance, and the fact that insulin
gression and cardiovascular events. treated patients may have a much longer duration
Coronary atherosclerosis in DM manifests as of the disease as insulin treatment is initiated at
generally smaller vessels with diffuse involve- a much advanced stage.
ment, involves multiple vessels and longer
segments and has more negative remodeling ITDM patients also have higher co-morbidities
such as congestive heart failure, stoke, hyper-

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tension, congestive heart failure and acute cor- tion following PCI with increased risk of resteno-
onary syndrome. Studies also show that ITDM sis, target vessel failure and adverse events.
patients have higher BMI, higher HbA1C levels In addition in ITDM patients, exogenous insu-
and blood urea nitrogen(BUN) than in NITDM lin promotes pro-inflammatory macrophage re-
patients. sponse, accelerates atherogenic response (23)
Insulin has important vascular actions to stimu- and is associated with increased platelet aggre-
late nitric oxide production from endothelium and gation thrombogenesis and impaired fibrinoly-
insulin resistance with endothelial dysfunction sis.
maybe the unifying factor that plays a common
role in hypertension, coronary heart disease and Outcomes after PCI in NIDDM and
atherosclerosis. Iatrogenic hyperinsulinemia can ITDM:
induce pro-inflammatory macrophage response
through release of pre-inflammatory mediators Tada et al evaluating the 3 year outcome in DM
such as Tumour necrosis factor and interleukin patients implanted with DES(SES) in the J-Cy-
1, stimulate hormonal over-activation of signal pher registry found an excessive risk of cardio-
transduction pathways affecting progression of vascular event, (death, myocardial infarction or
atherogenesis and disrupt the synthesis and re- stroke) only in the ITDM patients with an excess
lease of endothelial mediators. Serum levels of risk of Target vessel revascularisation(TVR) in
insulin, proinsulin, and insulin antibodies have both ITDM and NITDM patients. Akin et al, com-
been shown to be related to the risk of coronary paring SES (Sirolimus eluting stents) and PES
heart disease in patients with type 2 DM. (Paclitaxel eluting stents) in DM patients from
The actions of insulin on cellular growth and pro- the GERMAN DES(DES.DE) registry found that
liferation are mediated by the PI3K (Phosphatidyl adverse cardiac events were more likely in the
inositol 3-kinase) and (MAPK) mitogen activated ITDM patients.
protein-kinase pathway. The PI3K pathways are
usually hyper activated in the diabetic patient Outcomes after primary PCI in NIDDM
but in severe insulin resistance the MAPK path- and ITDM:
way becomes predominant with down regulation
of the PI3K pathway. IR causes imbalance be- Hoebers et al in 2014 compared otcomes be-
tween PI3K and MAPK pathways . tween non-DM, ITDM and NITDM patients ad-
mitted with myocardial infarction and treated with
Hyperinsulinemia causes up regulation of plas- primary PCI between 1997 to 2007 and found that
minogen activator inhibitor type 1(PAI-1) and ITDM patients had a significantly higher 5 year
increased expression of pro-atherogenic mole- mortality (36% vs 25%, p=0.01). ITDM emerged
cules such as vascular cell adhesion molecule-1 as a strong independent predictor of mortality
(VCAM-1) and E-selectin There is increased se- when compared to the two other groups. (27)
cretion of Endothelin-I(ET-1) and enhanced ET-1
activity with increased vascular tone . Hyperin- A more contemporary analysis on data collect-
sulinemia can also induce insulin resistance(IR) ed between 2008 and 2011 from 9224 patients
with impairment of signaling via PI3K pathways from a regional tertiary centre revealed that even
and excessive stimulation through MAPK depen- in this cohort with current aggressive risk factor
dent pathways with release of mediators oppos- control and newer anti platelet therapy, ITDM
ing Nitric oxide(NO) function and relative loss of patients had higher long-term mortality (4.7%
NO bioactivity and endothelial dysfunction and in NDM vs 6.8% in NITDM vs 12.7% in ITDM,
reduced endothelial NO production in response p<0.0001). (28) Therefore it does appear that
to insulin. following PCI in myocardial infarction (Primary
Vascular smooth cells are sensitive to the growth PCI) ITDM patients do have a much worse out-
stimulatory actions of insulin and insulin like come as compared to NITDM patients. This also
growth factors and might result in accelerated appears to hold true for NTSEMI patients as can
smooth cell proliferation, migration and activa- been seen in this figure reproduced from the
study by Noman et al.

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Thirty-day mortality rates. (a) Crude 30-day mortality rates in different diabetes groups (non-
diabetes mellitus [non-DM], non-insulin treated DM [NITDM] and insulin treated DM [ITDM])
following percutaneous coronary intervention (PCI) in different settings; (b) unadjusted and
adjusted odds ratios for 30-day mortality in NITDM and ITDM groups compared with non-DM
group. (a) Thirty-day mortality rates. (b) Odds ratios for 30-day mortality.(Noman et al, 28)

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Cardio Diabetes Medicine 2018 181

An interesting observation from both the above the PCI landscape for all-comers. Earlier studies
analyses is that with contemporary aggressive appeared to show equivalent or worse outcomes
risk factor control, NITDM patients well con- with limus drugs particularly for diabetic patients.
trolled on diet or oral hypoglycemics had similar (34,35,36) This is of interest in the context of
mortality to NDM patients following PCI after ad- sirolimus inhibiting the m-TOR protein which is
justment for differences in co-founders. modulated by the PI3K pathway which is hyper
Daemen et al in 2006 looked at 2 year outcome activated in diabetic patients. In severe insulin re-
in 708 consecutive real world patients(25% sistance however(ITDM) the biological effects of
were ITDM) as part of the RESEARCH and sirolimus could be attenuated when the MAPK is
T-SEARCH registries found that the cumulative unregulated. Paclitaxel , inhibits signalling down-
incidence of mortality was significantly higher stream independent of insulin resistance and
in IDDM patients (16.7%) compared with the this hypohtesis was tested in the earlier trials.
NIDDM patients (9.6%); (P = 0.013).(29) though Ong & Serruys et al, however, in a paper in 2005
TVR rates were comparable between the two showed no difference in adjusted outcomes be-
groups. tween ITDM and NITDM patients who received
Outcomes after CTO- PCI in NIDDM and ITDM: either sirolimus eluting stents or paclitaxel elut-
Claessen in 2011 showed that patients with in- ing stents at one year (37). A meta-analysis by
sulin treated DM(ITDM) had an increased risk of Bangalore et al in 2012 however, found limus
longer term mortality compared to patients with drugs to be safe in diabetic patients and subse-
non-insulin treated DM(NITDM) after PCI even in quently the “TUXEDO trial” demonstrated that
patients with chronic total occlusions(CTO) (30). limus drugs were indeed superior to paclitaxel in
DM patients, including ITDM patients. (38)
A large meta-analysis incorporating data from 21
studies(12 observational studies) with an aggre- Stent thrombosis also appears to be more
gate of 21,759 patients by Bundhun et al in 2015 frequent in ITDM patients especially early stent
found both short term and longterm(> one year), thrombosis(i.e <30 days (OR 1.81, 95% CI 1.04-
adverse outcomes were significantly higher in 3.15; p=0.04). However the meta-analysis by
the PCI treated ITDM patients (31). Chen et al (39) was not able to demonstrate
However there were other studies which con- this in late or very late thrombosis. These
tradicted these findings. In 2004 Mathew et al results were mirrored by the E FIVE registry
in a retrospective analysis of 1104 DM patients which showed early stent thrombosis in 1.6% in
who underwent PCI between 1996 to 2001 did ITDM vs 1% in NITDM patients (40). SPIRIT IV
not find that ITDM patients had a worse outcome however showed early stent thrombosis in 0.48%
after adjusting for differences in baseline charac- of Everolimus-eluting stents(EES) and 0.85% of
teristics {odds ratio 1.10, 95% confidence inter- Paclitaxel eluting stents in ITDM patients and
vals 0.77 to 1.58} (32). Kirtane et al in 2008 did the corresponding numbers in NITDM patients
not find any difference either with similar rates were 0.35% with EES and 0.36% with PES.
between DES and BMS treated patients irre- Interestingly ITDM patients had no late stent
spective of the diabetes therapy. Similarly in the thrombosis whereas for NITDM patients it varied
TUXEDO trial, Bangalore et al, comparing 747 between 0.18% to 0.76% (41). The Cypher
ITDM treated patients versus the 1083 NITDM J-PMS Registry showed no difference in early
patients, found that the significantly increased or late stent thrombosis in either group however.
risk of cardiovascular events in unadjusted mod- The consensus that emerges is that while
els is attenuated after propensity score adjust- there appears to be more frequent early stent
ments. This trial made use of the everolimus and thrombosis in ITDM patients, there is no clear
paclitaxel eluting second generation drug eluting difference in later stages of stent healing.
stents. (33). Similarly the outcomes after revascularisation
The choice of the drug eluted had been contro- with CABG appears to be different between ITDM
versial in the earlier days of DES, though by and and NITDM patients. While CABG was shown
far the limus drugs have now come to dominate to have less adverse outcomes as compared to

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Cardio Diabetes Medicine 2018 182

PCI in DM patients with multi-vessel disease in PMID: 430798.
trials such as CARDIA, SYNTAX FREEDOM and 3 Laakso M, Lehto S. Epidemiology of macrovas-
ASCERT, the difference in outcomes between cular disease in diabetes. Diabetes Rev 1997; 5:
the two groups based on DM treatment still is 294– 315
subject to debate. 4 Cardiovascular disease in type 2 diabetes:
challenge for treatment and prevention. Laakso
Munnee et al, (42) in a meta-analysis involving M, J Intern Med. 2001 Mar; 249(3):225-35.
64,152 patients from 11 studies, found that pa- 5 Geiss LS, Herman WM, Smith PJ. Diabetes in
tients with ITDM had a significantly higher rate America. 2nd ed. Bethesda, MD: NIH & NIDDK:
of mortality and Major Adverse Events (MAE) National Diabetes Information Clearing house;
compared with patients with NITDM after CABG 1995. Mortality in non-insulin-dependent dia-
both in the short and longterm. Stroke was also betes; pp. 233–55. In: National Diabetes Data
significantly higher in patients with ITDM during Group, editor.
a long-term follow-up period. The Freedom trial 6 Type 2 diabetes as a "coronary heart disease
also showed higher mortality at 5 years, stroke equivalent": an 18-year prospective popula-
and MI in the ITDM group. Similar outcomes tion-based study in Finnish subjects. Juutilainen
were noted by Deaton et al (43) and Koshizawa A, Lehto S, Rönnemaa T, Pyörälä K, Laakso M
et al (44). Diabetes Care. 2005 Dec; 28(12):2901-7.
7 Diabetes patients requiring glucose-lowering
Worse outcomes in ITDM patients could be re- therapy and nondiabetics with a prior myocardial
lated to the longer duration of DM with the asso- infarction carry the same cardiovascular risk: a
ciated hyperglycaemic insult, along with multiple population study of 3.3 million people. Schramm
co-morbidities and much severe coronary dis- TK, Gislason GH, Køber L, Rasmussen S, Ras-
ease. It may also be that NITDM patients have mussen JN, Abildstrøm SZ, Hansen ML, Folke
better control of lifestyle and better HbA1C as F, Buch P, Madsen M, Vaag A, Torp-Pedersen C
compared to ITDM patients. The pro inflammato- Circulation. 2008 Apr 15; 117(15):1945-54.
ry effects of insulin itself, in addition, could play 8 The relationship between glucose and incident
a role in worse outcomes after PCI or CABG. cardiovascular events. A meta regression analy-
Whether this indicates a self-selected group sis of published data from 20 studies of 95,783
of patients at higher risk because of the longer individuals followed for 12.4 years.Coutinho M,
duration of the disease with poor control and/or Gerstein HC, Wang Y, Yusuf S, Diabetes Care.
chronic under treatment of the hyperglycaemia 1999 Feb; 22(2):233-40.
or reflects a different physiological change due 9 FoxCS,SullivanL, D’Agostino RB Sr, Wilson
to severe IR or exogenous insulin therapy may PW.The significant effect of diabetes duration
need to be answered with more rigorous trials. on coronary heart disease mortality: the Fram-
In conclusion short and long-term outcomes ap- ingham Heart Study. Diabetes Care 2004;27:704
pear to be worse in ITDM patients compared to – 8.
NITDM after revascularisation in the real world 10 Brun E, Nelson RG, Bennett PH, Imperatore
even with contemporary medical therapy and G, Zoppini G, Verlato G et al. Diabetes duration
current standards of revascularisation. and cause-specific mortality in the Verona Dia-
betes Study. Diabetes Care 2000;23:1119 – 23.
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IMPROVING CV OUTCOMES IN DIABETES WITH NEW
ANTIDIABETIC MEDICATIONS: A NEW ERA HAS BEGUN

Dr.P.C. Manoria,MD,DM,FSACC,FESC, **Dr.Pankaj Manoria

Director ,Manoria Heart&Critical Care Hospital,
Farmer Prof and H.O.D Cardiology GMC,Bhopal

Abstract boundary of 95% CI is found to be <1.0 in a
subsequent statistical analysis1. In 2012, The
A new era of improving cardiovascular (CV) out- European Medicines Agency also issued simi-
comes in diabetes with new antidiabetic medi- lar guidelines2. As a consequence of this, since
cations has begun. The new agents like sodium/ post–2008, all newer antidiabetic agents ap-
glucose cotransporter 2 (SGLT2) inhibitors and proved by USFDA and EMA have underwent or
Glucagon-Like Peptide-1 Receptor Agonists currently undergoing CVOT.
(GLP-1RAs) in CV outcome trials (CVOTs) have
shown improved CV outcomes in patients of di- 2015 came with a breaking news, when 3 new
abetes with cardiovascular disease. In addition antidiabetic medications, Empaglifozin in the
the above new agents also have the potential EMPA-REG OUTCOME, Liraglutide in LEADER
to decreases weight and blood pressure there- and Semaglutide in SUSTAIN-6 trial showed
by improving co-morbidities and on top of this cardiovascular benefits for the first time in
they produce minimal or no hypoglycemia. Thus the history of diabetes. This represents a sea
we can kill three birds with the same stone, ie., change in the treatment paradigm for type 2 dia-
optimizing glycemic control, minimizing co-mor- betes with CVD. In addition to CV benefits, these
bidities and above all improving CV outcomes. medications also improve upon other limitations
of older antihyperglycemic medications, such
With better control of infective and metabolic as avoidance of weight gain and sodium reten-
complications, Diabetes has emerged as a car- tion and that too with minimal risk for hypogly-
diovascular disease (CVD). 70% diabetics die cemia. In fact the new medications like SGLT2i
because CVD particularly acute myocardial in- and GLP-1RA also decrease weight and blood
farction. For close to 100 years, to be precise pressure. In 2017 the CANVAS trial with cana-
upto 93 years since the introduction of insulin glifozin also showed improved CV outcomes in
for clinical use in 1922, no medication designed diabetics with CVD.
to treat hyperglycemia associated with type 2
diabetes mellitus had demonstrated benefit for CV Outcome trials with newer
cardiovascular risk in randomized cardiovascu- agents:
lar clinical outcomes trials (CVOTs).
Several CVOTs had been initiated to assess the
The Rosiglitazone controversy created a flutter effect of newer anti-diabetic medications on CV
and the US Food Drug Administration (USFDA) Outcomes. Eight trials have been completed
in the year 2008, mandated that all new antidia- and published while others are ongoing (Table
betic agents must undergo an adequately pow- -1). Indeed four CV outcome trials with newer
ered, glycemic‑equipoise CVOTs in high‑risk agents i.e, EMPAREG OUTCOME, LEADER
Type 2 diabetic patients, during postmarketing AND SUSTAIN-6 and CANVAS has shown im-
phase to demonstrate its safety by showing proved CV outcomes.
non-inferiority against placebo. The non-inferi-
ority was defined as hazard ratio (HR) of <1.3
for the upper bound of 95% confidence interval
(CI), superiority can also be claimed if upper

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Improving CV outcomes in diabetes with new antidiabetic medications: 187
A new era has begun

Table-1: Large non-insulin completed CV outcome trials in T2DM

Trials Drug Comparator Status Nu Established Results
CVD (%)

SAVOR3 Saxagliptin Placebo DPP-IV Inhibitors 78% CV neutral, ↑ hospitalization
Declared 2013 16492 for HF

EXAMINE4 Alogliptin Placebo Declared 2013 5380 100% CV neutral, numerical ↑ HF

TECOS5 Sitagliptin Placebo Declared 2015 14735 100% CV neutral, no increase in hos-
SGLT2 Inhibitors pitalization for HF

EMPA-REG6 Empagliflozin Placebo Declared 2015 7020 99% Positive CV outcome

CANVAS7 Canagliflozin Placebo Declared 2017 4330 67% Positive Cv outcome
81% Positive CV outcome
GLP1-RA

LEADER8 Liraglutide Placebo Declared 2015 9340

ELIXA9 Lixisenatide Placebo Declared 2015 6068 100% CV neutral

SUSTAIN 610 Semaglutide Placebo Declared 2016 3297 58.80% Positive CV outcome

The ongoing CVOT trials are outlined in Table 2.
Table 2: Large non-insulin ongoing CV outcomes trials in T2DM

Trials Drug Comparator Status Nu.
CAROLINA11
DPP-IV Inhibitors

Linagliptin Sulfonylurea Ongoing 6000

CARMELINA12 Linagliptin Placebo Ongoing 8300
Ongoing 17276
SGLT2 Inhibitors

DECLARE timi13 Dapagliflozin Placebo

Vertis CV14 Ertugliflozin Placebo Ongoing 12600
EXSCEL15
GLP1-RA

Exenatide Placebo Ongoing 14000

REWIND16 Dulaglutide Placebo Ongoing 9622

HARMONY17 Albiglutide Placebo Ongoing 7500

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Cardio Diabetes Medicine 2018 188

Major Adverse Cardiac Events in CVOTs contrast, the 3P‑MACE reduction in SUS-
TAIN‑610 was primarily attributed to a signifi-

a. DDP IVi inhibitors trials: cant reduction in the nonfatal stroke.

All the three DPP‑4Is trials, SAVOUR, EXAM- So, in summary, at the present state of time, the
INE and TECOS achieved the non-inferiority SGLT2 inhibitors, both empaglifozin and cangli-
margin on major adverse cardiac event (MACE) fozin show a clear and definite CV advantage
endpoints as laid down by the FDA in 2008, in high-risk patients with T2DM and established
thereby suggesting that saxagliptin, alogliptin, macrovascular complications. The ‘thumbprint,’
and sitagliptin all are CV neutral drugs. Howev- however, of individual members of the class
er, no superiority on MACE was observed with may be different with regard to not only individu-
any of the three DPP‑4Is3-5. al components of MACE but also with regard to

b. SGLT2 inhibitors: adverse effect profiles.

Surprisingly, empagliflozin in EMPA‑REG OUT- The mechanistic underpinnings of the CV ef-
COME6 trial not only achieved the non-inferiority fects of SGLT2 inhibitors still remain to be fully
but also demonstrated a substantial superiority elucidated. They potentially pertain to the drug’s
against placebo. EMPA‑REG found a significant glucoretic-natriuretic properties18. Another
relative risk reduction in the primary outcome school of thought points to the tendency for
of 3P‑MACE (composite of CV death, nonfatal these agents to shift fuel metabolism in favor of
myocardial infarction [MI], and nonfatal stroke) the consumption of ketones (instead of glucose
by 14% (HR = 0.86, 95% CI = 0.74–0.99, P = and free fatty acids)19. Such a change, it has
0.04 for superiority) compared to the placebo6. been proposed, may provide an energy advan-

The CANVAS7 trial with canaglifozin also tage for cardiomyocytes. Clearly, more mecha-
showed improved CV outcomes with exactly the nistic studies are needed to better understand
same relative risk reduction of 14% in the pri- these concepts, which might have implications
mary outcome of similar 3P-MACE (HR=,0.86; for the management of CVD.

95% confidence interval [CI], 0.75 to 0.97; The results of two ongoing CV outcome trials
P<0.001 for non-inferiority; P = 0.02 for superi- with other SGLT2 inhibitors in T2DM dapaglifoz-
ority) like the EMPA REG OUTCOME trial. How- in DECLARE (Dapaglifozin effect on Cardiovas-
ever, in CANVAS, while all three components cuLAR Events)13 and etruglfoozin in VERTIS
of MACE moved in the right direction (i.e., HR CV [Cardiovascuar Outcomes Following Ertug-
<1.0), none actually achieved statistical signifi- lifozin Treatment in Diabetes Mellitus Partic-
cance, perhaps reflecting the fact that the study ipants With Vascular Disease])14 are going to
involved a sizable subgroup about one third of be released over the next several years. We will
patients who had no prior history of CVD, unlike hopefully then have a better understanding of
EMPA which did not included any such patients. these issues at that time.
Interestingly, in the CANVAS primary prevention

subgroup, the hazard ratio for the primary out- c.GLP-1RAs trials:
come was 0.98, suggesting that those without

CVD do not experience the CV benefit as those From the three GLP‑1RAs trials, ELIXA9 found
with CVD. lixisenatide to be noninferior (4P MACE, HR =

It should also be noted that while 3P‑MACE re- 1.02; 95% CI = 0.89–1.17; P < 0.001 for nonin-
duction in EMPA‑REG was mainly attributed to feriority) to placebo while liraglutide in LEADER
reduction in the CV death which was majorly due and semaglutide in SUSTAIN-6 trials showed
to the reduction in death from HHF; 3P‑MACE superiority on similar 3P‑MACE compared to
reduction in LEADER8 was derived from sum- placebo.

mation of all CV end‑points although here also

reduction in the CV death contributed majorly.
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Improving CV outcomes in diabetes with new antidiabetic medications: 189

A new era has begun

Figure 1: Primary major adverse cardiac event in cardiovascular outcome trials

In LEADER8 found 13% relative risk reduction CV death in CVOTs
(HR = 0.87; 95% CI = 0.78–0.97; P = 0.01) and
SUSTAIN‑6 demonstrated even a larger 26% No benefit was observed in reducing CV death
relative risk reduction (HR = 0.74; 95% CI = in any CVOTs with DPP‑4Is against placebo.
0.58–0.95; P = 0.02) in 3P‑MACE.[7‑9] Similarly, two GLP‑1RAs, lixisenatide, and
semaglutide could not show any significant
Interestingly, both LEADER and SUSTAIN‑610 reduction in the CV death in ELIXA and SUS-
also demonstrated a significant reduction on the TAIN‑6, respectively. However, both empagli-
expanded composite outcome (death from CV flozin in EMPA‑REG and liraglutide in LEAD-
causes, nonfatal MI, nonfatal stroke, revascu- ER, significantly reduced CV death by 38%
larization or hospitalization for unstable angina, (HR = 0.62; 95% CI = 0.49–0.77; P < 0.0001)
or heart failure) by 12% (HR = 0.88; 95% CI = and 22% (HR = 0.78; 95% CI = 0.66–0.93;
0.81–0.96; P = 0.005) and 26% (HR = 0.74; 95% P = 0.007), respectively. This suggests that
CI = 0.62–0.89, P = 0.002), respectively, where- EMPA‑REG showed much larger reduction
as EMP‑REG could not demonstrate a signifi- in CV death compared to LEADER (38% vs.
cant reduction (HR = 0.89; 95% CI = 0.78–1.01; 22%) with more persuasive P value (<0.0001
P = 0.08) on expanded 4P‑MACE (3P‑MACE vs. 0.007).The CANVAS trial published recent-
plus unstable angina). Figure 1 depicts the re- ly showed a trend towards reduction in CVD.
duction in MACE in all eight CVOTs. Figure 2 depicts the outcome of CV death in all
eight CVOTs.

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Cardio Diabetes Medicine 2018 190

Figure 2: Cardiovascular death in cardiovascular outcome trials
Nonfatal MI in CVOTs

Figure 3: Nonfatal myocardial infarction in cardiovascular outcome trials
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Improving CV outcomes in diabetes with new antidiabetic medications: 191

A new era has begun

There was a non-statistical trend in reduction
of non-fatal MI in almost all CVOTs except EX-
AMINE and ELIXA. Figure 3 depicts this out-
come. Silent MI was assessed in all patients in
LEADER, and SUSTAIN‑6 but only in 50% pa-
tient in EMPA‑REG. Intriguingly, there was 28%
increased trend of silent MI in EMPA‑REG al-
though statistically insignificant.

Figure 4: Nonfatal stroke in cardiovascular outcome trials

TECOS had neutral outcome on nonfatal stroke. 1. Patients with age <65 years of age
SAVOR‑TIMI, ELIXA, EMPA REG showed (HR = 1.6, 95% CI = 1.03–2.49)
a non-significant trend of increase in stroke.
Stroke increased by 24% in empagliflozin arm 2. Patients from Europe
(HR = 1.24; 95% CI = 0.92–1.67; P = 0.16), al- (HR = 2.04, 95% CI = 1.26–3.29)
though it was statistically not significant. EXAM-
INE, LEADER ,CANVAS all showed a non-sig- 3. Patients with baseline HbA1c ≥8.5%
nificant trend of decrease in stroke. Interestingly, (HR = 2.13, 95% CI = 1.21–3.74)
SUSTAIN-6 showed a significant 39% relative
risk reduction in nonfatal stroke (HR = 0.61; 4. Patients treated with insulin
95% CI = 0.38–0.99; P = 0.04). but its P value (HR = 1.57, 95% CI = 1.03–2.41).
just reached statistical significance (P = 0.04).
Figure 4 depicts the nonfatal stroke outcome of
all eight CVOTs. Four subgroups of patients that
had significantly higher stroke in EMPA‑REG in
an independent analysis of FDA are:

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Cardio Diabetes Medicine 2018 192

Hospitalization Due to Unstable Angina in CVOTs

Figure 5: Unstable angina hospitalization in cardiovascular outcome trials

HNo statistically significant difference in hospi-
talization due to unstable angina was observed
in all eight CVOTs as shown in Figure 5 .

All Cause Mortality in CVOTs

Figure 6: All-cause mortality in cardiovascular outcome trials
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Improving CV outcomes in diabetes with new antidiabetic medications: 193

A new era has begun

Empagliflozin reduced all‑cause mortality by these studies and thus any sub-analysis could
32% (HR = 0.68; 95% CI = 0.57–0.82; P < be subject to statistical error or may be a play
0.0001), while LEADER reduced it by 15% (HR of chance.
= 0.85; 95% CI = 0.74–0.97; P = 0.02). This
suggests that EMPA‑REG had larger and ro- However, empagliflozin showed a robust reduc-
bust reduction in all‑cause mortality compared tion in HHF by 35% (HR = 0.65, 95% CI = 0.50–
to LEADER (32% vs.15%, respectively) with 0.85; P = 0.002) in EMPA‑REG. interestingly the
persuasive P value (<0.0001 vs. 0.02, respec- CANVAS showed identical trend in reduction in
tively). HF hospitalization (HR=.67;95% CI 0.52- 0.67).

The TECOS was neutral in all cause mortality LEADER had a nonsignificant reduction in
while SAVOR TIMI and SUSTAIN-6 showed a HHF, which definitely sounds encouraging for
non significant increase in it. The EXAMINE, liraglutide as earlier two trials conducted in pa-
ELIXA AND CANVAS showed a non-significant tients with exclusive heart failure subjects, had
decrease in all cause mortality. Figure 6 depicts disappointing results. While functional impact
the all cause mortality across all eight CVOTs. of GLP‑1 for heart failure treatment (n = 300)
conducted in patient with advanced heart failure
Heart failure Hospitalisations in CVOTs (median left ventricular ejection fraction of 25%)
with liraglutide (FIGHT) had a non-significant
Hospitalisation due to heart failure (HHF) was an trend of increase in HHF (HR = 1.30; 95% CI
exploratory end‑point in all the trials. Saxagliptin = 0.89–1.88; P = 0.17) and death (HR = 1.10;
in SAVOR‑TIMI showed a statistically signifi- 95% CI = 0.57–2.14; P = 0.78), the effect of li-
cant 27% increase in the relative risk of HHF raglutide on left ventricular function in chronic
(HR=1.27; 95% CI = 1.07–1.51, P = 0.007). This heart failure patients with and without Type 2 di-
HHF in SAVOR‑TIMI was more pronounced abetes mellitus (LIVE) also had a significant in-
within its first year of randomization. Similar crease in serious adverse cardiac events when
trend of increase (19%) was also observed compared to placebo (12 vs. 3, respectively,
with alogliptin in EXAMINE (HR = 1.19; 95% P = 0.04)27,28. Intriguingly, SUSTAIN‑6 had a
CI = 0.89–1.58; P = 0.24), although it was sta- non-significant increase in trend of HHF. Figure
tistically insignificant. Intriguingly, the post hoc 7 depicts the HHF in all CVOTs.
analyses from both SAVOR‑TIMI and EXAMINE
found that certain subgroups had a significant The CVD-REAL study29, the first large real
increase in HHF that included, patients with a world study assessed data from more than
history of heart failure and renal disease20-22. 300,000 patients across six countries, 87% of
Curiously, a post hoc analysis of EXAMINE also whom did not have a history of CV disease. The
suggested a significant increase in HHF in pa- data showed that across this broad population
tients without any history of heart failure (HR = of patients with T2DM, treatment with SGLT-2i
1.76, 95% CI = 1.07–2.90; P = 0.026)23. On the dapagliflozin, canagliflozin, empagliflozin re-
contrary, sitagliptin in TECOS found no signal of duced the rate of hospitalisation for heart failure
HHF. Further extensive analysis of TECOS also by 39% (p<0.001) and death from any cause
could not find any signal of the heart failure, re- by 51% (p<0.001), compared to other T2DM
gardless of time, subgroups and method of sta- medicines. For the composite endpoint of hos-
tistical analysis applied24,25. Meanwhile, FDA pitalisation for heart failure and death from any
put a warning on April 5, 2016 which states that cause, the reduction was 46% (p<0.001).
“safety review has found that Type 2 diabetes
medicine containing saxagliptin and alogliptin
may increase the risk of heart failure particularly
in the patients who already have heart or kidney
disease26. It should however be noted that HHF
was neither a primary or secondary objective of

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Cardio Diabetes Medicine 2018 194

Figure 7: Heart failure hospitalization in cardiovascular outcome trials

Safety analysis of CVOTs noted that liraglutide in LEADER also reported

an increased trend in retinopathy complication

All six CVOTs conducted with incretin‑based (HR = 1.15; 95% CI = 0.87–1.52; P = 0.33), al-

therapy almost ruled out any real increase in though it was nonsignificant.

pancreatitis or pancreatic cancer as was per-

ceived earlier. However, there was a slight From the existing data, it is clear that all the three

trend of increase in pancreatitis in DPP‑4Is arm DPP‑4Is saxagliptin,alogliptin and sitagliptin are

compared to the placebo. The only adverse ef- CV neutral drugs. Saxagliptin had undoubted in-

fect observed in the trial was a tripling of gen- crease in HHF in certain subgroups of patients.

ital infections, predominately due to candida, Alogliptin showed numerical increase in HHF.

a well-recognized complication of glucosuria. Sitagliptin in TECOS trial showed no signal of

However CANVAS showed two new side effects HHF. Among the GLP‑RAs trials, lixisenatide

not seen in the EMPA ,i.e, an increase in low- was found to be CV neutral without any obvi-

er limb amputations and bone fractures in the ous safety signals. LEADER had a concordant

canaglifozin group While LEADER showed a reduction in all the CV end‑points, some statisti-

significant increase in acute gallstone disease cally significant and some nonsignificant. SUS-

(P < 0.001) and acute cholecystitis (P = 0.046), TAIN‑6 had the largest reduction in 3P‑MACE

SUSTAIN‑6 showed a significant increase (HR but no reduction in the CV death, all‑cause

= 1.76; 95% CI = 1.11–2.78, P = 0.02) in reti- death, and HHF. EMPA‑REG had the largest

nopathy complication (includes vitreous hemor- and the most robust reduction in the CV death,

rhage, onset of diabetes‑related blindness, and all‑cause death, and HHF, but a discordant non-

the need for treatment with an intravitreal agent significant increase in silent MI (assessed in half

or retinal photocoagulation). It should also be patients only) and nonfatal stroke.

Cardio Diabetes Medicine

Improving CV outcomes in diabetes with new antidiabetic medications: 195

A new era has begun

The progression of kidney disease decreased 5. Green JB, Bethel MA, Armstrong PW, Buse
by 39% (p < 0.001) in the EMPA trial and inter- JB, Engel SS, Garg J, et al. Effect of sita gliptin
estingly ,the progression of CKD in the CANVAS on cardiovascular outcomes in type 2 diabetes.
trial was almost identical to it. N Engl J Med 2015;373:232‑42.

Several CVOT trials are ongoing with linagliptin 6. Zinman B, Wanner C, Lachin JM, Fitchett D,
(CARMELINA, CAROLINA), canagliflozin (CAN- Bluhmki E, Hantel S, et al. Empagliflozin, car-
VAS‑R), dapagliflozin (DECLARE‑TIMI), ertug- diovascular outcomes, and mortality in type 2
liflozin (VERTIS‑CV), exenatide once weekly diabetes. N Engl J Med 2015;373:2117‑28.
(EXCEL), dulaglutide (REWIND) and albiglutide 7.Zinman B, Wanner C, Lachin JM, et al.
(HARMONY) which will further enlighten us in Empagli ozin, cardiovascular outcomes, and
future. mortality in type 2 diabetes. N Engl J Med
2015;373:2117-28.
Conclusion

Thus the new agents SGLT2i and GLA-1 RA 8. Marso SP, Daniels GH, Brown‑Frandsen K,
have paved the way for a new therapeutic path Kristensen P, Mann JF, Nauck MA, et al. Lira-
for diabetes of optimizing glycemic control, glutide and cardiovascular outcomes in type 2
minimizing co-morbidities and improving CV diabetes. N Engl J Med 2016;375:311‑22.
outcomes coupled with minimal or no hypogly- 9. Pfeffer MA, Claggett B, Diaz R, Dickstein K,
cemia. Indeed this is the beginning of a new rev- Gerstein HC, Køber LV, et al. Lixisenatide in pa-
olution which we have desired for many many tients with type 2 diabetes and acute coronary
years . syndrome. N Engl J Med 2015;373:2247‑57.
  10. Marso SP, Bain SC, Consoli A,
Eliaschewitz FG, Jódar E, Leiter LA, et al. Sema-
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Cardio Diabetes Medicine 2018 197

SGLT2 ANTAGONISTS, NOVEL CARDIORENAL PROTECTIVE

MEDICATIONS?

Prof Luigi Gnudi, MD, PhD, FRCP, FASN
Head, Unit for Metabolic Medicine,

School of Cardiovascular Medicine & Science,
King’s College London School of Medicine & Life Sciences.

Abstract re-absorbed by the kidneys proximal tubule
every day. In individuals without diabetes, if
Diabetic nephropathy (DN) is currently the most plasma glucose concentration rises over around
feared chronic microvascular complication of di- 180-200 mg/dl the capacity of SGLT-2 transport-
abetes. DN is characterized by a progressive ers is exceeded, and excess filtered glucose
decline towards end stage renal disease (ESRD) appears in the urine resulting in glycosuria.
and by an increase in cardiovascular morbidity Patients with familial glycosuria present with
and mortality. The epidemic of type 2 diabetes, mutation of SGLT2 gene that leads to different
particularly in newly industrialized and develop- degree of SGLT2 malfunction and glycosuria.
ing countries, translates into a dramatic increase In patients with diabetes the excess of renally
of diabetic renal and cardiovascular disease, filtered glucose is paralleled by upregulation, in
that results in a significant social and economic rodents and humans, of SGLT2, and event that
burden. is paralleled by activation of the local angioten-
To face this health-related catastrophe enormous sin II system and growth factors (e.g. CTGF,
TGF-β1) implicated in tubular cell proliferation,
tubular hypertrophy and interstitial fibrosis.

efforts have been devoted to implement new SGLT2 inhibition is a novel important new tool
tools to prevent/treat chronic vascular diabetic that can be utilized for the treatment of hyper-
complications. Recent studies have demonstrat- glycaemia in patients with type 2 diabetes. By
ed that SGLT2 antagonist can, on top of stan- blocking the action of SGLT2 in patients with
dard medications, confer additional cardio and T2DM studies have shown an improvement in
renal protection independently from an improved glycaemic control paralleled by weight loss and
glycaemic control. by a modest, but clinically significant, fall in sys-
Different mechanisms have been postulated tolic and diastolic blood pressure. The SGLT2
and cardiorenal protective properties of this new inhibitors mode of action is insulin independent
class of drug is currently being investigated. and rarely results in hypoglycaemia unless the
SGLT2 inhibitor is utilized in conjunction with
insulin or beta cell secretagogues.

SGLT2: from physiology to pathophys- Recent clinical trials have demonstrated an
iology of disease and cardiorenal pro- important cardiovascular (1) and possibly a
renoprotective effect (2) of the SGLT2 inhibitor

tective mechanisms empaglifozin; importantly more recent clinical
trials and observational studies suggests that
SGLT2 is an energy-dependent sodium-coupled these cardo-renal protective effects could be
related to a SGLT2 inhibitors’ class effect (3)
glucose transporter, mainly localized in the renal (https://www.janssen.com/phase-3-credence-re-
nal-outcomes-trial-invokanar-canagliflozin-be-
proximal tubuli. SGLT2 mediates glucose tubular

reabsorption: in normal physiology around 180
grams of glucose are filtered and completely

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