Diabetic cardiomyopathy: Real

or imagined?
Dr Kim A Connelly MBBS PhD FRACP
St Michaels Hospital
Sunnybrook Health Sciences centre
President CanSCMR
Macrovascular complications Diabetes Canada CPG
Associate Professor of Medicine
University of Toronto
 Disclosures:
• Received honoraria, research support, advisory
board, patents from: Boehringer Ingelheim,
Merck, Astra Zeneca, Bristol Myers Squibb,
Servier, Eli-Lilly, Abbot, Janssen

• take what I say with a grain of salt!

 Objectives:
• to discuss the impact of diabetes upon CV
outcomes with a focus on heart failure

• to describe the key features of the diabetic heart

in persons with type 2 diabetes

• to convince you all Diabetic CardioMyopathy

(DCM) is real!!!
 DCM – real or imagined?

I believe in intuition and inspiration. Imagination is

more important than knowledge. For knowledge is
limited, whereas imagination embraces the entire
world, stimulating progress, giving birth to evolution.
It is, strictly speaking, a real factor in scientific
research.

— Albert Einstein
Cosmic Religion: With Other Opinions and Aphorisms (1931),
97.
- Diabetes prevalence is growing at epidemic levels across
Canada.
- Currently, one in four Canadians have diabetes or
prediabetes.
- one in 10 deaths directly related to diabetes
- Diabetes cost Canada $11.7 billion in 2010, and is
projected to rise to $16 billion by 2020
- Complications from diabetes account for 80% of diabetes
costs.
In Canada, People with Diabetes Account For…

1/3 2/5 2/3 1/2

of all heart of all heart of all non- all patients

attacks & failure traumatic starting dialysis
strokes admissions amputations

Booth et al. ; Hux et al; and Oliver et al., Diabetes in Ontario: An ICES Practice Atlas. 2003. www.ices.on.ca

6
 Definition:
WHO: 1995; Cardiomyopathies are defined as
diseases of the myocardium associated with cardiac
dysfunction

Typical definition of diabetic cardiomyopathy comprises

structural and functional abnormalities of the myocardium in
diabetic patients without coronary artery disease or
hypertension.

Aneja A, Tang WH, Bansilal S, Garcia MJ, Farkouh ME (2008) Diabetic cardiomyopathy: insights into pathogenesis, diagnostic challenges, and therapeutic options. Am J Med 121:748–757
 Diabetic Cardiomyopathy (DCM):
Rubler 1972
• Described 4 patients with autopsy findings of diabetic renal
microangiopathy and dilated left ventricles
Rubler, S, Dlugash, J, Yuceoglu, YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972; 30:595.

Kannel – Framingham 1974

• Diabetic subjects: have a two-fold increase in HF in men and a five-fold
increase in HF in women
• worse symptoms for their level of cardiac function with a higher
mortality.
• increased risk of HF persists after adjustment for other potential
contributors such as known coronary artery disease, age, blood
pressure and cholesterol.
• Kannel, W, Hjortland, M, Castelli, W. Role of diabetes in congestive heart failure. The Framingham Study. Am J Cardiol 1974; 34:29.

Multiple confirmatory epidemiological studies:

• United Kingdom Prospective Diabetes Study, Cardiovascular Health Study, Euro Heart Failure Surveys
 Stages, Phenotypes and Treatment of HF
At Risk for Heart Failure Heart Failure

STAGE A STAGE B STAGE C

At high risk for HF but Structural heart disease Structural heart disease STAGE D
without structural heart but without signs or with prior or current Refractory HF
disease or symptoms of HF symptoms of HF symptoms of HF

e.g., Patients with:

· HTN
· Atherosclerotic disease
e.g., Patients with: e.g., Patients with:
· DM Refractory
· Previous MI e.g., Patients with:
· Obesity Development of symptoms of HF · Marked HF symptoms at
Structural heart · LV remodeling including · Known structural heart disease and
· Metabolic syndrome disease
symptoms of HF at rest, despite rest
LVH and low EF · HF signs and symptoms
or
· Asymptomatic valvular
GDMT · Recurrent hospitalizations
Patients despite GDMT
disease
· Using cardiotoxins
· With family history of
cardiomyopathy

HFpEF HFrEF

THERAPY THERAPY THERAPY THERAPY THERAPY

Goals Goals Goals Goals Goals
· Control symptoms · Control symptoms
· Heart healthy lifestyle · Prevent HF symptoms · Control symptoms · Patient education · Improve HRQOL
· Prevent vascular, · Prevent further cardiac · Improve HRQOL · Prevent hospitalization · Reduce hospital
coronary disease remodeling · Prevent hospitalization · Prevent mortality readmissions
· Prevent LV structural · Prevent mortality · Establish patient’s end-
abnormalities Drugs Drugs for routine use of-life goals
· ACEI or ARB as · Diuretics for fluid retention
Strategies · ACEI or ARB Options
Drugs appropriate · Identification of comorbidities · Beta blockers · Advanced care
· ACEI or ARB in · Beta blockers as
· Aldosterone antagonists measures
appropriate · Heart transplant
appropriate patients for Treatment
vascular disease or DM · Diuresis to relieve symptoms Drugs for use in selected patients · Chronic inotropes
In selected patients · Hydralazine/isosorbide dinitrate · Temporary or permanent
· Statins as appropriate of congestion
· ICD · ACEI and ARB MCS
· Revascularization or · Follow guideline driven · Digoxin · Experimental surgery or
valvular surgery as indications for comorbidities, drugs
appropriate e.g., HTN, AF, CAD, DM In selected patients · Palliative care and
· Revascularization or valvular · CRT hospice
· ICD · ICD deactivation
surgery as appropriate
· Revascularization or valvular
surgery as appropriate
 1: Epidemiology

Diabetes and heart

failure

“frequent, forgotten and

often fatal”…..

Bell DS. Diabetes Care 26:2433-2441

 1: Epidemiology
Relationship between Plasma glucose and
HF hospitalization

Glucose levels predict hospitalization for congestive heart failure in patients at high cardiovascular risk.
Held C, Gerstein HC, Yusuf S, Zhao F, Hilbrich L, Anderson C, Sleight P, Teo K; ONTARGET/TRANSCEND Investigators.
Circulation. 2007 Mar 20;115(11):1371-5.
 1: Epidemiology
Heart Failure and Diabetes Mellitus

8% increased
For every 1%
risk of heart
increase in A1C
failure

Heart Failure

P<0.021
Hazard ratio

Prospective observation (n=4500) over 10.4 yrs: HbA1c and MACE

UKPDS-35
16% rise per 1% rise in A1c

6 7 8 9

A1C = glycated hemoglobin

Udell JA et al. Lancet Diabetes Endocrinol. 2015;3:356–366; McMurray JJ et al.
Lancet Diabetes Endocrinol. 2014;2:843-51;
Iribarren C et al. Circulation. 2001;103:2668-73.
 1: Epidemiology
Age-Associated Prevalence of Heart Failure in
Individuals With and Without Diabetes

Nichols GA et al. Diabetes Care. 2001 Sep;24(9):1614-9.

 1: Epidemiology
Diabetes predicts worse outcomes in
patients with HF

Clinical and Echocardiographic Characteristics and Cardiovascular Outcomes According to Diabetes Status in Patients With Heart Failure and Preserved Ejection Fraction
A Report From the I-Preserve Trial (Irbesartan in Heart Failure With Preserved Ejection Fraction)
Søren L. Kristensen, Ulrik M. Mogensen, Pardeep S. Jhund, Mark C. Petrie, David Preiss, Sithu Win, Lars Køber, Robert S. McKelvie, Michael R. Zile, Inder S. Anand, Michel Komajda, John S.
Gottdiener, Peter E. Carson, John J. V. McMurray: Circulation. 2017;135:724-735
 Causes of heart failure in
diabetes
1) Underlying coronary artery disease and
myocardial infarction

2) Diabetic cardiomyopathy
-defined as ventricular dysfunction that occurs
in diabetic patients independent of a
recognized cause (eg, coronary heart disease,
hypertension)
 1: Epidemiology

Does DCM impact on survival independent of CAD?

All cause mortality

--- DM ‘+’ IHD ‘+’
… NICM
__ DM ‘-’ IHD ‘+’
 2: Clinical findings
Clinical characteristics of
the diabetic heart
Suggested definition to include:

-evidence of cardiac hypertrophy

(Echo or CMR)

-evidence of LV diastolic
dysfunction (with or without LV
systolic dysfunction) either by
TDI, LA enlargement, or
subclinical involvement by novel
imaging techniques or provocative
testing
Diabetic Cardiomyopathy: Insights into Pathogenesis,Diagnostic Challenges, and Therapeutic
Options Ashish Aneja, MD, W. H. Wilson Tang, MD, Sameer Bansilal, MD, Mario J.
Garcia, MD, Michael E. Farkouh, MD, The American Journal of Medicine (2008) 121,
748-757
 2: Clinical findings

Clinical characteristics: Imaging

Diastolic dysfunction and diabetic cardiomyopathy: evaluation by Doppler echocardiography.

Galderisi M.
J Am Coll Cardiol. 2006 Oct 17;48(8):1548-51. Epub 2006 Sep 26. Review.
 2: Clinical findings
Does worse remodeling account for poor outcomes?
 2: Clinical findings

Wide spectrum of remodeling responses!

CV mortality and
hospitalization
 3: Pathological findings

Pathological Features of the

diabetic heart

Diastolic stiffness of the failing diabetic heart: importance of fibrosis, advanced glycation end products, and myocyte resting tension.
van Heerebeek L, Hamdani N, Handoko ML, Falcao-Pires I, Musters RJ, Kupreishvili K, Ijsselmuiden AJ, Schalkwijk CG, Bronzwaer JG, Diamant M, Borbély A, van der Velden J, Stienen GJ, Laarman GJ, Niessen HW, Paulus WJ.
Circulation. 2008 Jan 1;117(1):43-51. Epub 2007 Dec 10.
 3: Pathophysiology/Mechanisms

Mechanisms leading to DCM

Dei Cas A et al. JACC Heart Fail. 2015 Feb;3(2):136-45

 3: Pathological findings
DM and HF phenotypes
Cardiomyocyte cell
Coronary
death from
microvascular
oxidative stress
endothelial
because of tissue
dysfunction drives LV
hypoxia induced
remodelling and
by microvascular
dysfunction through
rarefaction,
lowering of
presence of
myocardial NO
autoimmunity-
bioavailability and
related
PKG activity. This
inflammatory cells,
releases the brake on
advanced
myocardial
glycation end-
hypertrophy, stiffens
products
cardiomyocytes and
deposition and
causes re-active
possibly
interstitial fibrosis. hyperglycaemia
and lipotoxicity.
 EMPA-REG OUTCOME and CANVAS
Hospitalisation for Heart Failure

EMPA-REG OUTCOME®1 CANVAS program2

HR 0.65 (95% CI 0.50-0.85) HR 0.67% 95%CI 0.52-0.87

p<0.002

35% 14%
33%

Direct comparison of agents and trials is not valid due to differences in study design, populations and
methodology

1. Zinman B et al. N Engl J Med 2015;373:2117; 2. Neal B et al. New Engl J Med 2017. DOI: 10.1056/NEJMoa1611925
24
Conclusion: DCM is real!
-diabetes is a major cause of heart failure
-DCM phenotype is heterogenous and driven by
complex, multifactorial mechanisms
-recent studies reveal different “phenotypes”
expression
-recent CVOT studies demonstrate significant
improvements in HF outcomes
-further studies into mechanisms, phenotypes and
therapies is required to impact DCM!