Transcript Diabetic Cardiomyopathy

Cardiomiopatia diabetica:
miti e realtà
Diabetic cardiomyopathy:
facts and myths
F. Fedele; MD
M. Mancone, MD
Dipartimento Scienze
Cardiovascolari, Respiratorie,
Nefrologiche, Anestesiologiche e
Geriatriche
«Sapienza» Università di Roma
Diabetic Cardiomyopathy
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Definition: “a distinct entity characterized by the
presence of abnormal myocardial performance or
structure in the absence of epicardial coronary artery
disease, hypertension and significant valvular
disease”
Original description: Rubler et al. in 4 diabetic
patients with HF but no evidence of CAD
Phenotype:
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Increased LVEDP
Normal LVEDV
Decreased LV compliance
Refs.Aneja, Tang, Bansilal et al. Am Jnl of Med 121. 2008
Rubler et al. American Jnl of Cardiology 30. 1972
Tarquini et al. Acta Diabetol 2010.
Diabetic Cardiomyopathy
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Epidemiology
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Diabetes affects 180 million worldwide
2/3 of patients with established CVD have
impaired glucose homeostasis; affects 30% of HF
patients
Every 1% increase in Hgb A1c leads to an 8%
increase in HF; in UKPDS, for Hgb A1c < 6%, 2.3
HF events/100 person-years; but for > 10%, 11.9
HF events/100 person – years
Prevalence of HF in general population: 1-4%
Prevalence of HF in diabetic population: 15%
Diabetic Cardiomyopathy
• Increased risk of HF in diabetic patients
with retinopathy c/w a microvascular
etiology of diabetic cardiomyopathy
[Cheung N, et al. JACC, 2008; 51: 1573 - 1578]
• Retinal arteriolar narrowing associated
with LV remodeling
Diabetic Cardiomyopathy
• Pathologically characterized by ventricular hypertrophy,
myocardial fibrosis and fat droplet deposition
• Other physical characteristics:
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Early changes in diastolic function – affects up to 75%
asymptomatic diabetic patients
Collagen deposition
Presence of advanced glycosylation end products [AGEs]
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Late compromise of LV systolic function
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• Earliest evidence is seen in long-axis systolic dysfunction with
NL EF
Diabetic Cardiomyopathy
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Mechanisms/Pathophysiology
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Hyperglycemia
• Increased ROS
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Hyperinsulinemia
• Activation of SNS & RAAS
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Advanced Glycation End Products
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Increased due to oxidative stress
RAGE [receptor for AGE] is also increased
Collagen Deposition
Change in cardiac myosin expression
Enhanced Free Fatty Acid Utilization
• Leads to FFA accumulation & lipotoxicity
Diabetic Cardiomyopathy
Circulation.
2007;115:3213
Potential contributors to the development of diabetic cardiomyopathy. Increased free FA (FFA) activates PPAR-α signaling,
leading to the increased transcription of many genes involved in FA oxidation. Increased FA oxidation leads to the generation
of ROS at the level of the electron transport chain. ROS, which also can be generated by extramitochondrial mechanisms such
as NADPH oxidase, plays a critical role in several pathways involved in the pathogenesis of diabetic cardiomyopathy,
including lipotoxicity, cell death, and tissue damage, as well as mitochondrial uncoupling and reduced cardiac efficiency. TG
indicates triglycerides; GLUTs, glucose transporters; PDK4, pyruvate dehydrogenase kinase 4; MCD, malonyl-coenzyme A
decarboxylase; MCoA, malonyl-coenzyme A; ACoA, acetyl-coenzyme A; ACC, acetyl coenzyme A carboxylase; CPT1,
carnitine palmitoyl-transferase 1; PDH, pyruvate dehydrogenase; CE, cardiac efficiency; PKC, protein kinase C; and AGE,
glycation end products.
Diagnostic clues of diabetic
cardiomyopathy
* MRS: magnetic resonance spectroscopy,
* SRI: strain/strain rate imaging.
J Am Coll
Cardiol.
2003;42(3):454
-457.
The hypothetical echocardiographic cascade of diabetic cardiomyopathy. Metabolic changes (non-enzymatic
glycation?) cause an early structural alteration (with inappropriate accumulation of myocardial connective
tissue?), which induces subclinical disturbances: variation in regional echodensity, blunted cyclic gray level
variation, alterations in diastolic function, alterations in systolic function, reduced coronary flow reserve,
reduction of inotropic reserve, and finally, the onset of resting wall motion abnormalities—regional at first and
global at a later stage. Only at this latter stage, the clinically overt manifestations of diabetic cardiomyopathy
appear. Each of these variables is detected by its specific ultrasound technology. Myocardial structural alterations
can be detected with tissue characterization; diastolic and systolic abnormalities by tissue Doppler imaging;
coronary flow reserve with transthoracic Doppler flowmetry of the left anterior descending coronary artery
(LAD); inotropic reserve reduction by stress echo; and regional dyssynergies by resting two-dimensional (2D)
TDI
Pulsed Power Doppler
Diabetic Cardiomyopathy
Clinical Classification of Coronary
Microvascular Dysfunction.
N Engl J Med. 2007;356:830-40
Coronary Flow Reserve
Acetilcolina CFR 1.5
Adenosina CFR 3.0
Acetilcolina CFR 1.5
Adenosina CFR 2.17
Diabetic Cardiomyopathy
Diabetic cardiomyopathy: mild myocardial interstitial
fibrosis stained in blue with Masson trichrome (white arrow) in
a patient with long-duration type 1 diabetes mellitus at autopsy,
with perivascular fibrosis (A) and mild fibrosis between
myocytes (B).
Diabetic Cardiomyopathy
A) Fibrotic infiltration in the myocardium
with Masson's trichrome staining. Area
stained blue represent fibrotic infiltration.
Magnification at 200×, scale bar is 100 μm.
B) Quantitative analysis of fibrosis. The
collagen volume fraction was higher in the
diabetic group than in the control group
Myocardial Cell Death in Human Diabetes
A Myth
• A myth is a story that may or may not be true.
• Myths are generally very old. This means there
are no records or other proof that they
happened.
• We know about them from older people telling
them to younger people.
• Some myths may have started as 'true' stories
but as people told and re-told them, they may
have changed some parts, so they are less 'true'.
• They may have changed them by mistake, or to
make them more interesting.
Facts
There is much evidence in favour of the existence of DCM:
• post-mortem and histological studies introduced the
DCM;
• epidemiological studies demonstrated
independent
risk
factor
for
that
concept of
diabetes is an
heart
failure;
• experimental studies explored the pathophysiology and
demonstrated an adverse effect of diabetes on the heart in animal
models;
• alteration of myocardial content (myocardial fibrosis and
steatosis)
GRAZIE
The pathophysiological continuum
Circulation 2006; 114; 2850-2870
Therapeutic strategies for diabetic
cardiomyopathy
Heart fail rev 2013
?
RISK FACTORS
TARGET ORGAN
Circulation 2006; 114; 2850-2870
DAMAGE