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 • 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:  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 • Epidemiology  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%

• Increased risk of HF in diabetic patients 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:  Early changes in diastolic function – affects up to 75% asymptomatic diabetic patients Collagen deposition Presence of advanced glycosylation end products [AGEs] Late compromise of LV systolic function • Earliest evidence is seen in long-axis systolic dysfunction with NL EF

Diabetic Cardiomyopathy • Mechanisms/Pathophysiology  Hyperglycemia • Increased ROS Hyperinsulinemia • Activation of SNS & RAAS Advanced Glycation End Products • Increased due to oxidative stress RAGE [receptor for AGE] is also increased Collagen Deposition Change in cardiac myosin expression Receptor for advanced glycation and product Nuclear factor Kappa-light-Chain-enhanced of activated B cells  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) echo.

Diabetic Cardiomyopathy Pulsed Power Doppler TDI

Clinical Classification of Coronary Microvascular Dysfunction. N Engl J Med. 2007;356:830-40

Coronary Flow Reserve Adenosina CFR 3.0 Acetilcolina CFR 1.5

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 concept of DCM; • epidemiological studies demonstrated that diabetes is an independent risk factor for 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

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RISK FACTORS TARGET ORGAN DAMAGE Circulation 2006; 114; 2850-2870