Cardiomiopatia diabetica: miti e

realtàDiabetic

cardiomyopathy: facts and myths

F. Fedele; MDM. 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 thepresence of abnormal myocardial performance orstructure in the absence of epicardial coronary arterydisease, hypertension and significant valvulardisease”Original description: Rubler et al. in 4 diabeticpatients with HF but no evidence of CAD

Phenotype:

Increased LVEDPNormal LVEDVDecreased LV compliance

Refs.Aneja, Tang, Bansilal et al. Am Jnl of Med 121. 2008Rubler et al. American Jnl of Cardiology 30. 1972Tarquini et al. Acta Diabetol 2010.

Diabetic Cardiomyopathy

• Epidemiology

Diabetes affects 180 million worldwide2/3 of patients with established CVD haveimpaired glucose homeostasis; affects 30% of HFpatientsEvery 1% increase in Hgb A1c leads to an 8%increase in HF; in UKPDS, for Hgb A1c < 6%, 2.3HF events/100 person-years; but for > 10%, 11.9HF events/100 person – yearsPrevalence of HF in general population: 1-4%Prevalence of HF in diabetic population: 15%

Diabetic Cardiomyopathy

• Increased risk of HF in diabetic patientswith retinopathy c/w a microvascularetiology of diabetic cardiomyopathy[Cheung N, et al. JACC, 2008; 51: 1573 - 1578]

• Retinal arteriolar narrowing associatedwith LV remodeling

Diabetic Cardiomyopathy

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Pathologically characterized by ventricular hypertrophy,myocardial fibrosis and fat droplet depositionOther physical characteristics:

Early changes in diastolic function – affects up to 75%asymptomatic diabetic patientsCollagen depositionPresence of advanced glycosylation end products [AGEs]Late compromise of LV systolic function

• Earliest evidence is seen in long-axis systolic dysfunction withNL EF

Diabetic Cardiomyopathy

• Mechanisms/Pathophysiology

Hyperglycemia• Increased ROS

Hyperinsulinemia• Activation of SNS & RAAS

Advanced Glycation End Products••••

Increased due to oxidative stressRAGE [receptor for AGE] is also increasedCollagen DepositionChange in cardiac myosin expression

Enhanced Free Fatty Acid Utilization• Leads to FFA accumulation & lipotoxicity

Diabetic Cardiomyopathy

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.

Circulation. 2007;115:3213

Diagnostic clues of diabetic cardiomyopathy

* MRS: magnetic resonance spectroscopy, * SRI: strain/strain rate imaging.

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.

J Am Coll Cardiol. 2003;42(3):454-457.

Diabetic Cardiomyopathy

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Clinical Classification of Coronary Microvascular Dysfunction.

N Engl J Med. 2007;356:830-40

Acetilcolina CFR 1.5 Adenosina CFR 3.0

Acetilcolina CFR 1.5 Adenosina CFR 2.17

Coronary Flow Reserve

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

Diabetic Cardiomyopathy

Myocardial Cell Death in Human Diabetes

• 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.

A Myth

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)

Facts

GRAZIE

The pathophysiological continuum

Circulation 2006; 114; 2850-2870

Therapeutic strategies for diabetic cardiomyopathy

Heart fail rev 2013

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Circulation 2006; 114; 2850-2870TARGET ORGAN DAMAGE

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