Διαβητική μυοκαρδιοπάθεια. Γεώργιος Λάζαρος Επιμελητής Α, Α Πανεπιστημιακή Καρδιολογική Κλινική Ιπποκράτειο Γ.Ν.Α.

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1 Διαβητική μυοκαρδιοπάθεια Γεώργιος Λάζαρος Επιμελητής Α, Α Πανεπιστημιακή Καρδιολογική Κλινική Ιπποκράτειο Γ.Ν.Α.

2 Prevalence of Diabetes Mellitus

3 2013: More than one-third of U.S. adults (35.7%) are obese

Cardiovascular complications in diabetes mellitus o Diabetes mellitus is responsible for diverse cardiovascular complications such as increased atherosclerosis in large arteries (carotids, aorta, and

4 Cardiovascular complications in diabetes mellitus o Diabetes mellitus is responsible for diverse cardiovascular complications such as increased atherosclerosis in large arteries (carotids, aorta, and femoral arteries) and increased coronary atherosclerosis, which increases the risk for myocardial infarction, stroke and limb loss. o Microangiopathy contributes to renal failure which may contribute to cardiac pathology as well. o Cardiovascular disease is responsible for 80% of deaths among diabetic patients much of which has been attributed to coronary artery disease. Diabetes Care 1998;21: Diabetes 1974;23: Microcirculation 2005;12: Diabetes Care. 1990;13:

5 Diagnosis of DM Eur Heart J 2013;34:

7 DM /CVD Eur Heart J 2013;34:

9 Prevalence of heart failure by sex and age Circulation 2014;129:e28-e292.

10 Hospital discharges for heart failure by sex (United States: ). Circulation 2014;129:e28-e292.

11 HF and diabetes o Heart failure and diabetes, often go hand in hand, with around 12 to 25% of patients with diabetes also having HF, and around 30% of patients with HF also having diabetes. o Diabetes is associated with poorer functional status and worse prognosis. ESC Heart Failure 2013 Late Breaking Trial

12 Diabetic Cardiomyopathy o This entity was originally described in 1972 (Rubler S, et al.) on the basis of observations in four diabetic patients who presented with HF (heart failure) without evidence of hypertension, CAD, valvular or congenital heart disease. o Thus, diabetic cardiomyopathy has been defined as ventricular dysfunction that occurs independently of coronary artery disease and hypertension. Am J Cardiol 1972;30: Circulation 2007;115:

o Since then, there is an increasing recognition that diabetic patients suffer from an additional cardiac insult termed diabetic cardiomyopathy.

13 o Since then, there is an increasing recognition that diabetic patients suffer from an additional cardiac insult termed diabetic cardiomyopathy. o The increasing recognition of this additional cardiac insult is supported by data from experimental, pathological, epidemiological, and clinical studies. Am J Cardiol 1972;30:

14 Epidemiological studies o The Framingham study demonstrated the increased incidence of congestive HF in diabetic males (2.4:1) and females (5:1) independent of age, hypertension, obesity, CAD and hyperlipidaemia. Am J Cardiol 1976;34:29 34.

o Other prospective studies also show that diabetic patients have a significantly increased lifetime risk of developing HF, and increased mortality from both Q-wave and non-q-wave myocardial

15 o Other prospective studies also show that diabetic patients have a significantly increased lifetime risk of developing HF, and increased mortality from both Q-wave and non-q-wave myocardial infarction. o This suggests that there is an additional insult to diabetic myocardium which predisposes it to more extensive damage and subsequent failure. Diabetes Care 1979;2: Eur Heart J 1988; 9: Acta Med Scand 1988;24:31 38.

16 o In contrast with the 4 6% prevalence of diabetes in the community, the overrepresentation of diabetic patients in HF trials such as SOLVD (26%), ATLAS (19%) and V-HeFT II (20%) attests to the increased prevalence of this condition among diabetic patients. Clinical Science 2004;107:

17 Diabetes and heart failure AGE=προϊόντα τελικής γλυκοζυλίωσης The pathogenesis of diabetic cardiomyopathy is multifactorial Rev Diabetic Stud 2006;3:

18 Pathogenesis of Diabetic Cardiomyopathy: Molecular mechanisms * *PPAR-a = peroxisome proliferator activated receptor-a, PKG=protein kinase AGE=προϊόντα τελικής γλυκοζυλίωσης, ceramides=κεραμίδια Circulation 2007;115:

Hyperglycaemia Εxcess generation of AGEs (advanced glycation endproducts), which deactivate NO (nitric oxide) and impair coronary vasodilation.

19 Hyperglycaemia Εxcess generation of AGEs (advanced glycation endproducts), which deactivate NO (nitric oxide) and impair coronary vasodilation. Sustained hyperglycaemia causes excess formation of mitochondrial ROS, which leads to myocardial inflammation and endothelial dysfunction. Advanced glycation of *SERCA2a has been shown to lead to a decrease in its activity and a prolongation of cardiac relaxation. *Sarcoplasmic reticulum Ca(2+) ATPase AGE=προϊόντα τελικής γλυκοζυλίωσης Diabetologia 2001;44: Mol Cell Biochem 1998;188: Circ Res 2001;89: Diabetes 2004;53: Clinical Science 2004;107:

20 Fatty acids

o In diabetes, glucose for energy production is, however, substantially lower, accounting for only about 10% of the myocardial energy production.

21 o In diabetes, glucose for energy production is, however, substantially lower, accounting for only about 10% of the myocardial energy production. o The shift to a more pronounced beta-oxidation of FFA causes therefore a higher oxygen utilization than under normal circumstances. o It has been proposed that prolonged intracellular accumulation of FFA and its metabolites (ceramide) may cause myocardial dysfunction (lipotoxicity). Eur Heart J 2007;28:

22 Rev Diabetic Stud 2006;3:

23 Επιπλέον στα άτομα με ΣΔ παρατηρείται υπέρμετρη ενεργοποίηση του άξονα ρενίνης-αγγειοτασίνης-αλδοστερόνης ανεξάρτητη από αιμοδυναμικούς παράγοντες ΑΥΞΗΜΕΝΗ ΕΝΑΠΟΘΕΣΗ ΚΟΛΛΑΓΟΝΟΥ Eur Heart J 2007;28: JACC 2006;47:

24 in summary Heart Metab 2009;45:10 14.

25 Clinical features Rev Diabetic Stud 2006;3:

Left ventricular hypertrophy LVH Similarly Framingham was demonstrated in one-third of patients with Type II diabetes independent of blood pressure or ACE inhibitor use.

26 Left ventricular hypertrophy LVH Similarly Framingham was demonstrated in one-third of patients with Type II diabetes independent of blood pressure or ACE inhibitor use. increased LV mass was found in Type I diabetic patients with microalbuminuria. study showed an association between diabetes mellitus and increased LV mass independent of conventional risk factors in women, but not in men. Am J Cardiol 1976;34: Diabetes Care 1979;2: Lancet 2002;359: Circulation 2000;101:2271.

27 Diastolic dysfunction In patients with well controlled type 2 diabetes revealed a prevalence of diastolic dysfunction in up to 30%. The use of flow and tissue Doppler techniques suggests an even greater prevalence of diastolic dysfunction (as much as 40 75%) in individuals with type 1 and type 2 diabetes without overt CAD. Acta Diabetol 1994;31: Diabet Med 1996;13: Am J Cardiol 2004;93: Am J Cardiol 2006;97:77 82.

28 Systolic dysfunction The Thus Using classical knowledge was that in the context of DCM, systolic dysfunction occurs late, often when patients have already developed significant diastolic dysfunction. studies have emerged that demonstrate subtle abnormalities in systolic function in association with a diagnosis of diastolic dysfunction. tissue Doppler strain analysis and measurements of peak systolic velocity, subtle abnormalities in systolic function have been described in up to 24% of randomly selected patients with diabetes mellitus after excluding subjects with CAD or LVH Heart Vessels 1994;9: Circulation 2002;105: Am Heart J 2005;149: Rev Endocr Metab Disord.; available in PMC 2010 September 1.

29 Treatment Glycaemic control o Poor glycaemic control has been associated with an increased risk of cardiovascular mortality, with an increase of 11% for every 1% rise in HbA1c levels, and a recent study has shown a link between HbA1c and HF. o Thus it has been assumed that improving glycaemic control should have a beneficial effect on cardiovascular morbidity and mortality. Circulation 2001;103: Am Heart J 1999;138:S353 S359.

31 Glucose and other risk factor control: Summary of treatment targets for managing patients with diabetes mellitus or impaired glucose tolerance and coronary artery disease Eur Heart J 2013;34:

32 β-βlockers o A meta-analysis of the six main β-blocker HF trials [CIBIS-II, BEST, ANZ, Carvedilol U.S. Trials, COPERNICUS and MERIT-HF] has subgroup data available which has enabled analysis of the diabetic cohort. o Of patients with chronic HF, 24.6% had diabetes. Am Heart J 2003;146:

33 o RR of mortality of DM vs. nondm 1,25 o RR of mortality in DM and CHF on β-blocker vs. placebo was 0,84. o In summary, β-blockers should be given to all diabetic patients with any evidence of HF, unless specifically contra-indicated. This, will result in a RR reduction in mortality. o However, the effect is not as pronounced as the introduction of β-blockers in non-diabetic patients. Am Heart J 2003;146:

ACE inhibitors o All patients with diabetes, in addition to metabolic control, should be treated with an angiotensin converting enzyme (ACE) nhibitor (unless contraindicated) regardless of the level

34 ACE inhibitors o All patients with diabetes, in addition to metabolic control, should be treated with an angiotensin converting enzyme (ACE) nhibitor (unless contraindicated) regardless of the level of left ventricular dysfunction. o Significant benefits were obtained for both cardiovascular morbidity and mortality in the HOPE (Heart Outcomes Prevention valuation) study with ramipril in high-risk patients (3577 diabetics), but this benefit was even more impressive in the diabetic patients. N Engl J Med 2000;342:

35 N Engl J Med 2000;342:

ARBs o The possible preventive effect of losartan in diabetic patients with type 2 diabetes was evaluated in subset analysis of two large randomized trials: RENAAL for renal protection and LIFE for

36 ARBs o The possible preventive effect of losartan in diabetic patients with type 2 diabetes was evaluated in subset analysis of two large randomized trials: RENAAL for renal protection and LIFE for hypertension with left ventricular hypertrophy. o Compared to placebo, losartan significantly reduced the incidence first hospitalization for HF: 39 versus 54% in RENAAL (adjusted HR 0.69); and 11 versus 19 percent in LIFE (adjusted HR 0.50). Am J Cardiol 2005;96:

37 Mineralocorticoid receptor antagonists (spironolactone-eplerenone) o To reduce the risk of hospitalization and premature death, a low-dose MRA is indicated in all patients with persisting symptoms [(NYHA) Class II IV] and an LVEF 35%, despite treatment with an ACE-I (or, if not tolerated, an ARB) and a beta-blocker. o The mortality benefit of spironolactone and eplerenone did not differ between patients with and without T2DM and heart failure. o Surveillance of kidney function and potassium is mandatory, considering the increased risk of nephropathy in patients with DM. Eur Heart J 2013;34:

38 Recommendations for management of heart failure in diabetes (i) Eur Heart J 2013;34:

39 Recommendations for management of heart failure in diabetes (ii) Eur Heart J 2013;34:

o Metformin is not recommended in patients with severe renal or hepatic impairment because

40 o Thiazolidinediones (glitazones) cause sodium and water retention and increased risk of worsening HF and hospitalization, and should be avoided. o Metformin is not recommended in patients with severe renal or hepatic impairment because of the risk of lactic acidosis, but is widely (and apparently safely) used in other patients with HF. Eur Heart J 2012;33,

41 Diabetologia 2012;55:

42 Gliptines and HF

43 Gliptines and HF VIVIDD study (ESC 2013) o Results show that the mean increase in the ejection fraction by 52 weeks (primary endpoint) was 4.1 in the vildagliptin group versus 3.5 in the placebo group (P=0.670, confirming non-inferiority) and that the mean glycated haemoglobin (HbA1c) difference between vildagliptin and placebo at 16 weeks (secondary endpoint) was 0.62% (P<0.001). ESC Heart Failure 2013 Late Breaking Trial

44 Prognosis in diabetic patients with heart failure Among patients with HF, those with diabetes have higher mortality rates. This relationship was demonstrated in a report from Studies of Left Ventricular Dysfunction (SOLVD) which enrolled patients, including with DM. Compared to nondiabetics, DM patients were significantly more likely to be admitted for HF (risk ratio 1.6) and had higher rates at one year of all-cause mortality (32 vs. 22%), CV mortality (28 vs. 19%) and mortality related to pump failure (11 vs. 6%). The increase in all-cause mortality associated with diabetes in SOLVD was limited to patients with an ischemic cardiomyopathy (adjusted relative risk 1.37 compared to 0.98 in patients with nonischemic cardiomyopathy) Am J Cardiol 1996;77: J Am Coll Cardiol 2001;38: % TOTAL MORTALITY CV MORTALITY PUMP FAILURE MORTALITY DM+ DM-

45 Cumulative mortality from all causes in patients with heart failure with and without diabetes o o In the DIAMOND-CHF trial of 5491 patients with heart failure (HF), 900 (16%) had DM mellitus. Mortality for patients with DM was significantly higher than for those without DM (31 vs. 23% at 1 year, adj RR 1.5, 95% CI 1.3 to 1.6). J Am Coll Cardiol 2004;43:

46 Συμπεράσματα Ο σακχαρώδης διαβήτης συνδέεται με αυξημένη καρδιαγγειακή νοσηρότητα και θνητότητα η οποία φαίνεται ανεξάρτητη από τη νόσο των επικαρδιακών στεφανιαίων αρτηριών. Υπάρχει πληθώρα πειραματικών, παθολογοανατομικών και επιδημιολογικών δεδομένων που υποστηρίζουν την ύπαρξη της διαβητικής μυοκαρδιοπάθειας ως ανεξάρτητης κλινικής οντότητας. Αν και υπάρχει σημαντική πρόοδος στην αποκωδικοποίηση των μηχανισμών της νόσου απέχουμε ακόμα από την πλήρη κατανόηση αυτών. Οι ασθενείς με διαβητική μυοκαρδιοπάθεια θα πρέπει να θεραπεύονται όπως και οι υπόλοιποι ασθενείς με διατατική μυοκαρδιοπάθεια, με έμφαση στην πρώιμη χορήγηση αναστολέων του μετατρεπτικού ενζύμου της αγγειοτασίνης.

47 Ευχαριστώ για την προσοχή σας

48 Back up slides

49 Diabetologia 2012;55:

51 Eur Heart J 2013;34:

The development of CVD in people with IR is a progressive process, characterized by early endothelial dysfunction and vascular inflammation

52 The development of CVD in people with IR is a progressive process, characterized by early endothelial dysfunction and vascular inflammation leading to monocyte recruitment, foam cell formation and subsequent development of fatty streaks and atheromas. Eur Heart J 2013;34:

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