Διαβήτης και καρδιακή ανεπάρκεια: επιδημιολογικά δεδομένα και διαγνωστικοί προβληματισμοί

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1 Διαβήτης και καρδιακή ανεπάρκεια: επιδημιολογικά δεδομένα και διαγνωστικοί προβληματισμοί Χριστίνα Χρυσοχόου Επιµ Α, Πανεπιστηµιακή Καρδιολογική Κλινική, ΙΓΝΑ

2 Σακχαρώδης διαβήτης και υγεία Τον 1ον αιώνα μ.χ. ο Αρεταίος Εφέσιος περιέγραψε την εικόνα του διαβήτη: πολυουρία, πολυδιψία, πολυφαγία «Ως δια σιφωνίου το ύδωρ διαβαίνει εις τα ούρα»

3 Σακχαρώδης διαβήτης Η παγκόσμια επίπτωση του ΣΔ 5,4% ως το % ΣΔ τύπου 2 Το 1/3 παραμένει αδιάγνωστο Τα 2/3 θανάτων από καρδιαγγειακές επιπλοκές Στην Ελλάδα ~10% του πληθυσμού 32% των ανδρών και 25% των γυναικών (Μελέτη ΙΚΑΡΙΑ, 75+/- 6 έτη)

4 Chain of events leading to heart failure CAD Atherosclerosis Coronary thrombosis Myocardial ischemia Stroke Myocardial infarction Neurohormonal activation Renal failure Arrhythmias Loss of muscle Remodeling Ventricular dilation Sudden death Risk factors Hyperlipidemia Hypertension Diabetes Smoking LV Hypertrophy Heart Failure Modified after Dzau & Braunwald Am Heart J 1991

5 Diabetes mellitus and Heart Failure

6 Diabetes Mellitus, Fas]ng Glucose, and Risk of Cause- specific Mortality The Emerging Risk Factors Collabora]on Hazard ra]os for major causes of death associated with diabetes among 820,900 people in 97 long- term prospec]ve studies Ν Engl J Med 2012

7 Diabetes in heart failure Ιn major clinical trials, diabetes is observed in 15%-25% of HF patients In patients hospitalized for HF, 25%-30% patient have diabetes In large-scale mortality trials, in HF patients with systolic dysfunction, diabetes was an independent risk factor for death. Randomized Evaluation of Strategies of Left Ventricular Dysfunction (RESOLVD) % had documented glucose abnormalities, 8% had previously undiagnosed DM 9% had impaired glucose tolerance.

8 Studies linking DM with HF

9 Παράγοντες που σχετίζονται με την εμφάνιση Καρδιακής ανεπάρκειας 1. Ηλικία 2. Διάρκεια διαβήτη 3. Χρήση ινσουλίνης 4. Ισχαιμική καρδιακή νόσος 5. Περιφερική αρτηριοπάθεια 6. Νεφρική λειτουργία 7. Πτωχός γλυκαιμικός έλεγχος 8. Μικροαλβουμινουρία

10 Μηχανισμοί πρόκλησης καρδιακής ανεπάρκειας Cardiovasc Res May 1; 78(2): 265

11 Diabewc cardiomyopathy The existence of a diabetic cardiomyopathy was first recognized by Rubler et al. at 1972 Friedman et al.(1982), demonstrated that diabetic patients had an increased end-systolic diameter and volume, a diminished ejection fraction, and a decreased minor axis shortening and velocity of circumferential fiber shortening Regan et al (1977) described modestly increased LV enddiastolic pressure, normal LV end-diastolic volume, and decreased LV compliance. J Clin Invest 1977; 60: Am J Cardiol 1972; 30: Am J Med 1982;3:

12 Μεταβολικές διαταραχές στον σακχαρώδη διαβήτη Διαταραχή αντλίας Ca-SERCA, Ca ATPάση, Na-Ca ανταλλάκτη Μείωση IGF-1 (αύξηση απόπτωσης) Αύξηση οξειδωτικού στρες, αύξηση σύνθεσης ΑΤΙΙ και φωσφορυλίωσης p53 που οδηγεί σε απόπτωση Αυξηµένη παραγωγή κολλαγόνου τύπου ΙΙΙ Οι δοµικές µεταβολές παρατηρούνται συχνότερα σε τύπου ΙΙ ΣΔ Στα αρχικά στάδια του ΣΔ παρατηρείται ενεργοποίηση συµπαθητικού ΝΣ Endocrine Reviews, August 2004, 25(4):

13 Διαβητική μικροαγγειοπάθεια και στεφανιαία νόσος Autonomic neuropathy myocardial catecholamine stores deplewon systolic/diastolic dysfuncwon Advanced glycawon end product deposiwon collagen cross- linking increase LV diastolic swffness Advanced glycawon end products/ free radicals NO inacwvawon impaired endothelium relaxawon abnormal epicardial vessel tone and microvascular dysfuncwon no relaxawon during compromised myocardial blood flow Decreased insulin availability/ responsiveness impairment of energy- independent transport of glucose increase in O2 consumpwon

14 Διαβητική μικροαγγειοπάθεια Histologic findings 1. Myocyte hypertrophy, 2. Inters]]al fibrosis and infiltra]on with periodic acid- Schiff (PAS)- posi]ve materials, 3. Altera]ons in the myocardial capillary basement membranes 4. Intramyocardial microangiopathy. Myocardial fibrosis correlated with increased risks for neuropathy, nephropathy, and rewnopathy. Whether these nonspecific structural findings have an underlying ischemic cause remains to be elucidated.

15 Diabetes and vessel wall remodeling Αύξηση πάχους έσω µέσου χιτώνα και αυξηµένη εναπόθεση κολλαγόνου Μειωµένη διατασιµότητα αρτηριών Διαστολική δυσλειτουργία αριστερή κοιλίας (ΣΔ τύπου ΙΙ) Ο έλεγχος της Hba1c βελτιώνει την µικροαγγειοπάθεια αλλά όχι την µακροαγγειοπάθεια Διαταραχή στη γλυκόλυση και οξείδωση γλυκόζης, οδηγεί σε µειωµένη µεταφορά γλυκόζης στο µυοκαρδιακό κύτταρο (έλλειψη υποδοχέων GLUTs), µειωµένη παραγωγή ΑΤΡ (αναστολή από την β οξείδωση λόγω υψηλών FFA) Η διαταραχή στην οξείδωση της γλυκόζης από τα υψηλά επίπεδα FFA είναι η κύρια αιτία της διαβητικής καρδιοπάθειας Η συστολική εφεδρεία της αριστερής κοιλίας είναι µειωµένη Cardiovasc Res May 1; 78(2): 265

16 Hyper- insulinemia Obesity Obesity, Insulin Resistance and Endothelial Dysfunction FFA IL- 1 IL- 6 PAI- 1 TNF- α FFA lepwn TNF- α adiponecwn lepwn resiswn adiponecwn CRP Endothelial Dysfunc]on Insulin Resistance Hyperglycemia Hypertension Dyslipidemia Altered coag/fib

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20 Στάδια διαβητικής μυοκαρδιοπάθειας Endocrine Reviews,2004, 25(4):

21 Diastolic dysfuncwon In pawents with well controlled type 2 diabetes revealed a prevalence of diastolic dysfuncwon in up to 30%. The use of flow and wssue Doppler techniques suggests an even greater prevalence of diastolic dysfuncwon (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.

22 Systolic dysfuncwon The classical knowledge was that in the context of DCM, systolic dysfuncwon occurs late, o en when pawents have already developed significant diastolic dysfuncwon. Thus studies have emerged that demonstrate subtle abnormaliwes in systolic funcwon in associawon with a diagnosis of diastolic dysfuncwon. Using wssue Doppler strain analysis and measurements of peak systolic velocity, subtle abnormaliwes in systolic funcwon have been described in up to 24% of randomly selected pawents with diabetes mellitus a er 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.

23 Diabetes and heart The presence of diastolic dysfunction in diabetic hearts may relate to uncoupling of the contractile apparatus (which drives early relaxation), without concomitant increases in chamber stiffness (which produces more late diastolic changes) Studies that have examined both systolic and diastolic dysfunction in both type I and type II diabetes suggest that the latter is more susceptible to preclinical changes The mechanism of protection of type I diabetic patients may relate to protective effects of insulin therapy and lack of insulin resistance. Indeed, animal data suggest correction of abnormal function with insulin therapy, with indices of cardiac performance significantly greater in insulin-treated rats when compared with control rats

24 Response to therapy The response to hypoglycemic therapy further confirms the correlation of myocardial functional and structural changes with glycemic control. 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. Evidence in vivo has shown that hyperglycemia directly induces apoptotic cell death and myocyte necrosis in the myocardium, triggered by reactive oxygen species derived from high levels of glucose; while glucose treatment renders the cardiomyocyte resistant to hypoxiainduced apoptosis and necrosis Am J Physiol Heart Circ Physiol 2000; 278:H1948 H1954

25 Therapeu]c Implica]ons of Diabe]c Cardiomyopathy Metformin reduces FFA efflux from fat cells, thereby suppressing hepatic glucose production, and indirectly improving peripheral insulin sensitivity and endothelial function. In contrast, thiazolidinediones improve peripheral insulin sensitivity by reducing circulating FFAs but also by increasing production of adiponectin, which improves insulin sensitivity and endothelium function. Combination of pioglitazone and metformin has also shown to significantly improve insulin sensitivity as compared with metformin monotherapy in patients recently diagnosed with type II diabetes Troglitazone has been shown to reduce plasma insulin levels and restore coronary circulation by improving insulin resistance in type II diabetic patients Finally, both ACE inhibitors and exercise may be beneficial for improving insulin resistance Endocrine Reviews, August 2004, 25(4):

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27 Diabetes treatment in Heart Failure Thiazolidinediones (glitazones) cause sodium and water retention and increased risk of worsening HF and hospitalization, and should be avoided 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. The safety of newer antidiabetic drugs in HF is unknown. Beta-blockers are not contraindicated in diabetes and are as effective in improving outcome in diabetic patients as in nondiabetic individuals, although different betablockers may have different effects on glycaemic indices. ESC 2012

28 β- βlockers A metaanalysis 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 diabewc cohort. Of pawents with chronic HF, 24.6% had diabetes. Heart 2003;146:

29 RR of mortality of DM vs. nondm 1,25 RR of mortality in DM and CHF on β- blocker vs. placebo was 0,84. In summary, β- blockers should be given to all diabewc pawents with any evidence of HF, unless specifically contra- indicated. This will result in an RR reducwon in mortality. However, the effect is not as pronounced as the introducwon of β- blockers in non- diabewc pawents, Heart 2003;146:

30 ACE inhibitors All pawents with diabetes, in addiwon to metabolic control, should be treated with an angiotensin converwng enzyme (ACE) nhibitor (unless contraindicated) regardless of the level of le ventricular dysfuncwon. Significant benefits were obtained for both cardiovascular morbidity and mortality in the HOPE (Heart Outcomes Prevenwon valuawon) study with ramipril in high- risk pawents (3577 diabewcs), but this benefit was even more impressive in the diabewc pawents. N Engl J Med 2000;342:

31 N Engl J Med 2000;342:

32 ARBs The possible prevenwve effect of losartan in diabewc pawents with type 2 diabetes was evaluated in subset analysis of two large randomized trials: RENAAL for renal protecwon and LIFE for hypertension with le ventricular hypertrophy. Compared to placebo, losartan significantly reduced the incidence first hospitalizavon 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;96:1530.

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34 Determining diabe]c status: an addi]onal prognos]c indicator in heart failure pa]ents? New York Heart Association (NHYA) class, Maximal VO2, left and right ventricular ejection fraction have been identified as powerful predictors of clinical outcome in HF patients with diabetes Prognostic impact of diabetes mellitus according to HF etiology. Subgroup analysis of the SOLVD trials. Cardiovascular Diabetology 2003, 2 Eur Heart J Cardiovasc Imaging Aug 16

35 Cumulawve mortality from all causes in pawents with heart failure with and without diabetes In the DIAMOND- CHF trial of 5491 pawents with heart failure (HF), 900 (16%) had DM mellitus. Mortality for pa1ents 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;43:771.

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