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Diabetic Cardiomyopathy: from Pathophysiology to Treatment Hellenic J Cardiol 2014; 55: 411-421 Review Article Diabetic Cardiomyopathy: From Pathophysiology to Treatment 1 1 2 2 KONSTANTINOS TRACHANAS , SKEVOS SIDERIS , CONSTANTINA AGGELI , EMMANOUIL POULIDAKIS , 2 2 1 KONSTANTINOS GATZOULIS , DIMITRIOS TOUSOULIS , IOANNIS KALLIKAZAROS 1Department of Cardiology, Hippokration General Hospital, 2First Department of Cardiology, National University of Athens, Hippokration General Hospital, Athens, Greece Key words: Diabetic he close relationship between di- As was demonstrated in the Framingham cardiomyopathy, abetes mellitus and heart failure Heart Study, diabetes is a strong and in- diastolic dysfunction, has been known for many years dependent risk factor for developing heart myocardial fibrosis, Tand includes many mechanisms. In 1881, failure, leading this group of patients to systolic dysfunction. Leyden first claimed that diabetic cardio- a worse prognosis. The risk of heart fail- myopathy is a common complication of ure was 2.4-fold and 5-fold higher in dia- diabetes and one worthy of attention. In betic men and women, respectively, than 1888, Mayer reported that diabetes is a in non-diabetic subjects. The incidence of disorder of metabolism that can lead to heart failure in diabetic patients is still in- heart disease. Finally, the term “diabet- creased even after adjustment for age, hy- ic cardiomyopathy” was introduced by pertension, obesity, coronary artery dis- Rubler in 1972, after post mortem stud- ease or dyslipidemia.5 The close correla- ies in diabetic patients with heart failure tion between diabetes and heart failure Manuscript received: in whom alcohol, hypertension, coronary has been demonstrated in many studies. November 21, 2012; disease and other structural heart disease In the United Kingdom Prospective Dia- Accepted: had been ruled out as possible causes.1 betes Study (UKPDS) an increased preva- June 1, 2014. lence of heart failure was recorded in pa- Epidemiology tients with diabetes mellitus type 2, cor- Address: relating with levels of glycosylated hemo- Skevos Sideris Diabetes mellitus has reached an epidem- globin (HbA1c).6 The incidence of heart ic level worldwide, with a prevalence of failure is 2.3 cases per 1000 person-years State Cardiology Division Hippokration Hospital 4% in 1995 and an anticipated prevalence in patients with HbA1c<6% in contrast 114 Vasilissis Sofias Ave. of 5.4% in 2025, corresponding to 300 mil- to 11.9 per 1000 person-years in patients 115 28 Athens, Greece lion adults with diabetes worldwide.2 Car- with significantly high HbA1c (>10%). [email protected] diovascular diseases represent the primary There are identifiable risk factors for de- cause of death in this population, due to veloping diabetic cardiomyopathy, such as coronary artery disease3 or associated hy- increased HbA1c,6 high body mass index, pertension, but also because of a direct advanced age, use of insulin, proteinuria, adverse effect of diabetes mellitus on the the coexistence of coronary artery disease heart, the so called diabetic cardiomyop- and/or peripheral target organ diseases athy. In diabetic patients the prevalence such as retinopathy and nephropathy.7,8 In of diabetic cardiomyopathy is 12% and a large case-control study, Bertoni et al9 reaches 22% in people over 64 years old.4 tested the hypothesis that diabetes melli- (Hellenic Journal of Cardiology) HJC • 411 K. Trachanas et al tus was independently associated with idiopathic car- sequence of the adverse effects of diabetes mellitus diomyopathy. After adjusting for age, sex, race, and in the heart.21 Newer echocardiographic techniques hypertension, diabetes mellitus was significantly as- should be used in order to evaluate the myocardial sociated with idiopathic cardiomyopathy (relative risk collagen content and its pivotal role in cardiac func- 1.58, 95% CI 1.55–1.62). Similarly in a large popula- tion. Backscatter is an ultrasound tissue characteriza- tion-based cohort study, the Reykjavik Study, Thrains- tion technique, based on the measurement of myocar- dottir et al10 explored the associations between heart dial tissue echoreflectivity, that is related to myocar- failure and abnormal glucose regulation (impaired dial collagen content.22 Di Bello et al23 demonstrated glucose tolerance or impaired fasting glucose). The an increase in myocardial echodensity, as assessed by odds ratio was 2.8 (95% CI 2.2–3.6) for the associa- the integrated backscatter index, in 26 insulin-depen- tion between diabetes mellitus type 2 and heart fail- dent diabetic normotensive patients compared with ure and 1.7 (95% CI 1.4–2.1) for the association be- 17 age- and sex-matched control subjects. Fang et al24 tween abnormal glucose regulation and heart failure. confirmed these results using backscatter in a larger study. Biomarkers of collagen synthesis (procollagen Pathophysiology type I carboxy-terminal peptide [PICP], aminotermi- nal propeptide of procollagen type I [PINP], carboxy- There are two main types of cardiomyopathy: (1) pri- terminal propeptide of procollagen type III [PIIICP], mary cardiomyopathy, where the cardiac function is aminoterminal propeptide of procollagen type III aggravated by a defect in the heart itself, and (2) sec- [PIIINP]), collagen degradation (CITP), markers ondary cardiomyopathy, where cardiac performance of extracellular matrix turnover (such as MMP) and is affected because of a systemic syndrome.11 Cardio- their inhibitors (TIMP, tissue inhibitors of MMP), myopathy leads to heart failure, which can be either can be used as markers in detecting myocardial fi- diastolic heart failure, with preserved ejection frac- brosis.25 Diabetic patients with diastolic dysfunction tion, or systolic heart failure, with reduced ejection demonstrated an increase in MMP-9 and a decrease fraction.12 Diabetes can lead to heart failure, not on- in TIMP-1/MMP-9.26 Finally, in a small group of dia- ly by augmenting the impact of classical cardiovascu- betic patients, a correlation was found between PICP lar risk factors (e.g. accelerating the appearance and and left ventricular (LV) systolic parameters (frac- progression of coronary artery disease through mac- tional shortening and midwall fractional shorten- roangiopathy), but also via a direct deleterious effect ing). More specifically, in diabetic patients, corrected on the myocardium per se. This condition is known endocardial (r=-0.56) and midwall shortening (r=- as diabetic cardiomyopathy, defined as the presence 0.38) was correlated with PICP, whereas the systol- of myocardial involvement in patients with diabe- ic and early diastolic velocities of the mitral annulus tes, characterized by dilatation and hypertrophy of were correlated with glutathione peroxidase (both the left ventricle, with the concomitant appearance r=0.44).27 of diastolic and/or systolic dysfunction, and its pres- ence is independent of the coexistence of ischemic or Hypertrophy of myocardial cells hypertensive or valvular heart disease.13,14 Myocar- dial fibrosis and myocyte hypertrophy are the most Studies of cardiac tissue from diabetic animals under frequently proposed mechanisms to explain cardiac the electron microscope have shown multiple abnor- changes in diabetic cardiomyopathy. Several studies malities in the structure of myocardial cells: (i) loss have shown that diabetes causes defects in cellular of microfibrils; (ii) loss of cell-to-cell connection in calcium transport,15 defects in myocardial contractile the intermediate discs; and (iii) increased lipid depo- proteins,16 and an increase in collagen formation,17 sition in the cytoplasm and loss of components of the which result in anatomic and physiological changes in endoplasmic reticulum.28 Furthermore, it has been the myocardium. reported that LV hypertrophy and concentric remod- eling are associated with diabetes mellitus, indepen- Myocardial fibrosis dently of other confounding factors such as age, obe- sity, and hypertension.29-32 Additionally the NOMAS Myocardial fibrosis, as initially described by Rubler Study described diabetes mellitus as an independent et al and confirmed in histological studies in both ex- determinant of LV mass, in addition to central obesi- perimental subjects and humans,18-20 is a major con- ty as assessed by waist circumference.33 Fischer et al, 412 • HJC (Hellenic Journal of Cardiology) Diabetes Mellitus and Heart Failure working with cardiac tissue samples from patients un- oxygen radicals (ROS-reactive oxygen species). The dergoing coronary artery bypass grafting, demonstrat- AGEs, for example, produced by glycation of colla- ed no differences in LV hypertrophy and fibrosis be- gen lead to its accumulation in the extracellular ma- tween diabetic and non-diabetic patients. They point- trix and eventually in fibrosis of the heart, resulting ed out that the only differences observed in cardiac in diastolic dysfunction. Furthermore, soluble AG- tissue were related to swelling of endothelial cells and Es connected in related receptors (RAGEs), trigger basement membrane thickening of capillaries.34 NADPH oxidase, leading to the production of per- oxide and ultimately of free oxygen radicals. These 41 Mechanisms of heart failure in diabetes mellitus in turn cause direct damage to myocyte DNA. Many pathophysiological mechanisms are involved Systolic dysfunction in diabetic cardiomyopathy in the stepwise progression from diabetes mellitus to heart failure. These include direct myocardial inju- Novel echocardiographic techniques, such as tissue ry (e.g. in myocardial ischemia or cardiomyopathy),
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