There are more than 194 million of people worldwide that suffer from diabetes mellitus, and the World Health Organization estimates that by the year 2025 the number of the diseased will increase to 350 million, that is, the number of the diseased will double compared to the year 2000 at an international level (1). It is well known that patients with diabetes mellitus more commonly have significant atherosclerotic changes in the epicardial coronary arteries compared to the general population with the microcirculatory disorder accompanied by a potential development of autonomic dysfunction, where all of this unfortunately contributes to their increased morbidity and mortality (2). These conditions rarely occur separately, but they usually overlap and are mutually potentiated (3). Anyway, it is known that diabetic patients are at an increased risk for heart failure (HF) even in the absence of above mentioned pathology.

In 1954 Lundbeak defined diabetic cardiomyopathy as myocardial disease caused by diabetes mellitus, but independent of vascular pathology (4), and later the definition is added by the fact that the disease is also independent of valvular defects and hypertension (5). Today, it is also referred to as non-ischemic diabetic cardiomyopathy in the literature. Through the literature the articles are followed which treat the diabetic cardiomyopathy as a myth (6). Owing to numerous clinical and experimental studies that have proven functional, morphological and biochemical changes in the myocardium (7) with consequential left ventricular dysfunction, both in patients with type 1 and type 2 of diabetes, it is difficult to ignore the existence of the entity, especially as the non-invasive diagnostic methods in daily clinical practice are used to diagnose patients with diabetic cardiomyopathy. Timely diagnosis with medical therapy assisted by changes in lifestyle, can provide patients an improved quality of life and delay of the occurrence of myocardial infarction symptoms.

The prevalence of diabetic cardiomyopathy is not known due to the lack of a large study in different populations of diabetic patients (8). However, the link between diabetes and HF has been well studied. The Framingham study proves that the risk of HF is 2.4 times higher in men and even five times in woman (9), but regardless of the presence of coronary heart disease (CHD) and hypertension. If we additionally exclude all patients with previously known coronary and rheumatic heart disease from the analysis, then the risk of developing HF increases to 3.8 in men and 5.5 in women with diabetes mellitus. Numerous other studies report similar results as well (10). New studies support the hypothesis that persons with diabetes and poor glycemic control are at significantly higher risk for developing cardiomyopathy (11). Thus, the cohort study involving 31.1997 patients, who predominantly had type 2 diabetes, demonstrated that for every 1% increase in HbA1c the risk of HF increases by 8% (11). Some studies suggest that people with insulin resistance, with no criteria for diagnosis of diabetes are also at a higher risk for HF (12). The prevalence of diastolic dysfunction in diabetic patients ranges from 30-60% (13). A recent prospective study in patients with type 1 diabetes which lasted at least 10 years gives results on the prevalence of myocardial dysfunction in 14.5% and HF in 3.7% after a seven-year followup (14).

In type 2 diabetic patients, the occurrence of diastolic dysfunction can be expected in 80% of patients, while the patients with poorer glycemic control and longer duration of the disease tend to have a more severe degree of diastolic dysfunction (15). In addition to hyperglycemia, the most often mentioned risk factors for the development of HF in diabetic patients are: older age (16), duration of diabetes, insulin therapy, CHD, peripheral arterial disease, elevation of serum creatinine and microalbuminuria (17). It is known that after myocardial revascularazation by angioplasty or stent implantation, the cardiac decompensation is more common in diabetic patients. The completely different statistics applies, in OPTIMIZE HF registry 42% of hospitalized patients were diabetic patients due to HF (18).

Diabetes mellitus leads to structural and functional abnormalities in the coronary microcirculation causing a reduction of blood flow through the myocardial tissue, although we find no significant pathomorphological changes in the epicardial arteries. Clinical and experimental studies have shown that diabetes causes myocardial hyperthrophy, apoptosis and necrosis of myocytes, matrix remodeling, increases interstitial tissue and leads to the activation of sympathicus and increases renal sodium absorption (19).

The pathogenesis of diabetic cardiomyopathy is complex and there are several mechanisms which explain the above mentioned situation. Metabolic imbalance as hyperglycemia (20), hyperlipidemia, hyperinsulinemia, defect of stimulation of glycolysis and glucose oxidation (21) lead to structural and functional changes in myocardial cells. The described changes cause damage and decay of myocytes by increased oxidative stress, development of undesired interstitial fibrosis, disorders in the transport of electrolytes and loss of homeostasis. It seems that hyperglycemia induces maladaptive mechanisms that damage myocardial metabolism and function of myofibrils resulting in changes in the cytoskeleton and elevated neurohumoral activity. The consequence of these mechanisms is the undesirable myocardial remodeling that leads to the vicious circle where HF increases insulin resistance and vice versa (11). However, using non-invasive diagnostic methods show that the fibrosis is the most responsible for the development of diabetic cardiomyopathy, because in diabetics type 1 and type 2 the amount of collagen in the myocardium is increased, which leads to the diastolic dysfunction at the beginning. Severe fibrosis of the myocardium can be perivascular, interstitial or combined. Disease progression leads to reduction of the number of myocytes, which are replaced by connective tissue (22, 23).

The elevated level of free fatty acids (24) is also considered one of the major factors that contribute to the development of the diabetic cardiomyopathy by increasing peripheral insulin resistance thereby inducing apoptosis of myocytes (25). The increased concentration of circulating free fatty acids, as well as intercellular ones, leads to the accumulation of potentially toxic metabolites during their degradation and to the reduction of the oxidation of glucose which is considered to be one of the most important causes of the development of diabetic cardiomyopathy. The severity of the clinical manifestations is contributed by the development of autonomic dysfunction with a reduction in heart rate variability and tachycardia (26) and development of endothelial dysfunction with a reduction of blood flow through the coronary arteries. Furthermore, interstitial accumulation of glycoproteins, a slow entry of calcium into sarcoplasmatic reticulum (27), a poor release of nitric oxide from the endothelium of coronary arteries (28) are often described as the potential causes of the development of diabetic cardiomyopathy.

In patients with type 2 DM there is a clear link between glycemic control and the insulin-like growth factor (IGF-I). Poorer glycemic control leads to lower concentrations of IGF-I concentrations in plasma. Experimental models have proved that IGF-I reduces myocyte apoptosis and improves myocardial function with multiple effects (29). Secretion of IGF, interleukin, cytokines and other pro-inflammatory agents cause the expression of micro RNA (MiRNA), especially mi R-155 and mi R-223, which have anti-inflammatory and cardioprotective function (30). MiRNA are small molecules, up to 22 nucleotides, which modulate gene expression and seem to be the key and promising site for potential treatment of cardiovascular and diabetic disease (31). Since their level has been altered in patients with diabetic heart, they are considered to be a good biomarker for cardiovascular disease, and the different expression of specific MiRNA in the circulation can be used for diagnostics of various degrees of diabetic cardiomyopathy.

The above explains that the treatment of metabolic disorders leads to the improvement of the function of myocytes. Unfortunately, the described functional changes to the left ventricle occur even in patients with good glycemic control (32).

Identifying diabetic cardiomyopathy at an early stage of the disease remains a challenge. Echocardiography is currently the most widely used method. In the earliest stage of the disease we can notice an increase in the myocardial density or abnormalities in the subendocardial function by using the strain and strain rate function. Tissue Doppler imaging may show the earliest abnormalities in diastolic flow, and as the disease progresses, it can be record an abnormal record by pulse-Doppler ultrasound of transvalvular mitral flow and pulmonary venous flow, which is the most common technique for proving diastolic dysfunction. The progression of the cardiomyopathy stage leads to exhaustion of inotropic reserve in physical strain, and at an advanced stage of the hypothetical “cardiomyopathic cascade” there are regional and later global contractile deficits even at rest (33). In patients with reduced systolic function we have recorded an eccentric myocardial hypertrophy, unlike the patients with diastolic dysfunction who have concentric myocardial hypertrophy. (34)

In diastolic HF, the left ventricle takes on characteristics of inelastic cavity, so that a part of the blood volumen in protodiastole affects the speed determined by the pressure gradient between the volume load and the velocity at which the ventricle relaxes. Filling of the left ventricle occurs in the meso- and tele-diastole with a significant increase in pressure in the left atrium and pulmonary veins, which can lead to congestion of the lungs and even to pulmonary edema (35). Increasing the pressure in the left atrium is a compensatory mechanism because it allows more efficient filling of the left ventricle. As the disease progresses, we can expect the occurrence of systolic dysfunction, and it is known that all patients known to have a different degree of systolic dysfunction certainly have an impaired diastolic function of the left ventricle as well (36). It seems that there is no disease that would only lead to systolic congestive myocardial failure with a preserved diastolic function.

The diagnosis of diabetic cardiomyopathy already at preclinical stage of the disease can be proved by magnetic resonance imaging, which is a highly selective tool for the detection of left ventricular hypotrophy, a change in its geometry or disorder in contractility, and provides the information about the degree of cardiomyopathy and potential arrhythmia. It is also a good method for diagnosing diastolic dysfunction as well as myocardial steatosis (37). If different radionuclides and positron emission tomography (PET) are used during the magnetic resonance imaging, we can also detect metabolic abnormalities, which enables the diagnosis of diabetic cardiomyopathy in the earliest stage of the disease.

There are serological biomarkers that facilitate the diagnosis and assessment of severity of cardiomyopathy, these are the following which are well known: HbA1c, NT-proBNP and troponin. The value of NT-proBNP above 90 pg/mL in diabetic patients with a highly positive predictive value of 96% detects the diastolic dysfunction of the left ventricle proven by echocardiography. Cardiac troponins (I, T, N) are released into the circulation in case of myocardial damage either due to ischemia or inflammation, and the role of elevated troponin levels in diabetic cardiomyopathy is not yet entirely clear. An increased concentration of matrix metalloproteinase (MMP), especially type 9 (MMP9), and a decreased concentration of tissue inhibitor of metalloproteinases (TIMPs) are good indicators of myocardial fibrosis (38). Metaloproteases participate in the degradation of extracellular matrix and lead to a change in the expression of a number of micro RNA (Mi RNA) which results in myocardial contractile dysfunction. An elevated concentration of the enzymes beta-N-acetylglucosamine (0-GlcNAc) can also be used as a predictor of diabetic cardiomyopathy. (39) A proper clinical meaning of the mentioned new biomolecules in diagnostics of diabetic cardiomyopathy will be known after the publication of the findings of the trials that are in progress.

Coronary angiography is often required in end-stage of diabetic cardiomyopathy.

Impaired relaxation and reduced myocardial extensibility lead to a significant increase in filling pressure even at the time of a small increase in filling volume, which in the stress test is presented as an early dyspnoa and an increase in systolic blood pressure. Advanced diastolic dysfunction eventually leads to pulmonary congestion, which is clinically manifested as intolerance of exertion, progressive and paroxysmal nocturnal dyspnea, orthopnea, cough and chronic fatigue in the later stages of the disease. Diastolic HF is about 50% of all HFs. In the physical status we can hear lung crepitations including the pulmonary edema, and we can see the swollen legs, enlarged liver, swollen neck veins and other signs of global HF.

Differential diagnosis of dyspnea is particularly difficult in elderly and obese patients, especially if the clinical examination finds no signs of congestion. In such a case it is necessary to use the echocardiography to exclude the initial diastolic HF. The patients with developed HF have a worse prognosis, regardless of their ejection fraction or a type of the failure. Annual mortality in diastolic HF is about 8%, and if a systolic-diastolic failure is concerned, the annual mortality rate is 19% (40).

The treatment of diabetic cardiomyopathy includes lifestyle changes, better glycemic and lipodogram control, the treatment of coexisting hypertension, as well as the treatment of HF.

The treatment of HF in patients with diabetic cardiomyopathy is no different from the treatment of non-diabetic HF, and is defined in the European Society of Cardiology Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012 (41). It has been emphasized that there is no treatment that could safely reduce mortality and morbidity in patients with diastolic HF. Diuretics are used to control sodium and water retention, and to mitigate the symptoms of dyspnea and edema. Henle’s loop diuretics (furosemide, torsemide, bumetanide) and thiazide diuretics (hydrochlorothiazide and indapamide) are used while potassium-sparing diuretics such as (spironolactone, eplerenone, amiloride and triamterene) are used in some patients. The importance of adequate treatment of hypertension, myocardial ischemia, as well as adequate control of ventricular response in patients with atrial fibrillation has been identified. The findings of three large studies on candesartan (42) (CHARM), perindopril (43) (PEP-CHF) and irbesatan (44) (I-Preserve) that have not proved the reduction in mortality of hospitalized patients with diastolic HF are discouraging.

The treatment of HF with the impaired left ventricular systolic function is conducted with the aim to reduce the symptoms, improve quality of life and increase functional capacity. This requires drugs from the three major neuro-humoral groups: angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARB), and mineralocorticoid receptor agonists. Diuretic therapy reduces symptoms and signs of congestion. SOLVD and SAVE studies have demonstrated that the benefit of the treatment by ACE inhibitors is equal in patients with and without diabetes (45).

The treatment with beta-blockers significantly increases the survival of patients with HF, regardless of whether they have diabetes or not with no difference in reduction in risk. Three key studies have proved the benefit of bisoprolol (46) (CIBIS II), metaprolol (47) (MERIT-HF) and carvediolol (48) (COPERNICUS) in reduction of mortality. Each study reports on a reduction in mortality by around 34% and a reduction in hospitalizations from 28-36% for HF during the year. More than 90% of patients in these studies with beta-blocker were treated with the ACE inhibitor or ARB.

A number of vasoactive drugs were investigated in patients with diabetic cardiomyopathy and in animal models. Most studies have been designed on drugs that block the reninangiotensin- aldosterone system. The production of angiotensin II in the myocardium was considered to be a potential mechanism of developing cardiomyopathy. Studies related to aliskiren (renin inhibitor), benazepril and valsartan have proved their protective role in the development of cardiomyopathy in animal models (49) and patients (50).

Drugs to be avoided in case of systolic and diastolic HF are: calcium channel blockers due to their negative inotropic effect other than amlodipine and felodipine, non-steroidal antirheumatic drugs and COX 2 inhibitors for salt and water retention and impairment of renal function, the combination of ACE inhibitor and ARB, and thiazolidinediones should be avoided (41).

Out of the drugs from the group of thiazolidinediones, pioglitazone is present in our market, with a significant side-effect such as a weight gain as a result of fluid retention in the body caused by renal sodium retention and reabsorption. It is contraindicated in patients with NYHA functional class III and IV, and can be considered in carefully selected patients with NYHA class I and II with careful monitoring for potential fluid retention (51). In animal models it has anti-inflammatory effect and may slow down the development of fibrosis and thus prevent diabetic cardiomyopathy (52).

Metformin is the most prescribed oral hyperglycemic agent in the world. It increases peripheral insulin sensitivity, improves glycemic control and it can prevent the development of diabetic cardiomyopathy in animal models, for which there is still no evidence in persons with advanced cardiomyopathy (53).

Abnormalities in lipid profile do much more harm to the patients with diabetes than to the non-diabetic population, due to their tendency for accelerated atherosclerosis. Statin therapy significantly reduces mortality of diabetic patients from cardiovascular events. Atorvastatin therapy, regardless of the amount of LDL cholesterol, reduces intramyocardial inflammation, fibrosis and improves left ventricular function in animal models (54). In the same way, the potency of fluvastatin that reduces interstitial myocardial fibrosis and its dysfunction has been proved. Although there are no clinical studies that would prove the efficacy of statins in the prevention of diabetic cardiomyopathy, the desirable effects of treatment of dyslipidemia play an important role in the primary prevention of the disease.

The role of antioxidants is intensively being tested on animal models. A potential effect of riboflavin, luteolin and resveratrol in the prevention of diabetic cardiomyopathy is being investigated. A beneficial antioxidat effect of triemthazidine for its effect on production of energy in the myocardium from glucose oxidation, not from free fatty acid has been proven so far. The drug has a promising effect on ischemic and dilated cardiomyopathy and seems to be slowing down the development of diabetic cardiomyopathy (55).

Diabetes mellitus is a relative contraindication for heart transplantation, although it was shown that carefully selected diabetic patients have significantly worse survival one year after the transplantation and after five years’ period (56). The studies with stem cells aimed at regenerating pancreatic beta cells and myocardial cells in order to improve glucose metabolism and recover the myocardial function are underway. (30)

Strict glycemic control is considered to be the most important factor in preventing the development of cardiomyopathy, but larger studies (UKPDS 33, ACCOD, ADVANCE, VADT) have not verified it (57). Strict glycemic control primarily prevents the development of microangiopathy, its role in the prevention of macroangiopathy is not clear yet. Since in the pathogenesis, diabetic cardiomyopathies have an important role in the disorder at the level of microcirculation, it is expected that a better glycemic control will result in a beneficial effect on its prevention. Preventive mechanisms depend on the degree of development of cardiomyopathy. In the earliest stage of lifestyle changes, even a proper diet low in fat and carbohydrates with a daily physical activity is proved to delay the development of cardiomyopathy. This includes the optimization of body weight and a daily physical activity. Physical activity is associated with a significant reduction in all-cause mortality and coronary heart disease in diabetic patients and it also reduces the incidence of diabetic cardiomyopathy demonstrated on animal models and studies on diabetics (58).

In the moderate cardiomyopathy with proper nutrition and physical activity, the metformin therapy for type 2 or insulin for type 1 disease and pioglitazone improve the diastolic function. At this stage, the beta blockers are the optimal choice for the blood pressure control.

In the late stage of diabetic cardiomyopathy, all the preventive measures mentioned for moderate degree of severity are required here, but along with angiography aimed at detecting macroangiopathy.

Diabetic cardimyopathy is often an unrecognized complication of diabetes, and is a consequence of morphological and structural changes in the myocardium that occur as a result of a number of metabolic reactions accompanying longterm, not controlled hyperglycemia. Due to myocardial remodeling in the initial stage, we can see the myocardial hypertrophy with a development of diastolic and then systolic dysfunction, which significantly increases HF and mortality of diabetic patients. Echocardiography is the most commonly used method for assessing myocardial function. It is necessary in asymptomatic diabetic patients, especially in those who complain of dyspnoea and intolerance of stress. The goal of the trials is to discover new specific biomarkers, where MiRNA is the most promising one, which can detect the disease as soon as the changes start to occur and which are used for scoring the severity of diabetic cardiomyopathy and conducting the target therapy. This paper presents the procedures that can slow down the development of cardiomyopathy, but we also need some new insights about the prevention and efficient therapy.