**5. Chronic heart failure and diabetes mellitus**

#### **5.1 Classification and epidemiology of heart failure**

LVEF is the criterion that is taken into consideration when diagnosing HF in groups. Based on the 'Report on the Universal Definition and Classification of HF' [90] and the last 2021 European Society of Cardiology (ESC) guidelines [91], there are three major categories of HF proposed: HF where EF is preserved (HFpEF, LVEF ≥50%), HF where EF is mildly reduced (HFmrEF, LVEF between 41 and 49%), and HF where EF is reduced (HFrEF, LVEF ≤40%). Improved LVEF is used to describe patients who have been previously diagnosed with HFrEF whose LVEF is now >40%.

Approximately 50% of all HF instances are caused by HFpEF, and its prevalence is rising—making this category of HF the most common one in the future [92, 93]. HFrEF has distinct risk factors including male gender and CVD history (for example, MI) [94]. In comparison with HFpEF, patients with HFrEF have a greater mortality rate [92, 95]. HF with mildly reduced EF, previously named "HF with mid-range EF" since similar therapies work for both patients with HFmrEF and HFrEF, is the latest type of HF (introduced by ACCF/AHA in 2013 [96] and by the ESC in 2016 [91, 94]).

Hypertension, CKD, obesity, and diabetes are all important predictors of HF [97, 98]. The etiological relationship between DM and HF is mutually directed. Prolonged diabetes contributes to the development of myocardial dysfunction and HF [99]. This is due to potentiation of endothelial dysfunction, dyslipidemia, and hypercoagulability, and is also the result of a direct effect of hyperglycemia on myocardial function and morphology. On the other hand, HF can be complicated by the development of DM as a result of organ hypoperfusion and hyperactivation of neurohumoral systems, which contribute to an increase in blood glucose concentration as a result of a decrease in glucose consumption by muscle tissue, increased

#### *Diabetes Mellitus Type 2, Prediabetes, and Chronic Heart Failure DOI: http://dx.doi.org/10.5772/intechopen.106391*

gluconeogenesis in the liver, and the contra-insular effect of catecholaminemia [100]. Also, HF in patients with DM is considered direct damage to the heart muscle as a result of prolonged hyperglycemia. Myocardial damage against the background of hyperglycemia is mediated by microangiopathy, impaired calcium transport, and fatty acid metabolism [101]. A classic example of the myocardial effect of hyperglycemia is diabetic cardiomyopathy.

Diabetic cardiomyopathy describes impaired cardiac function as a result of decreased glucose metabolism and increased fatty acid (FA) metabolism [102]. It also includes myocardial structural and performance anomalies in people with diabetes not diagnosed with coronary artery disease, valvular disease, or other CV risk factors such as hypertension and dyslipidemia [103]. Irregularities that are usually seen in diabetes, such as hyperglycemia, hyperinsulinemia, systemic insulin resistance, and inflammation, are the factors that directly lead to the development of cardiomyopathy in people with diabetes (CMiPD) [103]. Regardless of LVEF or HF etiology, insulin therapy may be linked with higher mortality compared to oral hypoglycemic agents [104].

Insulin therapy in type 1 diabetes improves hyperglycemia and increases myocardial ischemia and death of cardiomyocytes, thereby inducing HF. There is evidence of a direct relationship between myocardial tissue perfusion, oxygen supply, energy substrate availability, and myocardial function in patients with DM, suggesting microcirculatory damage as a cause of diabetic cardiomyopathy [105]. Thus, the prevalence of CMiPD is increasing at the same rate as T2D [103].

As CMiPD advances from the first stage through the last, muscle contraction is impaired and fibrosis develops [102]. Stage I is characterized by abnormal myocardial relaxation, however normal EF [102]. During stage IV, HF is developed due to overt ischemia and infarct [102]. Hyperglycemia, hyperinsulinemia, inflammation, and hyperlipidemia due to diabetes can lead to cardiac dysfunction along with changes in the structure of the heart [106]. In the case of CMiPD, insulin resistance causes glucose metabolism in the cardiac myocyte to be altered; more specifically, glucose uptake, glycolytic activity, and oxidation of pyruvates are decreased [102]. In CMiPD while glucose is available in small amounts, there is an accumulation of circulating FAs that act as an energy source for the cardiomyocytes [102]. As a result of overactive FA oxidation and metabolic inflexibility, the heart is exposed to a variety of secondary pathways making it less capable of dealing with increased workloads [102].

An increase in free FA and hyperglycemia leads to an undesirable accumulation of lipids in the heart. Cardiomyocytes are not adapted to the accumulation of large amounts of lipids that have a direct cytopathic effect on them, and lipid fragments lead to the activation of inflammatory signaling pathways, including protein kinase C, which interfere with insulin signaling. As a result, insulin resistance develops, which limits the consumption of glucose by cells and a shift happens toward fatty acid oxidation [107].

Particularly, as FA-rich cardiomyocytes produce ATP less effectively and accumulate diverse toxic intermediates and lipids, pro-inflammatory and profibrotic responses are induced [102]. These processes ultimately lead to CMiPD through cardiac hypertrophy and diastolic dysfunction [102].

The accumulation of end products is the driving force behind microvascular damage in DM and is associated with myocardial stiffness and collagen accumulation in the myocardium. The gradual increase in myocardial stiffness also leads to diastolic dysfunction, decreased myocardial tension, and atrial dilatation, which is associated with an increased prevalence of atrial fibrillation in patients with DM [108].

Mitochondrial dysfunction can also lead to CMiPD development. This happens because of excessive mitophagy causing an imbalance between mitophagy and mitochondrial biogenesis. As a result, myocardial cells are destructed more intensively [109].

It has been established that ketone metabolism can be an alternative to the energy supply of the heart muscle [110]. The concentrations of circulating ketone bodies increase in HF and they enter the cell as an insulin-independent energy substrate. The appearance of ketone enzymes in a hypertrophied and damaged heart leads to energy consumption for the oxidation of ketones with insufficient possibilities for oxidation of fatty acids [111]. The presence of DM contributes to the development of myocardial dysfunction and CHF due to the development and maintenance of endothelial dysfunction, dyslipidemia, hypercoagulation, and the direct effect of hyperglycemia on myocardial function and morphology [112]. At the same time, in HF, as a result of organ hypoperfusion and hyperactivation of neurohumoral systems (decrease in glucose consumption by muscle tissue, increased gluconeogenesis in the liver, contra-insular effects of catecholaminemia), blood glucose levels increase.

Thus, the development of HF in DM is due to the progression of atherosclerosis with subsequent progression of myocardial ischemia and immediate myocardial damage as a result of prolonged hyperglycemia. Myocardial damage against the background of hyperglycemia is mediated by microangiopathy, impaired calcium transport, and fatty acid metabolism. The presence of DM increases the risk of developing HF compared with that in the general population, and there is a significantly higher mortality among DM patients with HF. In addition, an increased risk of developing HF was found in individuals with elevated values of morning glycemia even in the absence of DM. Patients with HF have high insulin resistance and an increased risk of developing DM [113].
