Diabetes mellitus (DM) and heart failure (HF) have a bidirectional relationship and can affect each other. Ventricular dysfunction that occurs in the absence of coronary atherosclerosis and hypertension in patients with diabetes mellitus is called diabetic cardiomyopathy .
The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is closely related to DM and approximately 40% of patients with HFpEF have DM. Heart failure with reduced ejection fraction (HFrEF) is often associated with the progression of DM. HFrEF has a strong association with type 1 diabetes mellitus (T1DM).
During the early stages of diabetic cardiomyopathy, some structural and functional changes occur, some of which are left ventricular (LV) hypertrophy, fibrosis, and altered cell signaling. These changes evolve to HF and then to HFrEF.
The objective of this review is to summarize the current knowledge about diabetic cardiomyopathy, its current pathophysiology and new treatments.
| Methods |
A bibliographic search was carried out on diabetic cardiomyopathy and existing novel treatments in databases (PubMed and Google Scholar). 465 bibliographic search results were found with “diabetic cardiomyopathy” as a keyword and 36 bibliographic search results with “novel treatment”.
| Results |
> Diabetes Mellitus and Heart Failure
There is a strong association between DM and HF. There are 2 forms of heart failure described in DM: HFrEF (LVEF < 40%) and HFpEF (LVEF 41-49%). The prevalence of DM among patients with HFpEF is around 45%.
A large cohort study of people with DM found that the most common CV events were heart failure (14.1%) and peripheral arterial disease (PAD) (16.2%).
The correlation between IC and DM is not clear, but there are possible explanations. Patients with HF have reduced cardiac output, so the delivery of oxygen, insulin, and glucose to peripheral tissues is also decreased. Due to the alteration of blood flow, adrenaline and norepinephrine levels increase.
It is suggested that increased adrenaline and norepinephrine increases insulin resistance and decreases insulin production in the pancreas. Cortisol and catecholamines also increase, which increases blood glucose levels. Activation of the sympathetic system stimulates gluconeogenesis and glycogenolysis. Increased level of catecholamines can also cause insulin resistance.
> Pathophysiology of Diabetic Cardiomyopathy
Several mechanisms are believed to be responsible for heart failure associated with diabetes mellitus and are not limited to diabetic cardiomyopathy. Abnormal extracellular matrix, lipotoxicity in the myocardium, increased oxidative stress and inflammation, and mitochondrial dysfunction are some of the mechanisms responsible.
Elevated levels of glucose residues and metabolites increase the production of advanced glycation end products (AGEs), which can affect cardiomyocytes and endothelial cells. Figure 1 outlines some of the mechanisms thought to contribute to diabetic cardiomyopathy.
> Accumulation of Free Fatty Acids
Fatty acid intake and β-oxidation increase to maintain sufficient levels of ATP production, but β-oxidation over time cannot adequately metabolize all incoming fatty acids, resulting in the accumulation of free fatty acids ( AGL).
Ectopic fat , which accumulates in organs other than adipocytes from visceral fat and subcutaneous fat, causes dysfunction of cells and organs, such as the liver, pancreatic β cells, skeletal muscle, and myocardium, through deterioration of mitochondrial function. This condition is called lipotoxicity.
> Altered Calcium Signaling
Calcium ( Ca) plays a vital role in myocardial contraction. During an action potential, membrane depolarization induces an initial Ca signal so there is an influx of this ion to activate the ion channel and ultimately stimulate myofibril contraction. In both DM 1 and 2 there is a decrease in Ca influx.
> Increased oxidative stress
Chronic hyperglycemia leads to the generation of oxidative stress in pancreatic β cells.
Hyperglycemia promotes overproduction of reactive oxygen species by the mitochondrial electron transport chain and exacerbates the formation of AGEs.
AGEs have a dominant presence in the diabetic heart and may also play a role in the pathogenesis of diabetic cardiomyopathy.
> Mitochondrial dysfunction
The heart is an organ that is highly dependent on mitochondria, as this organelle constitutes up to 1/3 of the cardiac volume and produces adenosine triphosphate (ATP) from the oxidation of fatty acids and glucose. In a diabetic state where insulin production or action is reduced, the mitochondria will use fatty acids as a source to produce ATP instead of glucose. In the pathological condition, however, fatty acids only provide 50-70% of the energy needed by the human heart.
Increased oxidative stress and mitochondrial dysfunction can cause destructions of cells, proteins and nucleic acids leading to cell apoptosis.
> Structural changes
Being in a state of chronic hyperglycemia can alter the structure and function of the myocardium. In the patient with DM, there appears to be an increase in LV mass and, according to one study, a 1% increase in the HbA1C level contributes to a 3.0 g increase in LV mass, although it is necessary to perform further work to evaluate the duration of elevated HbA1C that may contribute to increased LV mass.
Another hallmark of diabetic cardiomyopathy is left ventricular diastolic dysfunction. The initial feature of diastolic dysfunction in patients with DM is prolonged and delayed LV filling and relaxation.
> Diagnosis
There are two stages of diabetic cardiomyopathy; The initial stage is characterized by concentric hypertrophy of the left ventricle, increased myocardial stiffness, increased atrial filling pressure, and impaired diastolic function; while the late stage is characterized by increased cardiac fibrosis, further deterioration of diastolic function and appearance of systolic dysfunction.
There are no differentiated criteria, biochemical markers or physical characteristics for the diagnosis of diabetic cardiomyopathy. Pathological changes during disease progression are usually asymptomatic, so the only way to detect any disease-related changes is through closer examination. Tissue Doppler imaging can be used to evaluate LV dysfunction.
Although it is often said that patients with diabetic cardiomyopathy usually have diastolic dysfunction, examination with stress imaging and cardiac magnetic resonance (CMR) has detected a subtle presence of systolic dysfunction and reduced longitudinal contractility without discrete diastolic dysfunction.
> New drugs to reduce glucose in heart failure
As mentioned above, DM is associated with poor prognosis and longer hospitalization for heart failure. Therefore, reducing the glycemic index has become a goal in the treatment of heart failure.
New classes of antihyperglycemic medications, such as glucagon-like peptide-1 (GLP-1) analogue and sodium-glucose cotransporter 2 inhibitors (SGLT2i), have been shown to reduce cardiovascular mortality and improve glycemic control.
However, treatment of patients with T2DM and heart failure with GLP-1 analogues remains controversial. Several studies in patients with DM have found that GLP-1 analogs did not affect any major adverse cardiovascular events. Other trials showed that these drugs have a significantly lower rate of cardiovascular mortality, myocardial infarction or non-fatal stroke, improve lipotoxicity and also protect cardiac function in patients with T2DM.
Patients with T2DM who received empagliflozin, a selective SGLT2i, have a lower rate of cardiovascular mortality, hospitalization for heart failure, myocardial infarction, or nonfatal stroke. Canagliflozin, another SGLT2i drug, also showed a significantly reduced risk of mortality from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, but had an increased risk of amputation.
Incretin-based drugs, such as dipeptidyl peptidase-4 (DPP-4) inhibitors, have no beneficial effects on heart failure but have been shown to reduce the occurrence of hepatic steatosis. The DPP-4 inhibitor that is not recommended for patients with or at risk of HF is saxagliptin, as it may increase the risk of hospitalization for HF and also increase the incidence of HF in patients with T2DM.
> New therapies for diabetic cardiomyopathy
MicroRNA (miRNA) has been reported to play a role in the pathophysiology of diabetic cardiomyopathy. MiRNA and anti-miRNA mimics are being studied and developed to treat the cardiac disorder.
Phenolic acids are beneficial for mitochondrial dysfunction as a protective agent of the heart against mitochondrial dysfunction and are obtained from plants such as nuts and fruits and can therefore be added to the diet.
| Conclusion |
There is a strong association between diabetes mellitus and the incidence of heart failure. Patients with heart failure have an increased risk of new-onset DM.
Proposed mechanisms underlying the pathophysiology of diabetic cardiomyopathy include lipotoxicity related to free fatty acid accumulation, impaired calcium signaling, increased oxidative stress due to chronic hyperglycemia leading to mitochondrial dysfunction, and alteration of the structure and function of the myocardium.
SGLT2i and new targeted therapies for diabetic cardiomyopathy are promising treatments, but require further research. It is important for physicians to be aware of diabetic cardiomyopathy to improve cardiovascular outcomes in diabetes mellitus.
