“The cardiovascular disease-related mortality with diabetes mellitus is ~65%. Therefore, diabetes mellitus is regarded as a risk equivalent to coronary heart disease. Diabetic heart disease is a growing and important public health risk. It affects the heart in three ways: cardiac autonomic neuropathy (CAN), coronary artery disease (CAD) due to accelerated atherosclerosis, and diabetic cardiomyopathy (DCM). DCM is characterized by lipid accumulation in cardiomyocytes, fetal gene reactivation, and left ventricular (LV) hypertrophy, which together result in contractile dysfunction.”1
“Diabetic cardiomyopathy is a concept that was introduced in 1972 by Rubler et al., who examined pathology of four autopsy cases with diabetic glomerulosclerosis and no known cause of heart failure. The current typical definition of diabetic cardiomyopathy comprises structural and functional abnormalities of the myocardium in diabetic patients without coronary artery disease or hypertension. Obviously, however, this type of cardiomyopathy should be present also in diabetics with coronary artery disease and/or hypertension, though it is difficult to separately assess the contribution of diabetic cardiomyopathy to overall ventricular dysfunction in such cases.”2
The existence of Diabetic Cardiomyopathy has long been debated since it was first introduced about 30 years ago. While almost every healthcare professional is aware of the increased morbidity and mortality rates of cardiac disease in diabetics, correlating cardiomyopathy as a result of hyperglycemia without taking into account current blood pressure and coronary artery disease has always given the medical community cause for pause. However, many fields of study point towards a reality where hyperglycemia is a major culprit of cardiac dysfunction as it relates to diabetes since chronically high levels of blood glucose cause physical damage to the microvasculature and coronary arteries. Due to the parallels in the rise of diabetes mellitus together with cardiomyopathy, it must be studied and researched further so as to clearly understand a diabetic induced cardiomyopathy.
Cardiac responses to diabetes
Various cardiac deformities and abnormal cardiac functions have been recorded in animals with diabetes. In the 70s and 80s, a team of researchers induced diabetes in canines by using a drug called Alloxan. By examining the hemodynamics, biochemical and histological findings of cardiac muscles of these animals, the researchers found a decrease in the quantity of blood the ventricles expel per contraction even though ventricular and diastolic pressure never faltered. Hardening of cardiac chambers was observed in the diabetes-induced dogs versus the healthy control dogs and could not be avoided by insulin.
In rats, extended isovolumetric contractions and diastole occurred along with ventricular hypertrophy and the aforementioned chamber hardening. The following biochemical alterations were observed:
- ATPase and Isoenzymes
- Impairment of Calcium Ion Transport
- Alterations in Receptor functionality
- Alterations in the metabolism of lipids, carbs and adenine nucleotide translocator
The findings in animal research vigorously reinforce the corollary between cardiomyopathy and diabetes.
“The pathophysiological mechanisms of DCM (diabetic cardiomyopathy) have not yet been sufficiently elucidated. The occurrence of DCM is multifactorial, and there are various proposed mechanisms including insulin resistance, microvascular impairment, subcellular component abnormalities, metabolic disturbances, cardiac autonomic dysfunction, alterations in the renin-angiotensin-aldosterone system (RAAS), and maladaptive immune responses.”3
Coronary artery disease develops at an earlier age for many diabetes patients, this is well known. Small vessel disease is partly responsible for diabetic cardiomyopathy but ventricular hypertrophy and its contributions to it are largely underestimated. Because of the strong association between hypertension and diabetes, it follows that ventricular hypertrophy is a result of said hypertension.
“There are different structural and functional modifications in the myocardial tissue after diabetes. These events emerge from metabolic alterations induced by hyperglycemia, insulin resistance and hyperlipidemia. The lack of insulin sensitivity and glucose assimilation in the heart is evident by the reduction in number of glucose transporters Glut1, and mainly, Glut4. In this line, impaired fasting glucose and left ventricular diastolic dysfunction have been correlated in middle-age adults. As a compensatory mechanism, fatty acid transporters are increased, and most ATP generation relies on fatty acid degradation. However, fatty acid may saturate ß-oxidation and accumulate in the cytosol, leading to lipotoxic effects by generation of ceramides, diacylglycerol and reactive species of oxygen (ROS). In this sense, hyperglycemia elicits also ROS and advanced glycation product (AGE) formation, which lead to cardiac glucotoxicity. Both, the lack of fuel and lipo/gluco-toxicity are promoters of calcium misbalance, mitochondrial/endoplasmic reticulum failure and apoptosis, triggering cardiac low-grade chronic inflammation, fibrosis and contractile dysfunction. Among others, the renin-angiotensin-aldosterone (RAA) and TGFß systems, together with specific cytokine/chemokine production, are remarkably enhanced.”4
Having said this, diabetic women seem to have a tendency towards larger ventricular sizes than diabetic men. As such, it is proposed that increased ventricular mass occurs in diabetic patients independently from high blood pressure, as shown by echocardiography. Common deformities affecting cardiac integrity in diabetic patients include:
- Microvascular narrowing
- Interstitial Fibrosis
If hypertension is added to the formula, cardiac problems are only compounded further and is a major red flag for predicting congestive heart failure.
“Currently, the best approach to the diagnosis of diabetic cardiomyopathy is detection of functional and structural changes in the LV (left ventricular) and exclusion of other heart diseases being responsible for the changes in a diabetic patient.”5
Diagnostic clues of diabetic cardiomyopathy
“LV (left ventricular) hypertrophy assessed by 2D echocardiography or CMR (cardiac magnetic resonance imaging). Increased integrated backscatter in the LV (left ventricular) (septal and posterior wall). Late Gd-enhancement of the myocardium in CMR (cardiac magnetic resonance imaging).”5
“LV (left ventricular) diastolic dysfunction assessed by pulsed Doppler echocardiography and TDI (tissue Doppler imaging). LV (left ventricular) systolic dysfunction demonstrated by TDI (tissue Doppler imaging) /SRI (strain/strain rate imaging). Limited systolic and/or diastolic functional reserve assessed by exercise TDI (tissue Doppler imaging).”5
“Reduced cardiac PCr/ATP detected by 31P-MRS (magnetic resonance spectroscopy)
Elevated myocardial triglyceride content detected by 1H-MRS (magnetic resonance spectroscopy).”5
“Diabetic patients arriving to emergency departments with symptoms of HF (heart failure) are examined by non-invasive tests such as chest X-ray, to assess fluid accumulation in the lungs, electrocardiography, to identify ventricular overload, and conventional cardiac ultrasound, to assess structural and functional abnormalities of the myocardium. Additionally, natriuretic peptides plasma levels may also be of help in the diagnosis of heart failure. Other biomarkers not used in the clinical practice in this setting, could provide also additional information. These biomarkers can be released after a wide variety of cardiac and/or skeletal muscle injuries such as inflammation (i.e., C-reactive protein), hypertrophy/stiffness and necrosis (i.e., troponins) in relation to different diseases such as myocardial infarction, arrhythmia, myocarditis, hypertension, or any secondary cardiac injury (i.e., chemotherapy, renal kidney disease). Thus, recent human and mainly pre-clinical data suggest new techniques for detection of premature DCM (diabetic cardiomyopathy) based on imaging and biomarkers analysis.”6
“Echocardiography. Nowadays, this non-invasive approach is the gold standard diagnostic tool to identify structural cardiac disorders. It provides a reliable identification of the structural abnormalities seen in early stages of DCM (diabetic cardiomyopathy), such as impaired diastolic filling and left ventricle hypertrophy. It can also be helpful for the assessment of the progression of the disease and evaluation of treatments. Echocardiography has been widely studied in rodent models even without using anesthesia, and thus, eluding the cardiodepressant effect. Several modalities can be used.”7
Risk factors for Diabetic Cardiomyopathy
Thanks to many experimental findings and data, diabetes is now accepted as a risk factor for the advancement of cardiac disease. Heart failure is doubly prevalent in men with diabetes than their healthy male counterparts. Diabetic women on the other hand suffer heart failure at 5 times a greater clip than non-diabetic females. This extreme hazard for congestive heart failure remains in spite of adjusting the data for age, weight and an underlying presence of hypertension, hypercholesterolemia and coronary heart disease. While diabetes and hypertension are independently deadly in and of themselves, there appears to be a synergy, or cooperation between the two that may ultimately lead to heart failure. It is believed that treating high blood pressure with ACE (Angiotensin Converting Enzyme Inhibitor) in diabetic patients will impede the progression of Diabetic Cardiomyopathy. However, the standardization of treatment with ACE is still in preparatory fazes as more data comes in and conclusive results emerge.
“Diabetes mellitus is a well-known risk factor for the development of heart failure. The Framingham Heart Study demonstrated that the frequency of heart failure is five times greater in diabetic women and two times greater in diabetic men compared with age-matched control subjects. Heart failure leads to a poor quality of life in affected individuals and complicates the treatment of diabetes mellitus by altering the pharmacokinetics of anti-diabetic medications. Thus, both the prompt diagnosis and early management of these patients are of utmost importance. However, DCM (Diabetic Cardiomyopathy) is poorly understood by most physicians, even cardiologists and diabetologists.”8
“There is a considerable body of epidemiological evidence that implicates obesity, linked to increased intake of refined carbohydrates and decreased exercise, in the increasing prevalence of diabetes and related heart disease throughout the world. Lifestyle changes such as aerobic exercise, weight control and smoking cessation are efficacious therapeutic approaches in the prevention of diabetic cardiomyopathy. Sustained glycemic control reduces the prevalence of diabetic cardiomyopathy and reduces cardiovascular disease (CVD). For example, normalization of glycaemia with insulin therapy reduced cardiomyocyte hypertrophy, collagen content and diastolic dysfunction and limited progression of diabetic cardiomyopathy in type 1 diabetic rodent models. There is emerging evidence that some glycemic therapies may have specific benefits. In a retrospective cohort study of 10,920 patients, metformin use was associated with a low risk of mortality in diabetic individuals with heart failure. Sodium–glucose cotransporter (SGLT) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists have beneficial effects on CVD (cardiovascular disease) outcomes in type 2 diabetic patients.”9
“The cardinal features of diabetic cardiomyopathy include cardiac stiffness, myocardial fibrosis and hypertrophy with cardiac diastolic dysfunction and subsequent progression to both systolic dysfunction and clinical heart failure. Importantly, hyperglycemia and systemic and cardiac insulin resistance are independently associated with the development and progression of cardiac dysfunction and heart failure in diabetes. From a mechanistic point of view, mitochondrial dysfunction, oxidative stress, increased formation and deposition of AGEs, impaired mitochondrial Ca2+ handling and function, inflammation, activation of RAAS (renin-angiotensin-aldosterone system) and SNS (central nervous system), cardiac autonomic neuropathy, endoplasmic reticulum stress, microvascular dysfunction, and cardiac metabolic disorders are involved in the pathophysiological process.”10
“Although diabetic cardiomyopathy appears to have an extensive preclinical course and the pathophysiological changes appear to be induced by the metabolic alterations in diabetes mellitus, a formal definition for diabetic cardiomyopathy as a distinct clinical entity remains vague due to a lack of accepted diagnostic criteria and information on subclinical CVD (cardiovascular disease) in the early stages of diabetes. Currently, there is not a specific histological property, biochemical marker, or clinical manifestation for the definitive diagnosis of diabetic cardiomyopathy. Also, there are no prospective clinical trials to support that hyperglycemia or hyperinsulinemia independently increase the risk for development of diabetic cardiomyopathy in the absence of other risk factors such as obesity, coronary heart disease, and hypertension. Recent scientific evidence for the potential use of exosome and circulating miRNAs as biomarkers for detection of diabetic cardiomyopathy highlights emerging methods for the diagnosis and prevention of diabetes and cardiomyopathy.”11
(1, 3, 8) Diabetic cardiomyopathy: where we are and where we are going. Lee, W.S. & Kim, J. Korean Journal of Internal Medicine. 2017. http://kjim.org/journal/view.php?doi=10.3904/kjim.2016.208
(2, 5) Diabetic cardiomyopathy: pathophysiology and clinical features. Miki, T., Yuda, S., Kouzu, H., & Miura, T. Heart Failure Reviews. 2013. https://link.springer.com/article/10.1007%2Fs10741-012-9313-3
(4, 6, 7) Diagnostic approaches for diabetic cardiomyopathy. Lorenzo-Almorós, A., Tuñón, J., Orejas, M. Cortés, M., Egido, J. & and Lorenz, Ó. Cardiovascular Diabetology. 2017. https://cardiab.biomedcentral.com/articles/10.1186/s12933-017-0506-x
(9, 10, 11) Diabetic cardiomyopathy: an update of mechanisms contributing to this clinical entity. Jia, G., Hill, M.A. & Sowers, J.R. Circulation Research. 2019. https://www.ahajournals.org/doi/10.1161/CIRCRESAHA.117.311586