The Mystery of Diabetic Cardiomyopathy: From Early Concepts and Underlying Mechanisms to Novel Therapeutic Possibilities.

Diabetic patients are predisposed to diabetic cardiomyopathy, a specific form of cardiomyopathy which is characterized by the development of myocardial fibrosis, cardiomyocyte hypertrophy, and apoptosis that develops independently of concomitant macrovascular and microvascular diabetic complications. Its pathophysiology is multifactorial and poorly understood and no specific therapeutic guideline has yet been established. Diabetic cardiomyopathy is a challenging diagnosis, made after excluding other potential entities, treated with different pharmacotherapeutic agents targeting various pathophysiological pathways that need yet to be unraveled. It has great clinical importance as diabetes is a disease with pandemic proportions. This review focuses on the potential mechanisms contributing to this entity, diagnostic options, as well as on potential therapeutic interventions taking in consideration their clinical feasibility and limitations in everyday practice. Besides conventional therapies, we discuss novel therapeutic possibilities that have not yet been translated into clinical practice.

Minireview: are SGLT2 inhibitors heart savers in diabetes?

Sodium-glucose cotransporter 2 (SGLT2) inhibitors, a class of drugs that promote urinary glucose excretion in the treatment of diabetes, have provoked large interest of scientific and professional community due to their positive and, somehow, unexpected results in the three major cardiovascular outcome trials (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, and DECLARE-TIMI 58 with dapagliflozin). In fact, along with the reduction of major adverse cardiovascular events, SGLT2 inhibitors reduced significantly hospitalization for heart failure regardless of existing atherosclerotic cardiovascular disease or a history of heart failure. The latter have reminded us of the frequent but neglected entity of diabetic cardiomyopathy which is currently poorly understood despite its great clinical importance. Physiological mechanisms responsible for the benefits of SGLT2 inhibitors are complex and multifactorial and still not well defined. Interestingly, the time frame of their effect excludes a glucose- and antiatherosclerotic-mediated effect. It would be of great importance to better understand SGLT2 inhibitor mechanisms of action since they could have a potential to be used in early stages of diabetes as cardioprotective agents. There are widely available biomarkers as well as echocardiography that are used in everyday clinical practice and could elucidate physiological mechanisms in the heart protection with SGLT2 inhibitors treatment but studies are still lacking. The purpose of this minireview is to summarize the latest concepts about SGLT2 inhibitors and its benefits regarding diabetic cardiomyopathy especially on its early stage development and to discuss controversies and potential future developments in the field.

Sodium-dependent glucose transporter 2 inhibitors effects on myocardial function in patients with type 2 diabetes and asymptomatic heart failure.

BACKGROUND: Sodium-dependent glucose transporter 2 inhibitors (SGLT2i) have shown efficacy in reducing heart failure (HF) burden in a very heterogeneous groups of patients, raising doubts about some contemporary assumptions of their mechanism of action. We previously published a prospective observational study that evaluated mechanisms of action of SGLT2i in patients with type 2 diabetes who were in HF stages A and B on dual hypoglycemic therapy. Two groups of patients were included in the study: the ones receiving SGLT2i as an add-on agent to metformin and the others on dipeptidyl peptidase-4 inhibitors as an add-on to metformin due to suboptimal glycemic control. AIM: To evaluate the outcomes regarding natriuretic peptide, oxidative stress, inflammation, blood pressure, heart rate, cardiac function, and body weight. METHODS: The study outcomes were examined by dividing each treatment arm into two subgroups according to baseline parameters of global longitudinal strain (GLS), N-terminal pro-brain natriuretic peptide, myeloperoxidase (MPO), high-sensitivity C-reactive protein (hsCRP), and systolic and diastolic blood pressure. To evaluate the possible predictors of observed changes in the SGLT2i arm during follow-up, a rise in stroke volume index, body mass index (BMI) decrease, and lack of heart rate increase, linear regression analysis was performed. RESULTS: There was a greater reduction of MPO, hsCRP, GLS, and blood pressure in the groups with higher baseline values of mentioned parameters irrespective of the therapeutic arm after 6 months of follow-up. Significant independent predictors of heart rate decrease were a reduction in early mitral inflow velocity to early diastolic mitral annular velocity at the interventricular septal annulus ratio and BMI, while the predictor of stroke volume index increase was SGLT2i therapy itself. CONCLUSION: SGLT2i affect body composition, reduce cardiac load, improve diastolic/systolic function, and attenuate the sympathetic response. Glycemic control contributes to the improvement of heart function, blood pressure control, oxidative stress, and reduction in inflammation.

Is the extent of left atrial fibrosis associated with body mass index in patients undergoing pulmonary vein isolation for atrial fibrillation?

BACKGROUND: Left atrial (LA) fibrosis is associated with a higher rate of recurrence of atrial fibrillation (AF) after pulmonary vein isolation (PVI). Body mass index (BMI) is strongly associated with the prevalence of AF, but there is insufficient data about the association between BMI and LA fibrosis. AIMS: The aim of the study was to examine the association between LA fibrosis and BMI in patients with AF undergoing PVI. METHODS: In 114 patients an electro-anatomical voltage map was created using the CARTO 3 three-dimensional system before PVI. The total fibrosis area (voltage criteria ≤0.5 mV), percentage, and the number of fibrotic areas were calculated. A general linear model was used to determine the differences in BMI with confounders between groups of patients with differing extents of fibrosis and numbers of focuses. RESULTS: Advanced fibrosis was found in 53 (47%) patients, in up to 9 areas with a median of 2 and an interquartile range (IQR) of 0-3. The median total fibrotic area was 27.3 cm2 with an IQR of 0.1-30.3 cm2. Patients were stratified by percentage of fibrotic area: <5%, 5%-20%, 20%-35%, and above 35%; no significant difference in mean BMI was found between the groups (P = 0.57). When stratified by the number of fibrotic areas (0, 1, 2, and ≥3 fibrotic areas), no difference in BMI was noted between the groups (P = 0.67). CONCLUSIONS: Fibrosis of the LA, as the strongest predictor of AF recurrence after PVI, does not correlate with BMI in patients with AF where PVI is indicated.

Prevention of cardiac allograft vasculopathy - A new possible indication for SGLT-2 inhibitors?

One of the main risk factors influencing patient survival after heart transplantation is cardiac allograft vasculopathy, the leading cause of death after the first year of transplantation. It is an entity of multifactorial origin including both humoral and cellular alloimmune responses as well as immunologic-independent factors such as graft injury, ischaemia-reperfusion injury, oxidative stress, cytomegalovirus infection, hyperlipidaemia, diabetes mellitus and hypertension. A fundamental characteristic of cardiac allograft vasculopathy is vascular remodelling, initially driven by the injury and apoptosis of endothelial cells, then by the migration of smooth muscle cells leading to intimal thickening and ultimately allograft vessel occlusion. Since cardiac allograft vasculopathy occurs within the first year of transplantation, prevention strategies should be implemented early. The disease could be partially prevented with overall cardiovascular risk reduction, mainly by controlling diabetes, hyperlipidemia and hypertension that can be related to the recipient but also induced or augmented by immunosuppressive drugs used. Current therapeutic options are only partially effective in postponing the development of vascular lesions. Diabetes is an important issue in the management of patients following cardiac transplantation. Although it is highly prevalent among heart transplant recipients (23% at 1 year increasing to 37% at 5 years after the procedure), no specific therapeutic protocols have been recommended yet. Sodium-glucose cotransporter-2 (SGLT-2) inhibitors are a novel class of antidiabetic drugs that produce glycosuric and natriuretic effects by inhibiting glucose and sodium reabsorption from the renal proximal tubules and have already shown benefits in cardiovascular outcome trials. Our hypothesis is that SGLT-2 inhibitors could prevent or delay the development of cardiac allograft vasculopathy targeting various mechanisms underpinning its pathogenesis due to their antidiabetic, antihypertensive, anti-inflammatory, antifibrotic, antioxidative and antiapoptotic effects, as well as through amelioration of endothelial dysfunction, ischaemia-reperfusion injury and modification of neurohumoral system. All the segments of the proposed theory that could interfere with evolution of vasculopathy are discussed separately within the main text. The implications for the science if the hypothesis were to be confirmed are as follows: prolongation of lifespan in heart transplant patients with diabetes, reduction of polypragmasia in posttransplant patients while targeting several mechanisms with one drug, and the possibility of spreading the indications even to patients without diabetes.

Sodium-glucose cotransporter 2 inhibitors' mechanisms of action in heart failure.

Three major cardiovascular outcome trials (CVOTs) with a new class of antidiabetic drugs - sodium-glucose cotransporter 2 (SGLT2) inhibitors (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program with canagliflozin, DECLARE-TIMI 58 with dapagliflozin) unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk, which seems to be the most sensitive outcome of SGLT2 inhibition. No other CVOT to date has shown any significant benefit on heart failure events. Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure: Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status. Nevertheless, despite their possible wide clinical implications, there is much doubt about the mechanisms of action and a lot of questions to unravel, especially now when their benefits translated to non-diabetic patients, rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucose-lowering and antiatherosclerotic-mediated effects and multiple other mechanisms, direct cardiac as well as systemic, are suggested to explain their early cardiorenal benefits. These are: Anti-inflammatory, antifibrotic, antioxidative, antiapoptotic properties, then renoprotective and hemodynamic effects, attenuation of glucotoxicity, reduction of uric acid levels and epicardial adipose tissue, modification of neurohumoral system and cardiac fuel energetics, sodium-hydrogen exchange inhibition. The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis. All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.