Impact of SGLT2 inhibitors on the mechanisms of myocardial dysfunction in type 2 diabetes: A prospective non-randomized observational study in patients with type 2 diabetes mellitus without overt heart disease.

AIMS: This prospective observational study evaluated the possible mechanisms of action of SGLT2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) without overt heart disease. METHODS: The study was designed to verify whether SGLT2i impact biomarkers of: myocardial stress-NT-proBNP, inflammation-high sensitivity C-reactive protein, oxidative stress -myeloperoxidase, functional and structural echocardiographic parameters, in patients with T2DM on metformin (heart failure stages A and B) who needed treatment intensification with a second antidiabetic agent. The patients were divided in two groups - the ones planned to receive SGLT2i or DPP-4 inhibitor (except saxagliptin). At baseline, and after six months of therapy, 64 patients underwent blood analysis, physical and echocardiography examination. RESULTS: There were no significant differences between the two groups in terms of biomarkers of myocyte and oxidative stress, inflammation and blood pressure. Body mass index, triglycerides, aspartate aminotransferase, uric acid, E/E', deceleration time and systolic pressure in the pulmonary artery significantly decreased, while stroke volume, indexed stroke volume, high-density lipoprotein, hematocrit and hemoglobin significantly increased in the group on SGLT2i. CONCLUSIONS: According to the results, SGLT2i mechanisms of action comprise rapid changes in body composition and metabolic parameters, reduced cardiac load and improvement in diastolic and systolic parameters.

Perimyocarditis as First Manifestation of Systemic Lupus Erythematosus Successfully Treated with Heart Failure and Immunosuppressive Therapy.

Systemic lupus erythematosus (SLE) myocarditis is presumed to be rare, but associated with adverse outcomes. If SLE diagnosis has not previously been established, its clinical presentation is often unspecific and difficult to recognize. Furthermore, there is a lack of data in the scientific literature regarding myocarditis and its treatment in systemic immune-mediated diseases, leading to its late recognition and undertreatment. We present the case of a young woman whose first lupus manifestations included acute perimyocarditis, among other symptoms and signs that provided clues to the diagnosis of SLE. Transthoracic and speckle tracking echocardiography were helpful in detecting early abnormalities in the myocardial wall thickness and contractility while waiting for cardiac magnetic resonance. Since the patient presented with acute decompensated heart failure (HF), HF treatment was promptly started in parallel with immunosuppressive therapy, with a good response. In the treatment of myocarditis with heart failure, we were guided by the clinical signs, echocardiographic findings, biomarkers of myocardial stress, necrosis, and systemic inflammation, as well as markers of SLE disease activity.

Validation of the fractional exhaled breath temperature measurement: reference values.

Exhaled breath temperature (EBT) is a known biomarker of inflammation and airways blood flow. As opposed to previous studies, we were able to measure temperature of separate fractions of exhaled breath (fEBT) (those from the peripheral and central airways). The aim was to validate the fEBT measurement method to determine the reference values and the influence of endogenous and exogenous factors on fEBT in healthy subjects. This cross-sectional study included 55 healthy adults in whom fEBT was repeatedly measured, two days in a row, using a FractAir®device. Also, basal metabolic rate, level of physical activity, distance from the main road, outdoor and ambient temperature, air pressure and humidity, haematology and inflammation markers, lung function, cumulative EBT and body temperature at characteristic points on the body were measured. The results showed that fEBT from central airways was lower compared to fEBT from the periphery and that fEBTs were not related to body temperature (p> 0.05 for all). We also showed repeatability of fEBT measurements for two consecutive days. All EBT fractions correlated significantly with ambient temperature (<0.01). No associations of fEBT with other personal and external factors were found using multivariate analysis. At room temperature of 22 °C, the physiological temperature values of the first fraction were 23.481 ± 3.150 °C, the second fraction 26.114 ± 4.024 °C and the third fraction 28.216 ± 3.321 °C. The proposed reference values represent the first part of validation of fEBT as the method for the use in clinical practice.

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.

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.

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.

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.

Do gender and age influence the frequency of Helicobacter pylori infection?

BACKGROUND: (13)C urea breath test (UBT) is a noninvasive method for detection of Helicobacter pylori (H. pylori) infection. The aim of this study was to determine age and gender differences in patients with positive UBT. PATIENTS AND METHODS: During the period 2008-2011, a total of 3,000 patients, who did not receive Hp eradication therapy before our study, underwent UBT in Laboratory of Clinical Hospital Sveti Duh. Data were analyzed according to age and gender. RESULTS: A total of 1,400 patients were positive (47 %), 670 males and 730 females (the male/female ratio for positive UBT was 0.92). The male predominance was found in people born between 1930 and 1939, 1940 and 1949, and 1960 and 1969, respectively. The majority infected are born between from 1940 and 1979, with the highest point from 1950-1969. CONCLUSIONS: Our study results confirm the importance of epidemiologic characteristics of Hp infection in our region.