Methods to predict heart failure in diabetes patients.

INTRODUCTION: Type 2 diabetes mellitus (T2DM) is one of the leading causes of cardiovascular disease and powerful predictor for new-onset heart failure (HF). AREAS COVERED: We focus on the relevant literature covering evidence of risk stratification based on imaging predictors and circulating biomarkers to optimize approaches to preventing HF in DM patients. EXPERT OPINION: Multiple diagnostic algorithms based on echocardiographic parameters of cardiac remodeling including global longitudinal strain/strain rate are likely to be promising approach to justify individuals at higher risk of incident HF. Signature of cardiometabolic status may justify HF risk among T2DM individuals with low levels of natriuretic peptides, which preserve their significance in HF with clinical presentation. However, diagnostic and predictive values of conventional guideline-directed biomarker HF strategy may be non-optimal in patients with obesity and T2DM. Alternative biomarkers affecting cardiac fibrosis, inflammation, myopathy, and adipose tissue dysfunction are plausible tools for improving accuracy natriuretic peptides among T2DM patients at higher HF risk. In summary, risk identification and management of the patients with T2DM with established HF require conventional biomarkers monitoring, while the role of alternative biomarker approach among patients with multiple CV and metabolic risk factors appears to be plausible tool for improving clinical outcomes.

Extracellular vesicles in heart failure.

Physiologically, extracellular vesicles (EVs) have been implicated as crucial mediators of immune response, cell homeostasis, angiogenesis, cell differentiation and growth, and tissue repair. In heart failure (HF) they may act as regulators of cardiac remodeling, microvascular inflammation, micro environmental changes, tissue fibrosis, atherosclerosis, neovascularization of plaques, endothelial dysfunction, thrombosis, and reciprocal heart-remote organ interaction. The chapter summaries the nomenclature, isolation, detection of EVs, their biologic role and function physiologically as well as in the pathogenesis of HF. Current challenges to the utilization of EVs as diagnostic and predictive biomarkers in HF are also discussed.

Predictors of Kidney Function Outcomes and Their Relation to SGLT2 Inhibitor Dapagliflozin in Patients with Type 2 Diabetes Mellitus Who Had Chronic Heart Failure.

INTRODUCTION: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) have a favorable impact on the kidney function in patients with heart failure (HF), while there is no clear evidence of what factors predict this effect. The aim of the study was to identify plausible predictors for kidney function outcome among patients with HF and investigate their association with SGLT2i. METHODS: We prospectively enrolled 480 patients with type 2 diabetes mellitus (T2DM) treated with diet and metformin and concomitant chronic HF and followed them for 52 weeks. In the study, we determined kidney outcome as a composite of ≥ 40% reduced estimated glomerular filtration rate from baseline, newly diagnosed end-stage kidney disease or kidney replacement therapy. The relevant medical information and measurement of the biomarkers (N-terminal natriuretic pro-peptide, irisin, apelin, adropin, C-reactive protein, tumor necrosis factor-alpha) were collected at baseline and at the end of the study. RESULTS: The composite kidney outcome was detected in 88 (18.3%) patients of the entire population. All patients received guideline-recommended optimal therapy, which was adjusted to phenotype/severity of HF, cardiovascular risk and comorbidity profiles, and fasting glycemia. Levels of irisin, adropin and apelin significantly increased in patients without clinical endpoint, whereas in those with composite endpoint the biomarker levels exhibited a decrease with borderline statistical significance (p = 0.05). We noticed that irisin ≤ 4.50 ng/ml at baseline and a ≤ 15% increase in irisin serum levels added more valuable predictive information than the reference variable. However, the combination of irisin ≤ 4.50 ng/ml at baseline and ≤ 15% increase in irisin serum levels (area under curve = 0.91; 95% confidence interval = 0.87-0.95) improved the discriminative value of each biomarker alone. CONCLUSION: We suggest that low levels of irisin and its inadequate increase during administration of SGLT2i are promising predictors for unfavorable kidney outcome among patients with T2DM and concomitant HF.

Low Plasma Levels of Irisin Predict Acutely Decompensated Heart Failure in Type 2 Diabetes Mellitus Patients with Chronic Heart Failure.

The aim of this study was to determine the discriminative value of irisin for acutely decompensated heart failure (ADHF) in type 2 diabetes mellitus (T2DM) patients with chronic HF. We included 480 T2DM patients with any phenotype of HF and followed them for 52 weeks. Hemodynamic performances and the serum levels of biomarkers were detected at the study entry. The primary clinical end-point was ADHF that led to urgent hospitalization. We found that the serum levels of N-terminal natriuretic pro-peptide (NT-proBNP) were higher (1719 [980-2457] pmol/mL vs. 1057 [570-2607] pmol/mL, respectively) and the levels of irisin were lower (4.96 [3.14-6.85] ng/mL vs. 7.95 [5.73-9.16] ng/mL) in ADHF patients than in those without ADHF. The ROC curve analysis showed that the estimated cut-off point for serum irisin levels (ADHF versus non-ADHF) was 7.85 ng/mL (area under curve [AUC] = 0.869 (95% CI = 0.800-0.937), sensitivity = 82.7%, specificity = 73.5%; p = 0.0001). The multivariate logistic regression yielded that the serum levels of irisin < 7.85 ng/mL (OR = 1.20; p = 0.001) and NT-proBNP > 1215 pmol/mL (OR = 1.18; p = 0.001) retained the predictors for ADHF. Kaplan-Meier plots showed a significant difference of clinical end-point accumulations in patients with HF depending on irisin levels (<7.85 ng/mL versus ≥7.85 ng/mL). In conclusion, we established that decreased levels of irisin were associated with ADHF presentation in chronic HF patients with T2DM independently from NT-proBNP.

Adropin Predicts Chronic Kidney Disease in Type 2 Diabetes Mellitus Patients with Chronic Heart Failure.

Adropin is a multifunctional secreted protein, which is involved in the metabolic modulation of the heart-brain-kidney axis in heart failure (HF). The aim of the study was to detect the plausible predictive value of serum levels of adropin for chronic kidney disease (CKD) grades 1-3 in type 2 diabetes mellitus (T2DM) patients with chronic HF. We enrolled 417 T2DM individuals with chronic HF and subdivided them into two groups depending on the presence of CKD. The control group was composed of 25 healthy individuals and 30 T2DM patients without HF and CKD. All eligible patients underwent an ultrasound examination. Adropin was detected by ELISA in blood samples at the study baseline. We found that adropin levels in T2DM patients without HF and CKD were significantly lower than in healthy volunteers, but they were higher than in T2DM patients with known HF. The optimal cut-off point for adropin levels was 2.3 ng/mL (area under the curve [AUC] = 0.86; 95% CI = 0.78-0.95; sensitivity = 81.3%, specificity = 77.4%). The multivariate logistic regression adjusted for albuminuria/proteinuria showed that serum levels of adropin <2.30 ng/mL (OR = 1.55; p = 0.001) independently predicted CKD. Conclusions: Low levels of adropin in T2DM patients with chronic CH seem to be an independent predictor of CKD at stages 1-3.

Cardiac Hepatopathy: New Perspectives on Old Problems through a Prism of Endogenous Metabolic Regulations by Hepatokines.

Cardiac hepatopathy refers to acute or chronic liver damage caused by cardiac dysfunction in the absence of any other possible causative reasons of liver injury. There is a large number of evidence of the fact that cardiac hepatopathy is associated with poor clinical outcomes in patients with acute or actually decompensated heart failure (HF). However, the currently dominated pathophysiological background does not explain a role of metabolic regulative proteins secreted by hepatocytes in progression of HF, including adverse cardiac remodeling, kidney injury, skeletal muscle dysfunction, osteopenia, sarcopenia and cardiac cachexia. The aim of this narrative review was to accumulate knowledge of hepatokines (adropin; fetuin-A, selenoprotein P, fibroblast growth factor-21, and alpha-1-microglobulin) as adaptive regulators of metabolic homeostasis in patients with HF. It is suggested that hepatokines play a crucial, causative role in inter-organ interactions and mediate tissue protective effects counteracting oxidative stress, inflammation, mitochondrial dysfunction, apoptosis and necrosis. The discriminative potencies of hepatokines for HF and damage of target organs in patients with known HF is under on-going scientific discussion and requires more investigations in the future.

The Impact of SGLT2 Inhibitor Dapagliflozin on Adropin Serum Levels in Men and Women with Type 2 Diabetes Mellitus and Chronic Heart Failure.

BACKGROUND: adropin plays a protective role in cardiac remodeling through supporting energy metabolism and water homeostasis and suppressing inflammation. Low circulating levels of adropin were positively associated with the risk of cardiovascular diseases and type 2 diabetes mellitus (T2DM). We hypothesized that sodium-glucose linked transporter 2 (SGLT2) inhibitor dapagliflosin might represent cardiac protective effects in T2DM patients with known chronic HF through the modulation of adropin levels. METHODS: we prospectively enrolled 417 patients with T2DM and HF from an entire cohort of 612 T2DM patients. All eligible patients were treated with the recommended guided HF therapy according to their HF phenotypes, including SGLT2 inhibitor dapagliflozin 10 mg, daily, orally. Anthropometry, clinical data, echocardiography/Doppler examinations, and measurements of biomarkers were performed at the baseline and over a 6-month interval of SGLT2 inhibitor administration. RESULTS: in the entire group, dapagliflozin led to an increase in adropin levels by up to 26.6% over 6 months. In the female subgroup, the relative growth (Δ%) of adropin concentrations was sufficiently higher (Δ% = 35.6%) than that in the male subgroup (Δ% = 22.7%). A multivariate linear regression analysis of the entire group showed that the relative changes (Δ) in the left ventricular (LV) ejection fraction (LVEF), left atrial volume index (LAVI), and E/e' were significantly associated with increased adropin levels. In the female subgroup, but not in the male subgroup, ΔLVEF (p = 0.046), ΔLAVI (p = 0.001), and ΔE/e' (p = 0.001) were independent predictive values for adropin changes. CONCLUSION: the levels of adropin seem to be a predictor for the favorable modification of hemodynamic performances during SGLT2 inhibition, independent ofN-terminal brain natriuretic pro-peptide levels.

Biomarkers in Heart Failure: From Research to Clinical Practice.

The aim of this narrative review is to summarize contemporary evidence on the use of circulating cardiac biomarkers of heart failure (HF) and to identify a promising biomarker model for clinical use in personalized point-of-care HF management. We discuss the reported biomarkers of HF classified into clusters, including myocardial stretch and biomechanical stress; cardiac myocyte injury; systemic, adipocyte tissue, and microvascular inflammation; cardiac fibrosis and matrix remodeling; neurohumoral activation and oxidative stress; impaired endothelial function and integrity; and renal and skeletal muscle dysfunction. We focus on the benefits and drawbacks of biomarker-guided assistance in daily clinical management of patients with HF. In addition, we provide clear information on the role of alternative biomarkers and future directions with the aim of improving the predictive ability and reproducibility of multiple biomarker models and advancing genomic, transcriptomic, proteomic, and metabolomic evaluations.

Interplay between Myokine Profile and Glycemic Control in Type 2 Diabetes Mellitus Patients with Heart Failure.

Type 2 diabetes mellitus (T2DM) remains a powerful predictor of progressive heart failure (HF), but it is not clear whether altered glycemic control interferes with HF progression via an impaired profile of circulating myokines. The aim was to investigate plausible effects of glucose control on a myokine signature in T2DM patients affected by chronic HF. We selected 372 T2DM patients from the local database and finally included 314 individuals suffering from chronic HF and subdivided them into two groups according to glycosylated hemoglobin (HbA1c) levels (<6.9% and ≥7.0%). Echocardiography and Doppler examinations along with biomarker measurements were performed at the baseline of the study. The results showed that irisin levels were significantly lower in patients with HbA1c ≥ 7.0% than in those with HbAc1 < 6.9%, whereas concentrations of apelin, myostatin and adropin did not significantly differ between these two groups. We also identified numerous predictors of poor glycemic control, but only N-terminal brain natriuretic propeptide (odds ratio [OR] = 1.07; 95% confidence interval [CI] = 1.02−1.10, p = 0.04) and irisin (OR = 1.09; 95% CI = 1.04−1.17, p = 0.001) remained independent predictors of the dependent variable. In conclusion, we found that decreased levels of irisin were associated with poor glycemic control in T2DM patients with HF regardless of clinical conditions and other biomarkers.

Predictive value of serum irisin for chronic heart failure in patients with type 2 diabetes mellitus.

We hypothesize that serum irisin can have additional discriminative potency for heart failure (HF) in individuals with type 2 diabetes mellitus (T2DM). The study group comprised 226 consecutive T2DM patients (153 patients with any HF phenotypes and 30 patients without HF) aged 41 to 65 years. The plasma levels N-terminal brain natriuretic pro-peptide (NT-proBNP) and irisin were detected by ELISA at the baseline of the study. We found that the most appropriate cut-off value of irisin (HF versus non-HF) were 10.4 ng/mL (area under curve [AUC] = 0.96, sensitivity = 81.0%, specificity = 88.0%; P = 0.0001). Cutoff point of NT-proBNP that distinguished patients with HF and without it was 750 pmol/L (AUC = 0.78; sensitivity = 72.7%, specificity 76.5%, p = 0.0001). Using multivariate comparative analysis we established that concentrations of irisin < 10.4 ng/mL (odds ration [OR] = 1.30; P = 0.001) and NT-proBNP > 750 pmol/mL (OR = 1.17; P = 0.042), left atrial volume index (LAVI) > 34 mL/m2 (OR = 1.06; P = 0.042) independently predicted HF. Irisin being added to NT-proBNP improved predictive modality for HF, whereas combination of NT-proBNP and LAVI > 34 mL/m2 did not. In conclusion, we established that irisin had independent predicted potency for HF in patients with established T2DM.

Discriminative Value of Serum Irisin in Prediction of Heart Failure with Different Phenotypes among Patients with Type 2 Diabetes Mellitus.

Recent studies have shown that circulating levels of irisin are prognostic factors in heart failure (HF), but no data are available on the predictive role of irisin in patients with type 2 diabetes mellitus (T2DM) and different phenotypes of HF. The aim of the study was to investigate whether serum levels of irisin predict HF in T2DM patients. We prospectively included 183 participants with T2DM aged 41 to 62 years (30 non-HF patients and 153 HF patients) and 25 healthy volunteers in the study and evaluated clinical data, hemodynamics and biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP) and irisin). Serum levels of irisin < 8.30 ng/mL were found to be a better indicator of HF with reduced ejection fraction (HFrEF) than irisin ≥ 8.30 ng/mL, but the predictive cut-off point for NT-proBNP remained the same as for HF with mildly reduced ejection fraction (HFmrEF). Serum levels of irisin < 10.4 ng/mL significantly improved the predictive ability of NT-proBNP for HF with preserved ejection fraction (HFpEF). In conclusion, we found that decreased serum levels of irisin significantly predicted HFpEF, rather than HFmrEF and HFrEF, in T2DM patients. This finding may open a new approach to HF risk stratification in T2DM patients.

The Effect of SGLT2 Inhibitor Dapagliflozin on Serum Levels of Apelin in T2DM Patients with Heart Failure.

Apelin is a multifunctional peptide that plays a pivotal role in cardiac remodeling and HF manifestation because of counteracting angiotensin-II. We hypothesized that positive influence of sodium-glucose co-transporter-2 (SGLT2) inhibitor on cardiac function in T2DM patients with HF might be mediated by apelin and that its levels seem to be a target of management. A total of 153 type 2 diabetes mellitus (T2DM) patients with II/III HF NYHA class and average left ventricular (LV) ejection fraction (EF) of 46% have been enrolled and treated with dapagliflosin. The serum levels of apelin and N-terminal brain natriuretic pro-peptide (NT-proBNP) were measured at baseline and over a 6-month period of dapagliflosin administration. We noticed that administration of dapagliflozin was associated with a significant increase in apelin levels of up to 18.3% and a decrease in NT-proBNP of up to 41.0%. Multivariate logistic regression showed that relative changes of LVEF, LA volume index, and early diastolic blood filling to longitudinal strain ratio were strongly associated with the levels of apelin, whereas NT-proBNP exhibited a borderline significance in this matter. In conclusion, dapagiflosin exerted a positive impact on echocardiographic parameters in close association with an increase in serum apelin levels, which could be a surrogate target for HF management.

Serum Levels of Irisin Predict Cumulative Clinical Outcomes in Heart Failure Patients With Type 2 Diabetes Mellitus.

Background: The aim of this study was to investigate the role of serum irisin level in predicting clinical outcome in heart failure (HF) patients with type 2 diabetes mellitus (T2DM). Methods: 153 T2DM patients with HF aged 41-62 years were prospectively recruited for the study. Serum levels of irisin and NT-proBNP were measured by ELISA. Laboratory tests including HbA1c, fasting glucose, blood creatinine, insulin, lipids and creatinine with estimation of GFR were performed along with echocardiography at baseline. The observation period was 56 weeks. Results: We identified 76 composite cardiovascular (CV) outcomes, which included CV death and death from all causes, resuscitated cardiac death, non-fatal/fatal acute myocardial infarction or stroke, and HF hospitalization. Therefore, the entire patient cohort was divided into 2 groups with (n = 76) and without (n = 77) composite CV outcomes. We found that the concentrations of NT-proBNP were higher in HF patients with T2DM who had a CV composite outcome than in patients without CV composite outcome (p = 0.001). In contrast, the relationship was exactly reversed for irisin, as HF and T2DM patients with CV composite outcome had significantly lower irisin levels (p = 0.001). Unadjusted multivariate Cox regression analyses showed that LVEF < 40%, LAVI > 39 ml/m2, NT-proBNP > 2,250 pmol/ml, and irisin < 6.50 ng/ml were the strongest predictors of CV outcomes in HF patients with T2DM. After adjustment for LVEF, serum levels of NT-proBNP and irisin remained independent predictors of end points. Furthermore, divergence of Kaplan-Meier curves pointed out that patients with NT-proBNP > 2,250 pmol/ml and irisin < 6.50 ng/ml had worse prognosis than those with any other compartment of the bomarkers' levels. Conclusion: Adding irisin to NT-proBNP significantly improved discriminative value of the whole model. HF patients with T2DM had significantly worse clinical outcomes when showing the constellation NT-proBNP > 2,250 pmol/ml and irisin < 6.50 ng/ml, respectively, in comparison to patients with opposite trends for both biomarkers.

Point-of-care heart failure platform: where are we now and where are we going to?

INTRODUCTION: Heart failure (HF) remains a leading cause of cardiovascular (CV) mortality in patients with CV disease. The point-of-care (POC) HF platform seems to be an ideal noninvasive workflow-adapted system for personally adjusted management of patients with HF. AREAS COVERED: In the present manuscript, we reviewed the literature covering some relevant studies regarding the role of point-of care heart failure platform in the risk stratification, earlier diagnosis and prognostically beneficial treatment of patients with different phenotypes of HF. EXPERT OPINION: POC HF platform including personal consultation, optimization of the comorbidity treatment, step-by-step HF diagnostic algorithm, single biomarker measurements, has also partially been provided in the current guidelines. Although there are several obstacles to implement POC in routine practice, such as education level, aging, affordability of health care, even partial implementation of POC can also improve clinical outcomes. POC seems to be an evolving model, more research studies are required to clearly see whether it helps to make better decisions with diagnosis and care of HF, as well helps to achieve better clinical outcomes.In summary, the POC HF platform is considered to be a more effective tool than conventional algorithm of HF management.

Extracellular Vesicles and Thrombogenicity in Atrial Fibrillation.

Extracellular vesicles (EVs) are defined as a heterogenic group of lipid bilayer vesicular structures with a size in the range of 30-4000 nm that are released by all types of cultured cells. EVs derived from platelets, mononuclears, endothelial cells, and adipose tissue cells significantly increase in several cardiovascular diseases, including in atrial fibrillation (AF). EVs are engaged in cell-to-cell cooperation, endothelium integrity, inflammation, and immune response and are a cargo for several active molecules, such as regulatory peptides, receptors, growth factors, hormones, and lipids. Being transductors of the intercellular communication, EVs regulate angiogenesis, neovascularization, coagulation, and maintain tissue reparation. There is a large amount of evidence regarding the fact that AF is associated with elevated levels of EVs derived from platelets and mononuclears and a decreased number of EVs produced by endothelial cells. Moreover, some invasive procedures that are generally performed for the treatment of AF, i.e., pulmonary vein isolation, were found to be triggers for elevated levels of platelet and mononuclear EVs and, in turn, mediated the transient activation of the coagulation cascade. The review depicts the role of EVs in thrombogenicity in connection with a risk of thromboembolic complications, including ischemic stroke and systemic thromboembolism, in patients with various forms of AF.

Discriminative Utility of Apelin-to-NT-Pro-Brain Natriuretic Peptide Ratio for Heart Failure with Preserved Ejection Fraction among Type 2 Diabetes Mellitus Patients.

BACKGROUND: Apelin is a regulatory vasoactive peptide, which plays a pivotal role in adverse cardiac remodeling and heart failure (HF) with reduced ejection fraction. The purpose of the study was to investigate whether serum levels of apelin is associated with HF with preserved election fraction (HFpEF) in patients with T2DM. METHODS: The study retrospectively involved 101 T2DM patients aged 41 to 62 years (48 patients with HFpEF and 28 non-HFpEF patients). The healthy control group consisted of 25 individuals with matched age and sex. Data collection included demographic and anthropometric information, hemodynamic performances and biomarkers of the disease. Transthoracic B-mode echocardiography, Doppler and TDI were performed at baseline. Serum levels of N-terminal pro-brain natriuretic peptide (NT-proBNP) and apelin were measured by ELISA in all patients at the study entry. RESULTS: Unadjusted multivariate logistic model yielded the only apelin to NT-proBNP ratio (OR = 1.44; p = 0.001), BMI > 34 кг/м2 (OR = 1.07; p = 0.036), NT-proBNP > 458 pmol/mL (OR = 1.17; p = 0.042), LAVI > 34 mL/m2 (OR = 1.06; p = 0.042) and E/e' > 11 (OR = 1.04; p = 0.044) remained to be strong predictors for HFpEF. After obesity adjustment, multivariate logistic regression showed that the apelin to NT-proBNP ratio < 0.82 × 10-2 units remained sole independent predictor for HFpEF (OR = 1.44; 95% CI: 1.18-2.77; p = 0.001) HFpEF in T2DM patients. In conclusion, we found that apelin to NT-proBNP ratio < 0.82 × 10-2 units better predicted HFpEF in T2DM patients than apelin and NT-proBNP alone. This finding could open new approach for CV risk stratification of T2DM at higher risk of HF.

The Association of Glucose Control with Circulating Levels of Red Blood Cell-Derived Vesicles in Type 2 Diabetes Mellitus Patients with Atrial Fibrillation.

Hyperglycemia is a trigger for structural alteration of red blood cells (RBCs) and their ability to release extracellular vesicles (EVs). The aim of the study was to elucidate whether glucose control in T2DM patients with concomitant HF and AF affects a circulating number of RBC-derived EVs. We prospectively included 417 T2DM patients with HF, 51 of them had atrial fibrillation and 25 healthy volunteers and 30 T2DM non-HF individuals. Clinical assessment, echocardiography examination and biomarker measures were performed at the baseline of the study. RBC-derived EVs were determined as CD235a+ PS+ particles by flow cytometry. NT-proBNP levels were measured by ELISA. AF patients with glycosylated hemoglobin (HbA1c) < 6.9% had lower levels of CD235a+ PS+ RBC-derived vesicles than those with HbA1c ≥ 7.0%. There were no significant differences in number of CD235a+ PS+ RBC-derived vesicles between patients in entire cohort and in non-AF sub-cohort with HbA1c < 6.9% and HbA1c ≥ 7.0%, respectively. Multivariate linear regression yielded that CD235a+ PS+ RBC-derived vesicles ≥ 545 particles in µL (OR = 1.06; 95% CI = 1.01−1.11, p = 0.044) independently predicted HbA1c ≥ 7.0%. Elevated levels of CD235a+ PS+ RBC-derived EVs independently predicted poor glycaemia control in T2DM patients with HF and AF.

Shift of conventional paradigm of heart failure treatment: from angiotensin receptor neprilysin inhibitor to sodium-glucose co-transporter 2 inhibitors?

Current clinical guidelines for heart failure (HF) contain a brand new therapeutic strategy for HF with reduced ejection fraction (HFrEF), which is based on neurohumoral modulation through the use of angiotensin receptor neprilysin inhibitors. There is a large body of evidence for the fact that sodium-glucose co-transporter 2 inhibitors may significantly improve all-cause mortality, cardiovascular mortality and hospitalization for HF in patients with HFrEF who received renin-angiotensin system blockers including angiotensin receptor neprilysin inhibitors, ß-blockers and mineralocorticoid receptor antagonists. The review discusses that sodium-glucose co-transporter 2 inhibitors have a wide spectrum of favorable molecular effects and contribute to tissue protection, improving survival in HFrEF patients.

Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes.

Heart failure (HF) is a global medical problem that characterizes poor prognosis and high economic burden for the health system and family of the HF patients. Although modern treatment approaches have significantly decreased a risk of the occurrence of HF among patients having predominant coronary artery disease, hypertension, and myocarditis, the mortality of known HF continues to be unacceptably high. One of the most important symptoms of HF that negatively influences tolerance to physical exercise, well-being, social adaptation, and quality of life is deep fatigue due to HF-related myopathy. Myopathy in HF is associated with weakness of the skeletal muscles, loss of myofibers, and the development of fibrosis due to microvascular inflammation, metabolic disorders, and mitochondrial dysfunction. The pivotal role in the regulation of myocardial and skeletal muscle rejuvenation, attenuation of muscle metabolic homeostasis, and protection against ischemia injury and apoptosis belongs to myokines. Myokines are defined as a wide spectrum of active molecules that are directly synthesized and released by both cardiac and skeletal muscle myocytes and regulate energy homeostasis in autocrine/paracrine manner. In addition, myokines have a large spectrum of pleiotropic capabilities that are involved in the pathogenesis of HF including cardiac remodeling, muscle atrophy, and cardiac cachexia. The aim of the narrative review is to summarize the knowledge with respect to the role of myokines in adverse cardiac remodeling, myopathy, and clinical outcomes among HF patients. Some myokines, such as myostatin, irisin, brain-derived neurotrophic factor, interleukin-15, fibroblast growth factor-21, and growth differential factor-11, being engaged in the regulation of the pathogenesis of HF-related myopathy, can be detected in peripheral blood, and the evaluation of their circulating levels can provide new insights to the course of HF and stratify patients at higher risk of poor outcomes prior to sarcopenic stage.

Emerging Role of Adipocyte Dysfunction in Inducing Heart Failure Among Obese Patients With Prediabetes and Known Diabetes Mellitus.

Adipose tissue dysfunction is a predictor for cardiovascular (CV) events and heart failure (HF) in patient population with obesity, metabolic syndrome, and known type 2 diabetes mellitus. Previous preclinical and clinical studies have yielded controversial findings regarding the role of accumulation of adipose tissue various types in CV risk and HF-related clinical outcomes in obese patients. There is evidence for direct impact of infiltration of epicardial adipocytes into the underlying myocardium to induce adverse cardiac remodeling and mediate HF development and atrial fibrillation. Additionally, perivascular adipocytes accumulation is responsible for release of proinflammatory adipocytokines (adiponectin, leptin, resistin), stimulation of oxidative stress, macrophage phenotype switching, and worsening vascular reparation, which all lead to microvascular inflammation, endothelial dysfunction, atherosclerosis acceleration, and finally to increase in CV mortality. However, systemic effects of white and brown adipose tissue can be different, and adipogenesis including browning of adipose tissue and deficiency of anti-inflammatory adipocytokines (visfatin, omentin, zinc-α2-glycoprotein, glypican-4) was frequently associated with adipose triglyceride lipase augmentation, altered glucose homeostasis, resistance to insulin of skeletal muscles, increased cardiomyocyte apoptosis, lowered survival, and weak function of progenitor endothelial cells, which could significantly influence on HF development, as well as end-organ fibrosis and multiple comorbidities. The exact underlying mechanisms for these effects are not fully understood, while they are essential to help develop improved treatment strategies. The aim of the review is to summarize the evidence showing that adipocyte dysfunction may induce the onset of HF and support advance of HF through different biological mechanisms involving inflammation, pericardial, and perivascular adipose tissue accumulation, adverse and electrical cardiac remodeling, and skeletal muscle dysfunction. The unbalancing effects of natriuretic peptides, neprilysin, and components of renin-angiotensin system, as exacerbating cause of altered adipocytokine signaling on myocardium and vasculature, in obesity patients at high risk of HF are disputed. The profile of proinflammatory and anti-inflammatory adipocytokines as promising biomarker for HF risk stratification is discussed in the review.