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.

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases.

This narrative review was conducted due to uncertainty in predicting the beneficial impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors on a dip of estimated glomerular filtration rate (eGFR), regardless of albuminuria presence, with the aim of elucidating plausible predictors of kidney function outcome among patients treated with SGLT2 inhibitors. The PubMed and Web of Science databases were searched in May 2023 for relevant articles published in English between 2013 and 2023. A total of 25 full-length scientific publications (comprising 11 large randomized trials and two cohort studies) were included for analysis. The majority of studies demonstrated a limited value of conventional biomarkers, such as initial decline in eGFR, a trajectory of eGFR during SGLT2 inhibitor administration, and urine albumin-to-creatinine ratio (UACR), in prediction of renoprotection. Included studies showed that the tendency to decreased eGFR, UACR, hemoglobin, glycosylated hemoglobin, lipid profile, serum uric acid, inflammatory biomarkers and natriuretic peptides did not predict clinical outcomes in groups without heart failure (HF) treated with SGLT2 inhibitors. In HF groups, biomarkers of inflammation, kidney injury, oxidative stress, mitochondrial dysfunction, ketogenesis, energy metabolism, and adipose tissue dysfunction (adropin and irisin), were detected with the aim of finding potential biomarkers. Biomarkers of adipose tissue dysfunction and inflammation may be promising for predicting SGLT2 inhibitor benefit compared with N-terminal pro-B-type natriuretic peptide and energy metabolism indicators.

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.

Cell-free DNA as a plausible biomarker of chronic kidney disease.

Circulating cell-free DNA (cf-DNA) is released from dead and/or apoptotic leukocytes and due to neutrophil extracellular traps contributing to an inflammatory response. Previous clinical studies have reported that the peak concentrations and dynamic changes of cf-DNA may be used as a noninvasive biomarker of worsening kidney function as well as a guide to the management of kidney allograft rejection. We hypothesized that the pattern and dynamic changes of cf-DNA might be a plausible predictive biomarker for patients at risk of chronic kidney disease (CKD), including individuals with type 2 diabetes mellitus, heart failure, cardiovascular disease and established CKD. Along with it, pre- and posthemodialysis levels of serum cf-DNA appear to be a independent predictor for all-cause mortality in patients with end-stage kidney disease.

What is this article about? The article focuses a new view on the risk of kidney function worsening and relating complications based on measurements of circulating fragments of DNA (called nucleotides). What were the results? The results showed that a measure of circulating fragments of DNA may detect both the risk of occurrence and the progression of chronic kidney disease in certain patient populations. What do the results of the study mean? The study indicates that a strategy of single and serial measurements of circulating DNA fragments is likely to be effective for personalized management of patients with chronic kidney disease, including those on dialysis and after kidney transplantation.

Missed Opportunities in Implementation and Optimization of Lipid-Lowering Therapies in Very-High-Risk Patients Presenting with ST-Segment Elevation Myocardial Infarction.

The aim of this retrospective study was to provide real-world data on lipid-lowering therapy (LLT) implementation and low-density lipoprotein cholesterol (LDL-C) target achievement in an ST-segment elevation myocardial infarction (STEMI) population, with a focus on very-high-risk patients according to European guidelines criteria. METHODS: Included were all STEMI patients with available LDL-C and total cholesterol treated at a large tertiary center in Salzburg, Austria, 2018-2020 (n = 910), with stratification into very-high-risk cohorts. Analysis was descriptive, with variables reported as number, percentages, median, and interquartile range. RESULTS: Among patients with prior LLT use, statin monotherapy predominated, 5.3% were using high-intensity statins, 1.2% were using combined ezetimibe therapy, and none were taking PCSK9 inhibitors at the time of STEMI. In very-high-risk secondary prevention cohorts, LLT optimization was alarmingly low: 8-22% of patients were taking high-intensity statins, just 0-6% combined with ezetimibe. Depending on the very-high-risk cohort, 27-45% of secondary prevention patients and 58-73% of primary prevention patients were not taking any LLTs, although 19-60% were actively taking/prescribed medications for hypertension and/or diabetes mellitus. Corresponding LDL-C target achievement in all very-high-risk cohorts was poor: <22% of patients had LDL-C values < 55 mg/dL at the time of STEMI. CONCLUSION: Severe shortcomings in LLT implementation and optimization, and LDL-C target achievement, were observed in the total STEMI population and across all very-high-risk cohorts, attributable in part to deficits in care delivery.

Early beta-blocker therapy improves in-hospital mortality of patients with non-ST-segment elevation myocardial infarction - a meta-analysis.

BACKGROUND: Although current guidelines endorse early beta-blocker therapy in stable patients with STEMI, there is no clear recommendation on the early use of these drugs in patients with NSTEMI. METHODS: Literature search was conducted by 3 independent researchers using PubMed/MEDLINE, CDSR, CENTRAL, CCAs, EBM Reviews, Web of Science and LILACS. Studies were eligible if (P) patients included were ≥ 18 years of age and had non-ST-segment elevation myocardial infarction (NSTEMI), (I) early (<24 h) treatment with intravenous or oral beta-blockers was compared to (C) no treatment with beta-blockers and data on (O) in-hospital mortality and/or in-hospital cardiogenic shock were depicted. Odds ratios and 95% confidence intervals were calculated using random effects models with the Mantel-Haenszel method. The Hartung-Knapp-Sidik-Jonkman method was used as estimator for τ2. RESULTS: 977 records were screened for eligibility, which led to the inclusion of 4 retrospective, nonrandomized, observational cohort studies comprising a total of N = 184,951 patients. After pooling of the effect sizes, early therapy with beta-blockers resulted in a reduction of in-hospital mortality (OR 0.43 [0.36-0.51], p = 0.0022) despite no significant effect on the prevalence of cardiogenic shock (OR 0.36 [0.07-1.91], p = 0.1196). CONCLUSION: Early treatment with beta-blockers was associated with an attenuation of in-hospital mortality despite no increase in cardiogenic shock. Thus, early therapy with these drugs could elicit beneficial effects on top of reperfusion therapy, similar to the effects seen in STEMI-patients. The low number of studies (k = 4) has to be considered when interpreting the findings of this analysis.

Biomarkers of Atrial Fibrillation Recurrence in Patients with Paroxysmal or Persistent Atrial Fibrillation Following External Direct Current Electrical Cardioversion.

Atrial fibrillation (AF) is associated with atrial remodeling, cardiac dysfunction, and poor clinical outcomes. External direct current electrical cardioversion is a well-developed urgent treatment strategy for patients presenting with recent-onset AF. However, there is a lack of accurate predictive serum biomarkers to identify the risks of AF relapse after electrical cardioversion. We reviewed the currently available data and interpreted the findings of several studies revealing biomarkers for crucial elements in the pathogenesis of AF and affecting cardiac remodeling, fibrosis, inflammation, endothelial dysfunction, oxidative stress, adipose tissue dysfunction, myopathy, and mitochondrial dysfunction. Although there is ample strong evidence that elevated levels of numerous biomarkers (such as natriuretic peptides, C-reactive protein, galectin-3, soluble suppressor tumorigenicity-2, fibroblast growth factor-23, turn-over collagen biomarkers, growth differential factor-15) are associated with AF occurrence, the data obtained in clinical studies seem to be controversial in terms of their predictive ability for post-cardioversion outcomes. Novel circulating biomarkers are needed to elucidate the modality of this approach compared with conventional predictive tools. Conclusions: Biomarker-based strategies for predicting events after AF treatment require extensive investigation in the future, especially in the presence of different gender and variable comorbidity profiles. Perhaps, a multiple biomarker approach exerts more utilization for patients with different forms of AF than single biomarker use.

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.

Myocardial Mechanical Dispersion Predicts Adverse Cardiac Remodeling in Patients with ST Segment Elevation Myocardial Infarction Who Underwent Primary Percutaneous Coronary Intervention.

OBJECTIVE: The aim of the study was to investigate whether increased left ventricular mechanical dispersion is an early predictor for adverse cardiac remodeling in ST-segment elevation myocardial infarction patients who had post-percutaneous coronary intervention thrombolysis in myocardial infarction (TIMI) flow grade > 2. METHODS: A total of 119 post-percutaneous coronary intervention ST elevation myocardial infarction patients with TIMI flow grade >2 were prospectively included in the study. Left ventricular global longitudinal strain was quantified by 2-dimensional speckletracking echocardiography, and left ventricular mechanical dispersion was determined at baseline and after 1 year to assess adverse cardiac remodeling. The levels of circulating biomarkers were measured at the baseline. TIMI score and the Global Registry of Acute Coronary Events score systems were used to evaluate the prognosis of patients. RESULTS: Patients with high quartile versus low quartile of left ventricular mechanical dispersion exerted higher Global Registry of Acute Coronary Events and TIMI score grades, left ventricular endsystolic volume, global longitudinal strain, and levels of the N-terminal fragment of brain natriuretic peptide and lower left ventricular ejection fraction. Multivariate log regression showed that N-terminal fragment of brain natriuretic peptide > 953 pg/mL, global longitudinal strain > -8%, and high quartile of left ventricular mechanical dispersion remained independent predictors for adverse cardiac remodeling. Addition of left ventricular mechanical dispersion to the N-terminal fragment of brain natriuretic peptide improved the discriminative potency of the whole model. CONCLUSION: Measurement of left ventricular mechanical dispersion might be useful in determining the risk of adverse cardiac remodeling in post-percutaneous coronary intervention ST elevation myocardial infarction patients.

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.