Metformin effects on cardiac parameters in non-diabetic Iraqi patients with heart failure and mid-range ejection fraction - a comparative two-arm parallel clinical study.

Heart failure (HF) remains a difficult challenge to the healthcare system, necessitating promoting interventions and multidrug management. Metformin, typically used to manage diabetes, has emerged as a promising intervention in the treatment of HF. This study aimed to assess the effect of adding metformin to the standard treatment of HF on cardiac parameters. This clinical study comprised 60 newly diagnosed HF patients randomly assigned to two groups: Group C received standard HF treatment, while Group M received standard HF treatment in addition to daily metformin (500 mg). After 3 months of treatment, group M showed a significantly higher ejection fraction (EF) compared to Group C (6.1% and 3.2%, respectively; p-value=0.023) and a reduction in the left ventricular end-diastolic pressure (LVEDD) (0.28, and 0.21 mm respectively; p-value=0.029). No significant differences were observed in the interventricular septal thickness (IVST) or left ventricular end-systolic pressure (LVESD). For cardiac markers, N-Terminal pro-BNP (NT-proBNP) showed the highest reduction in Group M compared to Group C (719.9 pg/ml and 271.9 pg/ml respectively; p-value=0.009). No significant changes were reported for soluble ST2. Metformin demonstrated cardiac protective effects by increasing EF and reducing NT-proBNP. Given its affordability and accessibility, metformin offers a valuable addition to the current HF treatment options. This positive effect may be attributed to mechanisms that enhance the impact of conventional HF treatments or vice versa.

Beneficial Effects of Dipeptidyl Peptidase-4 Inhibitors on Heart Failure With Preserved Ejection Fraction and Diabetes.

Background: Dipeptidyl peptidase-4 (DPP-4) inhibitors have been shown to exert pleiotropic effects on heart failure (HF) in animal experiments. Objectives: This study sought to investigate the impact of DPP-4 inhibitors on HF patients with diabetes mellitus (DM). Methods: We analyzed hospitalized patients with HF and DM enrolled in the JROADHF (Japanese Registry Of Acute Decompensated Heart Failure) registry, a nationwide registry of acute decompensated HF. Primary exposure was the use of a DPP-4 inhibitor. The primary outcome was a composite of cardiovascular death or HF hospitalization during the median follow-up of 3.6 years according to left ventricular ejection fraction. Results: Out of 2,999 eligible patients, 1,130 had heart failure with preserved ejection fraction (HFpEF), 572 had heart failure with midrange ejection fraction (HFmrEF), and 1,297 had heart failure with reduced ejection fraction (HFrEF). In each cohort, 444, 232, and 574 patients received a DPP-4 inhibitor, respectively. A multivariable Cox regression model showed that DPP-4 inhibitor use was associated with a lower composite of cardiovascular death or HF hospitalization in HFpEF (HR: 0.69; 95% CI: 0.55-0.87; P = 0.002) but not in HFmrEF and HFrEF. Restricted cubic spline analysis demonstrated that DPP-4 inhibitors were beneficial in patients with higher left ventricular ejection fraction. In HFpEF cohort, propensity score matching yielded 263 pairs. DPP-4 inhibitor use was associated with a lower incidence rate of the composite of cardiovascular death or HF hospitalization (19.2 vs 25.9 events per 100 patient-years; rate ratio: 0.74; 95% CI: 0.57-0.97; P = 0.027) in matched patients. Conclusions: DPP-4 inhibitor use was associated with better long-term outcomes in HFpEF patients with DM.

Prognosis in Patients With Cardiogenic Shock Who Received Temporary Mechanical Circulatory Support.

Background: Temporary mechanical circulatory support (MCS) is often used in patients with cardiogenic shock (CS), and the type of MCS may vary by cause of CS. Objectives: This study sought to describe the causes of CS in patients receiving temporary MCS, the types of MCS used, and associated mortality. Methods: This study used a nationwide Japanese database to identify patients receiving temporary MCS for CS between April 1, 2012, and March 31, 2020. Results: Of 65,837 patients, the cause of CS was acute myocardial infarction (AMI) in 77.4%, heart failure (HF) in 10.9%, valvular disease in 2.7%, fulminant myocarditis (FM) in 2.5%, arrhythmia in 4.5%, and pulmonary embolism (PE) in 2.0% of cases. The most commonly used MCS was an intra-aortic balloon pump alone in AMI (79.2%) and in HF (79.0%) and in valvular disease (66.0%), extracorporeal membrane oxygenation with intra-aortic balloon pump in FM (56.2%) and arrhythmia (43.3%), and extracorporeal membrane oxygenation alone in PE (71.5%). Overall in-hospital mortality was 32.4%; 30.0% in AMI, 32.6% in HF, 33.1% in valvular disease, 34.2% in FM, 60.9% in arrhythmia, and 59.2% in PE. Overall in-hospital mortality increased from 30.4% in 2012 to 34.1% in 2019. After adjustment, valvular disease, FM, and PE had lower in-hospital mortality than AMI: valvular disease, OR: 0.56 (95% CI: 0.50-0.64); FM: OR: 0.58 (95% CI: 0.52-0.66); PE: OR: 0.49 (95% CI: 0.43-0.56); whereas HF had similar in-hospital mortality (OR: 0.99; 95% CI: 0.92-1.05) and arrhythmia had higher in-hospital mortality (OR: 1.14; 95% CI: 1.04-1.26). Conclusions: In a Japanese national registry of patients with CS, different causes of CS were associated with different types of MCS and differences in survival.

Incidence, Clinical Correlates, and Prognostic Impact of Dementia in Heart Failure: A Population-Based Cohort Study.

Background: Heart failure (HF) may increase the risk of dementia via shared risk factors. Objectives: The authors investigated the incidence, types, clinical correlates, and prognostic impact of dementia in a population-based cohort of patients with index HF. Methods: The previously territory-wide database was interrogated to identify eligible patients with HF (N = 202,121) from 1995 to 2018. Clinical correlates of incident dementia and their associations with all-cause mortality were assessed using multivariable Cox/competing risk regression models where appropriate. Results: Among a total cohort aged ≥18 years with HF (mean age 75.3 ± 13.0 years, 51.3% women, median follow-up 4.1 [IQR: 1.2-10.2] years), new-onset dementia occurred in 22,145 (11.0%), with age-standardized incidence rate of 1,297 (95% CI: 1,276-1,318) per 10,000 in women and 744 (723-765) per 10,000 in men. Types of dementia were Alzheimer's disease (26.8%), vascular dementia (18.1%), and unspecified dementia (55.1%). Independent predictors of dementia included: older age (≥75 years, subdistribution hazard ratio [SHR]: 2.22), female sex (SHR: 1.31), Parkinson's disease (SHR: 1.28), peripheral vascular disease (SHR: 1.46), stroke (SHR: 1.24), anemia (SHR: 1.11), and hypertension (SHR: 1.21). The population attributable risk was highest for age ≥75 years (17.4%) and female sex (10.2%). New-onset dementia was independently associated with increased risk of all-cause mortality (adjusted SHR: 4.51; P < 0.001). Conclusions: New-onset dementia affected more than 1 in 10 patients with index HF over the follow-up, and portended a worse prognosis in these patients. Older women were at highest risk and should be targeted for screening and preventive strategies.

Impact of Age at Diagnosis on Cardiotoxicity in High-Grade Osteosarcoma and Ewing Sarcoma Patients.

Background: Osteosarcoma and Ewing sarcoma patients face a significant risk of cardiotoxicity as defined by left ventricular dysfunction and heart failure (HF). Objectives: This study sought to evaluate the association between age at sarcoma diagnosis and incident HF. Methods: A retrospective cohort study was performed at the largest sarcoma center in the Netherlands among patients with an osteosarcoma or Ewing sarcoma. All patients were diagnosed and treated over a 36-year period (1982-2018) and followed until August 2021. Incident HF was adjudicated through the universal definition of heart failure. Determinants including age at diagnosis, doxorubicin dose, and cardiovascular risk factors were entered as fixed or time-dependent covariates into a cause-specific Cox model to assess their impact on incident HF. Results: The study population consisted of 528 patients with a median age at diagnosis of 19 years (Q1-Q3: 15-30 years). Over a median follow-up time of 13.2 years (Q1-Q3: 12.5-14.9 years), 18 patients developed HF with an estimated cumulative incidence of 5.9% (95% CI: 2.8%-9.1%). In a multivariable model, age at diagnosis (HR: 1.23; 95% CI: 1.06-1.43) per 5-year increase, doxorubicin dose per 10-mg/m2 increase (HR: 1.13; 95% CI: 1.03-1.24), and female sex (HR: 3.17; 95% CI: 1.11-9.10) were associated with HF. Conclusions: In a large cohort of sarcoma patients, we found that patients diagnosed at an older age are more prone to develop HF.

Cardiovascular Toxicity of Proteasome Inhibitors: Underlying Mechanisms and Management Strategies: JACC: CardioOncology State-of-the-Art Review.

Proteasome inhibitors (PIs) are the backbone of combination treatments for patients with multiple myeloma and AL amyloidosis, while also indicated in Waldenström's macroglobulinemia and other malignancies. PIs act on proteasome peptidases, causing proteome instability due to accumulating aggregated, unfolded, and/or damaged polypeptides; sustained proteome instability then induces cell cycle arrest and/or apoptosis. Carfilzomib, an intravenous irreversible PI, exhibits a more severe cardiovascular toxicity profile as compared with the orally administered ixazomib or intravenous reversible PI such as bortezomib. Cardiovascular toxicity includes heart failure, hypertension, arrhythmias, and acute coronary syndromes. Because PIs are critical components of the treatment of hematological malignancies and amyloidosis, managing their cardiovascular toxicity involves identifying patients at risk, diagnosing toxicity early at the preclinical level, and offering cardioprotection if needed. Future research is required to elucidate underlying mechanisms, improve risk stratification, define the optimal management strategy, and develop new PIs with safe cardiovascular profiles.

Pharmacovigilance Analysis of Heart Failure Associated With Anti-HER2 Monotherapies and Combination Regimens for Cancer.

Background: Trastuzumab improves outcomes in patients with HER2-overexpressing malignancies but is associated with decreases in left ventricular ejection fraction. Heart failure (HF) risks from other anti-HER2 therapies are less clear. Objectives: Using World Health Organization pharmacovigilance data, the authors compared HF odds across anti-HER2 regimens. Methods: In VigiBase, 41,976 patients had adverse drug reactions (ADRs) with anti-HER2 monoclonal antibodies (trastuzumab, n = 16,900; pertuzumab, n = 1,856), antibody-drug conjugates (trastuzumab emtansine [T-DM1], n = 3,983; trastuzumab deruxtecan, n = 947), and tyrosine kinase inhibitors (afatinib, n = 10,424; lapatinib, n = 5,704; neratinib, n = 1,507; tucatinib, n = 655); additionally, 36,052 patients had ADRs with anti-HER2-based combination regimens. Most patients had breast cancer (monotherapies, n = 17,281; combinations, n = 24,095). Outcomes included comparison of HF odds with each monotherapy relative to trastuzumab, within each therapeutic class, and among combination regimens. Results: Of 16,900 patients with trastuzumab-associated ADRs, 2,034 (12.04%) had HF reports (median time to onset 5.67 months; IQR: 2.85-9.32 months) compared with 1% to 2% with antibody-drug conjugates. Trastuzumab had higher odds of HF reporting relative to other anti-HER2 therapies collectively in the overall cohort (reporting OR [ROR]: 17.37; 99% CI: 14.30-21.10) and breast cancer subgroup (ROR: 17.10; 99% CI: 13.12-22.27). Pertuzumab/T-DM1 had 3.4 times higher odds of HF reporting than T-DM1 monotherapy; tucatinib/trastuzumab/capecitabine had similar odds as tucatinib. Among metastatic breast cancer regimens, HF odds were highest with trastuzumab/pertuzumab/docetaxel (ROR: 1.42; 99% CI: 1.17-1.72) and lowest with lapatinib/capecitabine (ROR: 0.09; 99% CI: 0.04-0.23). Conclusions: Trastuzumab and pertuzumab/T-DM1 had higher odds of HF reporting than other anti-HER2 therapies. These data provide large-scale, real-world insight into which HER2-targeted regimens would benefit from left ventricular ejection fraction monitoring.

Inflammatory Macrophage Interleukin-1ß Mediates High-Fat Diet-Induced Heart Failure With Preserved Ejection Fraction.

Diabetes mellitus (DM) is a main risk factor for diastolic dysfunction (DD) and heart failure with preserved ejection fraction. High-fat diet (HFD) mice presented with diabetes mellitus, DD, higher cardiac interleukin (IL)-1ß levels, and proinflammatory cardiac macrophage accumulation. DD was significantly ameliorated by suppressing IL-1ß signaling or depleting macrophages. Mice with macrophages unable to adopt a proinflammatory phenotype were low in cardiac IL-1ß levels and were resistant to HFD-induced DD. IL-1ß enhanced mitochondrial reactive oxygen species (mitoROS) in cardiomyocytes, and scavenging mitoROS improved HFD-induced DD. In conclusion, macrophage-mediated inflammation contributed to HFD-associated DD through IL-1ß and mitoROS production.

Neprilysin Inhibitors in Heart Failure: The Science, Mechanism of Action, Clinical Studies, and Unanswered Questions.

This article provides a contemporary review and a new perspective on the role of neprilysin inhibition in heart failure (HF) in the context of recent clinical trials and addresses potential mechanisms and unanswered questions in certain HF patient populations. Neprilysin is an endopeptidase that cleaves a variety of peptides such as natriuretic peptides, bradykinin, adrenomedullin, substance P, angiotensin I and II, and endothelin. It has a broad role in cardiovascular, renal, pulmonary, gastrointestinal, endocrine, and neurologic functions. The combined angiotensin receptor and neprilysin inhibitor (ARNi) has been developed with an intent to increase vasodilatory natriuretic peptides and prevent counterregulatory activation of the angiotensin system. ARNi therapy is very effective in reducing the risks of death and hospitalization for HF in patients with HF and New York Heart Association functional class II to III symptoms, but studies failed to show any benefits with ARNi when compared with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker in patients with advanced HF with reduced ejection fraction or in patients following myocardial infarction with left ventricular dysfunction but without HF. These raise the questions about whether the enzymatic breakdown of natriuretic peptides may not be a very effective solution in advanced HF patients when there is downstream blunting of the response to natriuretic peptides or among post-myocardial infarction patients in the absence of HF when there may not be a need for increased natriuretic peptide availability. Furthermore, there is a need for additional studies to determine the long-term effects of ARNi on albuminuria, obesity, glycemic control and lipid profile, blood pressure, and cognitive function in patients with HF.

Stroke risk in older British men: Comparing performance of stroke-specific and composite-CVD risk prediction tools.

Stroke risk is currently estimated as part of the composite risk of cardiovascular disease (CVD). We investigated if composite-CVD risk prediction tools QRISK3 and Pooled Cohort Equations-PCE, derived from middle-aged adults, are as good as stroke-specific Framingham Stroke Risk Profile-FSRP and QStroke for capturing the true risk of stroke in older adults. External validation for 10y stroke outcomes was performed in men (60-79y) of the British Regional Heart Study. Discrimination and calibration were assessed in separate validation samples (FSRP n = 3762, QStroke n = 3376, QRISK3 n = 2669 and PCE n = 3047) with/without adjustment for competing risks. Sensitivity/specificity were examined using observed and clinically recommended thresholds. Performance of FSRP, QStroke and QRISK3 was further compared head-to-head in 2441 men free of a range of CVD, including across age-groups. Observed 10y risk (/1000PY) ranged from 6.8 (hard strokes) to 11 (strokes/transient ischemic attacks). All tools discriminated weakly, C-indices 0.63-0.66. FSRP and QStroke overestimated risk at higher predicted probabilities. QRISK3 and PCE showed reasonable calibration overall with minor mis-estimations across the risk range. Performance worsened on adjusting for competing non-stroke deaths. However, in men without CVD, QRISK3 displayed relatively better calibration for stroke events, even after adjustment for competing deaths, including in oldest men. All tools displayed similar sensitivity (63-73 %) and specificity (52-54 %) using observed risks as cut-offs. When QRISK3 and PCE were evaluated using thresholds for CVD prevention, sensitivity for stroke events was 99 %, with false positive rate 97 % suggesting existing intervention thresholds may need to be re-examined to reflect age-related stroke burden.

A bibliometric analysis of research on heart failure comorbid with depression from 2002 to 2021.

Heart failure (HF) with depression is a common comorbidity associated with worse clinical status and quality of life. Although there have been numerous high-quality studies and relevant reviews on HF comorbid with depression, few bibliometric analyses of this field have been reported. In order to understand the development process, research hotspots and future directions, this review analyzes the papers on HF comorbid with depression from January 2002 to December 2021 through CiteSpace and VOSviewer. Visual cooperative networks between countries, authors and institutions were conducted to understand the basic development status of HF comorbid with depression. Furthermore, we performed co-occurrence analysis, burst detection, and timeline analysis for keywords to understand this field's research directions and hotspots. Finally, a detailed review and analysis of the classical literature in this field were conducted based on co-citation analysis. This bibliometric analysis provides an overview of studies on HF comorbid with depression and emphasizes the research on comorbidity mechanisms and more effective interventions as a priority for future research.

Validation of a quantitative multiplex LC-MS/MS assay of carvedilol, enalaprilat, and perindoprilat in dried blood spots from heart failure patients and its cross validation with a plasma assay.

Introduction: Adherence to medication is an important determinant of outcomes in chronic diseases like heart failure. Drug assays provide objective adherence biomarkers. Dried blood spots (DBS) are appealing samples for drug assays due to less demanding transportation and storage requirements. Objectives: To analytically validate a LC-MS/MS method for the simultaneous quantification of carvedilol, enalaprilat, and perindoprilat in DBS and evaluate the feasibility of using the method as an adherence determining assay. To validate the assay further clinically by establishing correlation and agreement between plasma and DBS samples from a pharmacokinetic pilot study. Methods: The method was validated over a concentration range of 1.00-200 ng/mL according to FDA guidelines. Adherence tracking ability of the assay was evaluated using a pharmacokinetic pilot study. Correlation and agreement were evaluated through Deming regression and Bland-Altman analysis, respectively. Results: Accuracy, precision, selectivity, and sensitivity were proven with complete and reproducible extraction recovery at all concentrations tested. Stability of the analytes in the matrix and throughout sample processing was proven. The full range of concentrations of the pharmacokinetic pilot study could be quantified for enalaprilat, but not for carvedilol and perindoprilat. The difference between the observed and calculated plasma concentrations was less than 20 % of their mean for >67 % of samples for all analytes. Conclusions: The assay is suitable as a screening tool for carvedilol and perindoprilat, while suitable as an adherence determining assay for enalaprilat. Equivalence between observed and predicted plasma concentrations proves DBS and plasma concentrations can be used interchangeably.

Heart-Kidney Transplantation in a Transgender Woman.

We describe the care of a transgender woman with heart failure who underwent heart-kidney transplantation. Perioperative management of hormone therapy, considerations for future gender-affirming surgeries, and psychosocial aspects of care are discussed. Interdisciplinary collaboration is essential in the treatment of patients with advanced heart failure in the setting of gender-affirming therapies. (Level of Difficulty: Advanced.).

Percutaneous Decommissioning 11 Years After Initial CF-LVAD Placement.

An 80-year-old man with severe nonischemic cardiomyopathy status post left ventricular assist device (LVAD) placement 11 years prior presented for recurrent LVAD alarms from internal driveline fracture. Given his partial myocardial recovery and his preference to avoid surgical procedures, percutaneous LVAD decommissioning was performed by occlusion of the outflow graft and subsequently driveline removal. (Level of Difficulty: Advanced.).

Prognosis of Transthyretin Cardiac Amyloidosis Without Heart Failure Symptoms.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is increasingly recognized as a treatable cause of heart failure (HF). Advances in diagnosis and therapy have increased the number of patients diagnosed at early stages, but prognostic data on patients without HF symptoms are lacking. Moreover, it is unknown whether asymptomatic patients benefit from early initiation of transthyretin (TTR) stabilizers. Objectives: The aim of this study was to describe the natural history and prognosis of ATTR-CM in patients without HF symptoms. Methods: Clinical characteristics and outcomes of patients with ATTR-CM without HF symptoms were retrospectively collected at 6 international amyloidosis centers. Results: A total of 118 patients (78.8% men, median age 66 years [IQR: 53.8-75 years], 68 [57.6%] with variant transthyretin amyloidosis, mean left ventricular ejection fraction 60.5% ± 9.9%, mean left ventricular wall thickness 15.4 ± 3.1 mm, and 53 [45%] treated with TTR stabilizers at baseline or during follow-up) were included. During a median follow-up period of 3.7 years (IQR: 1-6 years), 38 patients developed HF symptoms (23 New York Heart Association functional class II and 14 functional class III or IV), 32 died, and 2 required cardiac transplantation. Additionally, 20 patients received pacemakers, 13 developed AF, and 1 had a stroke. Overall survival was 96.5% (95% CI: 91%-99%), 90.4% (95% CI: 82%-95%), and 82% (95% CI: 71%-89%) at 1, 3, and 5 years, respectively. Treatment with TTR stabilizers was associated with improved survival (HR: 0.31; 95% CI: 0.12-0.82; P = 0.019) and remained significant after adjusting for sex, age, ATTR-CM type, and estimated glomerular filtration rate (HR: 0.18; 95% CI: 0.06-0.55; P = 0.002). Conclusions: After a median follow-up period of 3.7 years, 1 in 3 patients with asymptomatic ATTR-CM developed HF symptoms, and nearly as many died or required cardiac transplantation. Treatment with TTR stabilizers was associated with improved prognosis.

Machine Learning Risk Prediction for Incident Heart Failure in Patients With Atrial Fibrillation.

Background: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little focus is placed on the risk stratification for, and prevention of, incident HF in patients with AF. Objectives: This study aimed to construct and validate a machine learning (ML) prediction model for HF hospitalization in patients with AF. Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We divided the data set of the registry into derivation (n = 2,383) and validation (n = 2,011) cohorts. An ML model was built to predict the incidence of HF hospitalization using the derivation cohort, and predictive ability was examined using the validation cohort. Results: HF hospitalization occurred in 606 patients (14%) during a median follow-up period of 4.4 years in the entire registry. Data of transthoracic echocardiography and biomarkers were frequently nominated as important predictive variables across all 6 ML models. The ML model based on a random forest algorithm using 7 variables (age, history of HF, creatinine clearance, cardiothoracic ratio on x-ray, left ventricular [LV] ejection fraction, LV end-systolic diameter, and LV asynergy) had high prediction performance (area under the receiver operating characteristics curve [AUC]: 0.75) and was significantly superior to the Framingham HF risk model (AUC: 0.67; P < 0.001). Based on Kaplan-Meier curves, the ML model could stratify the risk of HF hospitalization during the follow-up period (log-rank; P < 0.001). Conclusions: The ML model revealed important predictors and helped us to stratify the risk of HF, providing opportunities for the prevention of HF in patients with AF.

Distinct Mechanisms for Increased Cardiac Contraction Through Selective Alteration of Either Myosin or Troponin Activity.

Modulation of sarcomere contractility represents a new therapeutic opportunity for the treatment of heart failure by directly targeting the thick and thin filament proteins of the sarcomere to increase cardiac muscle contraction. This study compared the effect of 2 small molecules (M and T) that selectively alter myosin thick filament (M) or troponin thin filament (T) activity on overall cardiac muscle mechanics. This study revealed key differences related to the mechanism utilized by M and T to increase contractile force generation and suggests that targeting different proteins within the sarcomere may result in differentiating therapeutic profiles.

TNFR1 Contributes to Activation-Induced Cell Death of Pathological CD4+ T Lymphocytes During Ischemic Heart Failure.

CD4+ T cells turn pathological during heart failure (HF). We show that the expression of tumor necrosis factor (TNF)-α and tumor necrosis factor receptor (TNFR1) increases in HF-activated CD4+ T cells. However, the role of the TNF-α/TNFR1 axis in T-cell activation/proliferation is unknown. We show that TNFR1 neutralization during T-cell activation (ex vivo) or the loss of TNFR1 in adoptively transferred HF-activated CD4+ T cells (in vivo) augments their prosurvival and proliferative signaling. Importantly, TNFR1 neutralization does not affect CD69 expression or the pathological activity of HF-activated TNFR1-/- CD4+ T cells. These results show that during HF TNFR1 plays an important role in quelling prosurvival and proliferative signals in CD4+ T cells without altering their pathological activity.

Identification of predictive factors interacting with heart rate reduction for potential beneficial clinical outcomes in chronic heart failure: A systematic literature review and meta-analysis.

Background: There is an absence of clinical evidence on what factors modify the effect of heart rate (HR)-reducing treatment on mortality and morbidity in symptomatic heart failure patients with reduced ejection fraction (HFrEF). We performed a Bayesian meta-analysis and meta-regression to identify predictive factors that interact with HR-reducing therapy. Methods: A systematic review was performed to identify randomized placebo-controlled trials that enrolled symptomatic HFrEF patients. The primary objective was to evaluate how different predictive factors modify the efficacy of HR-reducing therapy on clinical outcomes. Secondary objectives included the evaluation of subgroups stratified by a HR reduction threshold of 10 bpm. Results: Data from 20 studies were synthesized and HR-reducing therapy was responsible for 16.7 %, 16.4 %, and 21.1 % risk reductions in all-cause mortality, cardiovascular (CV)-related mortality, and rehospitalization due to worsening HF (WHF), respectively. Empirical Bayes meta-regression showed that type 2 diabetes mellitus (T2DM) significantly modified the efficacy of HR-reducing therapy on all-cause mortality (slope = 0.012 in log risk ratio (RR) per 1 %-unit [95 % credible interval (CrI) 0.004, 0.021]) and CV-related mortality (0.01 in log RR per 1 %-unit [95 % CrI 0.0003, 0.0200]). There were insufficient studies to perform a meta-regression when stratifying by a HR reduction threshold of 10 bpm; however, when including all studies, we observed a significant effect modification for rehospitalization due to WHF (p = 0.004). Conclusions: This meta-analysis focused on the central tenet of HR-reducing therapy and revealed that T2DM is a predictor of HR-reducing treatment effect on all-cause mortality and CV-related mortality in HFrEF patients.

Clinical Benefits of Sodium-Glucose Cotransporter 2 Inhibitors and the Mechanisms Underlying Their Cardiovascular Effects.

In addition to showing antidiabetic effects, sodium-glucose cotransporter 2 (SGLT2) inhibitors also reduce cardiovascular events in patients with type 2 diabetes mellitus. In major trials of cardiovascular outcomes, SGLT2 inhibitors have been shown to improve cardiovascular and renal outcomes, including reduced rehospitalization in patients with heart failure, regardless of the presence of diabetes. A recent report showed that the benefits of SGLT2 inhibitors in terms of cardiovascular deaths/admissions caused by heart failure and reduced ejection fraction were greater in Asians than in Whites. In this review, the first part demonstrates the results of recent clinical trials and their clinical implications and outlines current trials and upcoming research areas. The second part provides a general overview of the current understanding of the mechanisms of the cardiovascular benefits of SGLT2 inhibitors.