Cardiac Myosin Activation with Omecamtiv Mecarbil in Systolic Heart Failure.

BACKGROUND: The selective cardiac myosin activator omecamtiv mecarbil has been shown to improve cardiac function in patients with heart failure with a reduced ejection fraction. Its effect on cardiovascular outcomes is unknown. METHODS: We randomly assigned 8256 patients (inpatients and outpatients) with symptomatic chronic heart failure and an ejection fraction of 35% or less to receive omecamtiv mecarbil (using pharmacokinetic-guided doses of 25 mg, 37.5 mg, or 50 mg twice daily) or placebo, in addition to standard heart-failure therapy. The primary outcome was a composite of a first heart-failure event (hospitalization or urgent visit for heart failure) or death from cardiovascular causes. RESULTS: During a median of 21.8 months, a primary-outcome event occurred in 1523 of 4120 patients (37.0%) in the omecamtiv mecarbil group and in 1607 of 4112 patients (39.1%) in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.86 to 0.99; P = 0.03). A total of 808 patients (19.6%) and 798 patients (19.4%), respectively, died from cardiovascular causes (hazard ratio, 1.01; 95% CI, 0.92 to 1.11). There was no significant difference between groups in the change from baseline on the Kansas City Cardiomyopathy Questionnaire total symptom score. At week 24, the change from baseline for the median N-terminal pro-B-type natriuretic peptide level was 10% lower in the omecamtiv mecarbil group than in the placebo group; the median cardiac troponin I level was 4 ng per liter higher. The frequency of cardiac ischemic and ventricular arrhythmia events was similar in the two groups. CONCLUSIONS: Among patients with heart failure and a reduced ejection, those who received omecamtiv mecarbil had a lower incidence of a composite of a heart-failure event or death from cardiovascular causes than those who received placebo. (Funded by Amgen and others; GALACTIC-HF ClinicalTrials.gov number, NCT02929329; EudraCT number, 2016-002299-28.).

Temporal Analysis in Outcomes of Long-Term Mechanical Circulatory Support: Retrospective Study.

BACKGROUND: Mechanical assist device indications have changed in recent years. Reduced incidence of complications, better survival, and the third generation of mechanical support devices contributed to this change. In this single-center study, we focused on two time periods that are characterized by the use of different types of mechanical support devices, different patient characteristics, and change in the indications. METHODS: The data were processed from the European Registry for Patients with Mechanical Circulatory Support (EUROMACS). We retrospectively defined two time intervals to reflect changes in ventricular assist device technology (period 1: 2007-2015; period 2: 2016-20222). A total of 181 patients underwent left ventricular assist device implantation. Device utilization was the following: HeartMate II = 52 (76.4%) and HeartWare = 16 (23.6%) in period 1 and HeartMate II = 2 (1.8%), HeartMate 3 = 70 (61:9%), HeartWare = 29 (25.7%), SynCardia TAH = 10 (8.8%), and BerlinHeart EXCOR = 2 (1.8%) in period 2. The outcomes of the time intervals were analyzed and evaluated. RESULTS: Survival was significantly higher during the second time period. Multivariate analysis revealed that age and bypass pump time are independent predictors of mortality. Idiopathic cardiomyopathy, bypass time, and the Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) score are independent predictors of adverse events. Furthermore, the first period was noted to be at an increased risk of the following adverse events: pump thrombosis, gastrointestinal bleeding, and bleeding events. CONCLUSION: Despite the higher risk profile of the patients and persistent challenges, during the second period, there was a significant decrease in mortality and morbidity. The use of the HeartMate 3 device may have contributed to this result.

Effects of omecamtiv mecarbil in heart failure with reduced ejection fraction according to blood pressure: the GALACTIC-HF trial.

AIM: Patients with heart failure with reduced ejection fraction and low systolic blood pressure (SBP) have high mortality, hospitalizations, and poorly tolerate evidence-based medical treatment. Omecamtiv mecarbil may be particularly helpful in such patients. This study examined its efficacy and tolerability in patients with SBP ≤100 mmHg enrolled in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF). METHODS AND RESULTS: The GALACTIC-HF enrolled patients with baseline SBP ≥85 mmHg with a primary outcome of time to cardiovascular death or first heart failure event. In this analysis, patients were divided according to their baseline SBP (≤100 vs. >100 mmHg). Among the 8232 analysed patients, 1473 (17.9%) had baseline SBP ≤100 mmHg and 6759 (82.1%) had SBP >100 mmHg. The primary outcome occurred in 715 (48.5%) and 2415 (35.7%) patients with SBP ≤100 and >100 mmHg, respectively. Patients with lower SBP were at higher risk of adverse outcomes. Omecamtiv mecarbil, compared with placebo, appeared to be more effective in reducing the primary composite endpoint in patients with SBP ≤100 mmHg [hazard ratio (HR), 0.81; 95% confidence interval (CI), 0.70-0.94] compared with those with SBP >100 mmHg (HR, 0.95; 95% CI, 0.88-1.03; P-value for interaction = 0.051). In both groups, omecamtiv mecarbil did not change SBP values over time and did not increase the risk of adverse events, when compared with placebo. CONCLUSION: In GALACTIC-HF, risk reduction of heart failure outcomes with omecamtiv mecarbil compared with placebo was large and significant in patients with low SBP. Omecamtiv mecarbil did not affect SBP and was well tolerated independent of SBP values.

Successful support of biventricular heart failure in an adult patient by the Berlin Heart EXCOR system as a bridge to transplant: literature review.

Right heart failure is a huge challenge in left ventricular assist device therapy and its occurrence is associated with increased mortality and morbidity. Other options include the use od temporary right ventricular assist device, use of two continous flow biventricular assist devices, use of total artificial heart and the use of paracorporeal biventricular assist devices.In this report we described the successful use of the paracorporeal pulsatile Berlin Heart EXCOR system as a bridge to transplant in a 62 years old patient with end-stage biventricular heart failure (Tab. 1, Fig. 3, Ref. 22). Keywords: biventricular heart failure, mechanical circulatory support, biventricular assist device, Berlin Heart EXCOR system, heart transplantation.

Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction.

BACKGROUND: The angiotensin receptor-neprilysin inhibitor sacubitril-valsartan led to a reduced risk of hospitalization for heart failure or death from cardiovascular causes among patients with heart failure and reduced ejection fraction. The effect of angiotensin receptor-neprilysin inhibition in patients with heart failure with preserved ejection fraction is unclear. METHODS: We randomly assigned 4822 patients with New York Heart Association (NYHA) class II to IV heart failure, ejection fraction of 45% or higher, elevated level of natriuretic peptides, and structural heart disease to receive sacubitril-valsartan (target dose, 97 mg of sacubitril with 103 mg of valsartan twice daily) or valsartan (target dose, 160 mg twice daily). The primary outcome was a composite of total hospitalizations for heart failure and death from cardiovascular causes. Primary outcome components, secondary outcomes (including NYHA class change, worsening renal function, and change in Kansas City Cardiomyopathy Questionnaire [KCCQ] clinical summary score [scale, 0 to 100, with higher scores indicating fewer symptoms and physical limitations]), and safety were also assessed. RESULTS: There were 894 primary events in 526 patients in the sacubitril-valsartan group and 1009 primary events in 557 patients in the valsartan group (rate ratio, 0.87; 95% confidence interval [CI], 0.75 to 1.01; P = 0.06). The incidence of death from cardiovascular causes was 8.5% in the sacubitril-valsartan group and 8.9% in the valsartan group (hazard ratio, 0.95; 95% CI, 0.79 to 1.16); there were 690 and 797 total hospitalizations for heart failure, respectively (rate ratio, 0.85; 95% CI, 0.72 to 1.00). NYHA class improved in 15.0% of the patients in the sacubitril-valsartan group and in 12.6% of those in the valsartan group (odds ratio, 1.45; 95% CI, 1.13 to 1.86); renal function worsened in 1.4% and 2.7%, respectively (hazard ratio, 0.50; 95% CI, 0.33 to 0.77). The mean change in the KCCQ clinical summary score at 8 months was 1.0 point (95% CI, 0.0 to 2.1) higher in the sacubitril-valsartan group. Patients in the sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Among 12 prespecified subgroups, there was suggestion of heterogeneity with possible benefit with sacubitril-valsartan in patients with lower ejection fraction and in women. CONCLUSIONS: Sacubitril-valsartan did not result in a significantly lower rate of total hospitalizations for heart failure and death from cardiovascular causes among patients with heart failure and an ejection fraction of 45% or higher. (Funded by Novartis; PARAGON-HF ClinicalTrials.gov number, NCT01920711.).

Effects of Serelaxin in Patients with Acute Heart Failure.

BACKGROUND: Serelaxin is a recombinant form of human relaxin-2, a vasodilator hormone that contributes to cardiovascular and renal adaptations during pregnancy. Previous studies have suggested that treatment with serelaxin may result in relief of symptoms and in better outcomes in patients with acute heart failure. METHODS: In this multicenter, double-blind, placebo-controlled, event-driven trial, we enrolled patients who were hospitalized for acute heart failure and had dyspnea, vascular congestion on chest radiography, increased plasma concentrations of natriuretic peptides, mild-to-moderate renal insufficiency, and a systolic blood pressure of at least 125 mm Hg, and we randomly assigned them within 16 hours after presentation to receive either a 48-hour intravenous infusion of serelaxin (30 µg per kilogram of body weight per day) or placebo, in addition to standard care. The two primary end points were death from cardiovascular causes at 180 days and worsening heart failure at 5 days. RESULTS: A total of 6545 patients were included in the intention-to-treat analysis. At day 180, death from cardiovascular causes had occurred in 285 of the 3274 patients (8.7%) in the serelaxin group and in 290 of the 3271 patients (8.9%) in the placebo group (hazard ratio, 0.98; 95% confidence interval [CI], 0.83 to 1.15; P = 0.77). At day 5, worsening heart failure had occurred in 227 patients (6.9%) in the serelaxin group and in 252 (7.7%) in the placebo group (hazard ratio, 0.89; 95% CI, 0.75 to 1.07; P = 0.19). There were no significant differences between the groups in the incidence of death from any cause at 180 days, the incidence of death from cardiovascular causes or rehospitalization for heart failure or renal failure at 180 days, or the length of the index hospital stay. The incidence of adverse events was similar in the two groups. CONCLUSIONS: In this trial involving patients who were hospitalized for acute heart failure, an infusion of serelaxin did not result in a lower incidence of death from cardiovascular causes at 180 days or worsening heart failure at 5 days than placebo. (Funded by Novartis Pharma; RELAX-AHF-2 ClinicalTrials.gov number, NCT01870778.).

Prediction of Left Ventricular Reverse Remodelling: A Mini Review on Clinical Aspects.

Improvement of left ventricular ejection fraction (LVEF) in patients after the first manifestation of heart failure with reduced ejection fraction (HFrEF) has currently been observed more frequently than it was years ago. This appears to be due to the early initiation of comprehensive HF therapy. According to these observations, a new HF syndrome category, heart failure with improved ejection fraction (HFimpEF), was introduced. In this short review, we present definitions of reverse remodelling, myocardial remission, and myocardial recovery. We provide an overview of clinical research aimed at evaluating reverse remodelling in different populations of patients with HFrEF. Clinical and imaging characteristics and biomarkers identified as predictors of reverse remodelling and improvement of the LVEF are discussed. We also briefly address the current views on the management of patients with HFimpEF. In-depth study and knowledge of the molecular mechanisms underlying the reverse remodelling process may lead to the identification of new individualized therapeutic approaches for HFrEF.

Impact of prehospital IV furosemide or nitrate application on hospital outcome in acute heart failure patients.

OBJECTIVES: This study aims to evaluate the association between prehospital intravenous therapy and clinical outcomes in the patients with acute heart failure. METHODS: We conducted a prospective, multicenter observational study of consecutive AHF patients. Univariate and logistic regression analysis were performed to determine association between prehospital furosemide or nitrates administration and hospital outcome (death, length of stay). RESULTS: Data on a total of 1239 patients were processed. The mean age in the whole cohort was 71 ± 11.8 years with a gender distribution (M/F) of 634/605 patients. By prehospital treatment whole cohort was divided into 4 groups: F+ group with prehospital IV furosemide administration of 602 patients (48.6 %), F- group without prehospital IV furosemide administration of 637 patients (51.4 %), N+ group with prehospital IV nitrates administration of 110 patients (8.9 %) and N- group without IV nitrates administration of 1129 patients (91.1 %). Group of combined F+/N+ was not created. Ninety-four patients (7.6 %) died during the index hospitalization. Hospital mortality (p = 0.138) and length of stay (p = 0.101) did not differ in F+ vs F-. The patients with prehospital nitrates administration did not differ in mortality, but a shorter length of stay in univariate analysis (p = 0.03) was recorded. After adjusting for age, systolic BP and mode of referral to hospitalization, early IV furosemide usage nor nitrates showed no impact on hospital mortality and length of stay. CONCLUSIONS: Prehospital treatment with IV furosemide or nitrates in AHF patients seemed to have no major impact on hospital mortality or length of hospitalization after adjustment for several cofounders (Tab. 2, Ref. 16).

Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF.

BACKGROUND: Unlike heart failure with reduced ejection fraction, there is no approved treatment for heart failure with preserved ejection fraction, the predominant phenotype in women. Therefore, there is a greater heart failure therapeutic deficit in women compared with men. METHODS: In a prespecified subgroup analysis, we examined outcomes according to sex in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in Heart Failure With Preserved Ejection Fraction), which compared sacubitril-valsartan and valsartan in patients with heart failure with preserved ejection fraction. The primary outcome was a composite of first and recurrent hospitalizations for heart failure and death from cardiovascular causes. We also report secondary efficacy and safety outcomes. RESULTS: Overall, 2479 women (51.7%) and 2317 men (48.3%) were randomized. Women were older and had more obesity, less coronary disease, and lower estimated glomerular filtration rate and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels than men. For the primary outcome, the rate ratio for sacubitril-valsartan versus valsartan was 0.73 (95% CI, 0.59-0.90) in women and 1.03 (95% CI, 0.84-1.25) in men (P interaction = 0.017). The benefit from sacubitril-valsartan was attributable to reduction in heart failure hospitalization. The improvement in New York Heart Association class and renal function with sacubitril-valsartan was similar in women and men, whereas the improvement in Kansas City Cardiomyopathy Questionnaire clinical summary score was less in women than in men. The difference in adverse events between sacubitril-valsartan and valsartan was similar in women and men. CONCLUSIONS: As compared with valsartan, sacubitril-valsartan seemed to reduce the risk of heart failure hospitalization more in women than in men. Whereas the possible sex-related modification of the effect of treatment has several potential explanations, the present study does not provide a definite mechanistic basis for this finding. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov. Unique identifier: NCT01920711.

Alternative RAS in Various Hypoxic Conditions: From Myocardial Infarction to COVID-19.

Alternative branches of the classical renin-angiotensin-aldosterone system (RAS) represent an important cascade in which angiotensin 2 (AngII) undergoes cleavage via the action of the angiotensin-converting enzyme 2 (ACE2) with subsequent production of Ang(1-7) and other related metabolites eliciting its effects via Mas receptor activation. Generally, this branch of the RAS system is described as its non-canonical alternative arm with counterbalancing actions to the classical RAS, conveying vasodilation, anti-inflammatory, anti-remodeling and anti-proliferative effects. The implication of this branch was proposed for many different diseases, ranging from acute cardiovascular conditions, through chronic respiratory diseases to cancer, nonetheless, hypoxia is one of the most prominent common factors discussed in conjugation with the changes in the activity of alternative RAS branches. The aim of this review is to bring complex insights into the mechanisms behind the various forms of hypoxic insults on the activity of alternative RAS branches based on the different duration of stimuli and causes (acute vs. intermittent vs. chronic), localization and tissue (heart vs. vessels vs. lungs) and clinical relevance of studied phenomenon (experimental vs. clinical condition). Moreover, we provide novel insights into the future strategies utilizing the alternative RAS as a diagnostic tool as well as a promising pharmacological target in serious hypoxia-associated cardiovascular and cardiopulmonary diseases.

Unrecognised cardiovascular disease in type 2 diabetes: is it time to act earlier?

Cardiovascular disease (CVD) is the most significant prognostic factor in individuals with type 2 diabetes (T2D). However, a significant number of individuals may develop CVD that does not present with the classic angina-related or heart failure symptoms. In these cases, CVD may seem to be 'silent' or 'asymptomatic', but may be more accurately characterised as unrecognised diabetic cardiac impairment. An initial step to raise awareness of unrecognised CVD in individuals with T2D would be to reach a consensus regarding the terminology used to describe this phenomenon. By standardising the terminologies, and agreeing on the implementation of an efficient screening program, it is anticipated that patients will receive an earlier diagnosis and appropriate and timely treatment. Given the availability of anti-diabetic medications that have been shown to concomitantly reduce CV risk and mortality, it is imperative to improve early identification and initiate treatment as soon as possible in order to enable as many patients with T2D as possible to benefit.

What we know about epidemiology of heart failure in Slovakia and globally.

Heart failure (HF) is nowadays some of the most significant causes of mortality and morbidity, as well as one of the leading causes of hospitalization. Increasing number of patients with HF is becoming one of the most burning problems not only for health care, but also for the social welfare system. The knowledge of the epidemiology is crucial for rational planning and management of curative and preventive health care and allocation of research capacities. The sources of data for description of basic epidemiological characteristic of HF in Slovakia come from cross sectional surveys of outpatient care and hospitalization records of patients with heart failure, publicized sources of the National health information center and database of health care provision gathered by health insurer Dôvera. Crude prevalence of HF in Slovakia is 2.3%. Age specific prevalence ranging from 31/1 000 in habitants aged 50-54 up to 189/1 000 in the 80-84 age group. Average age in male population was 61.8 (± 8) and women 65.6 (± 9.3) years. In the functional class NYNA I were 10 %, in class NYHA II 45%, NYHA III 32% a NYHA IV 3 % patients with chronic heart failure. The most prevalent dominant cause of HF, 50-60 % of cases, is ischemic heart disease. Left ventricular ejection fraction of less than 40 % was observed in 26 % of patients followed up in general practice and 43 % of patients in care of the specialists. The exact data on HF incidence in Slovakia are no available. Incidence of hospitalizations for the newly diagnosed HF was 120 in one hundred thousand people a year, which could be considered bottom limit of incidence. The number of hospitalizations for HF grows dramatically from 9 060 in 2005 to 22 112 in 2017. The average length of hospitalization in 2015 was 9.4 ± 9.7 days. Hospitalization mortality, despite trend to decline, remains high at 6.2 %. It is estimated that prevalence of chronic HF will grow further fueled by population aging, the treatment success of acute cardiovascular and congenital heart diseases, prevention of sudden heart failure, and also prolongation of life expectancy in patients with HF. Both material and human in health care resources need to adapt to this visible trend. Key words: heart failure - hospitalizations - incidence - prevalence.

Analysis of necroptotic proteins in failing human hearts.

BACKGROUND: Cell loss and subsequent deterioration of contractile function are hallmarks of chronic heart failure (HF). While apoptosis has been investigated as a participant in the progression of HF, it is unlikely that it accounts for the total amount of non-functional tissue. In addition, there is evidence for the presence of necrotic cardiomyocytes in HF. Therefore, the objective of this study was to investigate the necroptotic proteins regulating necroptosis, a form of programmed necrosis, and thereby assess its potential role in human end-stage HF. METHODS: Left ventricular samples of healthy controls (C) and patients with end-stage HF due to myocardial infarction (CAD) or dilated cardiomyopathy (DCM) were studied. Immunoblotting for necroptotic and apoptotic markers was performed. Triton X-114 fractionated samples were analyzed to study differences in subcellular localization. RESULTS: Elevated expression of RIP1 (receptor-interacting protein), pSer227-RIP3 and its total levels were observed in HF groups compared to controls. On the other hand, caspase-8 expression, a proapoptotic protease negatively regulating necroptosis, was downregulated suggesting activation of necroptosis signaling. Total mixed-lineage kinase domain-like protein (MLKL) expression did not differ among the groups; however, active cytotoxic forms of MLKL were present in all HF samples while they were expressed at almost undetectable levels in controls. Interestingly, pThr357-MLKL unlike pSer358-MLKL, was higher in DCM than CAD. In HF, the subcellular localization of both RIP3 and pThr357-MLKL was consistent with activation of necroptosis signaling. Expression of main apoptotic markers has not indicated importance of apoptosis. CONCLUSIONS: This is the first evidence showing that human HF of CAD or DCM etiology is positive for markers of necroptosis which may be involved in the development of HF.

Necroptotic cell death in failing heart: relevance and proposed mechanisms.

As cardiomyocytes have a limited capability for proliferation, renewal, and repair, the loss of heart cells followed by replacement with fibrous tissue is considered to result in the development of ventricular dysfunction and progression to heart failure (HF). The loss of cardiac myocytes in HF has been traditionally believed to occur mainly due to programmed apoptosis or unregulated necrosis. While extensive research work is being carried out to define the exact significance and contribution of both these cell death modalities in the development of HF, recent knowledge has indicated the existence and importance of a different form of cell death called necroptosis in the failing heart. This new cell damaging process, resembling some of the morphological features of passive necrosis as well as maladaptive autophagy, is a programmed process and is orchestrated by a complex set of proteins involving receptor-interacting protein kinase 1 and 3 (RIP1, RIP3) and mixed lineage kinase domain-like protein (MLKL). Activation of the RIP1-RIP3-MLKL signaling pathway leads to disruption of cation homeostasis, plasma membrane rupture, and finally cell death. It seems likely that inhibition of any site in this pathway may prove as an effective pharmacological intervention for preventing the necroptotic cell death in the failing heart. This review is intended to describe general aspects of the signaling pathway associated with necroptosis, to describe its relationship with cardiac dysfunction in some models of cardiac injury and discuss its potential relevance in various types of HF with respect to the underlying pathologic mechanisms.

[Liver in heart failure]. / Pecen pri srdcovom zlyhávaní

Heart failure (HF) is a syndrome with multiple organ manifestations. Liver is due to its high metabolic activity and the resulting demands on oxygenation and also due to its anatomical position close to the heart damaged by heart failure very often. Despite the signs of liver damage are common in heart failure, clinically significant impairment of liver function rarely occurs. Liver lesion is caused by impaired hepatic circulation in terms of congestion and/or hypoperfusion. Congestive lesion is more common. Typically manifests as painful hepatomegaly, increased direct bilirubin and alkaline phosphatase. Pure ischemic lesion is rare. It occurs in a cases with severe and prolonged liver hypoperfusion often in combination with hypoxemia and results to the sharp rise of total bilirubin and transaminase levels. Short-term prognosis of this disorder, unless the cause hypoperfusion treated successfully, is poor. Increase in bilirubin and transaminase tests as well as signs of impaired proteosynthetic liver function are associated with poor prognosis. The worst prognosis have patients with HF and current primary liver disease. Knowledge phenotypes hepatic lesions in HF is important in choosing the tactics of treatment of acute HF decompensation.

An Unexpected Diagnostic Twist in an Elderly Patient: No Heart Failure With Preserved Ejection Fraction.

Heart failure with preserved ejection fraction (HFpEF) is considered to be the dominant cause of dyspnea and pulmonary hypertension (PH) in elderly patients with preserved left ventricular systolic function and cardiovascular comorbidities. However, it is important to keep in mind that left ventricular diastolic dysfunction is not the only possible cause of PH in cases of late-onset clinical manifestation. A multiparametric approach is essential for accurate diagnosis and therapeutic decision-making. A 74-year-old patient was admitted due to progressive dyspnea and suspicion of PH. Given the patient's risk profile, HFpEF and concomitant post-capillary PH were anticipated. Despite negative findings on CT angiography and transesophageal echocardiography, right heart catheterization was performed, revealing discrepant oxygen saturations in the superior vena cava and right atrium. A partial anomalous pulmonary venous return and an atrial septal defect were identified through cardiac magnetic resonance imaging.

Analysis of the serum levels of RIP3 and Drp1 in patients with heart failure.

AIMS: As necroptosis involving receptor-interacting protein kinase 3 (RIP3) and dynamin-related protein 1 (Drp1)-mediated signalling is a crucial mechanism of cell loss in heart failure (HF), we aimed to determine the potential diagnostic use of these molecules. METHODS AND RESULTS: The serum samples of the healthy subjects (n = 8) and patients with HF with reduced ejection fraction (n = 31), being subdivided according to the aetiology and New York Heart Association (NYHA) class, were used to measure RIP3 and Drp1 levels by enzyme-linked immunosorbent assay. Although the serum levels of Drp1 in the patients with HF were comparable with those seen in healthy individuals, we found a trend of increase in the levels of RIP3 (P = 0.0697) in the diseased group. These changes were unlikely dependent on the HF aetiology or NYHA class. The circulating RIP3 correlated with neither the main parameters assessing cardiac function (left ventricular ejection fraction, left ventricular end-diastolic diameter, and N-terminal pro-brain natriuretic peptide) nor the marker of inflammation (C-reactive protein). CONCLUSIONS: In this pilot study, findings on serum RIP3 supported the importance of necroptosis in HF pathomechanisms. The potential diagnostic use of circulating RIP3, unlike Drp1, as an additional biomarker of HF has also been indicated; however, further large studies are needed to prove this concept.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

AIMS: To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. METHODS AND RESULTS: Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. CONCLUSIONS: FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Sex Differences in Heart Failure With Reduced Ejection Fraction in the GALACTIC-HF Trial.

BACKGROUND: Women with heart failure with reduced ejection fraction (HFrEF) receive less guideline-recommended therapy and experience worse quality of life than men. OBJECTIVES: The authors sought to assess differences in baseline characteristics, outcomes, efficacy, and safety of omecamtiv mecarbil between men and women enrolled in the GALACTIC-HF (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction) study. METHODS: In GALACTIC-HF, patients with symptomatic heart failure with EF of 35% or less, recent heart failure event, and elevated natriuretic peptides were randomized to omecamtiv mecarbil or placebo. The current analysis investigated differences in baseline characteristics, clinical outcomes, and efficacy and safety of omecamtiv mecarbil between men and women. RESULTS: Of 8,232 patients analyzed, 21.2% were women. Women more likely self-identified as being Black, had worse symptoms (lower Kansas City Cardiomyopathy Questionnaire Total Symptom Score [KCCQ-TSS]), and were less likely to be treated with angiotensin receptor/neprilysin inhibitor and devices at baseline. Compared with men, women had lower rates of the primary endpoint (adjusted HR: 0.80, 95% CI: 0.73-0.88). Sex did not significantly modify omecamtiv mecarbil's treatment effect (P interaction = 0.68). Women also had 20% less risk of cardiovascular death, heart failure event, and all-cause death. Women participants had lower rates of serious adverse events. CONCLUSIONS: Women participants of the GALACTIC-HF trial had worse quality of life and were less likely to be treated with guideline-based therapies at baseline. Despite KCCQ-TSS being predictive of poor outcomes in this population, women had a 20% lower risk of an HF event or cardiovascular death compared with men. The beneficial effect of omecamtiv mecarbil did not significantly differ by sex. (Registrational Study With Omecamtiv Mecarbil [AMG 423] to Treat Chronic Heart Failure With Reduced Ejection Fraction [GALACTIC-HF]; NCT02929329).