Heart Failure Clinical Trials Research Articles

Abstract 12936: Quality of Life Assessments as Inclusion Criteria in Heart Failure Clinical Trials

Background: Patient-reported quality of life (QoL) assessments, such as the Kansas City Cardiomyopathy Questionnaire (KCCQ) or Minnesota Living with Heart Failure Questionnaire (MLHFQ), reflect an individual’s health status and symptom severity at a given timepoint, and may have utility as inclusion criteria in heart failure (HF) clinical trials. Method: The Heart Failure Collaboratory-Academic Research Consortium, a group of stakeholders including patients, investigators, and representatives from government and industry, convened to review data from multiple HF clinical trials discuss the use of patient reported QoL-based inclusion criteria in clinical trials of HF. Result: Patient-reported QoL assessments, such as the KCCQ, have high test-retest reliability and, in contrast with the physician-assigned New York Heart Association (NYHA) class, are not subject to clinician bias or influenced by knowledge of prognostic variables such as Left Ventricular Ejection Fraction (LVEF) or N-terminal pro B-type Natriuretic Peptide (NT-proBNP). The U.S. FDA has qualified KCCQ as an effective clinical outcomes assessment for HF, and recent clinical trials that demonstrated substantial reductions in morbidity and mortality also showed improvements in KCCQ scores, provided patients had a decrement at baseline. However, KCCQ use is limited by both complicated clinical interpretability, with total symptom score consisting of aggregate scores from different physical and symptomatic domains and uncertainty around the threshold of clinically important difference, and by its length, with average completion time of 5 to 8 minutes. Conclusion: Patient-reported functional assessments have potential as inclusion criteria in clinical trials of HF by ensuring the enrollment of patients with a diminished QoL who have the potential to improve in response to therapeutic intervention, especially in clinical trials with QoL-based endpoints.

Abstract 18005: Underrepresentation of Women in Clinical Trials of Heart Failure With Reduced Ejection Fraction

Background: There are established sex-specific differences in heart failure with reduced ejection fraction (HFrEF) outcomes. Randomized clinical trials (RCTs) based on cardiovascular outcome benefits, typically either reduced cardiovascular mortality or hospitalization for heart failure (HHF), and influence current guidelines for therapy. Objectives: To evaluate the representation of women in HFrEF RCTs that observed reduced all-cause or cardiovascular mortality or HHF. Methods: We queried Excerpta Medica dataBASE, Medical Literature Analysis and Retrieval System Online, Cumulative Index to Nursing and Allied Health Literature, and PubMed for HFrEF RCTs that reported a statistically significant benefit of intervention resulting in improved mortality or HHF published from 1980 to 2021. We estimated representation using the participation-to-prevalence ratio (PPR). PPR was calculated based on the proportion of women with HFrEF in the Framingham cohort (40%). A PPR of 0.8 to 1.2 was considered representative. Results: The final analysis included 33 RCTs. All trials except two were mentioned in the 2022 American College of Cardiology/American Heart Association/Heart Failure Society of America Guidelines for the Management of Heart Failure. Women represented 23.2% of enrolled participants (n = 24,363/ 104,972), ranging from 11.4% to 40.1% per-trial. Overall PPR was 0.58, with per-trial estimates ranging from 0.29 - 1.00. Five trials (15.2%) had a PPR of women representative of the disease population. Representation didn’t change significantly by the decade examined. The proportion of women in North American and Multiregional trials was significantly greater than in trials conducted in Europe (p = 0.04). The proportion of women was greater in industry trials compared to government-funded trials (p = 0.05). Conclusions: Women are underrepresented in HFrEF RCTs that have demonstrated mortality or HHF benefits, which may affect the sex-specific generalizability of major trial results. Sustained efforts are warranted to ensure equitable and appropriate inclusion of women in HFrEF trials.

Abstract 17493: Racial/Ethnic Under-Representation in Early Phase Clinical Trials

Introduction: There is severe underrepresentation of racial and ethnic groups in many cardiovascular clinical trials. Early-phase clinical trials examine the action and safety limits of treatment and thus, underrepresentation may have particularly deleterious effects. Hypothesis: Ethnic and Racial groups are underrepresented in early-phase trials. Methods: Using the clinicaltrials.gov database, we examined the racial and ethnic representation in Phases 1, 2, 3, and 4 in completed heart failure clinical trials (N=89) with reported results from 2016-2021. We examined the proportion of trials with a representation equal or greater than % U.S. Census population (12% for African American (AA), 19% for Hispanic/Latino (HL), and 7% for Asian (AN)) and determined the median trial representation percentage for AA, HL, and AN groups. Using Chi-square analysis we compared the percent representation across the trial phases. Results: We found that 49%, 91%, and 87% Phase 1 and 2 trials have a lower AA, HL, and AN representation, respectively, compared to that in the U.S. Population (Table 1). HL and AN representation in Phase 1 and 2 trials is particularly low. There is significant variation in AA, HL, and AN representation across all trial phases(p<0.001). Conclusions: Significant underrepresentation of racial and ethnic groups persist in contemporary Phase 1 and 2 trials. Efforts to create a standard for collecting and reporting demographics along with increasing racial and ethnic group representation closer to US population may reduce the risk of future adverse events.

Abstract 14640: Community Socioeconomic Distress is Associated With Poor Access to Heart Failure Clinical Trials in the United States

Introduction: Clinical trials have historically lacked representation from minorities and individuals from lower socioeconomic backgrounds. Little is known about the role geographic access plays in recruiting diverse populations for clinical trials. Objectives: Given disparities in clinical trial enrollment, we sought to analyze how access to heart failure trials varies across demographic groups. Methods: We queried clinicaltrials.gov for trials classified under “heart failure” that are recruiting and enrolling adult patients. Trial site addresses were obtained using Google Maps. We calculated drive times from each US census tract to the closest trial site using ArcGIS Pro v3.1. Demographic information and urban / rural statuses for census tracts were obtained from the US Census Bureau. Distressed Community Index (DCI) scores (0 = no distress, 100 = severe distress) based on metrics including education level, poverty, and unemployment were collected. Data were analyzed using Python v3.8. Results: We identified 954 heart failure trials with 644 unique sites in the US. About 54% of the rural population lives more than 30 minutes from a trial site compared to 22% of the urban population (OR 0.23; p < 0.001). Analysis of DCI scores covering 328 million people revealed that drive times increase with higher socioeconomic distress ( p < 0.001; Figure). In both urban and rural settings, median drive times for individuals in the top 10% of distressed communities (56 min urban and 79 rural) are more than three times those of individuals in the lowest 10% of distressed communities (18 min urban and 23 rural). A larger proportion of non-white minorities live less than 30 minutes from a trial site compared to the white population (77% vs. 60%; OR 2.23; p < 0.001). Conclusions: Increased socioeconomic distress is associated with worse access to heart failure trial sites for both urban and rural populations. Geographic barriers should be addressed to improve diversity in trials.

Istaroxime: A Novel Therapeutic Agent for Acute Heart Failure.

Acute decompensated heart failure (ADHF) is a multifactorial process that is associated with high morbidity and mortality. Treatment with inotropes can rapidly improve hemodynamic status; however, their use has been associated with increased mortality and incidence of arrhythmias. Istaroxime is a first-in-class intravenous agent currently undergoing clinical trials for acute heart failure. It has the unique mechanism of action of both Na+/K+ ATPase inhibition and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a stimulation. Notably, its action on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a improves calcium handling, which is known to be abnormal in heart failure. Clinical trials have shown that istaroxime has beneficial hemodynamic effects; in particular, its ability to increase systolic blood pressure without causing significant increases in heart rate or clinically significant arrhythmias differentiates it from inotropes currently utilized for ADHF treatment, such as milrinone. While initial studies are encouraging, additional trials are needed to assess outcomes and to compare their performance to standard inotropes in patients hospitalized with ADHF. This article will review the relevant preclinical and clinical trials for istaroxime, as well as the relevant pharmacology.

Examining the Landscape of Surrogate Outcomes in Clinical Trials of Heart Failure With Preserved Ejection Fraction (HFpEF) Patients: A Narrative Review

Examining the Landscape of Surrogate Outcomes in Clinical Trials of Heart Failure With Preserved Ejection Fraction (HFpEF) Patients: A Narrative Review

Improving cardiovascular outcomes for patients with heart failure in sub-Saharan Africa: conference proceedings of the 2022 Nigerian Cardiovascular Symposium.

The Nigerian Cardiovascular Symposium is an annual conference held in partnership with cardiologists in Nigeria and the diaspora to provide updates in cardiovascular medicine and cardiothoracic surgery with the aim of optimising cardiovascular care for the Nigerian population. This virtual conference (due to the COVID-19 pandemic) has created an opportunity for effective capacity building of the Nigerian cardiology workforce. The objective of the conference was for experts to provide updates on current trends, clinical trials and innovations in heart failure, selected cardiomyopathies such as hypertrophic cardiomyopathy and cardiac amyloidosis, pulmonary hypertension, cardiogenic shock, left ventricular assist devices and heart transplantation. Furthermore, the conference aimed to equip the Nigerian cardiovascular workforce with skills and knowledge to optimise the delivery of effective cardiovascular care, with the hope of curbing 'medical tourism' and the current 'brain drain' in Nigeria. Challenges to optimal cardiovascular care in Nigeria include workforce shortage, limited capacity of intensive care units, and availability of medications. This partnership represents a key first step in addressing these challenges. Future action items include enhanced collaboration between cardiologists in Nigeria and the diaspora, advancing participation and enrollment of African patients in global heart failure clinical trials, and the urgent need to develop heart failure clinical practice guidelines for Nigerian patients.

Sex Differences in the Generalizability of Randomized Clinical Trials in Heart Failure with Reduced Ejection Fraction.

To understand how sex differences impact the generalizability of randomized controlled trials (RCTs) in patients with heart failure and reduced ejection fraction (HFrEF, we sought to compare clinical characteristics and clinical outcomes between RCTs and HF observational registries stratified by sex. Data from 2 HF registries and 5 HFrEF RCTs were used to create three subpopulations: one RCT population (n=16,917; 21.7% females), registry patients eligible for RCT inclusion (n=26,104; 31.8% females), and registry patients ineligible for RCT inclusion (n=20,910; 30.2% females). Clinical endpoints included all-cause mortality, CV mortality, and first HF hospitalization at one-year. Males and females were equally eligible for trial enrollment (56.9% of females and 55.1% of males in the registries). One-year mortality rates were 5.6%, 14.0%, and 28.6% for females and 6.9%, 10.7%, and 24.6% for males in the RCT, RCT-eligible, and RCT-ineligible groups. After adjusting for 11 HF prognostic variables, RCT females showed higher survival compared to RCT-eligible females (Standardized mortality ratio (SMR) 0.72; 95% CI 0.62 - 0.83), while RCT males showed higher adjusted mortality rates compared to RCT-eligible males (SMR 1.16; 95% CI 1.09-1.24). Similar results were also found for cardiovascular mortality (SMR 0.89; 95%CI 0.76-1.03 for females, SMR 1.43; 95%CI 1.33-1.53 for males). Generalizability of HFrEF RCTs differed substantially between the sexes, with females having lower trial participation and females trial participants having lower mortality rates compared to similar females in the registries, while males had higher than expected cardiovascular mortality rates in RCTs compared to similar males in registries. This article is protected by copyright. All rights reserved.

Characteristics of United States Counties in Which Heart Failure Clinical Trials of Pharmacotherapy Were Conducted.

HomeCirculation: Heart FailureAhead of PrintCharacteristics of United States Counties in Which Heart Failure Clinical Trials of Pharmacotherapy Were Conducted No AccessResearch ArticleRequest AccessAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toNo AccessResearch ArticleRequest AccessCharacteristics of United States Counties in Which Heart Failure Clinical Trials of Pharmacotherapy Were Conducted Elisabeth Cox, Muath A. Alsalloum, Marin Vander Schaaf, Abdulaziz S. Alfehaid, Marwah E. Alnewais and Erin R. Weeda Elisabeth CoxElisabeth Cox Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). Search for more papers by this author , Muath A. AlsalloumMuath A. Alsalloum Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). Department of Pharmacy Practice, College of Clinical Pharmacy, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia (M.A.A.). Search for more papers by this author , Marin Vander SchaafMarin Vander Schaaf Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). Search for more papers by this author , Abdulaziz S. AlfehaidAbdulaziz S. Alfehaid Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). Pharmaceutical Care Services, King Faisal General Hospital, Alahsa Health Cluster, Ministry of Health, Saudi Arabia (A.S.A.). Search for more papers by this author , Marwah E. AlnewaisMarwah E. Alnewais Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). College of Clinical Pharmacy, King Faisal University, Alahsa, Saudi Arabia (M.E.A.). Search for more papers by this author and Erin R. WeedaErin R. Weeda Correspondence to: Erin R. Weeda, PharmD, Medical University of South Carolina, Department of Clinical Pharmacy and Outcomes Sciences, 280 Calhoun St, QE213C MSC140, Charleston, SC 29425. Email E-mail Address: [email protected] https://orcid.org/0000-0001-7876-5802 Medical University of South Carolina College of Pharmacy, Charleston (E.C., M.A.A., M.V.S., A.S.A., M.E.A., E.R.W.). Search for more papers by this author Originally published16 May 2023Circulation: Heart Failure. 2023;0:e010449FootnotesThis work was conducted at the Medical University of South Carolina.For Sources of Funding and Disclosures, see page XXX.Correspondence to: Erin R. Weeda, PharmD, Medical University of South Carolina, Department of Clinical Pharmacy and Outcomes Sciences, 280 Calhoun St, QE213C MSC140, Charleston, SC 29425. Email [email protected]edu Previous Back to top Next FiguresReferencesRelatedDetails Advertisement Article InformationMetrics © 2023 American Heart Association, Inc.PMID: 37191025 Originally publishedMay 16, 2023 Keywordsapplicabilitysocial determinants of healthdiversitygeneralizableruralclinical trialsexternal validityPDF download Advertisement SubjectsHeart Failure

Editorial introductions.

Current Opinion in Cardiology was launched in 1985. It is part of a successful series of review journals whose unique format is designed to provide a systematic and critical assessment of the literature as presented in the many primary journals. The field of cardiology is divided into 14 sections that are reviewed once a year. Each section is assigned a Section Editor, a leading authority in the area, who identifies the most important topics at that time. Here we are pleased to introduce the Journal's Editor and Section Editors for this issue. SECTION EDITORS Ali J MarianAli J MarianDr Marian received his training in clinical cardiology and human molecular genetics at Baylor College of Medicine, Houston, USA. He was appointed as a faculty at the Section of Cardiology at Baylor College of Medicine, Houston, USA in 1992. He joined the Institute of Molecular Medicine in 2006 to lead the Center for Cardiovascular Genetics. Dr Marian is recognized for his research achievements in molecular genetics and clinical aspects of cardiomyopathies. He has published over 200 articles in peer-reviewed journals, which collectively have garnered over 12,000 citations and an H index of 60. He received the Young Investigator Award from the American College of Cardiology, the Established Investigator Award from the American Heart Association, the Clinician-Scientist Award in Translational Research from Burroughs Wellcome Fund, Distinguished Scientist Award from Baylor St Luke's Medical Center, and the Best Editor Award from the American Heart Association Circulation Research. Dr Marian is currently a Deputy Editor for Cardiovascular Research, Section Editor on Genetics for Current Opinion in Cardiology, and the Editor-in-Chief of The Journal of Cardiovascular Aging. He is a former Deputy Editor for Circulation Research, Associate Editor for Circulation and European Journal of Clinical Investigation. Dr Marian's research is supported by R01 grants from the NHLBI-NIH, Leducq Foundation Trans-Atlantic Network of Excellence, and local foundations. Gene KimGene KimDr Kim is a cardiologist with the Advanced heart failure, Cardiac transplant, and Mechanical Circulatory Support Program at the University of Chicago Medicine, USA. He is an Associate Professor of Medicine and the Advanced Heart Failure Fellowship Program Director. His medical school, residency, and fellowship training were completed at the University of Chicago, USA. Dr Kim also directs the Genetic Cardiomyopathy and Hypertrophic Cardiomyopathy Clinics at University of Chicago, USA. Dr Kim's research interests include the genetic and epigenetic regulation of heart failure and arrhythmogenesis with publications on the role of microRNAs in cardiomyopathy. His interests also include myocardial recovery, extracellular matrix in failing myocardium. He has published over 100 articles and book chapters and is an investigator in numerous clinical trials. Bhavadharini RamuBhavadharini RamuDr Bhavadharini (Dharini) Ramu is an Advanced Heart Failure & Transplant Cardiologist, Director of the Cardio-Obstetrics Program and an Associate Professor of Medicine at the University of Minnesota, USA. She completed her internal medicine residency and cardiology fellowship at the University of Connecticut, USA followed by Advanced Heart Failure Fellowship at the University of Minnesota, USA in 2016. She previously served on the faculty at the Medical University of South Carolina, USA from 2016 to 2023. Dr Ramu has been an invited faculty lecturer at scientific meetings of the American College of Cardiology (ACC), Heart Failure Society of America, American Society of Transplantation, and International Society of Heart & Lung Transplantation. She is a member of the ACC's Heart Failure & Transplant Section Leadership Council, the program planning committee for the ACC's Scientific Sessions, and serves on the leadership council of the Women in Heart Transplantation & MCS Network. Dr Ramu's research interests include increasing the understanding of and reducing the impact of health-related disparities in patients with advanced heart failure, with a goal of reducing health inequities and improving the health of disadvantaged and vulnerable populations. She has served as a peer reviewer for many journals and is an investigator in heart failure clinical trials.

Soluble Guanylate Cyclase Activators and Stimulators in Patients with Heart Failure

This review sought to summarize the current emerging soluble guanylate cyclase activators and stimulators in patients with heart failure, both heart failure with reduced and preserved ejection fraction, to provide a reference for soluble guanylate cyclase activators and stimulators discovery. Heart failure is a common disease with considerable morbidity, hospitalization, and mortality Soluble guanylate cyclase is a key enzyme in the nitric oxide signaling pathway and has attracted rapidly growing interest as a therapeutic target in heart failure. Currently, several soluble guanylate cyclase agonists are in clinical development. Cinaciguat and praliciguat have shown no clear clinical benefit in patients with heart failure in clinical trials. Riociguat increased the 6-min walk distance, cardiac index, and stroke volume index as well as decreased N-terminal pro-B-type natriuretic peptide. Although these populations cover nearly every range of ejection fractions, these were not clinical trials directly in patients with heart failure but were designed in patients with pulmonary hypertension. Vericiguat is recommended in the latest American guideline for patients with heart failure with reduced ejection fraction; however, it gets mixed results in patients with heart failure with preserved ejection fraction. To date, only vericiguat reduces the composite of death from cardiovascular causes or first hospitalization for heart failure in patients with heart failure with reduced ejection fraction and riociguat might improve clinical symptoms and quality of life in patients with heart failure, both heart failure with reduced and preserved ejection fraction. We need more exploration about soluble guanylate cyclase activators and stimulators in patients with heart failure.

Characteristics Of Heart Failure Clinical Trials Registered In Clinicaltrials.gov- A Cross Sectional Analysis

Characteristics Of Heart Failure Clinical Trials Registered In Clinicaltrials.gov- A Cross Sectional Analysis

PATIENT REPORTED OUTCOME MEASURES AND PATIENT ENGAGEMENT IN HEART FAILURE CLINICAL TRIALS: MULTI-STAKEHOLDER PERSPECTIVES.

There are many consequences of heart failure (HF), including symptoms, impaired health-related quality of life (HRQoL), and physical and social limitations (functional status). These have a substantial impact on patients' lives, yet are not routinely captured in clinical trials. Patient-reported outcomes (PROs) can quantify patients' experiences of their disease and its treatment. Steps can be taken to improve the use of PROs in HF trials, in regulatory and payer decisions, and in patient care. Importantly, PRO measures (PROMs) must be developed with involvement of patients, family members, and caregivers from diverse demographic groups and communities. PRO data collection should become more routine not only in clinical trials but also in clinical practice. This may be facilitated by the use of digital tools and interdisciplinary patient advocacy efforts. There is a need for standardisation, not only of the PROM instruments, but also in procedures for analysis, interpretation and reporting PRO data. More work needs to be done to determine the degree of change that is important to patients and that which is associated with increased risks of clinical events. This "minimal clinically important difference (MCID)" requires further research to determine thresholds for different PROMs, to assess consistency across trial populations, and to define standards for improvement that warrant regulatory and reimbursement approvals. PROs are a vital part of patient care and drug development, and more work should be done to ensure that these measures are both reflective of the patient experience and that they are more widely employed.

Serum Human Epididymis Protein 4 as a Prognostic Predictor of New-Onset Heart Failure among Women after Acute Coronary Syndrome: A Single-Center Retrospective Study

Introduction: Little is known about the prognostic factors among women with acute coronary syndrome (ACS), partly due to the small number of women included in heart failure (HF) clinical trials. Human epididymis protein 4 (HE4) has been proven to be a new biomarker for acute and chronic HF over the years. We hypothesize that HE4 could be a promising predictor. Methods: This retrospective study analyzed data from Zhejiang Provincial People’s Hospital. This study included 302 female patients with ACS between January 1, 2021, and December 1, 2021. The primary outcome was new-onset HF after ACS during the 12-month follow-up period. We used a logistic regression model to evaluate the association between serum HE4 levels and the incidence of HF. Serum HE4 levels were measured at baseline (within 24 h after admission). Results: Of the 302 female patients, 70 (23.2%) developed new-onset HF within 12 months. Serum HE4 levels in patients with adverse events were significantly higher than those in patients without events (8.9 [7.3–11.5] pmol/dL versus 5.9 [5.0–6.8] pmol/dL, p < 0.001). The levels of HE4, troponin I peak, left ventricular ejection fraction (LVEF), and estimated glomerular filtration rate (eGFR) were validated as independent predictors, with HE4 being the best laboratory predictor (area under the curve, 0.863; 95% confidence interval, 0.817–0.909). Serum HE4 concentrations of >6.93 pmol/dL distinguished patients at risk of HF with 82.9% sensitivity and 78.0% specificity (maximum Youden index J, 0.609). Moreover, HE4 levels were associated with an increased risk of HF. Discussion: We found a strong relationship between HE4 and the occurrence of HF after ACS among women, which might help identify patients at high risk of HF for whom close or intense management should be mandatory.

Erhalt von Leistungsfähigkeit und Lebensqualität bei chronischer Herzinsuffizienz (Teil 3)

Endpoints of large clinical intervention trials in heart failure are usually designed to assess the number of hospital admissions and cardiovascular mortality; however, patients with heart failure also suffer from reduced physical exercise capacity and poor quality of life. The aim of this 3‑part review article is to show therapeutic possibilities to maintain mobility and quality of life in patients with heart failure, covering the aspects of guideline-conform drug treatment, treatment of comorbidities, and physical training options. This third part shows that exercise training is safe and effective to improve performance and quality of life. Exercise training is recommended for all patients who think they are capable of doing this, which is independent of whether heart failure with preserved or reduced ejection fraction is present.

Sigma-1 Receptor Signaling: In Search of New Therapeutic Alternatives for Cardiovascular and Renal Diseases.

Cardiovascular and renal diseases are among the leading causes of death worldwide, and regardless of current efforts, there is a demanding need for therapeutic alternatives to reduce their progression to advanced stages. The stress caused by diseases leads to the activation of protective mechanisms in the cell, including chaperone proteins. The Sigma-1 receptor (Sig-1R) is a ligand-operated chaperone protein that modulates signal transduction during cellular stress processes. Sig-1R interacts with various ligands and proteins to elicit distinct cellular responses, thus, making it a potential target for pharmacological modulation. Furthermore, Sig-1R ligands activate signaling pathways that promote cardioprotection, ameliorate ischemic injury, and drive myofibroblast activation and fibrosis. The role of Sig-1R in diseases has also made it a point of interest in developing clinical trials for pain, neurodegeneration, ischemic stroke, depression in patients with heart failure, and COVID-19. Sig-1R ligands in preclinical models have significantly beneficial effects associated with improved cardiac function, ventricular remodeling, hypertrophy reduction, and, in the kidney, reduced ischemic damage. These basic discoveries could inform clinical trials for heart failure (HF), myocardial hypertrophy, acute kidney injury (AKI), and chronic kidney disease (CKD). Here, we review Sig-1R signaling pathways and the evidence of Sig-1R modulation in preclinical cardiac and renal injury models to support the potential therapeutic use of Sig-1R agonists and antagonists in these diseases.

Heart failure in systemic right ventricle: Mechanisms and therapeutic options.

d-loop transposition of the great arteries (d-TGA) and congenitally corrected transposition of the great arteries (cc-TGA) feature a right ventricle attempting to sustain the systemic circulation. A systemic right ventricle (sRV) cannot support cardiac output in the long run, eventually decompensating and causing heart failure. The burden of d-TGA patients with previous atrial switch repair and cc-TGA patients with heart failure will only increase in the coming years due to the aging adult congenital heart disease population and improvements in the management of advanced heart failure. Clinical data still lags behind in developing evidence-based guidelines for risk stratification and management of sRV patients, and clinical trials for heart failure in these patients are underrepresented. Recent studies have provided foundational data for the commencement of robust clinical trials in d-TGA and cc-TGA patients. Further insights into the multifactorial nature of sRV failure can only be provided by the results of such studies. This review discusses the mechanisms of heart failure in sRV patients with biventricular circulation and how these mediators may be targeted clinically to alleviate sRV failure.

Clinical and ethical implications of withdrawal treatment at the end of heart failure clinical trials

Clinical and ethical implications of withdrawal treatment at the end of heart failure clinical trials

Assessing clinical and biomarker characteristics to optimize the benefits of sacubitril/valsartan in heart failure.

Of the various medical therapies for heart failure (HF), sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor that combines sacubitril, a pro-drug that is further metabolized to the neprilysin inhibitor sacubitrilat, and the angiotensin II type 1 receptor blocker valsartan. Inhibition of neprilysin and blockade of the angiotensin II type 1 receptor with sacubitril/valsartan increases vasoactive peptide levels, increasing vasodilation, natriuresis, and diuresis. Left ventricular ejection fraction (LVEF) is widely used to classify HF, to assist with clinical decision-making, for patient selection in HF clinical trials, and to optimize the benefits of sacubitril/valsartan in HF. However, as HF is a complex syndrome that occurs on a continuum of overlapping and changing phenotypes, patient classification based solely on LVEF becomes problematic. LVEF measurement can be imprecise, have low reproducibility, and often changes over time. LVEF may not accurately reflect inherent disease heterogeneity and complexity, and the addition of alternate criteria to LVEF may improve phenotyping of HF and help guide treatment choices. Sacubitril/valsartan may work, in part, by mechanisms that are not directly related to the LVEF. For example, this drug may exert antifibrotic and neurohumoral modulatory effects through inhibition or activation of several signaling pathways. In this review, we discuss markers of cardiac remodeling, fibrosis, systemic inflammation; activation of neurohormonal pathways, including the natriuretic system and the sympathetic nervous system; the presence of comorbidities; patient characteristics; hemodynamics; and HF signs and symptoms that may all be used to (1) better understand the mechanisms of action of sacubitril/valsartan and (2) help to identify subsets of patients who might benefit from treatment, regardless of LVEF.

Representation matters: a call for inclusivity and equity in heart failure clinical trials.

The burden of heart failure remains substantial worldwide, and heart failure with reduced ejection fraction (HFrEF) affects approximately half of this population. Despite this global prevalence of HFrEF, the majority of contemporary clinical trials in HFrEF have underenrolled individuals from minoritized sex, gender, race, ethnicity, and socioeconomic groups. Moreover, significant disparities in access to HFrEF treatment and outcomes exist across these same strata. We provide a call to action for the inclusion of diverse populations in HFrEF clinical trials; catalogue several barriers to adequate representation in HFrEF clinical trials; and propose strategies to broaden inclusivity in future HFrEF trials.