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Importance Clinical trials in cardiovascular medicine aim to deliver high-quality evidence with greater efficiency, including smaller sample sizes and shorter timelines. The selection of sensitive and reliable end points is central to this goal. Right ventricular (RV) structure and function play a critical role in many cardiovascular conditions; however, RV-specific parameters remain underused and inconsistently applied in interventional clinical trials. In this article, the current and emerging role of RV-focused imaging and hemodynamic parameters as end points in clinical trials are explored and a comprehensive framework for their development, validation, and broader implementation is proposed. Observations Across multiple disease domains, RV-focused parameters derived from echocardiography, cardiac magnetic resonance imaging, computed tomography, and right-sided heart catheterization demonstrate potential value in assessing the therapeutic effects of new medicines or devices across a wide range of conditions including heart failure, cardiomyopathies, valve diseases, pulmonary hypertension, and congenital heart conditions. However, their use is inconsistent, and feasibility challenges are common, particularly in multicenter clinical trial settings. Key limitations include variability in imaging acquisition, incomplete data capture, lack of standardized protocols, and insufficient validation linking short-term RV changes to long-term clinical outcomes. Emerging tools such as artificial intelligence may improve reproducibility and efficiency, while collaborative, multidisciplinary efforts are essential for advancing end-point development. Conclusions and Relevance RV-specific end points hold substantial promise for enhancing the sensitivity and mechanistic insight of clinical trials but remain inadequately integrated into current practice. Optimal end-point selection requires balancing clinical relevance, analytical validity, and operational feasibility, with consideration of disease-specific pathophysiology and trial design. Standardization of acquisition, validation of clinically meaningful changes, and centralized data analysis are important next steps. Broader adoption of robust RV metrics supported by technological innovation and cross-sector collaboration has the potential to improve trial efficiency, accelerate therapeutic development, and ultimately enhance patient outcomes.

Abstract Background and Aims Whether hemodynamic and symptomatic benefits of the APTURE left atrial-to-coronary sinus shunt translate into clinical outcome benefit in heart failure with left ventricular ejection fraction >40% remains unknown. Methods In this post hoc analysis of ALT-FLOW EFS patients undergoing APTURE implantation, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score-predicted 1-year all-cause mortality was compared with observed mortality by Kaplan-Meier analysis of adjudicated events. Heart failure hospitalization (HFH) rates were compared for the 12 months before vs after implantation. Additional analyses included stratification by baseline sodium-glucose cotransporter 2 inhibitor (SGLT2i) use and N-terminal pro-B-type natriuretic peptide (NT-proBNP), recurrent HFH cumulative hazard estimation (Nelson-Aalen), and H2FPEF score calculation. Results Among 95 patients (mean age 70.9 ± 8.5 years; 50% women; 93% New York Heart Association Class III; 85.9% with H2FPEF score >3), MAGGIC-predicted 1-year mortality was 13.0%. Observed 1-year survival was significantly higher than predicted (94.7% vs 87.0%; P=0.04), consistent across SGLT2i subgroups (log-rank P=0.59). The proportion of patients with HFH declined from 37.9% pre implantation to 9.6% post implantation (P<0.0001), with event rates falling from 0.61 to 0.21 per patient-year (P<0.001) and a 1-year cumulative hazard of recurrent HFH of 0.19 (95% confidence interval, 0.12-0.31). HFHs were evenly distributed across NT-proBNP strata. Conclusions In ALT-FLOW EFS, observed 1-year mortality was lower than MAGGIC-predicted mortality, and post implantation HFH rates were lower than pre implantation rates. These hypothesis-generating findings will require confirmation in the randomized, sham-controlled ALT-FLOW II trial.

Abstract Aims Heart failure (HF) with preserved (HFpEF) and mildly reduced (HFmrEF) ejection fraction are prevalent, yet frequently underdiagnosed syndromes associated with high morbidity and mortality, impaired quality of life, and escalating healthcare expenditures. Although guideline-directed medications like SGLT2 inhibitors have been shown to reduce the risk of hospitalization and cardiovascular death, their use remains limited and substantial residual risk persists. This trial aims to evaluate the safety and performance of a novel left-atrium-to-coronary-sinus shunt (Edwards APTURE transcatheter shunt system) in HFpEF and HFmrEF patients. Methods ALT-FLOW II is a prospective multi-centre, randomized, sham-controlled, double-blinded (patient and assessor) trial. Approximately 100 symptomatic HF patients aged ≥18 years with left ventricular ejection fraction >40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg with a PCWP to right atrial pressure gradient ≥8 mm Hg will be randomized 1:1 to the APTURE shunt vs sham control. Key exclusion criteria include severe HF, significant valvular disease, and more than mild right ventricular dysfunction. The primary endpoints are the safety of the APTURE device at 30 days and change in workload-corrected PCWP normalized to bodyweight at 6 months. Secondary endpoints include changes in patient-reported outcomes, and hemodynamic and echocardiographic parameters through 5 years. The trial will also explore the impact of the device on short-term cardiac remodelling and intra-cardiac flow patterns using multi-modality imaging. Conclusions The ALT-FLOW II trial will evaluate the safety and performance of the APTURE system in symptomatic HFpEF and HFmrEF patients with elevated left atrial pressure.

Abstract Aims The efficacy and safety of vericiguat in patients with chronic heart failure with reduced ejection fraction (HFrEF) on contemporary heart failure (HF) therapies and without recent worsening was investigated in the VICTOR trial, yet some subgroups may be more susceptible to symptomatic hypotension. Methods and results Among VICTOR trial participants that received at least one dose of study drug or placebo, we describe the systolic blood pressure (SBP) trajectories over time (mean change from baseline), symptomatic hypotension events and efficacy of vericiguat in potentially vulnerable patient subgroups: lower baseline blood pressure (SBP ≤110 mmHg), older patients (>75 years) and those taking angiotensin receptor–neprilysin inhibitors (ARNI) or sodium–glucose co-transporter 2 inhibitors (SGLT2i) at baseline. The efficacy outcomes of cardiovascular death and HF hospitalization and cardiovascular death alone across baseline SBP were examined using Cox proportional hazards models. Overall SBP trajectories showed a small initial decline from baseline in vericiguat-treated patients compared with placebo (placebo-corrected differences of −1.17 [−1.84, −0.50], p = 0.0007) that was relatively stable throughout follow-up. This trajectory was similar in those >75 years (vs. younger) as well as those receiving ARNI or SGLT2i (as compared with those not receiving these) or those with SBP ≤110 mmHg at baseline (compared with >110 mmHg). Symptomatic hypotension occurred in 11.3% of vericiguat-treated patients compared with 9.2% of placebo-treated patients with an adjusted hazard ratio of 1.24 (95% confidence interval 1.06–1.46), which was similar across age, SBP, SGLT2i and ARNI groups (all interaction p >0.05). The treatment effect of vericiguat compared with placebo on the efficacy outcomes was similar across the spectrum of baseline SBP (both interaction p >0.15). Conclusions Vericiguat showed a slight adjusted decrease in SBP and resulted in more symptomatic hypotension compared with placebo but was overall well-tolerated in a broad population with HFrEF on contemporary therapy even among those predisposed to hypotension. Treatment effects on efficacy outcomes were consistent regardless of baseline SBP.

Abstract Background and Aims In the VICTOR trial (NCT05093933), vericiguat was neutral for the primary composite endpoint of cardiovascular death or hospitalization for heart failure (HF). VICTOR was powered to independently assess cardiovascular death. This study reports detailed analysis on the effects of vericiguat on mortality. Methods VICTOR, a double-blind, placebo-controlled, randomized trial, enrolled 6105 ambulatory patients with HF and reduced ejection fraction (HFrEF) without recent worsening and randomized them to vericiguat or placebo. The main outcome for this analysis was the pre-specified secondary endpoint of cardiovascular death. All-cause death, sudden cardiac death, and death related to HF were also assessed. Results Over a median of 19.7 months (inter-quartile range 14.6–25.4), cardiovascular deaths occurred in 292 patients (5.7 deaths per 100 patient-years) and 346 patients (6.8 deaths per 100 patient-years) in the vericiguat and placebo groups, respectively (hazard ratio [HR] 0.83, 95% confidence interval [CI] 0.71–0.97; P = .020). Risk of death from any cause was lower with vericiguat vs placebo (377 [7.3 deaths per 100 patient-years] vs 440 [8.6 deaths per 100 patient-years]; HR 0.84, 95% CI 0.74–0.97; P = .015). Sudden cardiac death and HF-related deaths were lower with vericiguat vs placebo (1.6 vs 2.2 events per 100 patient-years; HR 0.75, 95% CI 0.56–0.99; P = .042 and 1.7 vs 2.4 events per 100 patient-years; HR 0.71, 95% CI 0.54–0.94; P = .016, respectively). Lower mortality rates were consistent across subgroups including baseline therapy. Consistent cardiovascular and all-cause mortality benefit was seen across baseline N-terminal pro-B-type natriuretic peptide levels. Conclusions In ambulatory well-treated participants with HFrEF, vericiguat was associated with clinically meaningful reductions in the key secondary outcome of cardiovascular death, as well as all-cause mortality.

Abstract Aims Inter-atrial shunt device therapy has shown mixed results in clinical trials, with clinical ‘non-responders’ typically showing features of more advanced heart failure. We aimed to analyse the haemodynamic and clinical response of a novel left atrial to coronary sinus (LA-CS) shunt device in patients with higher natriuretic peptide (NP) levels, a marker of disease severity. Methods and results An analysis population (n = 95) of patients from the ALT-FLOW early feasibility study with left ventricular ejection fraction >40% and 1-year follow up was analysed. The cohort was divided into low and high subgroups based on NP levels [b-type natriuretic peptide (BNP) and n-terminal pro BNP (NT-proBNP)]. The mean BNP and NT-proBNP levels for low versus high subgroups were 64.2 ± 34.3 versus 261 ± 103 and 322 ± 269 versus 2050 ± 1070 pg/mL, respectively. Patients in the high NP subgroup had evidence of more advanced disease including worse haemodynamic profiles, lower estimated glomerular filtration rate, and higher percentages of atrial fibrillation. The high NP subgroup experienced significant improvements in KCCQ-OSS and NYHA functional class (P < 0.0001 and P < 0.001, respectively) and to a similar magnitude compared with the low NP subgroup. Compared with pre-implant baseline, workload adjusted pulmonary artery wedge pressure at peak exercise declined in the high NP subgroup (PCWL, 164.1 vs. 96.0 mmHg/W/kg at 6 months, P < 0.003) as well as the low NP subgroup (115.9 vs. 65.9 mmHg/W/keg at 6 months, P < 0.001). Importantly, in both NP subgroups, there was preservation of cardiac index through 6 months as well as right ventricular structure (right ventricular diastolic dimension) and function (tricuspid annular systolic plane excursion) through 1 year. Conclusions The quality-of-life, haemodynamic, and functional class improvements along with stable right heart function seen in ALT-FLOW study of LA-CS shunt remain consistent in the subgroup with highest NP levels. This suggests that shunting location could influence outcomes in symptomatic heart failure patients.

Abstract Aims To describe the baseline characteristics of the participants in the VICTOR (Vericiguat Global Study in Patients with Chronic Heart Failure; NCT05093933) trial and compare them to recent trials in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results Baseline characteristics were evaluated in 6105 patients randomized to vericiguat or placebo. The mean age of the participants was 67 ± 11 years, 23.6% were women, 64.4% were White, and 10.7% were self-identified Black. Overall, 29.1% of participants were enrolled in Latin and South America, 27.8% and 18.5% in Eastern and Western Europe, 14.0% in Asia-Pacific and 10.6% in North America. The mean left ventricular ejection fraction was 30 ± 7% and 79% had New York Heart Association class II symptoms. Mean estimated glomerular filtration rate was 70.9 ± 24.0 ml/min/1.73 m2. Median N-terminal pro-B-type natriuretic peptide level was 1476 (970–2495) pg/ml and 47.5% of participants had no prior hospitalization for heart failure. Baseline therapy included 94.4% beta-blockers, 94.3% renin–angiotensin system modulation (including 56.0% on an angiotensin receptor–neprilysin inhibitor), 77.7% mineralocorticoid receptor antagonists, 59.1% sodium–glucose cotransporter 2 inhibitors, and 32.9% implantable cardioverter-defibrillators. Overall characteristics were relatively similar to other recent HFrEF trials but the VICTOR trial enrolled a higher proportion of participants receiving contemporary drug and device therapy. Conclusion The VICTOR trial enrolled the most optimally treated population in a phase III heart failure trial. These features will facilitate assessment of the benefit of vericiguat and elucidate the outcomes of patients on up-to-date medical therapy.

Abstract Heart failure with reduced or preserved ejection fraction is associated with elevated left atrial pressure at rest due to fluid overload or during exercise, leading to pulmonary venous congestion. Even with available treatments, heart failure hospitalizations remain high, and improvements in quality-of-life scores and functional capacity are modest. Thus, there is growing interest in non-pharmacological methods to decompress the left atrium and improve heart failure symptoms and outcomes. Left-to-right shunts have emerged as a potential therapeutic option to reduce left atrial hypertension, improve quality of life, and impact long-term outcomes. This nascent field carries both potential therapeutic promise and many unanswered questions. Recent data have questioned whether the effects of this therapy vary based on the left ventricular ejection fraction, pulmonary vascular resistance, and/or right ventricular structure and function. This review discusses the basis for left-to-right shunt therapies, synthesizes past and ongoing clinical trials, and offers future directions.

Abstract Aims In the VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction) trial, the soluble guanylate cyclase stimulator vericiguat reduced the risk of hospitalization for heart failure (HHF) or cardiovascular death in patients with heart failure (HF) and reduced ejection fraction (HFrEF) with recent worsening HF. The effect of vericiguat in patients with HFrEF without recent worsening HF remains unknown. The VICTOR (Vericiguat Global Study in Participants with Chronic Heart Failure) trial was designed to assess the efficacy and safety of vericiguat in patients with ejection fraction ≤40% without recent worsening HF on a background of current foundational HFrEF therapy. Methods The primary endpoint for VICTOR is time to first event for the composite of HHF or cardiovascular death. The trial will also assess the effect of vericiguat on time to cardiovascular death, time to HHF, total HHF, and all-cause death. As an event-driven trial, at least 1080 primary events are expected, but follow-up will continue until the targeted number of at least 590 cardiovascular deaths has been reached. Approximately 6000 participants will be randomized to vericiguat or placebo. Conclusion VICTOR is the first large event-driven HFrEF trial performed in the contemporary era of quadruple foundational guideline-directed medical therapy, in a compensated ambulatory HF population. VICTOR will add important information to the evidence of the effects of vericiguat across the spectrum of patients with HFrEF.

Introduction: Through degradation of the cardio- and renal-protective second messenger cyclic GMP, phosphodiesterase-9 (PDE9) excess may contribute to cardiomyocyte hypertrophy, fibrosis, and renal dysfunction, common features in heart failure with preserved ejection fraction (HFpEF) development and progression. Hypothesis: Selective PDE9 inhibition with IMR-687 mitigates an adverse cardiac and renal phenotype in mouse models of HFpEF. Methods: Cardiac and renal responses to IMR-687 (60 mg/kg, 100 mg/kg) compared with vehicle were examined over 6-8 weeks in 3 adult male mouse models of HFpEF (1.5 mg/kg/d angiotensin-II infusion [ang-II]; uninephrectomy + 0.30 ug/h d-aldosterone infusion + 1% NaCl drinking water [neph-aldo]; and db/db [db]). Phenotyping included wheat germ agglutinin staining for cardiomyocyte cross-sectional area (CSA); RT-PCR for myocardial PDE9, natriuretic peptide, inflammatory and fibrosis marker transcript abundances; ELISA for plasma natriuretic peptides; and urinary albumin to creatinine ratio (UACR). Results: IMR-687 reduced median cardiomyocyte size (CSA) by 54, 58, and 35% compared with vehicle in the ang-II, neph-aldo, and db models, respectively; p < 0.003 for all. Myocardial PDE9, NPPA, NPPB, COL3A1, and IL-1β expression were decreased by IMR-687 in all models (Table). Median plasma BNP levels (pg/mL) were lower in IMR-687 vs. vehicle treated mice in all models (ang-II: 2376 vs. 5757; neph-aldo: 1216 vs. 1860; db: 830 vs. 1216); p < 0.007 for all, with similar findings for ANP (Table). UACR was lower in IMR-687 compared with vehicle treated mice in all models (Table). Heart rate and blood pressure did not differ between IMR-687 and vehicle treated mice. Conclusion: Selective PDE9 inhibition with IMR-687 was effective for prevention and treatment of cardiac hypertrophy and renal dysfunction in 3 different preclinical models of HFpEF. IMR-687 may be a promising candidate therapy for testing in clinical trials of human HFpEF.