Reddy, Yogesh N.V.

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.

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.

Background: Pulmonary vascular resistance (PVR) is commonly considered to reflect opposition to lung blood flow caused by the arteries (PVRa), but downstream venous resistance (PVRv) may also contribute to pulmonary hypertension (PH) associated with left heart diseases (PH-LHD). In patients referred for right heart catheterization, we investigated PVR distribution and its pathophysiologic implications in PH-LHD and other forms of PH. Methods: Patients with PH-LHD (n=292), pulmonary veno-occlusive disease (PVOD, n=10), chronic thromboembolic PH (CTEPH, n=36) and controls without PH (Ctrl, n=28) were included. Pulmonary capillary pressure (Pc) was calculated using the pulmonary artery occlusion technique. PVR was partitioned into PVRa ((mPAP-Pc)/CO) and PVRv ((Pc-PAWP)/CO) with each expressed as % of PVR. PH-LHD was divided into isolated post-capillary PH (IpcPH) and combined post- and pre-capillary PH (CpcPH). Further, PH-LHD was categorized as heart failure with preserved (HFpEF, EF≥50%) or reduced (HFrEF, EF<50%) ejection fraction or left valvular heart disease (L-VHD). In subsets, functional tests (n=71-81) and histological pulmonary venous (PV) remodeling (autopsy, n=15) were performed to investigate correlations with PVR distribution. Results: PVR distribution showed an arterial predominance in Ctrl and CTEPH, and increasing venous contribution in PH-LHD (both IpcPH and CpcPH) and PVOD (Figure A-F). In PH-LHD, patients with HFpEF had proportionately greater venous contribution to PVR than HFrEF and L-VHD (Figure G-I), though not to the extent observed in PVOD. In subsets, PVRv was more strongly correlated with E/e’, extravascular lung water estimated by sonographic B-lines, arterial PO 2 , pulmonary dead space fraction (VD/VT), DLCO, and, among the autopsy series, PV intimal thickness as compared to PVRa (Figure J-O). Conclusions: Pulmonary venous contributions to PVR are amplified in patients with PH-LHD, which is correlated with greater lung congestion, ventilatory and gas exchange abnormalities, and histological venous remodeling. Further study is required to determine the molecular mechanism and novel therapeutics of pulmonary venous disease in PH-LHD.

Introduction: Obesity is rising in prevalence worldwide and co-exists in patients with group 1 pulmonary hypertension (PH). Clinical and hemodynamic implications of having obesity in group 1 PH remain unknown. Hypothesis . We hypothesized that obese patients with group 1 PH would exhibit worse hemodynamic parameters including higher right atrial pressure (RAP) and pulmonary capillary wedge pressure (PCWP) compared to non-obese patients. Aims: To compare hemodynamic parameters obtained from right heart catheterization (RHC) and echo among group 1 PH with and without obesity. Methods: We evaluated a cohort of patients with group 1 PH who underwent RHC at Mayo Clinic Rochester between 2002 to 2021 with diagnosis adjudicated by detailed chart review and initiation of pulmonary vasodilator therapy. Patients with a mean pulmonary artery pressure (mPAP) ≥ 25 mm who were clinically diagnosed with WHO Group 1 PH and recommended pulmonary vasodilator therapy initiation were included. Results: Of 822 participants with group 1 PH, obesity was common, present in 325 patients (40%). There was no difference in survival among patients with and without obesity (HR 1.15; 95% CI 0.95-1.38; p=.15). Obese patients had higher RAP (12.8 ± 6.8 vs 10.4 ± 6.5 mm of Hg, p<.0001) and cardiac output (5.2 ± 2.2 vs 4.5 ± 1.8 L/min, p<.0001) compared to non-obese group (Table 1). Despite having group 1 PH, pulmonary capillary wedge pressure (PCWP) was higher with obesity (13.8 ± 6.3 vs 12.2 ± 6.5 mm of Hg, p=.001) compared to those without obesity. Along with higher PCWP, there was less pulmonary vascular disease severity with obese group 1 PH, with higher pulmonary artery compliance (PAC, 1.65 ± 1.06 vs 1.38 ± 0.84 mL/mm of Hg, p=.0002) and lower pulmonary vascular resistance (PVR, 7.9 ± 5.2 vs 9.4 ± 7.7 Wood Units, p=.0007). After accounting for age, gender, diabetes mellitus and systemic hypertension, the RAP, cardiac output, PAC and PCWP remained significantly higher, and PVR remained lower in obese patients (p<0.05 for all). Conclusions: Comorbid obesity is associated with higher biventricular filling pressures, higher cardiac output and lower pulmonary vascular disease severity in otherwise clinically diagnosed group 1 PH. These findings call for further study of whether targeting obesity with novel weight loss drugs such as glucagon like peptide 1 receptor agonists or other drugs can lower biventricular filling pressures and associated pulmonary hypertension in group 1 PH with obesity.

Introduction: Portopulmonary hypertension (POPH) and associated pulmonary vascular resistance (PVR) elevation is seen in the context of underlying portal hypertension and liver disease. In the systemic circulation, liver cirrhosis can cause inappropriate splanchnic and systemic vasodilation with decreased systemic vascular resistance (SVR). Midodrine is used to maintain blood pressure in the setting of low SVR. Pulmonary vasodilators have systemic vasodilatory effects; the implications of combined midodrine and pulmonary vasodilator use in POPH are unanswered questions. Hypothesis: We hypothesized that SVR would decrease over time in patients with POPH started on pulmonary vasodilators, and that use of midodrine (as a surrogate for depressed SVR), may be associated with increased risk of mortality in patients with POPH starting pulmonary vasodilator therapy. Methods: Patients from the 3 Mayo Clinic sites (Rochester, MN; Jacksonville, FL; Scottsdale, AZ) diagnosed with POPH from 1988-2020 were included in the database. Patients met hemodynamic criteria for POPH via right heart catheterization (RHC). Hemodynamics were obtained from echocardiography and RHC at initial and subsequent visits. The hazard ratio for risk of death was estimated using Cox proportional hazards method. SVR was calculated using mean arterial pressure and cardiac output. Results: Analysis included 147 POPH patients, 34 (23%) on midodrine and 113 (77%) not requiring midodrine. There were 116 patients with longitudinal SVR data. The mean initial SVR was 1224 Dyne sec cm-5 and decreased 251 Dyne sec cm-5 [95% CI -337 to -165 251 Dyne sec cm-5, p<0.0001] with no difference between midodrine groups (p=0.57). Patients in the midodrine POPH group had an increased risk of mortality compared to those without midodrine use (HR 1.51, 95% CI: 1.02-2.21, p=0.0371). Conclusions: Patients with POPH starting pulmonary vasodilator have a reduction in SVR related to vasodilator therapy. Midodrine use with pulmonary vasodilator therapy is associated with increased mortality in the POPH population. Further study of the safety of combined midodrine and pulmonary vasodilator use in POPH is needed along with exploration of more selective pulmonary vasodilators.

ImportanceSecondary tricuspid regurgitation (STR) is observed in multiple cardiac and pulmonary diseases. Heart failure with preserved ejection fraction (HFpEF) is a common cause of STR that may be overlooked, along with precapillary etiologies of pulmonary hypertension (PH).ObjectivesTo investigate the prevalence of HFpEF and precapillary PH in patients with severe STR of undefined etiology (isolated STR) referred for exercise right heart catheterization (RHC), and to evaluate the performance of noninvasive measures to identify HFpEF.Design, Setting, and ParticipantsThis retrospective cross-sectional study included consecutive adults with severe STR in the absence of EF less than 50%, hemodynamically significant left-sided valve disease, congenital heart disease, infiltrative or hypertrophic cardiomyopathy, pericardial disease, or prior cardiac procedures who underwent rest-and-exercise RHC between February 2006 and June 2023 at Mayo Clinic and transthoracic echocardiography less than 90 days prior. Diastolic dysfunction (DD) was defined by at least 3 of 4 or 2 of 3 abnormal diastolic parameters (medial e’, medial E/e’, tricuspid regurgitation [TR] velocity, left atrial volume index). HFpEF was diagnosed when pulmonary arterial wedge pressure was at least 15 mm Hg at rest, at least 19 mm Hg with feet up, or at least 25 mm Hg during exercise. Data analysis was performed from November 2023 to March 2024.Main Outcomes and MeasuresThe prevalence of HFpEF and precapillary PH in severe isolated STR was determined, and performance of noninvasive measures to identify HFpEF was evaluated.ResultsOverall, 54 patients with severe isolated STR (mean [SD] age, 70.8 [12.5] years; 34 [63%] female) were identified. The primary indication for RHC was evaluation of TR prior to potential intervention in 36 patients (67%), evaluation of PH in 13 (24%), and confirmation of HFpEF in 5 (9%). HFpEF was identified in 40 patients (74%) but was recognized prior to RHC in only 19 patients (35%). Of the 14 remaining patients without HFpEF, precapillary PH was diagnosed in 10 (71%). Guideline-defined DD was absent in 24 patients (60%) who were subsequently diagnosed with HFpEF. Left atrial emptying fraction (area under the receiver operating characteristic curve [AUC] = 0.90; 95% CI, 0.82-0.98) and strain (AUC = 0.91; 95% CI, 0.83-0.99) had robust discrimination for HFpEF.Conclusions and RelevanceThe findings suggest that HFpEF is underdiagnosed and should be rigorously evaluated for in patients with severe isolated STR, along with precapillary PH, as both have distinct requirements for management. Resting DD based on current guidelines is insufficiently sensitive in these patients, indicating a pressing need for other noninvasive diagnostic tools, such as left atrial function assessment.

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.