Hegde, Sheila M.

Background This study aims to characterize right ventricular dysfunction (RVD) in heart failure (HF) with preserved ejection fraction and understand the cumulative prognostic value of abnormal RV echocardiographic parameters in HF with preserved ejection fraction. Methods and Results Data from 809 patients in the PARAGON‐HF (Prospective Comparison of Angiotensin Receptor–Neprilysin Inhibitor With Angiotensin‐Receptor Blocker Global Outcomes in HF With Preserved Ejection Fraction) echocardiographic substudy (55% women, mean age 74±8 years) were analyzed. Correlates of RVD (defined as tricuspid annular plane systolic excursion <1.7 cm, fractional area change <35% or absolute RV free wall longitudinal strain <20%) were identified using multivariable logistic regression models. We further assessed the prognostic value of the number of abnormal RV parameters (0, 1, ≥2) on total HF hospitalizations (HFH) and cardiovascular death, total HFH, first HFH or cardiovascular death, all‐cause death, and cardiovascular death. RVD was identified in 461 (57%) patients. Correlates of RVD included older age, higher heart rate, atrial fibrillation/flutter, greater left ventricle wall thickness, higher N‐terminal pro‐B‐type natriuretic peptide levels, lower systolic blood pressure, and lower left ventricle absolute global longitudinal strain. These results were consistent across sexes, except atrial fibrillation/flutter and LV wall thickness, which were associated with a higher risk of RVD in men but not in women. Participants with ≥2 abnormal RV parameters had a significantly higher adjusted risk of total HFH and cardiovascular death (rate ratio, 2.13 [95% CI, 1.13–4.01]), first HFH or cardiovascular death, all‐cause death, and cardiovascular death. Conversely, an isolated abnormal RV parameter was not associated with a worse outcome. Conclusions RV measures may underestimate the burden of RVD in HF with preserved ejection fraction when considered in isolation. Clinicians should consider multiple dimensions to comprehensively assess RV function in patients with HF with preserved ejection fraction.

Abstract Aims To evaluate clinical outcomes, echocardiographic features, and the efficacy and safety of sacubitril/valsartan compared to valsartan across age groups in the PARAGON-HF trial. Methods and results A total of 4796 participants ≥50 years of age with chronic heart failure (HF) and left ventricular ejection fraction (LVEF) ≥45% were divided into three age groups: &lt;65 years (n = 825), 65–74 years (n = 1772), and ≥75 years (n = 2199). Echocardiograms of 1097 patients were analysed in a standardized fashion at a core imaging laboratory. The primary composite outcome was total HF hospitalizations and cardiovascular (CV) death. Older patients were more likely to experience primary composite outcomes (compared to patients &lt;65 years, adjusted rate ratio [aRR] for ≥75 years: 1.39, 95% confidence interval [CI] 1.21–1.61), total HF hospitalization (aRR 1.27, 95% CI 1.09–1.49), and CV death (adjusted hazard ratio [aHR] 2.04, 95% CI 1.44–2.87). Age did not modify the effect of sacubitril/valsartan compared to valsartan on primary composite endpoint (pinteraction = 0.79) in the overall population or in those with LVEF ≤57%. Older adults randomized to sacubitril/valsartan were more likely to develop hypotension compared to those receiving valsartan (pinteraction = 0.026). Older patients had smaller left ventricular chamber sizes, higher LVEF, and were more likely to have abnormal measures of diastolic function. Conclusion Older patients with HF with preserved ejection fraction had higher event rates than younger patients, more adverse events overall, and more hypotension when treated with sacubitril/valsartan; however, the treatment benefits of sacubitril/valsartan were retained in older patients.

Background The phase 2 PIONEER‐HCM (Phase 2 Open‐label Pilot Study Evaluating Mavacamten in Subjects With Symptomatic Hypertrophic Cardiomyopathy and Left Ventricular Outflow Tract Obstruction) study showed that mavacamten improved left ventricular outflow tract gradients, exercise capacity, and symptoms in patients with obstructive hypertrophic cardiomyopathy (HCM), but the results of longer‐term treatment are less well described. We report interim results from the PIONEER‐OLE (PIONEER Open‐Label Extension) study, the longest‐term study of mavacamten in patients with symptomatic obstructive HCM. Methods and Results Patients who previously completed PIONEER‐HCM (n=20) were eligible to enroll in PIONEER‐OLE. Patients received oral mavacamten, 5 mg once daily (starting dose), with individualized dose titration at week 6. Evaluations included serial monitoring of safety, echocardiography, Kansas City Cardiomyopathy Questionnaire–Overall Summary Score, and serum NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels. Thirteen patients enrolled and received mavacamten (median study duration at data cutoff, 201 weeks). Most patients (92.3%) received β‐blockers concomitantly. Treatment‐emergent adverse events were predominantly mild/moderate. One patient had an isolated reduction in left ventricular ejection fraction to 47%, which recovered and remained normal with continued treatment at a reduced dose. At week 180, mavacamten was associated with New York Heart Association class improvements from baseline (class II to I, n=9; class III to II, n=1; and unchanged, n=2), sustained reductions in left ventricular outflow tract gradients (mean [SD] change from baseline: resting, −50 [55] mm Hg; Valsalva, −70 [41] mm Hg), and serum NT‐proBNP levels (median [interquartile range] change from baseline: −498 [−2184 to −76] ng/L), and improved Kansas City Cardiomyopathy Questionnaire–Overall Summary Score (mean [SD] change from baseline: +17 [16]). Conclusions This long‐term analysis supports the continued safety and effectiveness of mavacamten for >3 years in obstructive HCM. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT03496168.

Introduction: Impaired tricuspid annular plane systolic excursion (TAPSE), fractional area change (FAC) and right ventricular free wall longitudinal strain (RVFWLS) have been individually associated with a worse prognosis in patients with heart failure with preserved ejection fraction (HFpEF). However, these parameters measure different aspects of RV function and understanding their cumulative effect may provide insights into the overall impact of RV dysfunction (RVD) in HFpEF patients. Goal: Assess the association between the number of echocardiographic RVD parameters and clinical outcomes. Methods: Patients from the echocardiographic sub-study of the PARAGON-HF trial with adequate image quality (N=809, 53% women, mean age 74±8 years) were categorized based on the number of measures of RVD, which included TAPSE <1.7 cm, FAC <35% or RVFWLS <20% (absolute value). Associations with total HF hospitalizations (HFH) and CV death, total HFH alone, first HFH or CV death, all-cause death and CV death were assessed by Groups, after accounting for confounders. Results: A total of 348 patients (43%) in Group 0 (no abnormal parameter), 355 (44%) in Group 1 (one abnormal parameter) and 106 (13%) in Group 2 (two or more abnormal parameters) were identified. After multivariable adjustment ( Table ), Group 2 was significantly associated with an increased risk of total HFH and CV death (RR 2.13, 95%CI 1.13-4.01), first HFH or CV death (RR 2.07, 95%CI 1.15-3.73), all-cause death (RR 2.61, 95%CI 1.19-5.74) and CV death (RR 3.08, 95%CI 1.14-8.31). The treatment effect of sacubitril/valsartan for total HFH and CV death was not modified by RVD Group (p-value for interaction=0.94). Conclusions: The presence of two or more RVD parameters was associated with a significantly worse prognosis, while an isolated RVD measure was not. These findings suggest that a more comprehensive approach to assessment of RV function may have better prognostic value in HFpEF.

Introduction: Right ventricular dysfunction (RVD) is a major prognostic factor in patients with heart failure with preserved ejection fraction (HFpEF), however determinants of RVD in HFpEF are not well described. Although sex-specific mechanisms have been incriminated in the development of HFpEF, it is unclear whether this is also true for RVD. Goals: (1) Assess the prevalence of RVD (defined as a tricuspid annular plane systolic excursion [TAPSE] <1.7 cm, a fractional area change [FAC] <35% or a RV free wall longitudinal strain [RVFWLS] <20%, absolute value) in patients with HFpEF; (2) identify determinants of RVD, overall and according to sex, in patients with HFpEF. Methods: We used data from patients enrolled in the echocardiographic sub-study of the PARAGON-HF trial with adequate image quality (N=809, 53% women, mean age 74±8 years). Determinants of RVD, in the whole study population and according to sex, were identified using a multivariable logistic regression model. Results: There were 461 patients (57%) with RVD. After multivariable adjustment, RVD was cross-sectionally associated with a history of atrial fibrillation of flutter (AFF), older age, higher heart rate, greater LV mean wall thickness and higher NT-proBNP values. Systolic blood pressure and LV global longitudinal strain (absolute value) showed an inverse association ( Figure ). These results were consistent between men and women, except for AFF and LV mean wall thickness, which were associated with a greater likelihood of RVD in men (OR 2.46, 95%CI 1.33-4.56, OR 1.61, 95%CI 1.18-2.21 respectively) but not in women (OR 0.99, 95%CI 0.58-1.68, OR 0.90 95%CI 0.69-1.17 respectively, p-values for interaction=0.028 and 0.006). Conclusions: RVD was highly prevalent in our study population. Determinants of RVD included AFF, LV remodeling and systolic impairment, and increased NT-proBNP levels. Differences between men and women suggest gender-specific mechanisms in the development of RVD in HFpEF.

Introduction: Heart failure with preserved ejection fraction (HFpEF) may have different characteristics by age groups. Aim Compare clinical and echocardiographic characteristics in patients with HFpEF enrolled in the PARAGON-HF echocardiography substudy by age groups. Methods: Echocardiography was performed in 1097 patients in PARAGON-HF (Prospective Comparison of ARNI with ARB Global Outcomes in HF with Preserved Ejection Fraction), where patients with left ventricular ejection fraction (LVEF) >=45% were enrolled. Clinical and echocardiographic characteristics were compared in patients who were <65, 65-74, and >75 years of age. Results: Younger patients were more likely to be male, obese, have prior myocardial infarction (MI) and diabetes, but less likely to have atrial fibrillation (AF, Table 1). Older patients had smaller left ventricular (LV) dimension indices, more likely to have concentric hypertrophy or remodeling, higher LVEF and better global longitudinal strain, and more likely to have left atrial enlargement and echocardiographic evidence of higher LV filling pressure (Table 1). Echocardiographic measures of pulmonary pressure and right ventricular function were similar across age groups. After adjusting for sex, race, region, history of MI, diabetes, AF, and body mass index, every 10 years of increase in age was associated with 5.1 mL/m 2 decrease in LV end-diastolic volume index (95% confidence interval [CI] 3.9 - 6.5, p < 0.001), 0.4% increase in absolute global longitudinal strain (95% CI 0.1% - 0.7%, p = 0.017), and 1.07 increase in E/e’ septal ratio (95% CI 0.42 - 1.73, p = 0.001). Conclusions: Compared with younger patients, older patients with HFpEF were more likely to be female with AF, have better systolic function and higher LV filling pressure. These findings demonstrated the heterogeneity in cardiac structure and function in HFpEF by age and may have implications for treatment and future clinical trial recruitment.

Introduction: The incidence of heart failure (HF) is higher in black than in white Americans, but the causes are unclear. We proposed that ethnic differences in ventricular-arterial interaction may contribute to this differential HF risk. Methods: We studied measures of arterial elastance (Ea) and left ventricle (LV) end-systolic elastance (Ees) in 5767 community-based elderly participants (76±5 years, 41% male, 22% black) who underwent echocardiography in the Atherosclerosis Risk in Community (ARIC) Study. Results: Black participants were more frequently women (66 vs 57%) and had a higher prevalence of obesity (46 vs 31%), hypertension (94 vs 80%), and diabetes mellitus (47 vs 34%). Adjusting for these baseline differences, the prevalence of LV hypertrophy was similar, but Ea, Ees and Ea/Ees ratio were higher in blacks than whites, particularly in black women (Figure). Ea was positively associated with LV mass index and E/e’ ratio in blacks, but not in whites (p for interaction < 0.001). Conclusion: These community-based data demonstrate that ventricular-arterial stiffening is greater in black than white Americans, coupled with more ventricular remodeling and dysfunction. The heightened afterload dependence in blacks suggests greater potential for risk reduction with anti-hypertensive therapy.

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) consists of a constellation of LV hypercontractility, LV outflow tract obstruction (LVOTO), and impaired relaxation, often resulting in dyspnea and reduced exercise capacity. In healthy dogs, the novel myosin modulator mavacamten (MAVA), decreased LV hypercontractility and improved compliance. In the PIONEER-HCM clinical study, improvements in post-exercise LVOT gradient, exercise capacity, and symptoms were reported. To examine whether MAVA could also limit residual myosin-actin cross-bridges during diastole, and improve LV compliance, its effects on diastolic indices were evaluated. Methods: In PIONEER-HCM, an open-label, multi-site, prospective study, oHCM subjects received MAVA for 12 weeks at either 10-20 mg/d (n = 11, Cohort A; 10 completed) or at 2-5 mg/d (n = 10, Cohort B). Echo-Doppler indices of LV filling and relaxation were compared at baseline to week 12. The p-values are from Wilcoxon signed rank tests, evaluating the distribution of within-subject 12-wk changes from baseline around a null of zero. Results: MAVA reduced hypercontractility in a dose-dependent fashion, with relief of LVOTO in all subjects achieving plasma MAVA concentration >350 ng/ml (data previously reported). There was also an increase in mitral annular velocity during early diastole (e’ lat ). There was a concomitant reduction in E/e’ lat and increase in LV end-diastolic volume (LVEDV) consistent with improved LV compliance (Table). MAVA improved dyspnea score with a trend towards reduction in NT-proBNP. Conclusions: Administration of MAVA is associated with improvement in measures of myocardial relaxation (e’ lat ) and compliance in parallel with reduction in LVOT gradient. These findings are consistent with preclinical findings reported in healthy dogs and support additional evaluation of MAVA in patients with obstructive or non-obstructive HCM.

Introduction: Obstructive hypertrophic cardiomyopathy (oHCM) is characterized by dynamic LV outflow tract (LVOT) obstruction resulting from ventricular hypertrophy and mitral valve systolic anterior motion (SAM), and by elevated left ventricular (LV) filling pressures, all of which result in a significant morbidity despite medical therapy. Mavacamten (Mava) is a novel inhibitor of cardiac myosin that significantly reduces LVOT gradients in oHCM, noted initially in the phase 2 PIONEER and more recently in the phase 3 EXPLORER-HCM studies. Additional echocardiographic analyses were performed to investigate the effect of Mava on focused measures of cardiac structure and function in oHCM. Methods: EXPLORER-HCM (NCT03470545) was a multicenter, double-blind, placebo-controlled, phase 3 study that randomized symptomatic oHCM patients (LV ejection fraction ≥55% and resting and/or provoked LVOT gradient ≥50 mmHg) 1:1 to Mava vs placebo for 30 weeks. Echocardiograms were performed serially every 2-4 weeks over 30 weeks. Results: In total, 251 patients with oHCM were enrolled and 244 patients completed the study (mean age 58.5; 40.6% female). Compared to placebo, 30-week treatment with Mava led to significant reductions in LA volume index (-7.5 ml/m 2 , p<0.0001), lateral E/e’ (-3.8, p<0.0001), septal E/e’ (-3.4, p<0.0001), and LV mass index (-15.5 g/m 2 , p<0.0001) ( Table ). Significantly more Mava-treated patients achieved resolution of mitral valve SAM compared to placebo (80.9% vs 34.0% of patients; difference of 46.8%; p<0.0001) and mitral regurgitation (MR) (9.0% vs 0.0% of patients; difference of 9.0%; p=0.0006). Conclusions: Treatment with Mava for 30 weeks led to improvement in LV hypertrophy and markers of left-sided filling pressures (LA volume and E/e’). Furthermore, Mava treatment was associated with reduction of SAM and MR. These findings suggest that Mava has beneficial effects on several adverse pathophysiologic processes that are hallmarks of oHCM.