Miranda, William R.

BACKGROUND: The right ventricular (RV) response to pressure overload is a crucial determinant of outcomes in pulmonary arterial (PA) hypertension. Sotatercept improves clinical outcomes, but its effects on the right ventricle have been inconsistent. We evaluated the effects of sotatercept on load-independent measures of RV contractility, RV–PA coupling, and right heart deformation at rest and exertion in patients with PA hypertension. METHODS: In this prospective trial among participants with PA hypertension recruited between July 2024 and May 2025, we performed simultaneous echocardiography and invasive pressure measurements during rest and exercise to evaluate changes in RV contractility (end-systolic elastance [Ees]), afterload (PA elastance [Ea]), RV–PA coupling (ratio of arterial Ea to Ees), and right heart deformation, including RV and right atrial strain, before and after 24 weeks of sotatercept using mixed models. RESULTS: Among 30 participants (n=21; 70% female; mean age, 49.3 years [SD 13.5]), sotatercept decreased PA Ea. These changes were associated with reduced RV contractility, PA pulsatility index, and the maximal rate of RV pressure increase over time (dP/dt max ; P <0.001 for all). The decrease in Ees was associated with a decrease in PA Ea (r=+0.70 [95% CI, +0.44 to +0.85]; P <0.0001) with preserved RV–PA coupling (mean difference, +0.08 [95% CI, −0.11 to +0.26]; P =0.42). Although systolic indices measured at the base of the right ventricle (tricuspid annular plane systolic excursion and systolic velocity of the lateral tricuspid annulus) decreased after sotatercept use, there was an increase in RV free wall–dependent systolic indices, including resting and exercise RV free wall strain (mean difference, +6.2% [95% CI, +4.5 to +7.8]; P <0.0001) and fractional area change ( P =0.0001). Beyond the right ventricle, there was also improved right atrial filling and contractile performance across rest and exercise ( P <0.0001 for all). CONCLUSIONS: Sotatercept decreases RV contractility in proportion to reduced afterload, while preserving the RV–PA coupling relationship. Despite decreased RV contractility, global measures of right heart performance, such as RV free wall strain and RA strain, improve, alongside redistribution of RV deformation from annular motion to free wall shortening. These data suggest that sotatercept causes an energetically favorable reduction in resting RV contractility to match the lower afterload, which does not appear physiologically detrimental when considering the concurrent improvement in RV free wall contractile mechanics and exertional right heart reserve. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT06409026.

Abstract Aims Significant secondary tricuspid regurgitation (STR) is associated with worse morbidity and mortality. To-date, evidence on isolated tricuspid valve surgery in STR remains controversial with uncertainty regarding management strategies. We aimed to investigate sex differences in the association of isolated tricuspid valve surgical repair/replacement (TVR) with outcomes of mortality and heart failure (HF) hospitalizations in STR. Methods and results Patients with severe STR without significant aortic valve or organic mitral valve disease, congenital heart disease, pacemakers, previous valve intervention, malignancy, or end-stage kidney/liver disease were identified. Isolated TVR was studied as a time-dependent covariate in association with mortality and HF hospitalizations. Among 2,857 patients (median age 76 years; 62% women), 143 underwent isolated TVR (58% repair; 42% replacement; 64% with low TRI-SCORE risk category) at median 56 days. Over median 1.6 (IQR 0.2-5.2) years, 1,771 patients died and 1,259 had HF hospitalization. When adjusting to age, comorbidities, left/right ventricular function, pulmonary hypertension, hemoglobin level, and dyspnea, isolated TVR was associated with lower mortality in females (HR 0.54 95% CI 0.35-0.83) but not males (HR 1.29 95% CI 0.90-1.83), p-interaction&lt;0.01; this remained the case when restricting to groups with normal left/right ventricular function. Isolated TVR was associated with HF hospitalization without interaction with sex (HR 0.68 95% CI 0.46-0.998), p-interaction=0.51. Conclusion Isolated TVR for STR was associated with decreased HF hospitalizations in both females and males but improved survival only in females. Future studies are needed to understand differences in the natural history of TR between sexes and stratify outcomes after TR intervention by sex.

Abstract Background Adults with congenital heart disease (ACHD) represent a rapidly expanding population with evolving mortality patterns. Despite improved survival, excess mortality persists. Objective To evaluate the incidence, causes, and predictors of mortality in a contemporary ACHD cohort. Methods We performed a retrospective cohort study of adults (≥18 years) first evaluated at Mayo Clinic from 2002–2023. Baseline clinical, imaging, and electrocardiographic data were analyzed. Vital status was determined using institutional records and the Accurint national mortality database. Kaplan-Meier analysis and Cox proportional hazard models were used to evaluate mortality and identify independent predictors of mortality Results A total of 7,678 ACHD patients were included, with median age of 36.8 years and median follow-up of 11.4 years. During 78,768 patient-years of follow-up, 1,116 patients died (median age at death 57.2 years), corresponding to an annual mortality rate of 1.4%. The cumulative rate of all-cause mortality at 5, 10, 15, and 20 years was 6.9%, 12.0%, 19.0%, and 26.2%, respectively. When stratified by CHD complexity, the annual death rate in patients with severe CHD (2.4%/year) was twice that of patients with moderate or mild CHD (both 1.2%/year). Older age and ACHD subtypes, specifically, cyanotic heart disease (HR 3.9, 95% CI 2.9–5.3) and Fontan physiology (HR 3.2, 95% CI 2.3–4.4), were strongly associated with increased mortality. Additional independent predictors included male sex, ventricular dysfunction, advanced NYHA class, prior heart failure hospitalization, hypertension, smoking, coronary artery disease, renal dysfunction, and abnormal hemoglobin levels. Cardiovascular causes accounted for 57.7% of deaths with known etiology, predominantly heart failure (48.9%) and sudden cardiac death (21.9%), while non-cardiovascular causes were driven mainly by infection and malignancy. Conclusions In this large contemporary ACHD cohort, mortality was driven by ventricular dysfunction, heart failure, and systemic end-organ involvement in addition to the underlying congenital anatomy. Both cardiovascular and non-cardiovascular causes contributed significantly to mortality. These findings underscore the need for comprehensive multidisciplinary ACHD care focused on early recognition of cardiac functional decline, management of acquired comorbidities, and end-organ dysfunction.

BACKGROUND: Some symptomatic patients manifest pulmonary hypertension (PH), despite normal pulmonary vascular resistance and pulmonary artery wedge pressure—a condition termed unclassified PH. Although hypothesized to reflect increased flow as seen in congenital heart disease, broader clinical implications remain unknown. METHODS: The current analysis included pulmonary vascular disease phenomics participants with either no PH or unclassified PH who underwent dynamic right heart catheterization and transpulmonary metabolomics. In a validation cohort, patients with no PH or unclassified PH underwent exercise right heart catheterization. In exploratory cohorts to understand the impact of increased flow, the prevalence of unclassified PH was assessed in (1) adult congenital heart disease and (2) high output heart failure. RESULTS: The overall prevalence of unclassified PH in pulmonary vascular disease phenomics (n=1046) and the validation cohort (n=1202) was 7.8% (175/2248), which was comparable to the 6.6% (66/1005) prevalence in adult congenital heart disease (n=1005), and lower than high output heart failure (n=159, prevalence 14.5% [23/159]; P =0.006). Increased flow occurred in a minority of unclassified PH from both pulmonary vascular disease phenomics (28%; 15/53) and the validation cohort (11%; 13/122). Unclassified PH (n=53) was associated with greater adiposity, higher heart failure with preserved ejection fraction (HFpEF)–age, body mass index, atrial fibrillation score probability, and more left heart remodeling compared with those with no PH (n=216). Metabolomics revealed lower glycine metabolites in unclassified PH indicative of metabolic dysfunction. Left heart remodeling, quality of life, exercise capacity, and glycine levels were all abnormal in unclassified PH relative to healthy controls (n=96). In the validation cohort, pulmonary artery wedge pressure, pulmonary vascular resistance, and pulmonary artery compliance were subtly abnormal at rest in unclassified PH (n=122) compared with no PH (n=312). With exercise testing, 59% (72/122) with unclassified PH had exertional pulmonary artery wedge pressure elevation consistent with undiagnosed HFpEF. CONCLUSIONS: The presence of PH without obvious cause most often reflects subclinical left heart and metabolic dysfunction consistent with unrecognized early-stage HFpEF. Dynamic provocation during right heart catheterization can unmask unrecognized HFpEF in over half of unclassified PH, which may help guide appropriate initiation of proven HFpEF therapies to improve symptoms and functional status. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02980887.

Background Cardiovascular biomarkers such as NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) are used for heart failure risk stratification in patients with acquired heart disease, but there are limited data about its role in patients with congenitally corrected transposition of the great arteries. The current study aims to assess the role of serial NT‐proBNP measurements for risk stratification in adults with congenitally corrected transposition of the great arteries. Methods We studied adults with congenitally corrected transposition of the great arteries with ≥2 NT‐proBNP measurements (2003–2024). Temporal change in NT‐proBNP was calculated as relative change from baseline levels. Results Of 152 patients (age 47±13 years, 45% men), baseline NT‐proBNP was 539 (interquartile range, 193–1549) pg/mL, and relative change from baseline levels of NT‐proBNP was 34% (interquartile range, −11 to 67). Of 152 patients, 45 (30%) had cardiovascular events (heart failure hospitalization [n=29], ventricular assist device [n=5], heart transplantation [n=11], and death [n=10]), yielding a 10‐year incidence of 26%. Higher baseline NT‐proBNP and relative change from baseline levels were associated with cardiovascular events. Serial NT‐proBNP measurements had incremental prognostic value compared with baseline measurement. The correlates of higher NT‐proBNP levels were atrial fibrillation, hypertension, right ventricular dilation and dysfunction, and atrioventricular valve regurgitation. Renin–angiotensin–aldosterone system antagonist was associated with lower NT‐proBNP levels and lower risk of cardiovascular events. Conclusions NT‐proBNP testing is inexpensive, widely available, and noninvasive, making it well suited for longitudinal surveillance in adults with congenital heart disease. Most of the correlates for elevated NT‐proBNP levels were modifiable, providing target for therapeutic interventions.

Background Mortality in adults with congenital heart disease (CHD) is strongly driven by disease complexity. Social determinants of health (SDOH) influence adult CHD (ACHD) health outcomes but their impact on mortality is unclear. This study examined the influence of clinical factors and SDOH on all‐cause mortality in patients with ACHD. Methods Single‐center retrospective cohort study of patients with ACHD in the Mayo ACHD Registry who had a verifiable residential address between January 1, 2004 and December 31, 2023. Clinical and SDOH indicators were extracted, including insurance type, language, rural–urban commuting area code, and a housing‐based socioeconomic index, an individual‐level measure of socioeconomic status derived from 4 objective housing characteristics and categorized into quartiles (Q1–Q4). Cox proportional‐hazards models were fitted to evaluate associations with mortality, incorporating CHD severity, arrhythmias, SDOH indicators, and other comorbidities. County of residence was included as a random effect, and model discrimination was assessed using the concordance statistic. Results Among 6134 patients with ACHD, the mean age was 38±16 years; 51% were male; 78.7% were White and 44.9% had rural residence. Independent predictors of mortality included cyanotic CHD (adjusted hazard ratio [aHR], 5.70 [95% CI, 2.90–11.23]), Fontan palliation (aHR, 4.98 [95% CI, 2.56–9.70]), ventricular tachycardia (aHR, 1.71 [95% CI, 1.16–2.52]), older age at first visit (aHR, 1.05 per year [95% CI, 1.04–1.05]), male sex (aHR, 1.19 [95% CI, 1.03–1.39]), public insurance (aHR, 1.60 [95% CI, 1.35–1.90]), rural residence (aHR, 1.25 [95%, CI 1.06–1.47]), and non‐English language (aHR 1.75 [95% CI 1.38–2.23]). The housing‐based socioeconomic index quartile was not associated with mortality. The final model achieved a concordance statistic of 0.77. Conclusions Mortality in patients with ACHD is strongly influenced by both clinical factors and SDOH, independent of socioeconomic status. Addressing barriers to care such as language, insurance, and geography is essential for improving ACHD survival particularly in those at increased mortality risk.

BACKGROUND: With pulmonary hypertension (PH), a pulmonary artery wedge pressure (PAWP)>15 mm Hg is used to diagnose left heart dysfunction, but some patients with adjudicated group 1 PH demonstrate PAWP>15 mm Hg. The primary objective of the study was to evaluate group 1 PH with high PAWP>15 mm Hg. METHODS: Patients with adjudicated group 1 PH from PVDOMICS between 2016 and 2019 were separated into high PAWP(>15 mm Hg) or normal PAWP and compared with adjudicated combined pre- and postcapillary (Cpc) PH related to heart failure with preserved ejection fraction (HFpEF). Participants underwent dynamic right heart catheterization and metabolomics. Findings were validated in 3 independent cohorts with adjudicated group 1 PH (validation cohorts 1 and 2 with exercise right heart catheterization and validation cohort 3 with resting right heart catheterization). RESULTS: Of 325 patients with group 1 PH (73% women, mean age 53.0±14.3 years), 15% (n=48) had high PAWP. Group 1 PH+high PAWP demonstrated greater obesity, left ventricular hypertrophy ( P <0.0002), left ventricular strain impairment ( P <0.0001), and decreased left ventricular compliance ( P <0.0001) compared with group 1 PH+normal PAWP, with changes comparable to Cpc-PH HFpEF (n=75). Compared with Cpc-PH HFpEF, left atrial function was better in group 1 PH+high PAWP with lower PAWP V wave, higher left atrial compliance, and left atrial ejection fraction ( P <0.0001 for all). Metabolomics demonstrated little difference between group 1 PH with high versus normal PAWP but large differences between group 1 PH+high PAWP versus Cpc-PH HFpEF (100 metabolites altered at false discovery rate P <0.05). Elevated PAWP was also observed in 18% of group 1 PH in the validation cohort 1 (n=402), with exercise PAWP response intermediately abnormal in group 1 PH+high PAWP relative to Cpc-PH HFpEF and group 1 PH+normal PAWP (interaction P <0.0001). Elevated PAWP was similarly observed in 22% and 19% of group 1 PH in validation cohorts 2 (n=55) and 3 (n=787), respectively. CONCLUSIONS: Approximately 1 in 5 adjudicated patients with group 1 PH has elevation in resting PAWP despite severe pulmonary vascular dysfunction and metabolomics consistent with traditionally defined group 1 PH. Despite resting PAWP elevation, these patients with group 1 PH were metabolomically and biologically distinct from Cpc PH HFpEF, with better left atrial function and diastolic reserve during exercise. These data emphasize the limitations of using resting PAWP alone to separate group 1 PH from HFpEF and call for development of more integrated clinical diagnostic criteria.

Abstract Background Left atrial pressure (LAP) is clinically estimated by the occluded pulmonary artery (PA) pressure (PA wedge pressure, PAWP), which should equalize with downstream LAP. Early studies reported the potential for PAWP to exceed LAP, but the frequency and clinical significance of this finding is unclear. Purpose This study aimed to investigate the hemodynamic characteristics, physiologic determinants, and prognostic impact of patients with PAWP exceeding LAP. Method Patients who underwent right heart catheterization (RHC) for diagnosis or treatment with PAWP and simultaneous measurement of LAP were identified. Patients were divided into two groups based on differences in PAWP and LAP. Pulmonary capillary pressure (Pc) was measured using the PA occlusion technique. Pulmonary vascular resistance (PVR) was then partitioned into upstream PVRa ([mean PA pressure (PAP)-Pc]/cardiac output [CO]) and downstream PVRv ([Pc-PAWP]/CO), with each expressed as a percentage of PVR. Results 675 patients underwent RHC with transseptal puncture allowing measurement of both PAWP and LAP simultaneously. A strong correlation and agreement between PAWP and LAP were demonstrated (r=0.92, P&lt;0.001; bias +0.5 mmHg), but 310 patients (46%) displayed PAWP exceeding LAP by at least 1 mmHg (mean difference 3±2 mmHg). Patients with PAWP exceeding LAP displayed higher mean PAP (Figure 1A) and PVR calculated using LAP as the downstream pressure (PVR-LA: 2.10 [1.13-3.53] vs 3.38 [2.19-5.66] WU, P&lt;0.001). PAWP was significantly higher in patients with PAWP exceeding LAP, although there was no significant difference in LAP between the groups (Figure 1B-C). PA compliance, which does not rely on either PAWP or LAP for calculation, was significantly lower in patients with PAWP exceeding LAP (2.7 [1.8-4.0] vs 2.1 [1.5-3.0] mL/mmHg, P&lt;0.001, Figure 1D). The difference between PAWP and LAP was significantly correlated with mean PAP (r=0.32, P&lt;0.001, Figure 1E). In 63 patients where Pc could be measured, those with PAWP exceeding LAP showed a higher Pc and greater pulmonary venous (vs arterial) distribution of PVR (Figure 1F-H). Over 5.4 (IQR 1.7-10.2) years, the composite outcome of all-cause death or heart failure hospitalization occurred in 326 patients (48%). Patients with PAWP exceeding LAP had a higher risk of the composite outcome than those without (log-rank P&lt;0.001, Figure 2). Patients with PAWP exceeding LAP had 37% greater risk of composite outcome than those without (hazard ratio 1.37, 95% CI 1.09-1.73; P=0.008) after adjusting for age, sex, hemoglobin, moderate or greater mitral regurgitation, and tricuspid regurgitation, LAP, and mean PAP. Conclusions While PAWP is a robust surrogate for LAP, the former commonly exceeds the latter, and patients with PAWP exceeding LAP have more severe pulmonary vascular disease, greater capillary hypertension and venous involvement, and a higher risk for adverse outcomes.