Nkomo, Vuyisile T

Abstract Aims Tricuspid valve regurgitation (TR) is common and associated with increased mortality. The interaction between the pulmonary artery (PA) circulation and the right ventricle (RV) and association with outcomes is incompletely understood. The effective PA elastance (PA Ea) is a composite measure of RV afterload that refers to the pulmonary vascular load that the RV must overcome to eject blood. Whether PA Ea discriminates mortality risk in unselected patients with significant TR is unknown. Methods and results In consecutive patients with ≥moderate TR, we compared all-cause mortality at 5 years based on the PA Ea (defined as the RV systolic pressure/stroke volume as measured by transthoracic echocardiography). In a total of 12 682 patients, the median PA Ea was 0.7 mm Hg/mL (interquartile range 0.5, 0.9). Increasing levels of PA Ea were associated with heart failure, liver and kidney disease, and clinical markers of risk such as the Tricuspid Regurgitation Impact on Outcomes score. Increasing levels of PA Ea were associated with larger RVs, worse RV systolic function, higher N-terminal pro-brain natriuretic peptide levels, and greater degrees of right heart failure. After adjusting for age and sex, PA Ea was associated with higher risk of death (hazard ratio 1.55 per 0.5 mm Hg/mL change of PA Ea; 95% confidence intervals 1.51–1.60; P < 0.0001). In multivariable modelling incorporating available clinical variables, PA Ea was independently predictive of outcome compared with other indexes of RV–PA coupling. Conclusion In patients with significant TR, higher PA Ea is progressively associated with RV dysfunction, right heart failure, and worse survival. Incorporating PA Ea into the routine echo assessment may help stratify risk.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

Abstract Aims Pulmonary regurgitation (PR) after reparative intervention for congenital heart disease has been studied extensively. However, the burden, distribution of causes, and outcome of PR in adults is unknown. The study aimed to evaluate the prevalence, types, and outcomes of moderate/severe PR in adults in the community setting. Methods and results A total of 398 adult residents of Olmsted County who had clinically indicated echocardiography 2004–2023 at Mayo Clinic, Rochester, and had moderate or severe PR were identified retrospectively. The median age was 77 years, 48% were females, and 61 (51%) had severe PR. The age- and sex-adjusted US prevalence was 0.11% (vs. 0.67% for ≥moderate tricuspid regurgitation). Moderate/severe PR was due to pulmonary hypertension in 77%, congenital/iatrogenic in 11%, primary pulmonary valve disease in 2% (88% due to carcinoid), and idiopathic isolated in 10%. In contrast, severe PR was due to congenital/iatrogenic disease in 52%, pulmonary hypertension in 39%, primary PR in 5%, and isolated idiopathic in 3%. The all-cause mortality rate per 100 person-year was 73 in primary (mostly carcinoid) PR, 16 in pulmonary hypertension–related PR (not different vs. propensity-matched patients without PR), and 6 in isolated idiopathic PR (not different vs. matched patients without PR). Conclusion Moderate or severe PR had a lower prevalence vs. TR. The most frequent cause was pulmonary hypertension for ≥moderate PR and congenital/iatrogenic for severe PR. Mortality in patients with acquired ≥moderate PR appeared to be related to the underlying cause, with no excess mortality compared with matched patients without PR. Whether specifically severe PR confers excess mortality requires future investigation.

Abstract Aims Aortic stenosis (AS) is a common and progressive disease, which, if left untreated, results in increased morbidity and mortality. Monitoring and follow-up care can be challenging due to significant variability in disease progression. This study aimed to develop machine learning models to predict the risks of disease progression and mortality in patients with mild AS. Methods and results A comprehensive database including 9611 patients with serial transthoracic echocardiograms was collected from a single institution across three clinical sites. The data set included parameters from echocardiograms, electrocardiograms, laboratory values, and diagnosis codes. Data from a single clinical site were preserved as an independent test group. Machine learning models were trained to identify progression to severe stenosis and all-cause mortality and tested in their performance for endpoints at 2 and 5 years. In the independent test group, the AS progression model differentiated those with progression to severe AS within 2 and 5 years with an area under the curve (AUC) of 0.86 for both. The feature of greatest importance was aortic valve mean gradient, followed by other valve haemodynamic measurements including valve area and dimensionless index. The mortality model identified those with mortality within 2 and 5 years with an AUC of 0.84 and 0.87, respectively. Smaller reduced-input validation models had similarly robust findings. Conclusion Machine learning models can be used in patients with mild AS to identify those at high risk of disease progression and mortality. Implementation of such models may facilitate real-time, patient-specific follow-up recommendations.

Abstract Background and Aims Incidence and types of secondary tricuspid regurgitation (TR) are not well defined in atrial fibrillation (AFib) and sinus rhythm (SR). Atrial secondary TR (A-STR) is associated with pre-existing AFib; however, close to 50% of patients with A-STR do not have AFib. The aim of this study was to assess incidence, types, and outcomes of ≥ moderate TR in AFib vs. SR. Methods Adults with and without new-onset AFib without structural heart disease or ≥ moderate TR at baseline were followed for the development of ≥ moderate TR. Tricuspid regurgitation types were pacemaker, left-sided valve disease, left ventricular (LV) dysfunction, pulmonary hypertension (PH), isolated ventricular, and A-STR. Results Among 1359 patients with AFib and 20 438 in SR, 109 and 378 patients developed ≥ moderate TR, respectively. The individual types of TR occurred more frequently in AFib related to the higher pacemaker implantation rates (1.12 vs. 0.19 per 100 person-years, P < .001), larger right atrial size (median 78 vs. 53 mL, P < .001), and higher pulmonary pressures (median 30 vs. 28 mmHg, P < .001). The most common TR types irrespective of rhythm were LV dysfunction-TR and A-STR. Among patients in SR, those with A-STR were older, predominantly women with more diastolic abnormalities and higher pulmonary pressures. All types of secondary TR were associated with all-cause mortality, highest in PH-TR and LV dysfunction-TR. Conclusions New-onset AFib vs. SR conferred a higher risk of the individual TR types related to sequelae of AFib and higher pacemaker implantation rates, although the distribution of TR types was similar. Secondary TR was universally associated with increased mortality.