Sabbah, Michael S.

Background The natural history of asymptomatic moderate or severe aortic regurgitation (AR) remains uncertain, with conflicting reports about its progression and surgical timing. We aimed to quantify adverse outcomes under conservative management and evaluate the association of aortic valve replacement/repair (AVR) with mortality. Methods Systematic searches (inception–July 2025) identified cohort studies of asymptomatic moderate/severe AR. Random-effects models estimated pooled incidence rates of adverse events; fixed-effects models were used for hazard ratios (HRs) of AVR vs conservative management. Results Twenty-seven studies (4720 patients; mean age 49 years; mean follow-up 3.9 years) were included. Pooled incidence rates per 100 person-years were 1.75 (95% CI 1.27 to 2.41) for all-cause mortality, 1.29 for cardiac death, 0.29 for sudden death, 4.30 for new symptoms and 7.01 for AVR. Asymptomatic low left ventricular ejection fraction occurred in only 0.9 per 100 person-years. Mortality rates were more than double those of the general population across age groups—2.45 (1.90 to 3.18) per 100 person-years for cohorts with mean age ≥50 years versus 0.59 (0.29 to 1.21) for younger cohorts. Early AVR was associated with lower mortality (pooled HR 0.33; 95% CI 0.30 to 0.37). Conclusion Asymptomatic moderate/severe AR carries significant excess mortality irrespective of age, contradicting its historically benign reputation. Given the rarity of asymptomatic LV dysfunction, earlier intervention guided by more sensitive markers of LV damage may improve outcomes, although heterogeneity and study quality warrant cautious interpretation. PROSPERO registration number CRD42024522683.

Background Atrial fibrillation (AF) impacts management decisions in valvular heart disease but its significance in patients with chronic aortic regurgitation (AR) is not well established. Objectives To evaluate the prevalence and prognostic role of AF in patients with chronic, haemodynamically significant AR. Methods Adults with chronic ≥moderate-to-severe AR, from March 2004 to April 2019, were retrospectively identified. Those with acute AR, moderate or worse other valve disease or prior valve surgery were excluded. Patients with AF were identified based on 12-lead ECGs, 1-lead ECGs (showing AF for ≥30 s), or episodes recorded by implanted cardiac devices. Primary outcome was all-cause mortality. Cox regression models were used to assess associations with mortality: model 1 adjusted for age, symptoms (New York Heart Association class II–IV), Charlson Comorbidity Index, left ventricle (LV) end-systolic volume index and AF; model 2 added left atrial volume index and model 3 further added systolic pulmonary artery pressure. Results Of the 1006 included patients (age 59±18 years; 822 (82%) men), 446 (46%) had hypertension and 364 (36%) had a bicuspid aortic valve. AF was present in 161 (16%) patients at the time of ≥moderate-to-severe AR diagnosis. During a median follow-up of 1.6 years (IQR 0.2–6.2), AF was associated with an increased mortality risk in univariate and in all three multivariable models (HR 1.61 (95% CI 1.07 to 2.43), HR 2.21 (95% CI 1.31 to 3.72) and HR 2.06 (95% CI 1.21 to 3.52), respectively), including after propensity matching (HR 1.58 (95% CI 1.01 to 2.48)). Conclusions AF is present in one in six patients with chronic≥moderate-to-severe AR and is associated with an increased risk of mortality even after adjusting for measures of LV systolic and diastolic function. There is a need for future prospective studies to validate these findings and evaluate AF as a potential trigger for early surgery.

Background Tricuspid valve surgery is recommended for severe isolated tricuspid regurgitation (TR) if symptoms persist despite optimal medical therapy. The definition of optimal therapy for TR is unclear beyond managing underlying conditions. Diuretics are the primary treatment for volume retention in TR, but it is unknown whether a “safe diuretic dose” exists for conservative management. We sought to evaluate the association between diuretic dose and outcomes. Methods Adult patients with ≥moderate–severe isolated TR were retrospectively identified from echocardiographic reports. Clinical and echocardiographic data were extracted from electronic medical records and manually reviewed. The primary end point was all‐cause mortality. Loop diuretic doses were converted to furosemide equivalent and categorized into 4 groups: <40 mg, 40 to 79 mg, 80 to 159 mg, and ≥160 mg daily. Results Of 1302 patients (age 72±13 years, 60% female), 565 (43%) had moderate–severe TR and 737 (57%) had severe TR. Median follow‐up was 8.7 (1.4, 14.0) years. Comorbidities increased with higher diuretic doses. A linear relationship between diuretic dose and mortality was observed in spline‐curve analysis. Hazard ratios (and CIs) for mortality adjusted for age, sex, coronary disease, chronic kidney disease, mild pulmonary hypertension, and New York Heart Association III/IV symptoms were 1.21 (0.96–1.53) ( P =0.12) for <40 mg, 1.50 (1.23–1.82) ( P <0.001) for 40 to 79 mg, 1.86 (1.46–2.37) ( P <0.001) for 80 to 159 mg, and 2.90 (2.18–3.88) ( P <0.001) for ≥160 mg furosemide equivalent. Any diuretic dose was associated with significant symptoms (New York Heart Association III–IV), with more patients experiencing symptoms at higher doses. Conclusion A daily loop diuretic dose ≥40 mg furosemide equivalent is associated with increased mortality and greater symptom severity in patients with TR.

This analysis provides a novel assessment of the relationship between the severity of right ventricular dysfunction (RVD) and blood volume expansion (BVE) on clinical outcomes in patients with chronic left-sided heart failure. Findings demonstrate that despite the high prevalence of moderate or greater RVD, persistent BVE was associated with better 1-year event-free survival relative to normal BV. Hypothesis-generating, this suggests that BVE may provide an adaptive response compensating in part for the impact of RVD in chronic HF.

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 &lt; 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 Transcatheter mitral valve replacement (TMVR) has become a feasible alternative to surgical mitral valve replacement (SMVR) in selected patients at high surgical risk. The risk of valve thrombosis following SMVR and TMVR, and the optimal antithrombotic therapy following these procedures, remains uncertain. We aimed to compare the incidence of bioprosthetic mitral valve thrombosis (bMVT) after SMVR and TMVR, and the incidence of bMVT between patients on different antithrombotic regimens. Methods and results A literature search of Medline, Embase, and Cochrane Library was performed between January 2000 and August 2024. Random-effects models were used to derive pooled estimates of the incidence of bMVT in the absence of prior or active endocarditis and valve thrombosis. A total of 47 studies (6170 patients, total follow-up 9541.8 patient-years) were eligible for inclusion. The overall incidence of bMVT was 5.05 [95% confidence interval (CI) 3.18–8.01, I2 = 82%] per 100-patient-years. Subclinical bMVT was more common than clinically significant bMVT: incidence 19.11 vs. 7.91 per 100-patient-years, adjusted incidence rate ratio (aIRR) 4.62 (95% CI 1.39–15.36), P = 0.012. bMVT was numerically more common after TMVR than SMVR, but the comparison was not statistically significant: incidence 7.03 vs. 0.58 per 100-patient-years, aIRR 2.19 (95% CI 0.72–6.72), P = 0.170. Patients on vitamin-K antagonists (VKA) had a lower incidence of bMVT than patients on direct oral anticoagulants (DOAC; incidence 5.72 vs. 17.08, aIRR 0.31, 95% CI 0.13–0.73, P = 0.007). Conclusions bMVT is not uncommon, with numerically higher incidence in transcatheter compared to surgical valves, but the comparison was not statistically significant. VKAs are associated with a lower incidence of bMVT compared to DOACs.