Enriquez‐Sarano, Maurice

Background Bicuspid aortic valve (BAV) is the most common congenital heart defect, associated with a lifetime morbidity burden exceeding 80% and an estimated 7% probability of transmission to first-degree relatives. Hence, echocardiographic screening of relatives is recommended. The aim of our study is to develop an artificial intelligence-enabled electrocardiogram (AI-ECG) model for the detection of BAV. Methods Between January 1, 1990, and June 30, 2023, the Mayo Clinic healthcare system database was searched for patients aged ≥18 years with echocardiograms performed for family history of BAV, abnormal auscultation, a BAV-related diagnosis, or to rule out the condition, and with an electrocardiogram (ECG) obtained within 6 months. Cases were patients with a confirmed BAV diagnosis, and controls were those with normal aortic valves. ECGs were randomly assigned into training (80%), internal validation (10%), and test (10%) groups. The AI-ECG model was built using Keras under TensorFlow. Results A total of 13,065 valid ECG–echocardiogram pairs were included (mean [SD] age, 58 [17] years; 44% women), with a median time of 1 day (interquartile range, 0–3 days) between studies. With a 45% BAV prevalence in the test group ( n = 1301), the area under the curve was 0.704, positive predictive value (PPV) 60.1%, and negative predictive value (NPV) 69.4%. At a prevalence of 7%, the NPV increased to 96.1%, but the PPV decreased to 12.2%. Conclusions In this retrospective cohort and using the current AI-ECG model, BAV detection showed modest diagnostic performance and limited standalone clinical utility, suggesting that ECG-only screening for BAV may require additional modalities or more refined phenotyping.

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<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.

Importance Current guidelines recommend consideration of surgical treatment for asymptomatic patients with severe mitral valve regurgitation, but the long-term prognosis and optimal treatment of those with moderate mitral regurgitation (MR) remain uncertain. Objective To evaluate the long-term prognostic value of baseline MR severity and the association of surgery with survival outcomes in asymptomatic patients. Design, Setting, and Participants This was a prospective cohort study with extended follow-up among 449 asymptomatic patients with holosystolic degenerative MR enrolled between January 1991 and November 2000 and followed up with through May 2025 (median [IQR] follow-up, 26 [14-29] years; maximum, 34 years) at a single tertiary referral center (the Mayo Clinic, Rochester, Minnesota). Exposure Baseline MR severity quantified by effective regurgitant orifice area (ERO). Patients were monitored under medical therapy and, when applicable, after subsequent surgical correction. Main Outcomes and Measures All-cause mortality, assessed according to baseline ERO using Cox proportional hazards models adjusted for cardiovascular risk factors. Results Among the 449 patients included, the mean (SD) age was 64 (14) years, and 278 participants (62%) were male. At baseline, 127 patients (28%) had ERO <20 mm 2 , 128 (28%) had ERO 20-39 mm 2 , and 194 (43%) had ERO ≥40 mm 2 . During follow-up, 254 patients (57%) underwent mitral valve surgery. Ten-year cumulative incidence of surgery was 18% for ERO <20 mm 2 , 64% for 20-39 mm 2 , and 88% for ≥40 mm 2 . Survival of medically treated patients declined progressively with increasing ERO category (5-year rate: 88% [<20 mm 2 ], 72% [20-39 mm 2 ], and 55% [≥40 mm 2 ]; P = .01), and multivariable analysis confirmed the incremental risk of higher ERO on a continuous scale (adjusted hazard ratio per IQR increase, 2.53; 95% CI, 1.30-4.93; P = .01). When extending the analysis through subsequent surgical follow-up, the survival difference between patients who did vs did not undergo operation widened with ERO (χ 2 3 = 8.4; interaction P = .04), starting at values above 30 mm 2 . Conclusions and Relevance In this 25-year follow-up cohort study, increasing ERO was associated with an increase in risk of mortality under medical therapy. Patients with upper-moderate MR (ERO 30-39 mm 2 ) at baseline demonstrated a significant association between surgical treatment and improved long-term survival.

Abstract Aims Prognosis in tricuspid regurgitation (TR) is shaped by complex clinical and haemodynamic interactions, complicating risk stratification. We aimed to use explainable artificial intelligence (EAI) to model these relationships and identify key predictors of outcomes. Methods and results We analysed long-term all-cause mortality in a large prospective registry of patients with native TR across the full severity spectrum. Patients underwent detailed clinical evaluation and quantitative Doppler-echocardiography. Supervised EAI models were applied to identify and rank predictors of mortality under medical therapy, capturing non-linear associations and interactions among baseline characteristics. Among 9761 patients [mean age 73 ± 15 years; 56.9% women; effective regurgitant orifice area (EROA) 40 (30–56) mm2; regurgitant volume 39 (29–53) mL/beat; 42% severe TR], 2676 deaths occurred during 3.8 ± 4.6 years of follow-up. EAI identified and ranked 20 prognostic determinants of survival. Haemodynamic measures, led by elevated pulmonary-artery systolic and right-atrial pressures, were strongest, followed by age and comorbidity. TR-related variables ranked next, led by right ventricular dysfunction and EROA, which outperformed integrative TR grade and TRIScore. Left-ventricular parameters were less influential. Non-linear effects, including those involving ejection fraction, and interactions such as higher EROA-related risk with elevated pulmonary pressures or lower TRIScore (both P < 0.03) were observed. Proportional hazards models confirmed EROA as the strongest TR severity marker (P < 0.0001), with excess mortality beginning at 40 mm2 and increasing further at 60 mm2. Conclusion EAI ranked mortality predictors in TR, highlighting patient factors, haemodynamics, TR-specific measures, and left-ventricular function. Among TR-specific measures, EROA and TRIScore were most prognostic. Recognizing their impact can refine risk stratification, guide intervention timing, and inform long-term management.

Abstract Objectives The progression of extra-mitral valve (MV) cardiac damage in patients with primary mitral regurgitation (MR) following surgical repair has not been described. We aimed to investigate the evolution of extra-MV cardiac damage after MV repair and to assess its prognostic significance. Methods Patients with severe primary MR undergoing surgical repair at 5 referral centres were included when echocardiographic follow-up assessment was available. Based on echocardiographic parameters at baseline and at a median follow-up of 7 (interquartile range [IQR] 4-11) months after MV repair, patients were hierarchically classified as follows: stage 0: no cardiac damage; stage 1: left ventricular dilatation and/or dysfunction; stage 2: left atrial dilatation and/or atrial fibrillation; stage 3: pulmonary hypertension and/or significant tricuspid regurgitation. The primary outcome was all-cause mortality. Results A total of 764 patients (mean age 62 ± 13 years, 70% men) were included. Compared to baseline, 43% improved at least 1 stage, 49% remained unchanged, and 8% worsened at least 1 stage during follow-up after MV repair. At a median follow-up of 91 months after MV repair, 94 patients (12%) died. By multivariate Cox regression analysis, after adjusting for potential confounders, extra-MV cardiac damage staging at follow-up (HR per-1-stage-increase = 1.571; P = .009) and cardiac damage evolution (improved group, HR = 0.467; P = .034; worsened group, HR = 2.481, P = .037) were independently associated with all-cause mortality and had incremental prognostic value over preprocedural assessment. Conclusions Extra-MV cardiac damage improves significantly after MV repair, and its evolution is independently associated with all-cause mortality, suggesting the importance of comparative echocardiographic assessment following MV repair to improve risk stratification.

Abstract Background The impact of treatment for tricuspid regurgitation (TR) across different levels of left ventricular ejection fraction (LVEF) remains uncertain. Purpose This study aimed to compare the outcomes of surgical and transcatheter tricuspid valve interventions (TTVI) to conservative (medical) management across all LVEF categories. Methods Patients with severe isolated TR from the TRIGISTRY, a multicenter international registry, were categorized based on LVEF (preserved EF-pEF:≥50%, mildly reduced EF-mrEF:41–49%, and reduced EF-rEF:≤40%). We assessed the impact of treatment modality and procedural success, defined as residual TR ≤mild-to-moderate, on two-year survival within each LVEF category. Results Among 2,384 patients, 1,383 had pEF, 400 had mrEF, and 601 had rEF. Compared to conservative management, surgery (P<0.0005) and TTVI (P<0.0001) were associated with a survival benefit in patients with pEF. No significant survival advantage was observed in patients with mrEF (P=0.28 for both), nor in those with rEF (P=0.76 and P=0.22 respectively). Similar results were obtained when surgical and transcatheter interventions were grouped together (P<0.0001, P=0.17 and P=0.29 in patients with pEF, mrEF and rEF respectively). Patients with significant residual TR after TTVI exhibited a trend toward worse survival compared to those managed conservatively across all LVEF categories (P=0.47, P=0.33, and P=0.008 respectively)(Figure 1). Conclusion Tricuspid valve intervention, whether surgical or transcatheter-based, was associated with improved survival in patients with preserved LVEF but not in those with mildly reduced or reduced LVEF. Residual TR remained a significant prognostic factor across the entire LVEF spectrum. These findings highlight the need for careful patient selection when considering tricuspid interventions in individuals with reduced LVEF.Figure 1

Abstract Background The tricuspid annular plane systolic excursion (TAPSE) to systolic pulmonary artery pressure (SPAP) ratio (TAPSE/SPAP) is touted as a measure of right ventricular (RV) to pulmonary artery (PA) coupling, but its intrinsic, independent and incremental impact on outcome remains uncertain, particularly across the quantified severity spectrum of tricuspid regurgitation (TR). Methods We enrolled a prospective repository of patients with native TR, in whom TR quantitation using proximal-isovelocity-surface-area (PISA), SPAP and TAPSE, were all prospectively measured between 09/2003 and 04/2023. We included only patients with functional TR, without congenital or organic heart disease and without indwelling catheter/lead. The primary outcome was mortality under medical management. Results A total of 3,436 patients (median age 77 years, 57.6% female, median effective-regurgitant-orifice-area 39 mm2) were included. The median TAPSE/SPAP ratio was 0.36 (interquartile-range 0.26-0.51). Over a mean follow-up period of 2.4±2.8 years, 854 (24.9%) patients died. Spline regression, adjusted for age, sex, left ventricular ejection fraction, EROA, comorbidity index, and heart failure severity (TriScore), demonstrated that a TAPSE/SPAP remain linked to mortality, with ratio below 0.4 significantly associated with excess mortality risk (Figure). Multivariable models confirmed that higher TAPSE/SPAP ratio remained independently inversely associated with mortality (adjusted-hazard-ratio 0.76 [0.72-0.80] per 0.1 increment, p<0.001). Furthermore TAPSE/SPAP ratio provided incremental and independent prognostic value above and beyond the individual values of TAPSE or SPAP (p<0.001) and threshold for excess mortality remained consistently at 0.4, irrespective of quantified TR severity. Conclusion The TAPSE/SPAP ratio measured prospectively in routine clinical practice, is a strong and independent prognostic indicator in patients with functional TR, that adds to the prognostic value of its components. A TAPSE/SPAP ratio below 0.4 consistently identifies a subgroup at high-risk of mortality under medical management. These data suggest that therapeutic interventions that may impact positively the TAPSE/SPAP ratio should be tested in patients with functional TR.Mortality risk across TAPSE/SPAP ratio

Abstract Background While tricuspid regurgitation (TR) is predominantly functional, it can arise from various cardiac conditions. This study aimed to evaluate whether the benefits of tricuspid valve intervention, compared to conservative management, differ based on the underlying etiology. Methods In the TRIGISTRY international cohort, which includes consecutive patients with severe isolated functional TR across 33 centers in 10 countries, we compared mortality rates at 2 years between patients who underwent a tricuspid valve intervention (surgical or transcatheter) versus conservative management according to TR etiology. Patients were classified into three groups: (1) Isolated TR (ITR), defined as left ventricular ejection fraction (LVEF) >60%, systolic pulmonary artery pressure (sPAP) <50 mmHg, and no prior left-heart intervention (LHI); (2) LHI-TR, comprising patients with a history of LHI; and (3) Undetermined TR (UTR), which included those who did not meet the criteria for ITR or LHI, as well as those with missing sPAP data. Given previous findings indicating that intervention provided no survival benefit for patients with a high TRI-SCORE, the present analysis was restricted to individuals with low to intermediate TRI-SCORE (≤5). Survival outcomes between groups were compared using restricted mean survival time (RMST). Results A total of 1,552 patients (72±13 years; 56% female) with severe functional TR and a low (48%) or intermediate (52%) TRI-SCORE were included. Of these, 772 (50%) underwent an intervention, while 780 (50%) were conservatively managed. TR was classified as ITR in 201 patients (13%), LHI in 395 (25%), and UTR in 956 (62%). Overall, patients with ITR exhibited the lowest comorbidity burden, whereas those with UTR had the highest. After adjusting for comorbidities and TRI-SCORE, a survival benefit of a tricuspid valve intervention was observed in patients with ITR (survival estimate: 0.17, 95% CI [0.009, 0.32], P=0.039) and, to a lesser extent, in patients with UTR (survival estimate: 0.09, 95% CI [0.0, 0.184], P=0.048), but not in those with prior LHI (survival estimate: 0.06, 95% CI [-0.08, 0.2], P=0.4). Similar results were found when excluding patients with moderate or greater residual TR after intervention. Conclusion In TRIGISTRY, patients with ITR appeared to derive the greatest benefit from tricuspid valve intervention, followed to a lesser extent by those with UTR, while no benefit was observed in patients with prior LHI. However, the potential influence of unaccounted confounders cannot be excluded, and further studies are needed to better identify patients’ subsets that may derive the most benefit from a tricuspid valve intervention.

Abstract Background Left ventricular (LV) remodeling in patients with valvular heart disease may vary according to the type of overload (pressure vs volume) as well as patients’ characteristics and comorbidities. Different LV remodeling patterns can be defined based on either an increase in LV mass index (LVMI), relative wall thickness (RWT), or both, and have been largely studied in patients with aortic valve disease but not in patients with primary mitral regurgitation (PMR). Purpose To describe the prevalence and baseline characteristics of the different LV remodeling patterns in PMR patients undergoing mitral valve (MV) surgery, and their association with outcome. Methods Four LV remodeling patterns were identified before MV surgery according to LVMI and RWT (Fig1-a). A cutoff of >115 g/m2 in males or >95 g/m2 in females was used to define high LVMI, and >0.42 was used to define high RWT. Patients with more than mild concomitant aortic stenosis were excluded. The study outcome was all-cause mortality. Results A total of 1538 patients were included, of which 362 (23.5%) had normal LV geometry (NG), 774 (50.3%) had eccentric hypertrophy (EH), 286 (18.6%) had concentric hypertrophy (CH), and 116 (7.5%) had concentric remodeling (Fig 1-a). Compared to the NG group (Fig 2), the EH group had more females, with larger LV size and left atrial volume index (LAVI). Compared to the NG group, patients in the CH group were significantly older and had more proportion of females. Moreover, they were more symptomatic, had higher prevalence of arterial hypertension, atrial fibrillation, and worse renal function, with smaller LV end-diastolic diameters and thicker LV walls.. Compared to the NG group, the CR group included patients with significantly smaller LV cavities and thicker LV walls, but interestingly similar LAVI and systolic pulmonary pressure, suggesting that this group might represent patients with a rather acute onset MR. Of note, there was no difference among the groups as regards LV systolic dysfunction (ejection fraction ≤ 60%, P=0.314). However, patients with CH and CR had significantly worse e’ and E/e’ ratio. After a median follow-up of 6.2 years, 211 (13.7%) patients died. Kaplan-Meier analysis showed similar survival between the NG and EH groups (91.4 vs 91.6%, P = 0.964), with significantly lower survival in the CH (76.6%, P<0.001) and CR (81.9%, P=0.028) groups, compared to NG (Fig 1-b). On multivariable analysis, after correcting for all the significant variables (Fig 1-c), CH and CR patterns carried higher risk of mortality (HR 1.7, P=0.024 and 2.0, P=0.017) compared to NG, while EH carried no additional risk (P=0.768). Conclusion LV remodeling patterns help in phenotyping patients with PMR undergoing MV surgery, and are independently associated with different risks of post-operative mortality.Figure 1:Prevalence and outcome Figure 2:Baseline characteristics

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.