Benfari, Giovanni

Background Emerging data suggest important prognostic value to left atrial (LA) characteristics, but the independent impact of LA function on outcome remains unsubstantiated. Thus, we aimed to define the incremental prognostic value of LA coupling index (LACI), coupling volumetric and mechanical LA characteristics and calculated as the ratio of left atrial volume index to tissue Doppler imaging a′, in a large cohort of patients with isolated floppy mitral valve. Methods and Results All consecutive 4792 patients (61±16 years, 48% women) with isolated floppy mitral valve in sinus rhythm diagnosed at Mayo Clinic from 2003 to 2011, comprehensively characterized and with prospectively measured left atrial volume index and tissue Doppler imaging a′ in routine practice, were enrolled, and their long‐term survival analyzed. Overall, LACI was 5.8±3.7 and was <5 in 2422 versus ≥5 in 2370 patients. LACI was independently higher with older age, more mitral regurgitation (no 3.8±2.3, mild 5.1±3.0, moderate 6.5±3.8, and severe 7.8±4.3), and with diastolic (higher E/e′) and systolic (higher end‐systolic dimension) left ventricular dysfunction (all P ≤0.0001). At diagnosis, higher LACI was associated with more severe presentation (more dyspnea, more severe functional tricuspid regurgitation, and elevated pulmonary artery pressure, all P ≤0.0001) independently of age, sex, comorbidity index, ventricular function, and mitral regurgitation severity. During 7.0±3.0 years follow‐up, 1146 patients underwent mitral valve surgery (94% repair, 6% replacement), and 880 died, 780 under medical management. In spline curve analysis, LACI ≥5 was identified as the threshold for excess mortality, with much reduced 10‐year survival under medical management (60±2% versus 85±1% for LACI <5, P <0.0001), even after comprehensive adjustment (adjusted hazard ratio, 1.30 [95% CI, 1.10–1.53] for LACI ≥5; P =0.002). Association of LACI ≥5 with higher mortality persisted, stratifying by mitral regurgitation severity of LA enlargement grade (all P <0.001) and after propensity‐score matching ( P =0.02). Multiple statistical methods confirmed the significant incremental predictive power of LACI over left atrial volume index (all P <0.0001). Conclusions LA functional assessment by LACI in routine practice is achievable in a large number of patients with floppy mitral valve using conventional Doppler echocardiographic measurements. Higher LACI is associated with worse clinical presentation, but irrespective of baseline characteristics, LACI is strongly, independently, and incrementally determinant of outcome, demonstrating the crucial importance of LA functional response to mitral valve disease.

Background: Left atrial assessment is complex, particularly in heart failure with reduced ejection fraction due to interactions with functional mitral regurgitation (FMR). Pilot data suggest that left atrial volumetric/mechanical coupling index (LACI) may be useful, but large outcome data are lacking. Methods: We enrolled a comprehensively characterized cohort of patients in sinus rhythm with heart failure with reduced ejection fraction diagnosis at Mayo Clinic from 2007 to 2011. Routinely measured left atrial volume index and tissue-doppler-imaging a’ allowed LACI calculation as (left atrial volume index)/(tissue-doppler-imaging a’). Survival was the outcome measured. Results: The cohort’s 4196 patients (69 [58–77] years, ejection fraction 40 [31–45]%) had mild FMR in 1505 and moderate-severe FMR in 1068. LACI was overall 5.06 (3.50–8.10) and increased with each FMR grade (3.86 [2.94–5.29] without FMR, 5.38 [3.80–8.02] with mild, 5.45 [1.49–8.07] with moderate/severe FMR; P <0.0001). At diagnosis, higher LACI was independently determined by more severe FMR and by higher left ventricular mass index, lower ejection fraction, higher E/e’, and lower glomerular filtration rate (all P <0.0001). During follow-up 1588 (38%) patients died. In spline modeling, excess mortality appeared around LACI=6 and steeply increased thereafter (5-year survival 72±1% with LACI<6 and 49±2% with LACI ≥6, P <0.0001). Multivariable comprehensive adjustment showed LACI strong association with excess mortality (adjusted hazard ratio, 1.41 [1.23–1.61], P <0.0001 for LACI ≥6). Independent link to mortality persistent across FMR grades (adjusted hazard ratio, 1.45 [1.13–1.86], P =0.004 without FMR, 1.42 [1.16–1.77], P =0.0008 with mild FMR, and 1.38 [1.01–1.66], P =0.04 with moderate/severe FMR) without interaction ( P =0.3). LACI independent impact on outcome was incremental to that of left atrial volume index, tissue-doppler-imaging a’, or any other characteristic including the Meta-Analysis Global Group in Chronic-score (least significant P =0.02). Conclusions: In this large cohort, left atrial volumetric/mechanical coupling measured by LACI in routine practice integrates the influence of several morphological/hemodynamic determinants but displays progressive deterioration with increasing FMR severity in heart failure with reduced ejection fraction. About outcome, higher LACI is strongly, independently, and incrementally associated with excess mortality, irrespective of FMR grade and in all subsets. Hence, LACI is a novel and critical measure in heart failure with reduced ejection fraction, quantifiable in routine practice, which should be integrated in prognostication and decision-making.

Abstract Funding Acknowledgements Type of funding sources: None. Background Pulmonary hypertension is a frequent complication of severe degenerative mitral regurgitation (DMR) associated with major outcome implications. However, whether pulmonary hypertension is linked with worse outcome in less that severe MR is uncertain and even more unsubstantiated is the link of elevated systolic pulmonary artery pressure (sPAP) &lt; 50mmHg with clinical presentation and outcome. Purpose To assess the outcome implication of sPAP elevation, even moderate, among mitral regurgitation severity subgroups. Methods The MIDA-Quantitative (MIDA-Q) unprecedented registries included 7373 consecutive patients (age 64 ± 17 years, 45% women, follow-up 5.5 ± 3.4 years) with isolated DMR diagnosed at tertiary (European/North-American/Middle East) centers in which systolic pulmonary artery pressure (sPAP) was measured prospectively at baseline. Long-term survival overall, under medical management and post-mitral surgery was analyzed. Results Elevated pulmonary pressure (sPAP &gt;50mmHg) was observed in 1371 patients (19%, mean 63 ± 13mmHg) and moderate increase in pulmonary pressure (35&lt; sPAP &lt; 50mmHg) in 1874 patients (25%, mean 41 ± 14mmHg), with no/mild MR in 4067 (50%), moderate in 2073 (25%), and severe or above in 2047 (25%), mean ERO 0.24 ± 24cm2, RVol 37 ± 35mL and posterior leaflet prolapse in 34%. sPAP severe but also moderate both strongly and independently linked to more severe clinical presentation, with more dyspnea, more AFib, and impaired renal function (P ≤ 0.0001). &lt;SPAP&lt; &gt;By sPAP categories, 35 &lt; sPAP&lt; 50mmHg (vs. 35mmHg) was independently associated with worse outcome under medical management adjusted-HR 1.62[1.40-1/87], with considerable excess-mortality for sPAP &gt; 50mmHg (vs. &lt;35mmHg) adjusted-HR 2.54[2.17-2.96], all P &lt; 0.0001. As continuous variable, sPAP was associated with worse outcome adjusted-HR 1.25[1.21-1.29], P &lt; 0.0001 per 10mmHg-increase. Mitral valve surgery (performed in 2378 patients, 32%) improved outcome without alleviating completely higher mortality associated with sPAP &gt; 50mmHg (P &lt; 0.0001). Conclusion In this very large international cohort of patients with DMR of all range and prospective sPAP grading, higher sPAP is associated at diagnosis with more severe clinical presentation. Long term, sPAP &gt; 50mmHg but also 35-50mmHg is independently of all confounders, associated with worse mortality. Thus careful assessment and consideration for mitral surgery/transcatheter therapy is warranted even in patients with sPAP &lt;50mmHg.&lt;/SPAP&lt; &gt; Abstract Figure. Survival stratified by sPAP Categories Abstract Figure. Postop survival by sPAP Categories

Abstract Aims Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of &gt;2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. Methods and results We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Conclusion We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Abstract Background Randomized clinical trials demonstrated transcatheter edge-to-edge repair (TEER) efficacy in improving outcome vs. medical management for functional mitral regurgitation, but limited randomized data are available for the treatment of degenerative mitral regurgitation (DMR). We aimed to compare the outcome of older patients treated with TEER vs. unoperated DMR. Methods and results Registries including consecutive patients ≥65 years with symptomatic severe DMR treated with TEER (MitraSwiss and Minneapolis Heart Institute registries) or unoperated (MIDA registry) were analysed. Survival was compared overall and after matching for age, sex, EuroSCORE II, and ejection fraction. The study included 1187 patients (872 treated with TEER and 315 unoperated). During 24 ± 17 months of follow-up, 430 patients died, 18 ± 1% at 1 year and 50 ± 2% at 4 years. Patients undergoing TEER had similar age (82 ± 6 vs. 82 ± 7 years) and sex to unoperated patients, but higher surgical risk/comorbidity (EuroSCORE II 3.98 ± 4.28% vs. 2.77 ± 2.46%), more symptoms, and atrial fibrillation (P &lt; 0.0001). Transcatheter edge-to-edge repair was associated with lower mortality accounting for age, sex, EuroSCORE II, New York Heart Association class, atrial fibrillation, and ejection fraction [hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.37–0.58; P &lt; 0.0001]. After propensity matching (247 pairs of patients), TEER consistently showed better survival compared with unoperated patients (49 ± 6% vs. 37 ± 3% at 4 years, P &lt; 0.0001) even in comprehensive multivariable analysis (HR: 0.60, 95% CI: 0.40–0.91; P = 0.03). Procedural failure was infrequent but post-procedural mitral regurgitation, remaining moderate-to-severe in 66 (7.6%) patients, was associated with excess mortality vs. trivial residual regurgitation (30 ± 6% vs. 11 ± 1% at 1 year, P &lt; 0.0001). Conclusion Amongst older patients with severe symptomatic DMR at high surgical risk, mitral TEER was associated with higher survival vs. unoperated patients. Successful control of mitral regurgitation was key to survival improvement with mitral TEER, which should be actively considered in patients deemed inoperable.

Abstract Background The Mitral Regurgitation International Database (MIDA) score is a validated tool for Degenerative Mitral Regurgitation (DMR) management, being able to position a given patient within a continuous spectrum of short and long term mortality. However, whether this score may be applicable and incremental in the entire span of Floppy Mitral Valves (FMV), regardless of DMR severity, remains unsubstantiated. Methods The MIDA-Quantitative (MIDA-Q) unprecedented registries include 8187 consecutive patients (age 64±17 years, 45% women, follow-up 5.5±3.4 years) with isolated degenerative mitral valve disease diagnosed at tertiary (European/ North-American/ Middle Eastern) centers in whom DMR severity used both integrative and quantitative grading. The MIDA-Q Score ranged from 0 to 15 depending on accumulating risk factors. Long-term survival overall, under medical management and post-mitral surgery was analysed. Results By quantitative grading, MR was no/trivial in 1938 (24%), mild in 1423 (17%), moderate in 2027 (25%) and severe in 2799 (34%), with ERO 0.24±24cm2, RVol 37±35mL, and posterior leaflet prolapse in 49%. MIDA-Q Scores stratified in 8 categories were 0 (score 0, n=851), 1 (score 1–2, n=1301), 2 (score 3–4, n=2043), 3 (score 5–6, n=1581), 4 (score 7–8, n=1273), 5 (score 9–10, n=718), 6 (score 11–12, n=331) and 7 (score 13–15, n=89). In the whole MIDA-Q population (n=8187 patients), 5-year survival under medical management with Scores categories 0–1, 2–4, and 5–7 was 96±1%, 73±1%, and 61±3% respectively (P&lt;0.0001). Five-year mortality ranged from 3% with MIDA Q-score 0 to 95% with MIDA Q-score 13–15 (P&lt;0.0001). After mitral surgery, 1-year mortality with Scores categories 0–1, 2–4, and 5–7 was 0%, 1%, and 6% respectively and 5-year post-operative survival was 99±1%, 94±1%, and 82±2% (all P&lt;0.0001). In models including age, sex and all guideline-provided prognostic markers, the EuroScoreII and the MIDA Score without DMR severity, the MIDA-Q Score provided incremental prognostic information (P&lt;0.001). Conclusion This unheard international cohort of patients with FMV and prospective mitral severity quantitative grading, enables for the first time the calculation of a MIDA-Q Score, highly determinant of survival after diagnosis of FMV with any degree of DMR, that may be very useful for mitral valve prolapse management. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): Mayo Fundation Figure 1

With stress echo (SE) 2020 study, a new standard of practice in stress imaging was developed and disseminated: the ABCDE protocol for functional testing within and beyond CAD. ABCDE protocol was the fruit of SE 2020, and is the seed of SE 2030, which is articulated in 12 projects: 1-SE in coronary artery disease (SECAD); 2-SE in diastolic heart failure (SEDIA); 3-SE in hypertrophic cardiomyopathy (SEHCA); 4-SE post-chest radiotherapy and chemotherapy (SERA); 5-Artificial intelligence SE evaluation (AI-SEE); 6-Environmental stress echocardiography and air pollution (ESTER); 7-SE in repaired Tetralogy of Fallot (SETOF); 8-SE in post-COVID-19 (SECOV); 9: Recovery by stress echo of conventionally unfit donor good hearts (RESURGE); 10-SE for mitral ischemic regurgitation (SEMIR); 11-SE in valvular heart disease (SEVA); 12-SE for coronary vasospasm (SESPASM). The study aims to recruit in the next 5 years (2021–2025) ≥10,000 patients followed for ≥5 years (up to 2030) from ≥20 quality-controlled laboratories from ≥10 countries. In this COVID-19 era of sustainable health care delivery, SE2030 will provide the evidence to finally recommend SE as the optimal and versatile imaging modality for functional testing anywhere, any time, and in any patient.

Stress echo (SE) 2030 study is an international, prospective, multicenter cohort study that will include >10,000 patients from ≥20 centers from ≥10 countries. It represents the logical and chronological continuation of the SE 2020 study, which developed, validated, and disseminated the “ABCDE protocol” of SE, more suitable than conventional SE to describe the complex vulnerabilities of the contemporary patient within and beyond coronary artery disease. SE2030 was started with a recruitment plan from 2021 to 2025 (and follow-up to 2030) with 12 subprojects (ranging from coronary artery disease to valvular and post-COVID-19 patients). With these features, the study poses particular challenges on quality control assurance, methodological harmonization, and data management. One of the significant upgrades of SE2030 compared to SE2020 was developing and implementing a Research Electronic Data Capture (REDCap)-based infrastructure for interactive and entirely web-based data management to integrate and optimize reproducible clinical research data. The purposes of our paper were: first, to describe the methodology used for quality control of imaging data, and second, to present the informatic infrastructure developed on RedCap platform for data entry, storage, and management in a large-scale multicenter study.

Dysfunction of the left ventricle (LV) with impaired contractility following chronic ischemia or acute myocardial infarction (AMI) is the main cause of ischemic mitral regurgitation (IMR), leading to moderate and moderate-to-severe mitral regurgitation (MR). The site of AMI exerts a specific influence determining different patterns of adverse LV remodeling. In general, inferior-posterior AMI is more frequently associated with regional structural changes than the anterolateral one, which is associated with global adverse LV remodeling, ultimately leading to different phenotypes of IMR. In this narrative review, starting from the aforementioned categorization, we proceed to describe current knowledge regarding surgical approaches in the management of IMR.