Essayagh, Benjamin

Abstract Aims Indications for surgery in patients with degenerative mitral regurgitation (DMR) are increasingly liberal in all clinical guidelines but the role of secondary outcome determinants (left atrial volume index ≥60 mL/m2, atrial fibrillation, pulmonary artery systolic pressure ≥50 mmHg and moderate to severe tricuspid regurgitation) and their impact on post-operative outcome remain disputed. Whether these secondary outcome markers are just reflective of the DMR severity or intrinsically affect survival after DMR surgery is uncertain and may have critical importance in the management of patients with DMR. To address these gaps of knowledge the present study gathered a large cohort of patients with quantified DMR, accounted for the number of secondary outcome markers and examined their independent impact on survival after surgical correction of the DMR. Methods and results The Mitral Regurgitation International DAtabase-Quantitative registry includes patients with isolated DMR from centres across North America, Europe, and the Middle East. Patient enrolment extended from January 2003 to January 2020. All patients undergoing mitral valve surgery within 1 year of registry enrolment were selected. A total of 2276 patients [65 (55–73) years, 32% male] across five centres met study eligibility criteria. Over a median follow-up of 5.6 (3.6 to 8.7) years, 278 patients (12.2%) died. In a comprehensive multivariable Cox regression model adjusted for age, EuroSCORE II, symptoms, left ventricular ejection fraction (LVEF), left ventricular end-systolic diameter (LV ESD) and DMR severity, the number of secondary outcome determinants was independently associated with post-operative all-cause mortality, with adjusted hazard ratios of 1.56 [95% confidence interval (CI): 1.11–2.20, P = 0.011], 1.78 (95% CI: 1.23–2.58, P = 0.002) and 2.58 (95% CI: 1.73–3.83, P < 0.0001) for patients with one, two, and three or four secondary outcome determinants, respectively. A model incorporating the number of secondary outcome determinants demonstrated a higher C-index and was significantly more concordant with post-operative mortality than models incorporating traditional Class I indications alone [the presence of symptoms (P = 0.0003), or LVEF ≤60% (P = 0.006), or LV ESD ≥40 mm (P = 0.014)], while there was no significant difference in concordance observed compared with a model that incorporated the number of Class I indications for surgery combined (P = 0.71). Conclusion In this large cohort of patients treated surgically for DMR, the presence and number of secondary outcome determinants was independently associated with post-surgical survival and demonstrated better outcome discrimination than traditional Class I indications for surgery. Randomised controlled trials are needed to determine if patients with severe DMR who demonstrate a cardiac phenotype with an increasing number of secondary outcome determinants would benefit from earlier surgery.

Background: Mitral valve prolapse (MVP) is responsible for a considerable disease burden but is widely heterogeneous. The lack of a comprehensive prognostic instrument covering the entire MVP spectrum, encompassing the quantified consequent degenerative mitral regurgitation (DMR), hinders clinical management and therapeutic trials. Methods: The new Mitral Regurgitation International Database Quantitative (MIDA-Q) registry enrolled 8187 consecutive patients (ages 63±16 years, 47% women, follow-up 5.5±3.3 years) first diagnosed with isolated MVP, without or with DMR quantified prospectively (measuring effective regurgitant orifice [ERO] and regurgitant volume) in routine practice of 5 tertiary care centers from North America, Europe, and the Middle East. The MIDA-Q score ranges from 0 to 15 by accumulating guideline-based risk factors and DMR severity. Long-term survival under medical management was the primary outcome end point. Results: MVP was associated with DMR absent/mild (ERO <20 mm 2 ) in 50%, moderate (ERO 20–40 mm 2 ) in 25%, and severe or higher (ERO ≥40 mm 2 ) in 25%, with mean ERO 24±24 mm 2 , regurgitant volume 37±35 mL. Median MIDA-Q score was 4 with a wide distribution (10%–90% range, 0–9). MIDA-Q score was higher in patients with EuroScore II ≥1% versus <1% (median, 7 versus 3; P < 0.0001) but with wide overlap (10%–90% range, 4–11 versus 0–7) and mediocre correlation ( R 2 0.18). Five-year survival under medical management was strongly associated with MIDA-Q score, 97±1% with score 0, 95±1% with score 1 to 2, 82±1% with score 3 to 4, 67±1% with score 5 to 6, 60±1% with score 7 to 8, 44±1% with score 9 to 10, 35±1% with score 11 to 12, and 5±4% with MIDA-Q score ≥13, with hazard ratio 1.31 [1.29–1.33] per 1-point increment. Excess mortality with higher MIDA-Q scores persisted after adjustment for age, sex, and EuroScore II (adjusted hazard ratio, 1.13 [1.11–1.15] per 1-point increment). Subgroup analysis showed persistent association of MIDA-Q score with mortality in all possible subsets, in particular, with EuroScore II<1% (hazard ratio, 1.08 [1.02–1.14]) or ≥1% (hazard ratio, 1.11 [1.08–1.13]) and with no/mild DMR (hazard ratio, 1.14 [1.10–1.19]) or moderate/severe DMR (hazard ratio, 1.13 [1.10–1.16], all per 1-point increment with P <0.0001). Nested-model and bootstrapping analyses demonstrated incremental prognostic power of MIDA-Q score (all P <0.0001). Conclusions: This large, international cohort of isolated MVP, with prospective DMR quantification in routine practice, demonstrates the wide range of risk factor accumulation and considerable heterogeneity of outcomes after MVP diagnosis. The MIDA-Q score is strongly, independently, and incrementally associated with long-term survival after MVP diagnosis, irrespective of presentation, and is therefore a crucial prognostic instrument for risk stratification, clinical trials, and management of patients diagnosed with all forms of MVP.

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 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 majority of patients with of Mitral-valve-prolapse (MVP) have a excellent prognosis. Until recently most cases of mortality were thought to be related to mitral regurgitation and left ventricular dysfunction. The concept of the arrhythmic MVP emerged to describe cases of sudden cardiac death (SCD) in the presence of isolated MVP yet it’s phonotype remains incompletely and inconsistently defined. Purpose To analyze the prevalence, severity and characteristics of ventricular-arrhythmia (VA), to determine it’s phenotypical context and independent impact on outcome in patients with MVP. Methods A cohort of 595 (65 ± 16 years, 278 female) consecutive patients with MVP and comprehensive clinical, arrhythmia (24hour-Holter) and Doppler-echocardiographic characterization, was identified and long-term outcome analyzed. Results VA was frequent, present in 43% of patients with at least ventricular ectopy≥5%, but was most often moderate (ventricular-tachycardia—VT 120-179bpm) in 27% and rarely severe (VT≥180/min) in 8.6%. Presence of VA was associated with older age, male sex, bileaflet-prolapse, marked leaflet redundancy, mitral-annulus-disjunction (MAD), larger left-atrium and left ventricular end-systolic diameter, and T-wave-inversion/ST-depression (all P ≤ 0.001). Severe VA was independently associated with presence of MAD, leaflet-redundancy and T-wave-inversion/ST-depression (all P &lt; 0.0001) but not with mitral regurgitation severity or ejection-fraction. Outcome primary endpoint of overall survival after arrhythmia diagnosis (8-year 87 ± 2%) was strongly associated with arrhythmia-severity (8-year 90 ± 2% for no/trivial arrhythmia, 85 ± 3% for mild/moderate and 76 ± 7% for severe arrhythmia. P = 0.02, Figure). Excess-mortality was substantial for severe-arrhythmia (univariate-hazard-ratio 2.70[1.27-5.77], P = 0.01 vs. no/trivial arrhythmia), even adjusted comprehensively including for MVP-characteristics (adjusted-hazard-ratio 2.94[1.36-6.36], P = 0.006) ). Conclusions This large cohort of isolated consecutive MVP characterized with 24-hour-Holter monitoring, clinical and Echocardiographic assessment, demonstrates that VA are frequent with MVP but rarely severe. The arrhythmic MVP was independently and strongly associated with specific ECG and morphologic patterns, particularly ST-T changes, MAD presence and marked leaflet redundancy, suggestive of a specific arrhythmic MVP phenotype, independently of MR-severity. Arrhythmia, particularly severe, is associated with long-term excess-mortality, independently of any other characteristics, including MR severity and LVEF. These findings lay the foundation for novel risk-stratification of MVP for the conduct of prospective controlled studies evaluating the management of MVP high-risk patients. Figure – Impact on survival of ventricular arrhythmia Overall survival of MVP stratified by ventricular arrhythmia (Panel A) or ventricular arrhythmia severity (Panel B) throughout follow-up. Abstract Figure.

Abstract Aims To assess functional tricuspid regurgitation (FTR) determinants, consequences, and independent impact on outcome in degenerative mitral regurgitation (DMR). Methods and results All patients diagnosed with isolated DMR 2003–2011, with structurally normal tricuspid leaflets, prospective FTR grading and systolic pulmonary artery pressure (sPAP) estimation by Doppler echocardiography at diagnosis were identified and long-term outcome analysed. The 5083 DMR eligible patients [63 ± 16 years, 47% female, ejection fraction (EF) 63 ± 7%, and sPAP 35 ± 13 mmHg] presented with FTR graded trivial in 45%, mild in 37%, moderate in 15%, and severe in 3%. While pulmonary hypertension (PHTN-sPAP ≥ 50 mmHg) was the most powerful FTR severity determinant, other strong FTR determinants were older age, female sex, lower left ventricle EF, DMR, and particularly atrial fibrillation (AFib) (all P ≤ 0.002). Functional tricuspid regurgitation moderate/severe was independently linked to more severe clinical presentation, more oedema, lower stroke volume, and impaired renal function (P ≤ 0.01). Survival (95% confidence interval) throughout follow-up [70% (69–72%) at 10 years] was strongly associated with FTR severity [82% (80–84%) for trivial, 69% (66–71%) for mild, 51% (47–57%) for moderate, and 26% (19–35%) for severe, P &lt; 0.0001]. Excess mortality persisted after comprehensive adjustment [adjusted hazard ratio 1.40 (1.18–1.67) for moderate FTR and 2.10 (1.63–2.70) for severe FTR, P ≤ 0.01]. Excess mortality persisted adjusting for sPAP/right ventricular function (P &lt; 0.0001), by matching [adjusted hazard ratios 2.08 (1.50–2.89), P &lt; 0.0001] and vs. expected survival [risk ratio 1.79 (1.48–2.16), P &lt; 0.0001]. Within 5-year of diagnosis valve surgery was performed in 73% (70–75%) and 15% (13–17%) of severe and moderate DMR and in only 26% (19–34%) and 6% (4–8%) of severe and moderate FTR. Valvular surgery improved outcome without alleviating completely higher mortality associated with FTR (P &lt; 0.0001). Conclusion In this large DMR cohort, FTR was frequent and causally, not only linked to PHTN but also to other factors, particularly AFib. Higher FTR severity is associated at diagnosis with more severe clinical presentation. Long term, FTR is independently of all confounders, associated with considerably worse mortality. Functional tricuspid regurgitation moderate and even severe is profoundly undertreated. Thus careful assessment, consideration for tricuspid surgery, and testing of new transcatheter therapy is warranted.