Michelena, Héctor I.

Abstract Aims The current guidelines recommend aortic valve intervention in patients with severe aortic regurgitation (AR) with the onset of symptoms, left ventricular enlargement, or systolic dysfunction. Recent studies have suggested that we might be missing the window of early intervention in a significant number of patients by following the guidelines. Methods and results The overarching goal was to determine if machine learning (ML)-based algorithms could be trained to identify patients at risk for death from AR independent of aortic valve replacement (AVR). Models were trained with five-fold cross-validation on a dataset of 1035 patients, and performance was reported on an independent dataset of 207 patients. Optimal predictive performance was observed with a conditional random survival forest model. A subset of 19/41 variables was selected for inclusion in the final model. Variable selection was performed with 10-fold cross-validation using random survival forest model. The top variables included were age, body surface area, body mass index, diastolic blood pressure, New York Heart Association class, AVR, comorbidities, ejection fraction, end-diastolic volume, and end-systolic dimension, and the relative variable importance averaged across five splits of cross-validation in each repeat were evaluated. The concordance index for predicting survival of the best-performing model was 0.84 at 1 year, 0.86 at 2 years, and 0.87 overall, respectively. Conclusion Using common echocardiographic parameters and patient characteristics, we successfully trained multiple ML models to predict survival in patients with severe AR. This technique could be applied to identify high-risk patients who would benefit from early intervention, thereby improving patient outcomes.

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.

Abstract Background Little is known about clinical outcomes in patients with bicuspid aortic valve (BAV) and ascending aortic diameters ≥50 mm where the elective surgical-indication zone begins. Purpose To assess incident aortic dissection (AoD), post-surgical survival and guideline implementation. Methods Multi-center retrospective study of BAV patients (≥18 years) with maximal root or tubular-ascending aortic diameters ≥50mm detected by transthoracic echocardiography at baseline. Ascertainment of aortic surgery, AoD and death was carried-out at their respective institutions. The primary outcome was AoD: “confirmed” AoD by surgery or death certificate, or “possible” AoD defined as sudden cardiac death of unknown cause by death certificate. Secondary outcomes were aortic surgery, post-surgical survival and guideline implementation. Results We included 506 consecutive BAV patients, mean age 61±14 years, 83% men, mean maximal aortic diameter 52±2 mm at baseline, ascending aorta was the most common segment ≥50mm (85%). During a median follow-up of 7.7 years, 356 (71%) underwent elective surgery (89% of class 1 patients). Early-surgery (≤6 months from baseline) occurred in 195 patients and 311 patients remained “under-surveillance”. Surgery under-surveillance (&gt;6 months from baseline) occurred in 161/311 (52%) patients at 2.6 [IQR: 1.5–4.7] years of follow-up. Surgical mortality was 1.4%. Ten-year post-surgical survival was &gt;90% and similar between early-surgery and surgery under-surveillance (p=0.8). Of 8 AoD events, 3 confirmed and 5 possible (all occurring in unoperated patients under-surveillance), 5 events occurred with maximal aortic baseline diameter ≥55 mm and/or &gt;1 year without clinical follow-up; therefore, under guideline non-compliance. Incidence of confirmed plus possible aortic dissection was 0.37% per year with size 50–54mm, 1.13% per year between 55–59mm, and 10.41% per year with size ≥60mm. Aortic stenosis was associated with AoD (p=0.04) and all-cause death in unoperated patients (p=0.001). Conclusions Our results suggest that BAV patients can be safely followed as per guidelines after aortic diameters enter the elective surgical zone (≥50mm), with excellent post-surgical survival regardless of whether surgery is early- or under-surveillance. Appropriate guideline implementation for surgical thresholds and interval clinical follow-up could have prevented most AoD events. Valvular disease guideline should also be followed to prevent AoD and improve survival in these patients. Funding Acknowledgement Type of funding sources: None.

AbstractBackgroundMitral transcatheter edge‐to‐edge repair (MTEER) is an established therapeutic approach for mitral regurgitation (MR). Functional mitral regurgitation originating from atrial myopathy (A‐FMR) has been described.ObjectivesWe sought to assess the clinical, echocardiographic and hemodynamic considerations in A‐FMR patients undergoing MTEER.MethodsFrom 2014 to 2020, patients undergoing MTEER for degenerative MR (DMR), functional MR (FMR), and mixed MR were assessed. A‐FMR was defined by the presence of MR > moderate in severity; left ventricular (LV) ejection fraction (LVEF) ≥ 50%; and severe left atrial (LA) enlargement in the absence of LV dysfunction, leaflet pathology, or LV tethering. The diagnosis of A‐FMR (vs. ventricular‐FMR [V‐FMR]) was confirmed by three independent echocardiographers. Baseline characteristics, procedural outcomes as well as clinical and echocardiographic follow‐up are reported. Device success was defined as final MR grade ≤ moderate; MR reduction ≥1 grade; and final transmitral gradient <5 mmHg.Results306 patients underwent MTEER, including DMR (62%), FMR (19%), and mixed MR (19%). FMR cases included 37 (63.8%) V‐FMR and 21 (36.2%) A‐FMR. Tricuspid regurgitation (≥ moderate) was higher in A‐FMR (80.1%) compared to V‐FMR (54%) and DMR (42%). Device success did not significantly differ between A‐FMR and V‐FMR (57% vs. 73%, p = 0.34) or DMR (57% vs. 64%, p = 1.0). The A‐FMR cohort was less likely to achieve ≥3 grades of MR reduction compared to V‐FMR (19% vs. 54%, p = 0.01) and DMR (19% vs. 49.7%, p = 0.01). Patients with V‐FMR and DMR demonstrated significant reductions in mean left atrial pressure (LAP) and peak LA V‐wave, though A‐FMR did not (LAP −0.24 ± 4.9, p = 0.83; peak V‐wave −1.76 ± 9.1, p = 0.39). In follow‐up, echocardiographic and clinical outcomes were similar.ConclusionsIn patients undergoing MTEER, A‐FMR represents one‐third of FMR cases. A‐FMR demonstrates similar procedural success but blunted acute hemodynamic responses compared with DMR and V‐FMR following MTEER. Dedicated studies specifically considering A‐FMR are needed to discern the optimal therapeutic approaches.

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 Intracranial aneurysms are reported in 6%–10% of patients with bicuspid aortic valve (BAV), and routine intracranial aneurysm surveillance has been advocated by some. We assessed the prevalence and features of the most important patient‐outcome: aneurysmal sub‐arachnoid hemorrhage (aSAH), as compared with controls without aSAH, and tricuspid aortic valve (TAV) with aSAH. Methods and Results Adult patients with accurate diagnosis of aSAH and at least one echocardiogram between 2000 and 2019 were identified from a consecutive prospectively maintained registry of aSAH admissions. Controls without a diagnosis of SAH were age‐ and sex‐matched. BAV prevalence was confirmed echocardiographically. Severity of aSAH was categorized using modified Fisher and World Federation of Neurological Scale. Neurologic outcome was assessed using modified Rankin score. A total 488 aSAH cases and 990 controls were identified and BAV status was confirmed. Prevalence of BAV in patients with aSAH was 1.2% (6/488) versus 3.5% (35/990) in controls, P =0.01. BAV+aSAH were noted to be younger than TAV+aSAH (56±11 versus 68±14; P =0.03) with smaller aneurysms (5±2 versus 7±4; P =0.31). The severity of aSAH was lesser in BAV+aSAH than TAV (modified Fisher grade>2 50% versus 74%; P =0.19, World Federation of Neurological Scale grade>3 17% versus 36%; P =0.43). BAV+aSAH had less severe neurologic disability (modified Rankin score 3%–6 33% versus 49% in TAV; P =0.44) and comparable in‐hospital mortality rates ( P =0.93). BAV had lower odds for aSAH on multivariate analysis (odds ratio 0.23[CI 0.08–0.65]; P =0.01). Conclusions Prevalence of BAV was 3 times lower in the aSAH registry than in controls without aSAH. BAV+aSAH had clinically smaller aneurysms, clinically smaller bleeds, and better neurologic outcome as compared with TAV+aSAH, which needs to be confirmed in larger studies. These findings argue against routine surveillance for intracranial aneurysms in patients with BAV without aortic coarctation.

Introduction: Subclinical cardiovascular involvement in COVID-19 patients has not been well described. 2D-Speckle Tracking Echocardiography derived global longitudinal strain (GLS) and systolic and early diastolic strain rate (SRs, SRe) measurements are more sensitive than standard echocardiographic parameters to diagnose subclinical mechanical dysfunction in patients with normal Left Ventricle Ejection Fraction (LVEF). Hypothesis: Evaluate subclinical myocardial mechanical function and reserve in active COVID-19 systemic disease patients with normal LVEF vs controls and between survivors and non survivors of COVID-19 in the longitudinal domain of contractility. Methods & Results: 166 adult patients with active COVID 19 having normal LVEF were included and compared to 89 healthy volunteers. Baseline parameters were recorded. Peak GLS, SRs and SRe, were measured offline. Mean age was 62.53 ± 18.96 years and 87 (52%) were males and Mean LVEF was 62±5%. COVID-19 patients had higher GLS compared to controls (-20.93%±0.30 vs. -18.48%±0.40; p value <0.0001), SRs was similar (-0.97 s -1 ±0.10 vs. -0.98 s -1 ±0.02, p value 0.2528) and SRe was lower (0.85 s -1 ±0.0 vs. 1.05 s -1 ±0.02; p value <0.0001) respectively. After adjusting for age and sex, GLS, SRs and SRe was significant (p<0.001). GLS, SRs and SRe were similar in survivors vs. non survivors (p NS), both groups had elevated biomarkers (cardiac troponin, NT-pro BNP, CRP), but non survivors had higher levels (3.22±0.18 vs 3.62±0.28, p = 0.2371, 5.86±0.19 vs 7.15±0.27, p = 0.0004, 3.75±0.14 vs 4.31±0.21, p = 0.0422, 7.64±0.17 vs 8.26±0.25, p=0.0487 respectively) (Table 1). Conclusions: In our cohort, COVID-19 patients had better systolic reserve and abnormal relaxation compared to controls. There was no significant difference in strain (GLS) and strain rate (SRs & SRe) amongst survivors and non survivors in the longitudinal domain of contractility despite of higher inflammatory biomarkers in non-survivors.

Introduction: Heart failure (HF) is a clinical syndrome with high mortality. Left ventricular ejection fraction (EF) determines clinical phenotyping and HF is classified most often as preserved (HFpEF) or reduced (HFrEF) EF. The importance of expanding phenotyping beyond EF is recognized. We hypothesized that machine learning applied to echocardiography will provide information important for deep phenotyping. Methods: We collected clinical and echo data in a HF community cohort between 2013 and 2017. Unsupervised clustering was applied to 23 echo variables using partitioning around medoids (PAM), with Gower dissimilarity used to address the mixed variable types. Proportional hazards regression examined the association between cluster assignment and death. Results: We identified 4978 persons with HF [mean age 73.9 years (SD 13.9), 47% women] with echocardiography within 6 months of diagnosis. We identified 2 primary clusters using echo variables, as depicted using t-Distributed Stochastic Neighbor Embedding (t-SNE) applied to the dissimilarity matrix (Figure). Diastolic function variables exhibited the largest differences by clusters as shown by absolute standardized differences (Table). After 3.2 + 1.9 years of follow up, 2001 deaths occurred. Assignment to cluster 2 was associated with a near 20% excess risk of death independent of age, sex, comorbidity, and EF [HR 1.17 (1.07, 1.28) p<0.001]. Conclusions: Unsupervised clustering applied to echocardiography in a large community HF cohort identified 2 distinct clusters, which defined HF subgroups with different characteristics and were independently associated with risk of death.