Benfari, Giovanni

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): Mayo Clinic Foundation Background Left atrial (LA) volume is linked to outcome in degenerative mitral regurgitation (DMR) but does not encompass LA function assessment. Thus, we ought to determine the prognostic role of left atrial coupling-index (LACI), as left atrial volume-index (LAVI) by Tissue-Doppler-Imaging a’ (TDI-a’), in a large cohort of DMR. Methods All consecutive 4792 patients (61 ± 16 years, 48% women) with isolated degenerative mitral valve disease diagnosed at Mayo Clinic 2003-2011, comprehensively characterized, in whom LAVI and TDI-a’ in sinus rhythm was prospectively measured in routine practice, was enrolled and their long-term survival analyzed. Results LACI (5.8 ± 3.7–T1 < 3.8; T2 3.8-6.3; T3 > 6.3) was significantly higher through different DMR grades (no, mild, moderate, severe DMR: 3.77 ± 2.26, 5.08 ± 2.95, 6.54 ± 3.74 and 7.84 ±4.29 respectively; p < 0.0001). Independent determinants of LA dysfunction assessed by LACI were age, E/e’, left-ventricle (LV) end-systolic-diameter, mitral-regurgitation (MR) grade, and LV ejection-fraction (all P ≤ 0.0001). LACI > 6 was independently associated with dyspnea, edema, more severe functional tricuspid-regurgitation and elevated pulmonary artery pressure, irrespective of age, sex, Charlson-comorbidity-index, ventricular function and MR severity. Total follow-up was 7.03 ± 3.0 years, during which 1146 (24%) underwent mitral-valve surgery (94% repair-6% replacement) and 880 (18%) died, 780 under medical treatment and 100 after surgery. Overall survival throughout follow-up (10-year 76 ± 1%) was strongly associated with LACI (88 ± 1% vs. 78 ± 1% and 62 ± 2% for LACI <3.8, 3.8-6.3 and ≥6.3, P < 0.0001) even adjusting comprehensively, including for DMR severity (adjusted-hazard-ratio 1.23[1.07-1.43] for LACI > 5.79, P = 0.005). Mortality under medical management was profoundly affected by LACI (adjusted-hazard-ratio 1.11[1.05-1.18] per 3 unit increment; 1.35[1.15-1.58] for LACI > 5.79 vs. ≤5.79, both P = 0.0002). Survival improved after mitral surgery (time-dependent adjusted-hazard-ratio 0.40[0.28-0.65], P < 0.0001) but remained humbly linked to LACI (10-year 93 ± 3% vs. 90 ± 2% and 80 ± 3% for LACI tertiles, P = 0.0008). Most importantly, LACI provided incremental prognostic information over LAVI and other conventional determinants of survival (P < 0.0001) with Net-reclassification-improvement vs. LAVI of 0.21 ± 0.02, P < 0.0001. Conclusion LA function assessed by LACI in routine practice, by conventional echocardiographic measurements, displays incremental and independent link to excess-mortality, considerable under medical management and partially alleviated by mitral surgery. Thus, LACI is a simple tool of crucial interest in DMR risk-stratification. Abstract Figure. LACI in DMR

Abstract Background Mitral-annulus-disjunction (MAD), often described in mitral-valve-prolapse (MVP) patients, remains incompletely defined and its clinical outcome consequences are unknown. Objectives To assess MAD prevalence, clinical and echocardiographic characteristics, and independent impact on outcome in patients with isolated-MVP. Methods A cohort of 595 (65±16 years, 278 female) consecutive patients with MVP and comprehensive clinical, rhythmic and Doppler-echocardiographic characterization, was identified. Primary-endpoint was overall-survival, or occurrence of ventricular-arrhythmia. To eliminate clinical differences, we matched MAD-patients 1:1 with no-MAD based on propensity score for overall survival analysis using a greedy 5-to-1 digit-matching algorithm. Results MAD was frequent, present in 186 (31%) of MVP-patients and independently associated to bileaflet-MVP, leaflet-redundancy, younger-age, female-sex, enlarged left-ventricle-endsystolic-diameter and higher left-ventricle-ejection-fraction (all P≤0.04). Outcome primary-endpoint of survival after MVP diagnosis in matched-cohort (10-year 95±1%) was not associated with MAD presence (10-year 93±2% for no-MAD and 97±1% for MAD, P=0.4). Mortality was comparable for MAD (univariate-hazard-ratio 0.64 [0.25–1.65], P=0.4 vs. no-MAD), even adjusted-comprehensively including for MVP-characteristics (adjusted-hazard-ratio 1.17 [0.39–3.50], P=0.8). However, 220 (51%) MVP-patients were diagnosed ventricular-arrhythmia (161 with ventricular-tachycardia only) and long-term, MAD was associated with lower arrhythmia- and ventricular-tachycardia- overall freedom (adjusted-hazard-ratio for MAD 2.35 [1.75–3.15], P<0.0001 vs. no-MAD and 2.71 [1.93–3.82], P<0.0001 respectively). Hence, 10-year freedom of significant ventricular-arrhythmia in overall-cohort was severely reduced with MAD (41±4% vs. 62±3% for no-MAD). Conclusion In this unique MVP cohort, with arrhythmia and MAD comprehensively-characterized, MAD presence was frequent and independently associated to bileaflet-MVP and leaflet-redundancy. Long-term, MAD compared to no-MAD is not independently associated with higher-mortality but to reduced arrhythmia-freedom occurrence. Survival overall and by V arrhythmia Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Mayo Foundation

Abstract Background Bicuspid aortic valve (BAV) is an important cause of AR; these patients belong to a young and male predominant population and are distinctively different from tricuspid aortic valve (TAV). However, the differences between BAV and TAV in AR have not been completely explored. Purpose To explore differences between patients with BAV and TAV in hemodynamically significant aortic regurgitation (AR). Methods Consecutive patients with ≥moderate-severe AR were retrospectively identified from 2006 to 2017. Results Of 798 patients (502 with TAV, mean age 67±14 years; 296 with BAV, mean age 46±14 years) followed for 6.1±3.6 years, 403 underwent AV surgery (AVS); 154 died during follow-up. BAV men (94%) tended to become symptomatic when left ventricle enlarged; TAV patients became symptomatic before left ventricular (LV) enlargement. During follow-up, BAV patients had lower mortality (hazard ratio [HR], 0.19; P<0.0001) and higher incidence of AVS (HR, 1.28; P=0.01) than TAV, which attenuated after adjusted on age, sex, comorbidities, LV ejection fraction (LVEF), functional class, and time-dependent AVS. In a propensity-matched cohort, differences of survival and incidence of AVS between BAV and TAV were not demonstrated. After a median of 6.3 (IQR: 3.3–9.3) years, 53 patients died post-AVS; TAV patients having class I surgical triggers had poor survival than TAV-non-class I patients and BAV patients with and without class I triggers (Figure). Class I triggers had no effect on BAV patients regarding post-AVS survival. LVEF<60% was associated with increased mortality in both TAV and BAV. Conclusions The correlation between larger LV size and symptomatic status only applied in BAV men. Patients with BAV and significant AR tended to have better survival and higher incidence of AVS, likely driven by inherent younger age and less comorbidity than patients with TAV. Class I surgical triggers had heavier negative impact on poor survival in TAV patients. The cutoff of LV dysfunction in AR may be LVEF 60%. Figure 1. Kaplan-Meier curves post-AVS Funding Acknowledgement Type of funding source: None

Objective To comprehensively explore contemporary differences between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with chronic haemodynamically significant aortic regurgitation (AR). Methods Consecutive patients with chronic ≥moderate-severe AR from a tertiary referral centre (2006–2017) were included. All-cause mortality, surgical indications and aortic valve surgery (AVS) were analysed. Results Of 798 patients (296 BAV-AR, age 46±14 years; 502 TAV-AR, age 67±14 years, p<0.0001) followed for 5.5 (IQR: 2.9–9.2) years, 403 underwent AVS (repair in 96) and 154 died during follow-up. The 8-year AVS incidence was 60%±3% versus 53%±3% for BAV-AR and TAV-AR, respectively (p=0.014). The unadjusted (real-life) 8-year total survival was 93%±7% versus 71%±2% for BAV-AR and TAV-AR, respectively (p<0.0001), and became statistically insignificant after sole adjustment for age (p=0.14). The within-group relative risk of death in BAV-AR patients demonstrated a large age-dependent increase (two fold at 50–55 years, up to 10-fold at 70 years). The presence of baseline symptoms was significantly associated with death for both BAV-AR (p=0.039) and TAV-AR (p<0.0001), but the strength of the association decreased with age adjustment for BAV-AR (age-adjusted HR 2.43 (0.92–6.39), p=0.07) and not for TAV-AR (age-adjusted HR, 2.3 (1.6–3.3), p<0.0001). As compared with general population, TAV-AR exhibited baseline excess risk which further increased at left ventricular ejection fraction (LVEF) <60% and left ventricular end-systolic dimension index (LVESDi) >20 mm/m2; similar thresholds were observed for BAV-AR patients. Conclusion BAV-AR patients were two decades younger than TAV-AR and underwent AVS more frequently, resulting in a considerable real-life survival advantage for BAV-AR that was determined primarily by age and not valve anatomy. Pragmatically, regardless of valve anatomy, patients with haemodynamically significant AR and age >50–55 years require a low-threshold for surgical referral to prevent symptom development where LVEF <60% and LVESDi >20 mm/m2 seem appropriate referral thresholds.

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.

The need for multiple transducer positions, especially from right parasternal windows, is consistently mentioned in the recommendations for the accurate measurement of peak velocities across a stenotic aortic valve, but yet poorly adopted. We performed a subanalysis of the largest prospective series on the right parasternal acoustic windows in patients with aortic stenosis (330 consecutive) to calculate the degree of misalignment and estimate the potential outcome implication of this often-forgotten approach. The right parasternal view was highly feasible with an average estimated misalignment from the apical view of 14 ± 16 degree; in 10 cases, an estimated misalignment >40 degree. Right parasternal assessment (vs. apical alone) provided a significant reclassification from moderate to severe or even very-severe aortic valve stenosis. Considering a wellestablished survival benefit provided by either percutaneous or surgical valve replacement in patients with severe aortic stenosis the reclassification would result in approximately 1 life-year saved for every 30–35 patients in whom parasternal view were effectively utilized.

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.

Background: Functional tricuspid regurgitation (FTR) is common in heart failure with reduced ejection fraction and mostly consequent to pulmonary hypertension. However, the intrinsic clinical implications of FTR are not fully understood. Methods: The cohort of all Mayo Clinic patients from 2003 to 2011 diagnosed with heart failure stage B-C and ejection fraction<50%, with FTR grading and systolic pulmonary artery pressure estimation by Doppler echocardiography was identified and outcomes were analyzed. Patients with pacemakers/defibrillators, organic valve disease, or previous valve surgery were excluded. The primary outcome measure was overall mortality (censored at implantation of a defibrillator, ventricular assist device, or cardiac transplantation), adjusting for clinical and echocardiographic associates with mortality and major comorbidities. Results: Among 13 026 patients meeting inclusion criteria, FTR was detected in 88% (N=11 507: 33% trivial, 32% mild, 17% moderate, and 6% severe), aged 68±14 years, 35% women, ejection fraction 36±10%, systolic pulmonary artery pressure 41±14 mm Hg with 20% atrial fibrillation. Covariates independently associated with FTR included elevated systolic pulmonary artery pressure, older age, female sex, lower ejection fraction, mitral regurgitation, and atrial fibrillation (all P <0.0001). FTR was independently associated with more dyspnea, impaired kidney function, and lower cardiac output ( P <0.003 for all). For long-term outcome, higher FTR degree compared with trivial tricuspid regurgitation was independently associated with higher mortality (adjusted hazard ratios 1.09 [1.01-1.17] for mild FTR, 1.21 [1.11-1.33] for moderate FTR and 1.57 [1.39-1.78] for severe FTR); hence, 5-year survival was substantially lower with increasing severity of functional FTR, 68±1% for trivial FTR, 58±2% for mild FTR, 45±2% for moderate FTR, and 34±4% for severe FTR. Conclusions: In this large cohort of patients with heart failure with reduced ejection fraction, FTR was common and independently associated with pulmonary hypertension, atrial fibrillation, and more severe heart failure presentation. Long-term, higher FTR severity is associated with considerably worse survival, independently of baseline characteristics. Given these untoward outcomes associated with FTR in patients with heart failure with reduced ejection fraction, clinical trials should be directed at testing FTR treatment.

Abstract Aims To define the hitherto unknown aetiology/mechanism distributions of mitral regurgitation (MR) in the community and the linked clinical characteristics/outcomes. Methods and results We identified all isolated, moderate/severe MR diagnosed in our community (Olmsted County, MN, USA) between 2000 and 2010 and classified MR aetiology/mechanisms. Eligible patients (n = 727) were 73 ± 18 years, 51% females, with ejection fraction (EF) 49 ± 17%. MR was functional (FMR) in 65%, organic (OMR) in 32% and 2% mixed. Functional MR was linked to left ventricular remodelling (FMR-v) 38% and isolated atrial dilatation (FMR-a) 27%. At diagnosis FMR-v vs. FMR-a, vs. OMR displayed profound differences (all P &lt; 0.0001) in age (73 ± 14, 80 ± 10, 68 ± 21years), male-sex (59, 33, 51%), atrial-fibrillation (28, 54, 13%), EF (33 ± 14, 57 ± 11, 61 ± 10%), and regurgitant-volume (38 ± 13, 37 ± 11, 51 ± 24 mL/beat). Dominant MR mechanism was Type I (normal valve-movement) 38%, Type II (excessive valve-movement) 25%, Type IIIa (diastolic movement-restriction) 3%, and Type IIIb (systolic movement-restriction) 34%. Outcomes were mediocre with excess-mortality vs. general-population in FMR-v [risk ratio 3.45 (2.98–3.99), P &lt; 0.0001] but also FMR-a [risk ratio 1.88 (1.52–2.25), P &lt; 0.0001] and OMR [risk ratio 1.83 (1.50–2.22), P &lt; 0.0001]. Heart failure was frequent, particularly in FMR-v (5-year 83 ± 3% vs. 59 ± 4% FMR-a, 40 ± 3% OMR, P &lt; 0.0001). Mitral surgery during patients’ lifetime was performed in 4% of FMR-v, 3% of FMR-a, and 37% of OMR. Conclusion Moderate/severe isolated MR in the community displays considerable aetiology/mechanism heterogeneity. Functional MR dominates, mostly FMR-v but FMR-a is frequent and degenerative MR dominates OMR. Outcomes are mediocre with excess-mortality particularly with FMR-v but FMR-a, despite normal EF incurs notable excess-mortality and frequent heart failure. Pervasive undertreatment warrants clinical trials of therapies tailored to specific MR cause/mechanisms.