Malouf, Joseph F.

Abstract Aims Operating on patients with severe degenerative mitral regurgitation (DMR) is based on ACC/AHA or ESC/EACTS guidelines. Doubts persist on best surgical indications and their potential association with postoperative survival loss. We sought to investigate whether guideline-based indications lead to late postoperative survival loss in DMR patients. Methods and results We analysed outcome of 2833 patients from the Mitral Regurgitation International Database registry undergoing surgical correction of DMR. Patients were stratified by surgical indications: Class I trigger (symptoms, left ventricular end-systolic diameter ≥ 40 mm, or left ventricular ejection fraction < 60%, n = 1677), isolated Class IIa trigger [atrial fibrillation (AF), pulmonary hypertension (PH), or left atrial diameter ≥ 55 mm, n = 568], or no trigger (n = 588). Postoperative survival was compared after matching for clinical differences. Restricted mean survival time (RMST) was analysed. During a median 8.5-year follow-up, 603 deaths occurred. Long-term postoperative survival was lower with Class I trigger than in Class IIa trigger and no trigger (71.4 ± 1.9, 84.3 ± 2.3, and 88.9 ± 1.9% at 10 years, P < 0.001). Having at least one Class I criterion led to excess mortality (P < 0.001), while several Class I criteria conferred additional death risk [hazard ratio (HR): 1.53, 95% confidence interval (CI): 1.42–1.66]. Isolated Class IIa triggers conferred an excess mortality risk vs. those without (HR: 1.46, 95% CI: 1.00–2.13, P = 0.05). Among these patients, isolated PH led to decreased postoperative survival vs. those without (83.7 ± 2.8% vs. 89.3 ± 1.6%, P = 0.011), with the same pattern observed for AF (81.8 ± 5.0% vs. 88.3 ± 1.5%, P = 0.023). According to RMST analysis, compare to those operated on without triggers, operating on Class I trigger patients led to 9.4-month survival loss (P < 0.001) and operating on isolated Class IIa trigger patients displayed 4.9-month survival loss (P = 0.001) after 10 years. Conclusion Waiting for the onset of Class I or isolated Class IIa triggers before operating on DMR patients is associated with postoperative survival loss. These data encourage an early surgical strategy.

Introduction: Mitral paravalvular leak (PVL) occurs in 7-17% of patients after mitral valve surgery. The percutaneous closure of these defects has become a novel treatment to prevent repeat operations. Hypothesis: We hypothesize flow dynamics correlate with clinical outcomes of patients undergoing percutaneous mitral PVL closure. Methods: We retrospectively studied 148 patients who underwent percutaneous PVL closure between 2004 and 2014 at Mayo Clinic. We measured the continuous wave (CW) Doppler time velocity integral (TVI), E velocity (as a surrogate for V wave) across the mitral valve and left ventricular ejection fraction (LVEF) by transthoracic echocardiogram within 7 days before and after PVL closure. We identified patients as non-responders if there was moderate to severe residual mitral regurgitation. t-Test was used for continuous variables and Fisher exact test was used mortality. Results: Overall, the mean CW TVI was markedly reduced by PVL closure (93±14 vs. 58±5cm, p<0.02). The E velocity also decreased after closure (3.1±0.4 vs. 1.9±0.1m/sec, p<0.04). LVEF, however, was reduced after PVL closure (62%±2 vs. 53%±1.5, p<0.02). Among non-responders (34/148 patients), there was no significant difference between the CW and E velocity before and after the procedure (CW TVI: 96±16 vs. 83+13cm, E velocity: 2.5±0.5 vs. 2.3±0.3m/sec, p=NS). The estimated 5-year mortality of patients with no or mild residual mitral regurgitation was markedly lower compared to non-responders, 43% vs 71%, p<0.05. Conclusions: The flow dynamics across the mitral valve immediately after PVL closure may correlate with long term clinical outcomes. Real time assessment of flow by transesophageal echocardiogram can be used to guide the extent of PVL closure required to change the long term clinical outcomes. Further validation and prospective studies are required.

Background: Very few long-term data are available on patients undergoing mitral valve surgery for chronic ischemic mitral regurgitation (CIMR). Objective:to identify determinants of survival and adverse cardiovascular events, at very long-term outcome. Methods and Results: We reviewed complete left and right ventricular echocardiographic data, six-minute walking test (6-MWT) and BNP levels at pre, peri and follow-up, on 137 consecutive patients who underwent restrictive mitral annuloplasty (RMA) or mitral valve replacement (MVR) and CABG, for CIMR. Combined adverse cardiovascular events were defined as composite of death, heart failure, angina, myocardial infarction and re-hospitalization. Mean age was 67±0.7. Preoperative EF was 35±06%. Among 137 patients, 46% underwent RMA and 54% had MVR. Median follow- up was 7 years (range: 0.3-15.4). Early mortality was 7% (p=NS). In the RMA 42% of patients experienced MR recurrence. Overall survival at 5, 10 and 15 years were 84, 76 and 62% in RMA, and 87, 62 and 54% in MVR (p=0.65). At univariate analysis, preop B-blocker, 6-MWT, mean transmitral gradients and RV size were predictors of adverse events.The Cox Hazard multivariate analysis identified preoperative atrial fibrillation (p=0.005), preop BNP (p=0.025) as independent predictors of long-term mortality.Freedom from cardiovascular events at 5, 10 and 15 years were 90, 75 and 48% in RMA, and 90, 62 and 45% in MVR (p=0.57). . The Cox Hazard multivariate analysis identified preop B-blocker therapy (p=0.001), atrial fibrillation (p=0.01), postoperative mean transmitral gradients (p=0.047 ) and indexed effective orifice area (p=0.02) as independent predictors of adverse cardiovascular events. Conclusions: Our study confirms an high rate of true MR recurrence, at very long-term follow-up. Among collected variables, preoperative BNP and atrial fibrillation were independent predictors of survival, whereas B-blocker therapy, atrial fibrillation, postoperative mean transmitral gradients and indexed effective orifice area were independent predictors of adverse cardiovascular events. Type of surgery did not affect the very long-term outcome.

Introduction: Left ventricular longitudinal strain (LV-LS) 1) predicts mortality in patients with aortic stenosis (AS) and 2) is highly correlated to type-B natriuretic peptide (BNP) values. The BNP ratio (measured BNP/maximal expected BNP value specific for age and sex) is a powerful independent predictor of death in patients with AS. Hypothesis: we hypothesize that BNP activation (i.e. BNP ratio >1) affects the association between LV-LS and mortality in patients with asymptomatic AS and preserved LV ejection fraction (EF ≥50%). Methods: 315 patients (age 74±12 years, 56% men and mean aortic valve area = 1.02±0.15cm2) underwent simultaneous Doppler echocardiographic and BNP measurements. LV-LS was calculated as the average of 12 LV segments from apical 2- and 4-chamber views using Velocity Vector Imaging. Results: Mean LV-LS was -16.8±3.2%, LV EF 66±7%, median BNP level 121 (interquartile 48-320) pg/ml. 58% of patients had BNP activation. Better LV-LS was associated with lower log BNPratio (regression coefficient 0.10, p<0.001). After a median follow-up of 6.5 yrs (interquartile: 3.6-8.2), 119 deaths occurred. After adjustment for age, sex, Charlson score index, hemoglobin level, aortic valve replacement (as a time dependent variable), LV-LS and log BNPratio were separately associated with increased risk for death (all p<0.01). Further adjustment for predictors of mortality, LV-LS and log-BNP ratio remained associated with increased risk for death (hazard ratio HR [95%CI]: 1.09 [1.03-1.15]; p=0.003 and 1.82 [1.52-2.19]; p<0.0001 respectively). In patients without BNP activation (i.e. normal BNP), LV-LS was associated with mortality (HR: 1.22 [1.04-1.43]; p=0.01) while it was not in patients with BNP activation (p=0.22). Conclusions: In patients with asymptomatic AS, without clinically obvious myocardial impairment (i.e. normal LVEF), a notable proportion of patients present with myocardial alterations detected by an elevated BNPratio or reduced LV-LS. These signs of myocardial alterations were predictive of mortality after diagnosis. Thus both BNP and LV-LS should be assessed in the clinical setting to provide complementary information on prognosis in patients with asymptomatic AS and preserved LV EF.

Introduction: Left atrial appendage (LAA) flow depends largely on left ventricular compliance and may play a role in mediating the regulation of left atrial volume-pressure relationships. Hypothesis: We hypothesize that LAA emptying flow velocity (LAAEV) is a predictive factor of long-term outcomes (e.g. recurrent AF, stroke, and survival) after cardioversion for non-valvular AF. Method: We identified 3,251 consecutive patients with non-valvular AF who underwent successful TEE-guided electrical cardioversion (ECV) at our institution between May 2000 and March 2012. Successful ECV was defined as sinus rhythm at time of discharge from the cardioversion unit. Patients were monitored following their ECV procedure for first documentation of recurrent AF, stroke or death. Multivariate Cox proportional hazards models were used to identify independent predictors of long-term outcomes. Patients with >= moderate valvular regurgitation or stenosis were excluded. Results: Among the 3,251 patients who were successfully cardioverted to sinus rhythm, the mean (±SD) LAAEV was 38.43±23 cm/s and the median was 33 cm/s, (interquartile range [IQR], 20-50). Patients with LAAEV <=33 cm/s had higher CHA 2 DS 2 -VASc score (2.6±1.2 vs. 1.9±1.3, P =.009), larger LAVI (52.0±20.9 cc/m 2 vs. 43.3±13.6 cc/m 2 , P <.001) than those with LAAEV >33 cm/s. Pre or post-procedure antiarrhythmic drug use was similar between the two groups. During 1-year follow-up, patients with LAAEV <=33 cm/s had significantly higher rate of AF recurrence than those with LAAEV >33 cm/s (55% vs 45%, P <.001). Likewise, during a mean follow-up of 4.9±3.6 years, similar patterns in 5-year rates were observed for first recurrence of AF (81% vs 73%, P <.001), stroke (7% vs 4%, P =.003) and mortality (31% vs 23%, P <.001) for LAAEV <=33 vs > 33cm/s, respectively. Stepwise multivariate Cox regression analysis revealed that LAAEV <=33 cm/s, age, CHA 2 DS 2 -VASc score were independent predictors of AF recurrence, stroke and mortality. Conclusions: LAA emptying flow velocity is an effective and convenient method for risk stratification of patients undergoing cardioversion for AF. Our data showed that patients with reduced LAAEV have an increased risk for AF recurrence, stroke and death following electrical cardioversion.

Introduction: Levels of type-B natriuretic peptide (BNP) adjusted for age and sex are a powerful predictor of mortality after the diagnosis of aortic stenosis (AS). Objective: To assess whether BNP activation (compared to normal values) affects mortality after aortic valve replacement (AVR). Methods: In 494 patients with AS, plasma level of BNP was measured pre-operatively at the time of Doppler-Echocardiography. BNP was normalized as BNPratio (BNP measured/BNP maximum normal value for age and sex) to evaluate the impact of BNP activation on post-operative outcomes. Results: Mean age was73±11 years and 300 (61%) patients were male. Mean aortic valve area was 0.82±0.20cm2, mean gradient 51±16mmHg, and mean Left Ventricular Ejection Fraction 59±15%. Incidence of hypertension was 65%, diabetes 27% and chronic kidney disease 22%. Median of BNP was 211 (interquartile: 87-508) and BNPratio 2.2 (1.0-5.2). After adjustment age, gender, body surface area, Charlson score index, presence of symptoms, creatinine, hemoglobin, systolic blood pressure, indexed aortic valve area and left ventricular ejection fraction, the BNPratio (log transformed) was a predictor of long-term mortality (p<0.0001) with an hazard ratio 1.34 (1.14-1.60). Moreover, stratification by BNPratio showed increasing long-term post-operative mortality with BNPratios>2 (Figure). Conclusions: BNP activation defined using BNPratios (normalized for age and sex) is a powerful independent predictor of long-term mortality after aortic valve replacement for AS. Furthermore, patients with a BNPratio>2 before aortic valve replacement incur excess mortality during follow-up in relation to the increasing BNPratio. These data support the use of the BNPratio to guide the timing of AVR.

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 Introduction: Atrial fibrillation (AF) represents a cardiovascular syndrome which can lead to embolic stroke. Several AF clinical trials have shown a decrease risk of stroke with anticoagulation using warfarin. Currently, there are two approaches for anticoagulation in AF patients. For outpatients, warfarin is used with an INR goal 2.0–3.0. For inpatients requiring cardioversion, unfractionated heparin (UFH, IV) is used as a bridge to therapeutic warfarin. More recently, anticoagulation with a low molecular weight heparin, enoxaparin, has been reported to give a more predictable anticoagulant response than UFH in TEEguided cardioversion. The present study compares the markers of inflammation and thrombin generation in patients included in the ACUTE II study. Methods: This was a randomized multicenter trial of 155 patients from 17 clinical sites, the anticoagulant activity of LMWH (enoxaparin, 1 mg/kg sc bid, Sanofi-Aventis, n=76) was compared to that of UFH (APTT 1.5 – 2.5 x control, n=79). Blood samples were drawn at enrollment (baseline), day 2 (peri cardioversion) and day 4 in both groups. Day 2 and day 4 samples were taken 3–4 hours after the injection of LMWH in patients in the LMWH group. Blood samples were evaluated for inflammation: C-reactive protein (CRP), CD 40 ligand (CD 40L), monocyte chemotactic protein 1 (MCP-1) and anticoagulant effect: thrombin antithrombin complex (TAT) and prothrombin fragment (F 1.2). Results: The APTT and anti-Xa levels indicated therapeutic anticoagulation was achieved (previously reported). In addition, both TAT and F1.2 levels were increased at baseline and were significantly decreased with LMWH (p&lt;0.01) in comparison to UFH. The CRP, CD40L, MCP-1 were decreased after treatment in both groups of patients. These results suggest that AF patients treated with LMWH demonstrate a stronger anticoagulant effect as measured by a significant reduction in the markers of thrombin generation. Furthermore, anticoagulation with either UFH of LMWH results in a decrease in inflammation which was not different between groups. Conclusion: In the ACUTE II trial, anticoagulation with LMWH in AF patients may be a better alternate than UFH during TEE-guided cardioversion due to a a stronger anticoagulant.

Abstract Background Transcatheter edge-to-edge mitral valve repair (TMVR; MitraClip, Abbott Vascular) is clinically approved for treatment of severe, symptomatic mitral regurgitation (MR) in high or prohibitive surgical risk patients. Iatrogenic mitral stenosis is a known complication of TMVR, but determinants of increased post-procedure mean diastolic gradient are not well defined. Purpose We aimed to investigate the determinants of increased mitral mean diastolic gradient after TMVR. Methods We retrospectively reviewed 59 patients. 2D and 3D TEE data sets acquired before and immediately after procedure were analyzed. 4D Cardio-View and 4D MV-Assessment (TomTec, Germany) were used for the analysis of the 3D volume data set. Quantitative mitral valve analysis was done at the end of systole. Increased mitral mean diastolic gradient after TMVR was correlated with pre-procedure 2D and 3D echocardiographic data. Results 34 patients had primary MR, 25 patients had mixed/secondary MR. Baseline mean mitral diastolic gradient was 2.0 ± 0.9mmHg and increased to 3.9 ± 1.8mmHg post-TMVR and the mean 3D planimetric mitral valve area decreased from 5.3 ± 1.5cm2 to 2.6 ± 1.0cm2. Implantation of multiple clips was performed less frequently in patients with smaller baseline mitral valve area; 8% vs 47% in the lowest quartile vs all others (p = 0.006). 12(20%) of patients had a mean diastolic gradient &gt;5mmHg post-TMVR and 15(25%) of patients had a post-TMVR mitral valve area &lt;2.0 cm2. There was no significant difference in post-procedure heart rate between patients with mean diastolic gradient ≤5mmHg vs &gt;5mmHg (p = 0.08). Patient characteristics according to post-TMVR mean diastolic gradient are shown in the Table. Post-TMVR mean diastolic gradient &gt;5mmHg was more common in patients with increased pre-procedure mean diastolic gradient(p = 0.006), post-TMVR mitral valve area &lt;2.0 cm2(40% vs 14%, p = 0.03), and ≥moderate residual mitral regurgitation(38% vs 11%, p = 0.02). Post-TMVR mitral valve area &lt;2.0cm2 was present in 50% vs 19% of patients with vs without a mean gradient &gt;5mmHg(p = 0.04). Conclusions Elevated post-TMVR mean diastolic gradient is multifactorial and related to mitral stenosis, but residual mitral regurgitation also appears to be an important contributor to increased gradients in some patients. Larger cohorts are likely needed to assess the concurrent impact of mitral annular calcification, leaflet calcification, and other variables on post-TMVR mean gradient. Abstract P1798 Figure. 2D and 3D Echocardiographic Parameters

AbstractBackgroundMitraClip is an effective transcatheter therapy for mitral regurgitation (MR). However, MitraClip is challenging in commissural MR and the optimal therapeutic approach is unclear.MethodsWe describe a case series of six consecutive patients with severe commissural primary mitral regurgitation who underwent MitraClip insertion followed by an Amplatzer Vascular Plug (AVP) II occluder between the commissure and the MitraClip.ResultsThe procedure was successful in all patients. MR was reduced from severe to mild/trivial in 50% and moderate in 50% of cases. On 30‐day follow‐up, NYHA class had improved from III (6 patients) to I (2 patients), II (2 patients), and III (2 patients). The mean transmitral gradient was 2.5 ± 1.8 mmHg at baseline and 4.8 ± 2.6 mmHg following the procedure. One patient developed hemolysis immediately post procedure. The other five patients remained well during a median follow‐up of 20 months (range 5–50 months) with no reported device dislodgement.ConclusionsElective treatment of severe commissural MR with a laterally or medially placed MitraClip coupled with an AVP II occluder between the clip and the commissure is feasible and safe. This approach may provide a useful management alternative in selected patients.