Suri, Rakesh M.

Background— Fibro-elastic deficiency (FED) and diffuse myxomatous degeneration (DMD) are phenotypes of degenerative mitral valve disease defined morphologically. Whether physiological differences in annular and valvular dynamics exist between these phenotypes remains unknown. Methods and Results— We performed triple quantitation of cardiac remodeling and of mitral regurgitation severity and of annular and valvular dimensions by real-time 3-dimensional-transesophageal-echocardiography. Forty-nine patients with degenerative mitral valve disease classified as FED (n=31) and DMD (n=18) by surgical observation showed no difference in age (65±10 versus 59±13; P =0.5), body surface area (2.0±0.2 versus 2.0±0.2 m 2 ; P =0.5), left ventricular and atrial dimensions (all P >0.55), and mitral regurgitation regurgitant orifice ( P =0.62). On average, annular dimensions were larger in DMD versus FED, but height was similar resulting in lower saddle shape. Dynamically, annular DMD versus FED display poorer contraction and saddle-shape accentuation in early systole and abnormal enlargement, particularly intercommissural, in late-systole (all P <0.05). Valvular dynamics showed stable valvular area in systole in FED versus considerable systolic increased area in DMD ( P <0.001). Prolapse height and volume increased little throughout systole in FED versus marked increase in DMD ( P <0.001). Conclusions— Our novel observations show that FED and DMD, although both labeled myxomatous, display considerable physiological phenotypic differences. In DMD, the annular increased size and profoundly abnormal dynamics demonstrate DMD-specific annular degeneration compared with the enlarged but relatively normal FED annulus. DMD does not incur more severe mitral regurgitation, despite larger prolapse and valve redundancy, underscoring potential compensatory role of tissue redundancy of DMD (or aggravating role of tissue paucity of FED) on mitral regurgitation severity.

Objectives Cleft-like indentations (CLI) are deep separations between scallops of the mitral posterior leaflet observed in myxomatous mitral valve disease (MMVD), but their diagnosis, mechanisms and implications are unknown. Using 3D transoesophageal echocardiography (3DTOC), we aimed at assessing diagnostic accuracy and defining mechanisms of CLI in patients undergoing surgery for MMVD. Methods 3DTOC of mitral valve was acquired in 49 patients with MMVD and severe regurgitation prior to valve repair. Qualitative review compared 3DTOC diagnosis of CLI with surgical inspection. Mitral, annular and leaflet dimensions were quantified with dedicated software and compared between those with and without CLI. Results Diagnosis of CLI was made by 3DTOC in 17 (35%) while none was identified by 2D and was confirmed in 15 (88%) by surgical inspection. Mechanistically, LV diameters and mitral regurgitant volume (RVol) were similar with and without CLI (p>0.49). Conversely, mitral annulus was smaller with CLI (anteroposterior diameter 42.2±7.1 vs 47.0±7.5 mm, p=0.04; circumference 133±16 vs 148±19 mm, p=0.009; area 1289±326 vs 1619±427 mm2, p=0.008). Prolapse volume tended to be smaller with CLI (1.9±1.2 vs 4.0±4.3 mL, p=0.06) involving single posterior scallop at surgery (82% vs 44%, p=0.007) with smaller 3DTOC leaflet area (1574±409 vs 2019±652 mm2, p=0.01). During valve repair, surgical closure of all surgically diagnosed CLI was required. Conclusions Posterior leaflet CLI are frequent in MMVD, are identified by 3DTOC with high accuracy and require closure during valve repair. CLI are mechanistically not related to excess annular enlargement or excess prolapse. Conversely, CLI occur in the context of single scallop prolapse with tissue paucity causing excess separation of scallops. These 3DTOC data enhance diagnostic and mechanistic comprehension of the diversity of MMVD phenotypical presentation.

Background— Tricuspid regurgitation (TR) and right ventricular (RV) dysfunction adversely affect outcomes in patients with heart failure or mitral valve disease, but their impact on outcomes in patients with aortic stenosis treated with transcatheter aortic valve replacement has not been well characterized. Methods and Results— Among 542 patients with symptomatic aortic stenosis treated in the Placement of Aortic Transcatheter Valves (PARTNER) II trial (inoperable cohort) with a Sapien or Sapien XT valve via a transfemoral approach, baseline TR severity, right atrial and RV size and RV function were evaluated by echocardiography according to established guidelines. One-year mortality was 16.9%, 17.2%, 32.6%, and 61.1% for patients with no/trace (n=167), mild (n=205), moderate (n=117), and severe (n=18) TR, respectively ( P <0.001). Increasing severity of RV dysfunction as well as right atrial and RV enlargement were also associated with increased mortality ( P <0.001). After multivariable adjustment, severe TR (hazard ratio, 3.20; 95% confidence interval, 1.50–6.82; P =0.003) and moderate TR (hazard ratio, 1.60; 95% confidence interval, 1.02–2.52; P =0.042) remained associated with increased mortality as did right atrial and RV enlargement, but not RV dysfunction. There was an interaction between TR and mitral regurgitation severity ( P =0.04); the increased hazard of death associated with moderate/severe TR only occurred in those with no/trace/mild mitral regurgitation. Conclusions— In inoperable patients treated with transcatheter aortic valve replacement, moderate or severe TR and right heart enlargement are independently associated with increased 1-year mortality; however, the association between moderate or severe TR and an increased hazard of death was only found in those with minimal mitral regurgitation at baseline. These findings may improve our assessment of anticipated benefit from transcatheter aortic valve replacement and support the need for future studies on TR and the right heart, including whether concomitant treatment of TR in operable but high-risk patients with aortic stenosis is warranted. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01314313.

Background— In asymptomatic patients with severe aortic stenosis, guidelines recommend left ventricular ejection fraction (LVEF) of <50% as the threshold for referral for aortic valve replacement. We investigated the importance of LVEF on long-term outcome after aortic valve replacement in symptomatic and asymptomatic patients with severe aortic stenosis. Methods and Results— We retrospectively identified 2017 patients with severe aortic stenosis (aortic valve area<1 cm 2 , mean gradient≥40 mm Hg, or indexed aortic valve area<0.6 cm 2 /m 2 ) who underwent surgical aortic valve replacement from January 1995 to June 2009. Patients were divided into 4 groups depending on preoperative LVEF (<50% in 300 [15%] patients, 50%–59% in 331 [17%], 60%–69% in 908 [45%], and ≥70% in 478 [24%]). During follow-up of 5.3±4.4 years, 1056 (52%) patients died. A decrease in mortality was observed with increasing LVEF, P <0.0001; 5-year mortality estimates (95% confidence interval) were 0.41 (0.35–0.47), LVEF<50%; 0.35 (0.29–0.41), LVEF 50% to 59%; 0.26 (0.23–0.29), LVEF 60% to 69%; and 0.22 (0.18–0.26), LVEF≥70%. Compared with patients with LVEF≥60%, patients with LVEF 50% to 59% had increased mortality (hazard ratio [HR], 1.58; P <0.001), with similar risk increase in both symptomatic (HR, 1.56; P <0.001) and asymptomatic patients (HR, 1.58; P =0.006). Correcting for risk factors, LV mass index, aortic valve area, and stroke volume index, LVEF was independently predictive of mortality (HR, 0.88 per 10%; P <0.001). When this analysis was repeated in the subset of 1333 patients without history of coronary artery disease, LVEF remained associated with mortality (HR, 0.90 per 10%; P =0.009). Conclusions— LVEF is a powerful predictor of outcome in patients with severe aortic stenosis undergoing aortic valve replacement, independent of the presence of valve-related symptoms.

Background— The higher risk of adverse outcomes after transapical (TA) versus transfemoral (TF) transcatheter aortic valve replacement (TAVR) could be attributable to TA-TAVR being an open surgical procedure or to clinical differences between TA- and TF-TAVR patients. We compared outcomes after neutralizing patient differences using propensity score matching. Methods and Results— From April 2007 to February 2012, 1100 Placement of Aortic Transcatheter Valves (PARTNER)-I patients underwent TA-TAVR and 1521 underwent TF-TAVR with Edwards SAPIEN balloon-expandable bioprostheses. Propensity matching based on 111 preprocedural variables, exclusive of femoral access morphology, identified 501 well-matched patient pairs (46% of possible matches), 95% of whom had peripheral arterial disease. Matched TA-TAVR patients experienced more adverse procedural events, longer length of stay (5 versus 8 days; P <0.0001), and slower recovery (New York Heart Association class I, 31% versus 38% at 30 days, equalizing by 6 months at 51% versus 47%); stroke risk was similar (3.4% versus 3.3% at 30 days and 6.0% versus 6.7% at 3 years); mortality was elevated for the first 6 postprocedural months (19% versus 12%; P =0.01); but aortic regurgitation was less (34% versus 52% mild and 8.9% versus 12% moderate to severe at discharge, P =0.001; 36% versus 50% mild and 10% versus 15% moderate to severe at 6 months, P <0.0001). Conclusions— The likelihood of adverse periprocedural events and prolonged recovery is greater after TA-TAVR than TF-TAVR in vasculopathic patients after accounting for differences in cardiovascular risk factors, although stroke risk is equivalent and aortic regurgitation is less. As smaller delivery systems permit TF-TAVR in many of these patients, we recommend a TF-first access strategy for TAVR when anatomically feasible. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.

Background— Pathological processes underlying myxomatous mitral valve degeneration (MMVD) remain poorly understood. We sought to identify novel mechanisms contributing to the development of this condition. Methods and Results— Microarrays were used to measure gene expression in 11 myxomatous and 11 nonmyxomatous human mitral valves. Differential gene expression (thresholds P <0.05; fold-change >1.5) and pathway activation (Ingenuity) were confirmed using quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Contributions of bone morphogenetic protein 4 and transforming growth factor (TGF)-β2 to differential gene expression were evaluated in vitro. Contributions of angiotensin II to differential pathway activation were examined in mice in vivo. A total of 2602 genes were differentially expressed between myxomatous and nonmyxomatous valves. Canonical TGF-β signaling was increased in MMVD because of increased ligand expression and derepression of SMA mothers against decapentaplegic 2/3 signaling and was confirmed with quantitative reverse transcriptase polymerase chain reaction and immunohistochemistry. Myxomatous valves demonstrated activation of canonical bone morphogenetic protein and Wnt/β-catenin signaling and upregulation of their common target runt-related transcription factor 2. Our data set provided transcriptional and immunohistochemical evidence for activated immune cell infiltration. In vitro treatment of mitral valve interstitial cells with TGF-β2 increased β-catenin signaling at mRNA and protein levels, suggesting interactions between TGF-β2 and Wnt signaling. In vivo infusion of mice with angiotensin II recaptured several changes in signaling pathways characteristic of human MMVD. Conclusions— These data support a new disease framework whereby activation of TGF-β2, bone morphogenetic protein 4, Wnt/β-catenin, or immune signaling plays major roles in the pathogenesis of MMVD. We propose these pathways act in a context-dependent manner to drive phenotypic changes that fundamentally differ from those observed in aortic valve disease and open novel avenues guiding future research into the pathogenesis of MMVD.

BackgroundTranscatheter aortic valve replacement (TAVR) with the balloon‐expandable Sapien transcatheter heart valve improves survival compared to standard therapy in patients with severe aortic stenosis (AS) and is noninferior to surgical aortic valve replacement (AVR) in patients at high operative risk. Nonetheless, a significant proportion of patients may require pre‐emptive or emergent support with cardiopulmonary bypass (CPB) and/or intra‐aortic balloon pump (IABP) during TAVR due to pre‐existing comorbid conditions or as a result of procedural complications. Objectives: We hypothesized that patients who required CPB or IABP would have increased periprocedural complications and reduced long‐term survival. In addition, we sought to determine whether preprocedural variables could predict the need for CPB and IABP. Methods: The study population included 2,525 patients in the PARTNER Trial (Cohort A and B) and the continuing access registry (CAR). Patients that received CPB or IABP were compared to patients that did not receive either, and then further divided into those that received support pre‐TAVR and those that were placed on support emergently. Results: One‐hundred sixty‐three patients (6.5%) were placed on CPB and/or IABP. The use of CPB or IABP was associated with higher 1 year mortality (49.1% vs. 21.6%, P < 0.001). In multivariable analysis, utilization of CPB or IABP was an independent predictor of 30 day (HR 6.95) and 1‐year (HR 2.56) mortality. Although mortality was highest in emergent cases, mortality was also greater in planned CPB and IABP cases compared with non‐CPB/IABP cases (53.3% and 40.3% vs. 21.6%, P < 0.001). Conclusions: These findings indicate that CPB and IABP use in TAVR portends a poor prognosis and its utilization, particularly in the setting of pre‐emptive use, needs reconsideration. © 2015 Wiley Periodicals, Inc.

Background— In patients with severe aortic stenosis, transcatheter aortic valve replacement (TAVR) improves survival when compared with nonsurgical therapy but with higher in-hospital and lifetime costs. Complications associated with TAVR may decrease with greater experience and improved devices, thereby reducing the overall cost of the procedure. Therefore, we sought to estimate the effect of periprocedural complications on in-hospital costs and length of stay of TAVR. Methods and Results— Using detailed cost data from 406 TAVR patients enrolled in the Placement of Aortic Transcatheter Valve (PARTNER) I trial, we developed multivariable models to estimate the incremental cost and length of stay associated with specific periprocedural complications. Attributable costs and length of stay for each complication were calculated by multiplying the independent cost of each event by its frequency in the treatment group. Mean cost for the initial hospitalization was $79 619±40 570 ($50 891 excluding the valve); 49% of patients had ≥1 complication. Seven complications were independently associated with increased hospital costs, with major bleeding, arrhythmia, and death accounting for the largest attributable cost per patient. Renal failure and the need for repeat TAVR, although less frequent, were also associated with substantial incremental and attributable costs. Overall, complications accounted for $12 475 per patient in initial hospital costs and 2.4 days of hospitalization. Conclusions— In the PARTNER trial, periprocedural complications were frequent, costly, and accounted for ≈25% of non-implant–related hospital costs. Avoidance of complications should improve the cost-effectiveness of TAVR for inoperable and high-risk patients, but reductions in the cost of uncomplicated TAVR will also be necessary for optimal efficiency. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00530894.