Darshan Doshi

Transcatheter or Surgical Aortic-Valve Replacement in Intermediate-Risk Patients

BACKGROUND Previous trials have shown that among high-risk patients with aortic stenosis, survival rates are similar with transcatheter aortic-valve replacement (TAVR) and surgical aortic-valve replacement. We evaluated the two procedures in a randomized trial involving intermediate-risk patients. METHODS We randomly assigned 2032 intermediate-risk patients with severe aortic stenosis, at 57 centers, to undergo either TAVR or surgical replacement. The primary end point was death from any cause or disabling stroke at 2 years. The primary hypothesis was that TAVR would not be inferior to surgical replacement. Before randomization, patients were entered into one of two cohorts on the basis of clinical and imaging findings; 76.3% of the patients were included in the transfemoral-access cohort and 23.7% in the transthoracic-access cohort. RESULTS The rate of death from any cause or disabling stroke was similar in the TAVR group and the surgery group (P=0.001 for noninferiority). At 2 years, the Kaplan-Meier event rates were 19.3% in the TAVR group and 21.1% in the surgery group (hazard ratio in the TAVR group, 0.89; 95% confidence interval [CI], 0.73 to 1.09; P=0.25). In the transfemoral-access cohort, TAVR resulted in a lower rate of death or disabling stroke than surgery (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P=0.05), whereas in the transthoracic-access cohort, outcomes were similar in the two groups. TAVR resulted in larger aortic-valve areas than did surgery and also resulted in lower rates of acute kidney injury, severe bleeding, and new-onset atrial fibrillation; surgery resulted in fewer major vascular complications and less paravalvular aortic regurgitation. CONCLUSIONS In intermediate-risk patients, TAVR was similar to surgical aortic-valve replacement with respect to the primary end point of death or disabling stroke. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

Paravalvular regurgitation after transcatheter aortic valve replacement with the Edwards sapien valve in the PARTNER trial: characterizing patients and impact on outcomes

AIM The impact of paravalvular regurgitation (PVR) following transcatheter aortic valve replacement (TAVR) remains uncertain. In this analysis, we sought to evaluate the impact of varying degrees of PVR on both mortality and changes in ventricular geometry and function. METHODS AND RESULTS Clinical and echocardiographic outcomes of patients who underwent TAVR from the randomized cohorts and continued access registries in the PARTNER trial were analysed after stratifying by severity of post-implant PVR, which was graded as none/trace in 52.9% (n = 1288), mild in 38.0% (n = 925), and moderate/severe in 9.1% (n = 221). There were significant differences in baseline clinical and echocardiographic characteristics. After TAVR, all the patients demonstrated increase in left ventricular (LV) function and reduction in the LV mass index, although the magnitude of mass regression was lower in the moderate/severe PVR group. The 30-day mortality (3.1 vs. 3.4 vs. 4.5%, P = 0.56) and stroke (3.4 vs. 3.7 vs. 2.3%, P = 0.59) were similar in all groups (none/trace, mild, and moderate/severe). At 1 year, there was increased all-cause mortality (15.9 vs. 22.2 vs. 35.1%, P < 0.0001), cardiac mortality (6.1 vs. 7.4% vs. 16.3%, P < 0.0001) and re-hospitalization (14.4 vs. 23.0 vs. 31.3%, P < 0.0001) with worsening PVR. A multivariable analysis indicated that the presence of moderate/severe PVR (HR: 2.18, 95% CI: 1.57-3.02, P < 0.0001) or mild PVR (HR: 1.37, 95% CI: 1.14-1.90, P = 0.012) was associated with higher late mortality. CONCLUSION Differences in baseline characteristics in patients with increasing severities of PVR may increase the risk of this complication. Despite these differences, multivariable analysis demonstrated that both mild and moderate/severe PVR predicted higher 1-year mortality.

Hemodynamics of Mechanical Circulatory Support.

An increasing number of devices can provide mechanical circulatory support (MCS) to patients with acute hemodynamic compromise and chronic end-stage heart failure. These devices work by different pumping mechanisms, have various flow capacities, are inserted by different techniques, and have different sites from which blood is withdrawn and returned to the body. These factors result in different primary hemodynamic effects and secondary responses of the body. However, these are not generally taken into account when choosing a device for a particular patient or while managing a patient undergoing MCS. In this review, we discuss fundamental principles of cardiac, vascular, and pump mechanics and illustrate how they provide a broad foundation for understanding the complex interactions between the heart, vasculature, and device, and how they may help guide future research to improve patient outcomes.

Protein kinase C isoforms differentially phosphorylate Ca(v)1.2 alpha(1c).

The regulation of Ca(2+) influx through the phosphorylation of the L-type Ca(2+) channel, Ca(v)1.2, is important for the modulation of excitation-contraction (E-C) coupling in the heart. Ca(v)1.2 is thought to be the target of multiple kinases that mediate the signals of both the renin-angiotensin and sympathetic nervous systems. Detailed biochemical information regarding the protein phosphorylation reactions involved in the regulation of Ca(v)1.2 is limited. The protein kinase C (PKC) family of kinases can modulate cardiac contractility in a complex manner, such that contractility is either enhanced or depressed and relaxation is either accelerated or slowed. We have previously reported that Ser(1928) in the C-terminus of alpha(1c) was a target for PKCalpha, -zeta, and -epsilon phosphorylation. Here, we report the identification of seven PKC phosphorylation sites within the alpha(1c) subunit. Using phospho-epitope specific antibodies to Ser(1674) and Ser(1928), we demonstrate that both sites within the C-terminus are phosphorylated in HEK cells in response to PMA. Phosphorylation was inhibited with a PKC inhibitor, bisindolylmaleimide. In Langendorff-perfused rat hearts, both Ser(1674) and Ser(1928) were phosphorylated in response to PMA. Phosphorylation of Ser(1674), but not Ser(1928), is PKC isoform specific, as only PKCalpha, -betaI, -betaII, -gamma, -delta, and -theta, but not PKCepsilon, -zeta, and -eta, were able to phosphorylate this site. Our results identify a molecular mechanism by which PKC isoforms can have different effects on channel activity by phosphorylating different residues.

Effect of Tricuspid Regurgitation and the Right Heart on Survival After Transcatheter Aortic Valve Replacement Insights From the Placement of Aortic Transcatheter Valves II Inoperable Cohort

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.

Sex-Specific Differences at Presentation and Outcomes Among Patients Undergoing Transcatheter Aortic Valve Replacement: A Cohort Study

Context Whether female sex is associated with an increased risk for adverse events among patients having transcatheter aortic valve replacement (TAVR) is unclear. Contribution In this secondary analysis of data from the Placement of Aortic Transcatheter Valves trial, women who had TAVR had more postprocedural major bleeding and vascular complications and improved 1-year survival than men. Caution Other factors, such as paravalvular leak or patientprosthesis mismatch, may have confounded the results. Implication The sex-specific risk associated with TAVR is the reverse of that for surgical aortic valve replacement, for which female sex is associated with an increased risk for adverse events. During the past 50 years, the standard of care for patients with severe, symptomatic aortic stenosis (AS) has been surgical aortic valve replacement (SAVR), which has been shown to prolong survival and alleviate symptoms compared with medical therapy alone (1, 2). However, at least one third of patients with AS are deemed to be high-risk or inoperable for SAVR due to comorbidities or unfavorable anatomy (3). For these patients, transcatheter aortic valve replacement (TAVR) has emerged as an alternative (1, 2, 411). The PARTNER (Placement of Aortic Transcatheter Valves) trial was the first to show the safety and efficacy of TAVR compared with accepted standard therapies in high-risk and inoperable patients with AS (49). The results of this trial ultimately led to the approval of the SAPIEN transcatheter valve (Edwards Lifesciences) by the U.S. Food and Drug Administration. Since the PARTNER trial, many other trials and international registries have shown the benefits of TAVR in higher-risk patients (1012). Female sex has been shown to be associated with increased risk for adverse events after SAVR (1317) but has been shown to be a potentially favorable characteristic for patients having TAVR (1823). However, prior trials examining sex-based differences in patients having TAVR have been limited in size or have involved only single- or dual-center experiences. Furthermore, not all studies agree that TAVR may be more beneficial in women, with some finding no difference in outcomes or increased adverse events in women (2428). Given the conflicting data in the literature, we sought to perform a comprehensive analysis of sex-based differences in patients having TAVR by using the clinical trial structure of the PARTNER experience (encompassing all TAVR patients treated in not only the randomized PARTNER trials but also the randomized and nonrandomized continued access registries). We report the baseline demographic characteristics and core laboratoryassessed echocardiographic parameters of women and men treated with TAVR, as well as adjudicated 30-day and 1-year outcomes stratified by sex. Methods Study Design and Patients The PARTNER trial incorporated 2 parallel prospective, multicenter, randomized, active treatmentcontrolled clinical trials. Patients were divided into 2 cohorts. Cohort A comprised patients who were considered to be high-risk candidates for surgery, as defined by a Society of Thoracic Surgeons Predicted Risk of Mortality (STS-PROM) score of at least 8% (on a scale of 0% to 100%, with higher scores indicating greater risk for death within 30 days after surgery) (13) and/or by the presence of coexisting conditions associated with a 15% or greater risk for death at 30 days. Cohort B comprised those who were not considered to be suitable candidates for surgery because they had coexisting conditions associated with a 50% or greater probability of death or serious irreversible morbidity after surgery based on a multidisciplinary heart team assessment. In cohort A, patients were randomly assigned to TAVR or SAVR; in cohort B, patients were randomly assigned to TAVR or medical therapy. Patients in cohort A were enrolled from 11 May 2007 to 28 August 2009, and those in cohort B were enrolled from 11 May 2007 to 16 March 2009. After enrollment in the randomized PARTNER trial, sites were able to continue to consecutively enroll patients in a continued access registry using the same inclusion and exclusion criteria. The purpose of the continued access registry was to accumulate greater real-world experience with regard to the safety and efficacy of TAVR while approval by the U.S. Food and Drug Administration was pending. At the time of initiation of the registry, TAVR could not be performed in the United States unless the patient was formally enrolled in the registry or a comparable clinical trial. Because enrollment in the inoperable trial (cohort B) was completed 6 months before enrollment in the high-risk trial (cohort A) was completed, investigators decided to extend randomization of cohort B into the continued access registry to prevent enrollment bias in the ongoing high-risk trial. Once enrollment in the high-risk trial was completed, both cohorts were enrolled in a nonrandomized continued access registry. Enrollment in this registry concluded on 9 January 2012. The same data collection procedures and follow-up used for the randomized PARTNER trial were used for the continued access registry. The same clinical events committee, adjudication process, and core laboratory interpretation of echocardiographic data were also used for both the randomized and continued access portions of the PARTNER trial. The institutional review board at each site approved the study, and all patients provided written informed consent. End Points The 30-day and 1-year frequencies of all-cause mortality, cardiovascular mortality, rehospitalization, stroke, major vascular complications, major bleeding, myocardial infarction, acute kidney injury, and need for a permanent pacemaker were recorded per the PARTNER trial protocol (4, 5). Major vascular complications were defined as any thoracic aortic dissection; access site or access-related vascular injury leading to death, need for significant blood transfusions, or unplanned percutaneous or surgical intervention; or distal embolization from a vascular source. Major bleeding was defined as a bleeding event that caused death or permanent disability, caused or prolonged a hospitalization, or required an open or endovascular procedure or a transfusion. All adverse events were fully adjudicated by an independent clinical events committee. Echocardiograms were obtained at baseline; at discharge or 7 days, whichever came first; and at 30 days, 6 months, and 1 year after the procedure. All echocardiograms were analyzed at an independent core laboratory that followed the American Society of Echocardiography standards for echocardiography core laboratories (29). Statistical Analysis The current analysis was an as-treated analysis, which included all TAVR patients from cohort A, cohort B, and the continued access registry. Patients were stratified on the basis of sex. Continuous variables are presented as means and SDs and were compared using the t test; categorical variables were compared by using the chi-square test or the Fisher exact test, as appropriate. KaplanMeier techniques were used for outcomes that contained all-cause death. All nonmortality outcomes were modeled by using a proportional subdistribution hazards regression to account for the competing risk for death; the corresponding hazard ratios (HRs) and P values are reported from this model. For each sex, the cumulative incidence for 30-day and 1-year outcomes is summarized in the presence of all-cause death. A 2-sided level of 0.05 was used to indicate statistical significance. To assess the association between sex and all-cause mortality at 1 year, Cox multivariable regression analyses were performed. The multivariable model was created by forcing sex into a stepwise model selection procedure with clinically relevant candidate variables using an entry/stay criterion of a P value less than 0.10. Variables of clinical interest were included if the variable was significant (P< 0.10) in the univariate Cox model. A supplemental model included moderate or severe paravalvular regurgitation at discharge and any major vascular complication as a time-dependent covariate along with variables selected in the final model. Using the same variables as those selected for the multivariable model for mortality, we tested for an association between sex and rehospitalization while accounting for the competing risk for death. We also tested for an interaction between sex and treatment approach (transfemoral vs. transapical TAVR) on 1-year all-cause mortality. Analyses were done using the FREQ, TTEST, UNIVARIATE, PHREG, and LIFETEST procedures in SAS, version 9.2 (SAS Institute). Clinical Trial Registration The PARTNER trial was registered at ClinicalTrials.gov on 14 September 2007, slightly more than 4 months after the first patient was enrolled on 11 May 2007. Only 41 (1.3%) of the 3216 total patients were enrolled before registration of the trial, and no interval analysis was conducted between enrollment of the first patient and registration of the trial. Role of the Funding Source The PARTNER trial was funded by Edwards Lifesciences, and the protocol was developed collaboratively by the sponsor and the steering committee. The funding source had no involvement in the design, analysis, or interpretation of this substudy or the decision to publish the manuscript. Results Baseline Characteristics All 2559 patients who had TAVR in the PARTNER trial were analyzed on the basis of their sex (Table 1). Of these, 2000 were in the nonrandomized continued access registry, 40 were in the randomized continued access registry, and 519 were in the randomized trial. Five patients in cohort A, 1 in cohort B, and none in the continued access registries were lost to follow-up. A total of 47.7% of all patients were women, and 52.3% were men. Table 1. Study Population The baseline presenting characteristics varied between sexes in terms of demographic variables and comorbidities

Cardiac L-type calcium channel (Cav1.2) associates with γ subunits

The cardiac voltage‐gated Ca2+ channel, Cav1.2, mediates excitation‐contraction coupling in the heart. The molecular composition of the channel includes the pore‐forming α1 subunit and auxiliary α2/δ‐1 and β subunits. Ca2+ channel γ subunits, of which there are 8 isoforms, consist of 4 transmembrane domains with intracellular N‐ and C‐terminal ends. The γ1 subunit was initially detected in the skeletal muscle Cav1.1 channel complex, modulating current amplitude and activation and inactivation properties. The γ1 subunit also shifts the steady‐state inactivation to more negative membrane potentials, accelerates current inactivation, and increases peak currents, when coexpressed with the cardiac α1c subunit in Xenopus oocytes and human embryonic kidney (HEK) 293 cells. The γ1 subunit is not expressed, however, in cardiac muscle. We sought to determine whether γ subunits that are expressed in cardiac tissue physically associate with and modulate Cav1.2 function. We now demonstrate that γ4, γ6, γ7, and γ8 subunits physically interact with the Cav1.2 complex. The γ subunits differentially modulate Ca2+ channel function when coexpressed with the β1b and α2/δ‐1 subunits in HEK cells, altering both activation and inactivation properties. The effects of γ on Cav1.2 function are dependent on the subtype of β subunit. Our results identify new members of the cardiac Cav1.2 macro‐molecular complex and identify a mechanism by which to increase the functional diversity of Cav1.2 channels.—Yang, L., Katchman, A., Morrow, J. P., Doshi, D., Marx, S. A. Cardiac L‐type calcium channel (CaV1.2) associates with γ subunits. FASEB J. 25, 928–936 (2011). www.fasebj.org

A Randomized Evaluation of the SAPIEN XT Transcatheter Heart Valve System in Patients With Aortic Stenosis Who Are Not Candidates for Surgery

OBJECTIVES The purpose of this study was to determine the safety and effectiveness of the SAPIEN XT versus SAPIEN systems (Edwards Lifesciences, Irvine, California) in patients with symptomatic, severe aortic stenosis (AS) who were not candidates for surgery. BACKGROUND Transcatheter aortic valve replacement (TAVR) has become the standard of care for inoperable patients with severe, symptomatic AS. In the PARTNER (Placement of Aortic Transcatheter Valves) IB trial, a reduction in all-cause mortality was observed in patients undergoing TAVR with the balloon-expandable SAPIEN transcatheter heart valve compared with standard therapy, but the SAPIEN valve was associated with adverse periprocedural complications, including vascular complications, major bleeding, and paravalvular regurgitation. The newer, low-profile SAPIEN XT system was developed to reduce these adverse events. METHODS A total of 560 patients were enrolled at 28 sites in the United States from April 2011 to February 2012. Patients were randomized to receive the SAPIEN or SAPIEN XT systems. The primary endpoint was a nonhierarchical composite of all-cause mortality, major stroke, and rehospitalization at 1 year in the intention-to-treat population, assessed by noninferiority testing. Pre-specified secondary endpoints included cardiovascular death, New York Heart Association functional class, myocardial infarction, stroke, acute kidney injury, vascular complications, bleeding, 6-min walk distance, and valve performance (by echocardiography). RESULTS Both overall and major vascular complications were higher at 30 days in patients undergoing TAVR with SAPIEN compared with SAPIEN XT (overall: 22.1% vs. 15.5%; p = 0.04; major: 15.2% vs. 9.5%; p = 0.04). Bleeding requiring blood transfusions was also more frequent with SAPIEN compared with SAPIEN XT (10.6% vs. 5.3%; p = 0.02). At 1-year follow-up, the nonhierarchical composite of all-cause mortality, major stroke, or rehospitalization was similar (37.7% SAPIEN vs. 37.2% SAPIEN XT; noninferiority p value <0.002); no differences in the other major pre-specified endpoints were found. CONCLUSIONS In inoperable patients with severe, symptomatic AS, the lower-profile SAPIEN XT is noninferior to SAPIEN with fewer vascular complications and a lesser need for blood transfusion. (The PARTNER II Trial: Placement of AoRTic TraNscathetER Valves; NCT01314313).

Location of the β4 Transmembrane Helices in the BK Potassium Channel

Large-conductance, voltage- and Ca2+-gated potassium (BK) channels control excitability in a number of cell types. BK channels are composed of α subunits, which contain the voltage-sensor domains and the Ca2+- sensor domains and form the pore, and often one of four types of β subunits, which modulate the channel in a cell-specific manner. β4 is expressed in neurons throughout the brain. Deletion of β4 in mice causes temporal lobe epilepsy. Compared with channels composed of α alone, channels composed of α and β4 activate and deactivate more slowly. We inferred the locations of the two β4 transmembrane (TM) helices TM1 and TM2 relative to the seven α TM helices, S0–S6, from the extent of disulfide bond formation between cysteines substituted in the extracellular flanks of these TM helices. We found that β4 TM2 is close to α S0 and that β4 TM1 is close to both α S1 and S2. At least at their extracellular ends, TM1 and TM2 are not close to S3–S6. In six of eight of the most highly crosslinked cysteine pairs, four crosslinks from TM2 to S0 and one each from TM1 to S1 and S2 had small effects on the V50 and on the rates of activation and deactivation. That disulfide crosslinking caused only small functional perturbations is consistent with the proximity of the extracellular ends of TM2 to S0 and of TM1 to S1 and to S2, in both the open and closed states.

Management strategies and future challenges for aortic valve disease.

The management of aortic valve disease has been improved by accurate diagnosis and assessment of severity by echocardiography and advanced imaging techniques, efforts to elicit symptoms or objective markers of disease severity and progression, and consideration of optimum timing of aortic valve replacement, even in elderly patients. Prevalence of calcific aortic stenosis is growing in ageing populations. Conventional surgery remains the most appropriate option for most patients who require aortic valve replacement, but the transcatheter approach is established for high-risk patients or poor candidates for surgery. The rapid growth of transcatheter aortic valve replacement has been fuelled by improved technology, evidence-based clinical research, and setting up of multidisciplinary heart teams. Aortic regurgitation can be difficult to diagnose and quantify. Left ventricular dysfunction often precedes symptoms, needing active surveillance by echocardiography to determine the optimum time for aortic valve replacement. Development of transcatheter approaches for aortic regurgitation is challenging, owing to the absence of valvular calcification and distortion of aortic root anatomy in many patients.