Citations

The field of gene transfer has developed in an era of expanding biomedical knowledge. The potential for gene transfer to treat cardiovascular disease is great, yet identified and unidentified barriers remain. Gene transfer and its ultimate application, gene therapy, require extensive details of not only the mechanism of disease but the biological implications of the vectors used to deliver the therapeutic genes as well. Many of these details are becoming available via the study of genomics. Genomics, the study of complete genetic sequences, holds the potential for enabling and amplifying the therapeutic hopes for gene transfer. Identification of new therapeutic genes, new regulatory sequences, and establishing the patterns of gene expression from tissues exposed to vectors and transgenes will rapidly advance the application of gene transfer. Finally, there are historical and ongoing lessons learned from the development of gene transfer that may be applicable to the challenging field of genomics and may enable its future success.

The failing ventricular myocardium is characterized by reduction of high-energy phosphates and reduced activity of the phosphotransfer enzymes creatine kinase (CK) and adenylate kinase (AK), which are responsible for transfer of high-energy phosphoryls from sites of production to sites of utilization, thereby compromising excitation-contraction coupling. In humans with chronic atrial fibrillation (AF) unassociated with congestive heart failure (CHF), impairment of atrial myofibrillar energetics linked to oxidative modification of myofibrillar CK has been observed. However, the bioenergetic status of the failing atrial myocardium and its potential contribution to atrial electrical instability in CHF have not been determined. Dogs with ( n = 6) and without ( n = 6) rapid pacing-induced CHF underwent echocardiography (conscious) and electrophysiological (under anesthesia) studies. CHF dogs had more pronounced mitral regurgitation, higher atrial pressure, larger atrial area, and increased atrial fibrosis. An enhanced propensity to sustain AF was observed in CHF, despite significant increases in atrial effective refractory period and wavelength. Profound deficits in atrial bioenergetics were present with reduced activities of the phosphotransfer enzymes CK and AK, depletion of high-energy phosphates (ATP and creatine phosphate), and reduction of cellular energetic potential (ATP-to-ADP and creatine phosphate-to-Cr ratios). AF duration correlated with left atrial area ( r = 0.73, P = 0.01) and inversely with atrial ATP concentration ( r = −0.75, P = 0.005), CK activity ( r = −0.57, P = 0.054), and AK activity ( r = −0.64, P = 0.02). Atrial levels of malondialdehyde, a marker of oxidative stress, were significantly increased in CHF. Myocardial bioenergetic deficits are a conserved feature of dysfunctional atrial and ventricular myocardium in CHF and may constitute a component of the substrate for AF in CHF.

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— Racial and ethnic minorities are under-represented in clinical trials of primary prevention implantable cardioverter-defibrillators (ICDs). This analysis investigates the association between primary prevention ICDs and mortality among Medicare, racial/ethnic minority patients. Methods and Results— Data from Get With The Guidelines-Heart Failure Registry and National Cardiovascular Data Registry’s ICD Registry were used to perform an adjusted comparative effectiveness analysis of primary prevention ICDs in Medicare, racial/ethnic minority patients (nonwhite race or Hispanic ethnicity). Mortality data were obtained from the Medicare denominator file. The relationship of ICD with survival was compared between minority and white non-Hispanic patients. Our analysis included 852 minority patients, 426 ICD and 426 matched non-ICD patients, and 2070 white non-Hispanic patients (1035 ICD and 1035 matched non-ICD patients). Median follow-up was 3.1 years. Median age was 73 years, and median ejection fraction was 23%. Adjusted 3-year mortality rates for minority ICD and non-ICD patients were 44.9% (95% confidence interval [CI], 44.2%–45.7%) and 54.3% (95% CI, 53.4%–55.1%), respectively (adjusted hazard ratio, 0.79; 95% CI, 0.63–0.98; P =0.034). White non-Hispanic patients receiving an ICD had lower adjusted 3-year mortality rates of 47.8% (95% CI, 47.3%–48.3%) compared with 57.3% (95% CI, 56.8%–57.9%) for those with no ICD (adjusted hazard ratio, 0.75; 95% CI, 0.67%–0.83%; P <0.0001). There was no significant interaction between race/ethnicity and lower mortality risk with ICD ( P =0.70). Conclusions— Primary prevention ICDs are associated with lower mortality in nonwhite and Hispanic patients, similar to that seen in white, non-Hispanic patients. These data support a similar approach to ICD patient selection, regardless of race or ethnicity.

Background— Temporary interruption of oral anticoagulation for procedures is often required, and some propose using bridging anticoagulation. However, the use and outcomes of bridging during oral anticoagulation interruptions in clinical practice are unknown. Methods and Results— The Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry is a prospective, observational registry study of US outpatients with atrial fibrillation. We recorded incident temporary interruptions of oral anticoagulation for a procedure, including the use and type of bridging therapy. Outcomes included multivariable-adjusted rates of myocardial infarction, stroke or systemic embolism, major bleeding, cause-specific hospitalization, and death within 30 days. Of 7372 patients treated with oral anticoagulation, 2803 overall interruption events occurred in 2200 patients (30%) at a median follow-up of 2 years. Bridging anticoagulants were used in 24% (n=665), predominantly low-molecular-weight heparin (73%, n=487) and unfractionated heparin (15%, n=97). Bridged patients were more likely to have had prior cerebrovascular events (22% versus 15%; P =0.0003) and mechanical valve replacements (9.6% versus 2.4%; P <0.0001); however, there was no difference in CHA 2 DS 2 -VASc scores (scores ≥2 in 94% versus 95%; P =0.5). Bleeding events were more common in bridged than nonbridged patients (5.0% versus 1.3%; adjusted odds ratio, 3.84; P <0.0001). The incidence of myocardial infarction, stroke or systemic embolism, major bleeding, hospitalization, or death within 30 days was also significantly higher in patients receiving bridging (13% versus 6.3%; adjusted odds ratio, 1.94; P =0.0001). Conclusions— Bridging anticoagulation is used in one quarter of anticoagulation interruptions and is associated with higher risk for bleeding and adverse events. These data do not support the use of routine bridging, and additional data are needed to identify best practices concerning anticoagulation interruptions. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01165710.

Objectives: Somali people are among the largest refugee populations to resettle in North America and Europe over the past 2 decades, and health disparities are well documented, including barriers to effective navigation of primary health care systems. Patient–provider gender discordance has been described as a barrier to health-seeking behaviors and effective communication by Somali women in past qualitative work. The objective of this study was to elucidate provider and interpreter preferences during clinical encounters according to gender and race among Somali women in the United States. Methods: Fifty Somali women empanelled to a large primary care practice completed pictorial surveys to elucidate preferences of Somali women for providers of different genders and race for different components of the clinical examination using a Likert-type scale. Results: We found that Somali women generally preferred a female provider for conducting the physical examination, particularly for the pelvic, breast, and abdominal examinations. Likewise, Somali women strongly preferred female interpreters to be present during the physical examination. There was no stated preference for patient–provider racial concordance. Conclusions: These findings have implications for structural health care changes aimed at delivering culturally sensitive and effective primary care to Somali patients.

There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.