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Objective: Mitral regurgitation (MR) induced by systolic anterior motion in patients with hypertrophic cardiomyopathy (HCM) can frequently be abolished with a proficient septal myectomy (SM) without the need for mitral-valve replacement (MVR). ACC guidelines stress the importance of volume in improving outcomes after SM, but there is a lack of data measuring the impact of volume on the need for MVR during SM. This study was designed to assess the impact of institutional volume on MVR rates using national outcomes data. Methods: The Nationwide Inpatient Sample was queried from 1998 to 2011 and a total of 6,207 patients had a diagnosis of HCM and a procedure code for SM. Outcomes were compared between patients who underwent SM (group I) and SM and MVR (group II). Furthermore, patients were stratified into 3 groups based on the number of SMs at the performing institution: low experience (1–24 cumulative SMs), medium experience (25–49 SMs), and high experience (>50 SMs). These patients underwent multivariable analysis to determine the impact of institutional volume on MVR rate. Results: The total MVR rate was 26%. Perioperative outcomes were worse, i.e., there were higher rates of mortality, kidney injury, and urinary complications, in group II than in group I. Only 37.6% of patients were operated on at institutions meeting the guideline criteria of >50 cumulative SMs. When compared to patients in the high-experience group, patients in the low- (OR 2.7, 95% CI 2.3–3.2, p < 0.05) and medium-experience (OR 3.0, 95% CI 2.5–3.6, p < 0.05) groups were more likely to undergo MVR. Conclusion: Compared to reports from SM reference centers, national data suggest that MVR rates are quite high at SM. Patients undergoing SM at centers that do not meet the guideline standard have >2.5× the odds of undergoing MVR compared to those operated on at guideline-endorsed centers.

Stroke remains a significant complication of left ventricular assist device (LVAD) therapy. We performed a single-center retrospective study evaluating patients undergoing first-time HeartWare HVAD (Medtronic Inc) or HeartMate 3 (Abbott Inc) implantation from September 2009-February 2018.Exclusion criteria were age18 and preoperative ECMO. The primary endpoint was stroke-free survival. Stroke was defined as new neurological deficits persisting24 hours with corresponding radiographic evidence. Risk factors evaluated included demographics, medical comorbidities, heart failure etiology, LVAD indication, INTERMACS profile, and device type. Univariate predictors (P .15) and variables clinically suspected to raise stroke risk were entered in a multivariate hazard regression model, specified using backward selection of covariates and accounting for competing risks of transplant/LVAD exchange.A total of 163 HVAD and 84 HM3 patients were analyzed. Median follow up (until death, censoring for transplant/LVAD removal, or end of follow up) was 1.2 years in HVAD patients and 1.4 years in HM3 patients. Stroke occurred in 24 HVAD patients (15 ischemic, 9 hemorrhagic) and 6 HM3 patients (4 ischemic, 2 hemorrhagic). One-year stroke-free survival was 76.8% for HVAD and 84.3% for HM3. Thirty-day mortality following stroke was 41.7% for HVAD and 66.7% for HM3; 54.2% of HVAD strokes were disabling compared to 83.3% of HM3 strokes. Age, LVAD indication, and device type were associated (P .15) with stroke on univariate analysis. On multivariate analysis, the HVAD was associated with significantly higher stroke risk (hazard ratio, 2.57; 95% confidence interval, 1.02-6.44; P = .045).Different LVAD models appear to be associated with significantly different stroke risks.

Purpose Cardiac gene therapy remains limited by inefficient transgene delivery with currently available methods (intravenous infusion, transcatheter coronary artery infusion, direct myocardial injection). We previously demonstrated in a porcine heterotopic heart transplant model that cardiac allograft gene transfer can be achieved using ex vivo perfusion with adenovirus (Ad). Adeno-associated viral (AAV) vectors generally achieve lower transgene expression compared to Ad. However, AAV vectors also achieve a significantly longer duration of expression, and thus are more suitable for therapies with genes that are effective even at lower levels but require prolonged expression. The purpose of this study is to evaluate whether ex vivo perfusion can also be used as a platform for cardiac allograft gene therapy using AAV. Methods Heart transplantation was performed using blood type-matched and swine leukocyte antigen-matched Yucatan mini pigs (n=2 transplants). Donor hearts received ex vivo perfusion for two hours with a perfusate including AAV vector bearing the firefly luciferase gene (dosed at 2 × 10^13 and 1 × 10^14 genome-containing vectors for transplants 1 and 2, respectively). The allograft was implanted heterotopically into the recipient abdomen. Recipients were survived for 30 days on oral immunosuppression and then euthanized. Transgene expression in allograft and native recipient tissues was assessed using a luciferase enzymatic assay, and transgene detection was performed using qPCR on DNA extracted using a modified Hirt protocol. Results Luciferase activity was detected in the allograft in both experiments. While luciferase activity was undetectable in the right and left atria and coronary arteries from the allograft exposed to the lower dose, the higher dose of AAV resulted in detectable luciferase activity throughout the entire heart and at high levels. Luciferase activity was undetectable in all recipient tissues (heart, lung, liver, spleen, and psoas muscle). Additionally, luciferase DNA was detectable on qPCR in allograft specimens (1.5-1.9 × 10^3 transgene copies per 100 ng of DNA). Conclusion Ex vivo perfusion can be used as a platform for cardiac allograft gene therapy using AAV vectors, with robust transgene expression detectable 30 days following transplant.

Hypertrophic cardiomyopathy (HCM) is the most commonly inherited cardiac disease-recent studies suggest a prevalence as high as 1 in 200. For symptomatic patients with obstructive HCM who are refractory to medical therapy, septal reduction is indicated. Septal myectomy (SM) is considered the gold standard septal reduction technique. However, due to a shortage of surgeons who are experienced in this technique, alcohol septal ablation (ASA) has overtaken SM as the most commonly performed procedure for obstructive HCM. In this review, we summarize the existing literature comparing SM with ASA and describe recent innovations in operative technique, including a detailed description of the approach used at our institution.

Background Pulmonary embolism (PE) results in more than 250,000 hospitalizations annually in the United States, with high mortality. Outcome data are limited, and reperfusion strategies remain controversial. Here we evaluated the outcomes of thrombolysis and surgical embolectomy in patients with acute PE using a statewide database. Methods Among 174,322 patients hospitalized with PE in New York State between 1999 and 2013, we performed a retrospective comparison of 2111 adults with acute PE who underwent either thrombolysis (n = 1854; 88%) or surgical embolectomy (n = 257; 12%) as first-line therapy. Patients were identified using a mandatory database. The median follow-up was 4.2 years (range, 0-16.3 years). The primary study endpoint was all-cause mortality; secondary outcomes included recurrent PE, recurrent deep vein thrombosis, reintervention, and stroke. Results In 2111 patients who underwent reperfusion, there was no difference in 30-day mortality between those who underwent thrombolysis and those who underwent surgical embolectomy (15.2% vs 13.2%; odds ratio [OR], 1.12, 95% confidence interval [CI], 0.72-1.73). Thrombolysis was associated with higher risk of stroke (1.9% vs 0.8%; OR, 4.70; 95% CI, 1.08-20.42) and reintervention (3.8% vs 1.2%; OR, 7.16; 95% CI, 2.17-23.62) at 30 days. Five-year actuarial survival was similar in the 2 groups (72.4% [95% CI, 70.3%-74.5%] vs 76.1% [95% CI, 70.2%-81.0%]; hazard ratio (HR) for death, 1.11; 95% CI, 0.83-1.49). Thrombolysis was associated with a higher rate of recurrent PE necessitating inpatient readmission (7.9% [95% CI, 6.9%-9.4%] vs 2.8% [95% CI, 1.1%-5.8%]; HR, 3.38; 95% CI, 1.48-7.73). Conclusions Pulmonary embolectomy and thrombolysis are associated with similar early and long-term survival, supporting guideline recommendations for embolectomy when thrombolysis is contraindicated.

While recent ACC guidelines for hypertrophic cardiomyopathy (HCM) state the importance of institutional case volume as a key determinant of successful outcomes at septal myectomy (SM), there is a lack of data on the impact of institutional volume on surgical quality. Mitral regurgitation (MR)

Importance In nonelderly patients with mitral disease requiring valve replacement, deciding between bioprosthetic and mechanical prosthetic valves is challenging because long-term survival and morbidity are not well defined. Objective To quantify survival and major morbidity after mitral valve replacement in patients aged 50 to 69 years. Design, Setting, and Participants Retrospective cohort analysis of 3433 patients (aged 50-69 years) who underwent primary, isolated mitral valve replacement in New York State hospitals from 1997-2007. Follow-up ended November 30, 2013; median duration was 8.2 years (range, 0-16.8 years). Propensity score matching for 19 baseline characteristics yielded 664 patient pairs. Exposures Bioprosthetic vs mechanical prosthetic mitral valve replacement. Main Outcomes and Measures All-cause mortality, stroke, reoperation, and major bleeding events. Results No survival difference was observed between use of mechanical prosthetic and bioprosthetic mitral valves in patients aged 50 to 69 years matched by propensity score (209 and 221 deaths, respectively), or in a subgroup analysis of age by decade. Actuarial 15-year survival was 57.5% (95% CI, 50.5%-64.4%) after mechanical replacement vs 59.9% (95% CI, 54.8%-65.0%) after bioprosthetic valve replacement (hazard ratio [HR], 0.95 [95% CI, 0.79-1.15], P = .62). The 15-year cumulative incidence of stroke was higher after mechanical (65 strokes; 14.0% [95% CI, 9.5%-18.6%]) vs bioprosthetic valve replacement (41 strokes; 6.8% [95% CI, 4.5%-8.8%]) (HR, 1.62; 95% CI, 1.10-2.39). The 15-year cumulative incidence of reoperation was lower for mechanical (28 reoperations; 5.0% [95% CI, 3.1%-6.9%]) compared with bioprosthetic (47 reoperations; 11.1% [95% CI, 7.6%-14.6%]) valves (HR, 0.59; 95% CI, 0.37-0.94). The 15-year cumulative incidence of a bleeding event was higher for mechanical (72 events; 14.9% [95% CI, 11.0%-18.7%) vs bioprosthetic (49 events; 9.0% [95% CI, 6.4%-11.5%]) valves (HR, 1.50; 95% CI, 1.05-2.16). Conclusions and Relevance Among patients aged 50 to 69 years undergoing mitral valve replacement in New York State, there was no significant survival difference at 15 years in patients matched by propensity score who underwent mechanical prosthetic vs bioprosthetic mitral valve replacement. Mechanical prosthetic valves were associated with lower risk of reoperation but greater risk of bleeding and stroke. Even though these findings suggest bioprosthetic mitral valve replacement may be a reasonable alternative to mechanical prosthetic valve replacement in patients aged 50 to 69 years, the 15-year follow-up was insufficient to fully assess lifetime risks, particularly of reoperation.

BackgroundBicuspid aortic valves are associated with valve dysfunction, ascending aortic aneurysm and dissection. Management of the ascending aorta at the time of aortic valve replacement (AVR) in these patients is controversial and has been extrapolated from experience with Marfan syndrome, despite the absence of comparative long-term outcome data.ObjectivesThis study sought to assess whether the natural history of thoracic aortopathy after AVR in patients with bicuspid aortic valve disease is substantially different from that seen in patients with Marfan syndrome.MethodsIn this retrospective comparison, outcomes of 13,205 adults (2,079 with bicuspid aortic valves, 73 with Marfan syndrome, and 11,053 control patients with acquired aortic valve disease) who underwent primary AVR without replacement of the ascending aorta in New York State between 1995 and 2010 were compared. The median follow-up time was 6.6 years.ResultsThe long-term incidence of thoracic aortic dissection was significantly higher in patients with Marfan syndrome (5.5 ± 2.7%) compared with those with bicuspid valves (0.55 ± 0.21%) and control group patients (0.41 ± 0.08%, p < 0.001). Thoracic aortic aneurysms were significantly more likely to be diagnosed in late follow-up in patients with Marfan syndrome (10.8 ± 4.4%) compared with those with bicuspid valves (4.8 ± 0.8%) and control group patients (1.4 ± 0.2%) (p < 0.001). Patients with Marfan syndrome were significantly more likely to undergo thoracic aortic surgery in late follow-up (10.4 ± 4.3%) compared with those with bicuspid valves (2.5 ± 0.6%) and control group patients (0.50 ± 0.09%) (p < 0.001).ConclusionsThe much higher long-term rates of aortic complications after AVR observed in patients with Marfan syndrome compared with those with bicuspid aortic valves confirm that operative management of patients with bicuspid aortic valves should not be extrapolated from Marfan syndrome and support discrete treatment algorithms for these different clinical entities.

The choice between bioprosthetic and mechanical aortic valve replacement in younger patients is controversial because long-term survival and major morbidity are poorly characterized.To quantify survival and major morbidity in patients aged 50 to 69 years undergoing aortic valve replacement.Retrospective cohort analysis of 4253 patients aged 50 to 69 years who underwent primary isolated aortic valve replacement using bioprosthetic vs mechanical valves in New York State from 1997 through 2004, identified using the Statewide Planning and Research Cooperative System. Median follow-up time was 10.8 years (range, 0 to 16.9 years); the last follow-up date for mortality was November 30, 2013. Propensity matching yielded 1001 patient pairs.Primary outcome was all-cause mortality; secondary outcomes were stroke, reoperation, and major bleeding.No differences in survival or stroke rates were observed in patients with bioprosthetic compared with mechanical valves. Actuarial 15-year survival was 60.6% (95% CI, 56.3%-64.9%) in the bioprosthesis group compared with 62.1% (95% CI, 58.2%-66.0%) in the mechanical prosthesis group (hazard ratio, 0.97 [95% CI, 0.83-1.14]). The 15-year cumulative incidence of stroke was 7.7% (95% CI, 5.7%-9.7%) in the bioprosthesis group and 8.6% (95% CI, 6.2%-11.0%) in the mechanical prosthesis group (hazard ratio, 1.04 [95% CI, 0.75-1.43). The 15-year cumulative incidence of reoperation was higher in the bioprosthesis group (12.1% [95% CI, 8.8%-15.4%] vs 6.9% [95% CI, 4.2%-9.6%]; hazard ratio, 0.52 [95% CI, 0.36-0.75]). The 15-year cumulative incidence of major bleeding was higher in the mechanical prosthesis group (13.0% [95% CI, 9.9%-16.1%] vs 6.6% [95% CI, 4.8%-8.4%]; hazard ratio, 1.75 [95% CI, 1.27-2.43]). The 30-day mortality rate was 18.7% after stroke, 9.0% after reoperation, and 13.2% after major bleeding.Among propensity-matched patients aged 50 to 69 years who underwent aortic valve replacement with bioprosthetic compared with mechanical valves, there was no significant difference in 15-year survival or stroke. Patients in the bioprosthetic valve group had a greater likelihood of reoperation but a lower likelihood of major bleeding. These findings suggest that bioprosthetic valves may be a reasonable choice in patients aged 50 to 69 years.

International audience; Production of specialized cells from precursors depends on a tightly regulated sequence of proliferation and differentiation steps. In the gonad of Drosophila melanogaster, the daughters of germ line stem cells (GSC) go through precisely four rounds of transit amplification divisions to produce clusters of 16 interconnected germ line cells before entering a stereotypic differentiation cascade. Here we show that animals harbouring a transposon insertion in the center of the complex nucleoporin98-96 (nup98-96) locus had severe defects in the early steps of this developmental program, ultimately leading to germ cell loss and sterility. A phenotypic analysis indicated that flies carrying the transposon insertion, designated nup98-96(2288), had dramatically reduced numbers of germ line cells. In contrast to controls, mutant testes contained many solitary germ line cells that had committed to differentiation as well as abnormally small clusters of two, four or eight differentiating germ line cells. This indicates that mutant GSCs rather differentiated than self-renewed, and that these GSCs and their daughters initiated the differentiation cascade after zero, or less than four rounds of amplification divisions. This phenotype remained unaffected by hyper-activation of signalling pathways that normally result in excessive proliferation of GSCs and their daughters. Expression of wildtype nup98-96 specifically in the germ line cells of mutant animals fully restored development of the GSC lineage, demonstrating that the effect of the mutation is cell-autonomous. Nucleoporins are the structural components of the nucleopore and have also been implicated in transcriptional regulation of specific target genes. The nuclear envelopes of germ cells and general nucleocytoplasmic transport in nup98-96 mutant animals appeared normal, leading us to propose that Drosophila nup98-96 mediates the transport or transcription of targets required for the developmental timing between amplification and differentiation.

Background Mechanisms underlying the attenuation of body weight gain and insulin resistance in response to high fat diet (HFD) by the curry compound curcumin need to be further explored. Although the attenuation of the inflammatory pathway is an accepted mechanism, a recent study suggested that curcumin stimulates Wnt signaling pathway and hence suppresses adipogenic differentiation. This is in contrast with the known repressive effect of curcumin on Wnt signaling in other cell lineages. Methodology and Principal Findings We conducted the examination on low fat diet, or HFD fed C57BL/6J mice with or without curcumin intervention for 28 weeks. Curcumin significantly attenuated the effect of HFD on glucose disposal, body weight/fat gain, as well as the development of insulin resistance. No stimulatory effect on Wnt activation was observed in the mature fat tissue. In addition, curcumin did not stimulate Wnt signaling in vitro in primary rat adipocytes. Furthermore, curcumin inhibited lipogenic gene expression in the liver and blocked the effects of HFD on macrophage infiltration and the inflammatory pathway in the adipose tissue. Conclusions and Significance We conclude that the beneficial effect of curcumin during HFD consumption is mediated by attenuating lipogenic gene expression in the liver and the inflammatory response in the adipose tissue, in the absence of stimulation of Wnt signaling in mature adipocytes.