BackgroundStudies of the functional consequences of DCM-causing mutations have been limited to a few cases where patients with known mutations had heart transplants. To increase the number of potential tissue samples for direct investigation we performed whole exon sequencing of explanted heart muscle samples from 30 patients that had a diagnosis of familial dilated cardiomyopathy and screened for potentially disease-causing mutations in 58 HCM or DCM-related genes.ResultsWe identified 5 potentially disease-causing OBSCN mutations in 4 samples; one sample had two OBSCN mutations and one mutation was judged to be not disease-related. Also identified were 6 truncating mutations in TTN, 3 mutations in MYH7, 2 in DSP and one each in TNNC1, TNNI3, MYOM1, VCL, GLA, PLB, TCAP, PKP2 and LAMA4. The mean level of obscurin mRNA was significantly greater and more variable in healthy donor samples than the DCM samples but did not correlate with OBSCN mutations. A single obscurin protein band was observed in human heart myofibrils with apparent mass 960 ± 60 kDa. The three samples with OBSCN mutations had significantly lower levels of obscurin immunoreactive material than DCM samples without OBSCN mutations (45±7, 48±3, and 72±6% of control level).Obscurin levels in DCM controls, donor heart and myectomy samples were the same.Conclusions OBSCN mutations may result in the development of a DCM phenotype via haploinsufficiency. Mutations in the obscurin gene should be considered as a significant causal factor of DCM, alone or in concert with other mutations.

Dilated cardiomyopathy (DCM) is an important cause of heart failure. Single gene mutations in at least 50 genes have been proposed to account for 25–50% of DCM cases and up to 25% of inherited DCM has been attributed to truncating mutations in the sarcomeric structural protein titin (TTNtv). Whilst the primary molecular mechanism of some DCM-associated mutations in the contractile apparatus has been studied in vitro and in transgenic mice, the contractile defect in human heart muscle has not been studied. In this study we isolated cardiac myofibrils from 3 TTNtv mutants, and 3 with contractile protein mutations (TNNI3 K36Q, TNNC1 G159D and MYH7 E1426K) and measured their contractility and passive stiffness in comparison with donor heart muscle as a control. We found that the three contractile protein mutations but not the TTNtv mutations had faster relaxation kinetics. Passive stiffness was reduced about 38% in all the DCM mutant samples. However, there was no change in maximum force or the titin N2BA/N2B isoform ratio and there was no titin haploinsufficiency. The decrease in myofibril passive stiffness was a common feature in all hearts with DCM-associated mutations and may be causative of DCM.

Objective: To systematically review temporal changes in perioperative safety of carotid endarterectomy (CEA) in asymptomatic individuals in trial and registry studies. Methods:The MEDLINE and EMBASE databases were searched using the terms "carotid" and "endarterectomy" and "asymptomatic" from 1947 to August 23, 2014. Articles dealing with 50%-99% stenosis in asymptomatic individuals were included and low-volume studies were excluded. The primary endpoint was 30-day stroke or death and the secondary endpoint was 30-day all-cause mortality. Statistical analysis was performed using random-effects metaregression for registry data and for trial data graphical interpretation alone was used.Results: Six trials (n 5 4,431 procedures) and 47 community registries (n 5 204,622 procedures) reported data between 1983 and 2013. Registry data showed a significant decrease in postoperative stroke or death incidence over the period 1991-2010, equivalent to a 6% average proportional annual reduction (95% credible interval [CrI] 4%-7%; p , 0.001). Considering postoperative all-cause mortality, registry data showed a significant 5% average proportional annual reduction (95% CrI 3%-9%; p , 0.001). Trial data showed a similar visual trend.Conclusions: CEA is safer than ever before and high-volume registry results closely mirror the results of trials. New benchmarks for CEA are a stroke or death risk of 1.2% and a mortality risk of 0.4%. This information will prove useful for quality improvement programs, for health care funders, and for those re-examining the long-term benefits of asymptomatic revascularization in future trials. Carotid endarterectomy (CEA) in asymptomatic individuals was introduced in the 1970s for long-term prevention of ipsilateral stroke 1 and now comprises the bulk of those undergoing endarterectomy in the United States.2 However, the 10-year absolute risk reduction in stroke or death risk in the largest and most recent trial, the Asymptomatic Carotid Surgery Trial 1 (ACST-1), was only 4.6%, demonstrating small absolute benefit of CEA. 3,4On modern medical therapy, ipsilateral ischemic stroke rates have fallen, 5 with 3 recent cohort studies demonstrating annual ipsilateral ischemic stroke risks in patients with 50%-99% asymptomatic stenosis of 0.3%-0.8%, 6-8 less than the 0.96% risk in ACST. 4 If CEA is to prove effective in the future, one of the prerequisites is that perioperative outcomes must become safer not only in trials, but in wider clinical practice.The aim of this systematic review was to examine temporal trends in perioperative safety of CEA in asymptomatic individuals with 50%-99% internal carotid artery stenosis. When compared with symptomatic patients, 9 the benefits of asymptomatic revascularization are less pronounced, and without marked improvements in operative safety, asymptomatic revascularization faces becoming a historical footnote. This analysis will provide valuable information for From the Academic Section of Vascular Surgery (A.B.M., M.I.Q., A.T.,

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