Alex B. Munster

OBSCN Mutations Associated with Dilated Cardiomyopathy and Haploinsufficiency.

Background Studies 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. Results We 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.

Temporal trends in safety of carotid endarterectomy in asymptomatic patients

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 meta-regression for registry data and for trial data graphical interpretation alone was used. Results: Six trials (n = 4,431 procedures) and 47 community registries (n = 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.

Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes

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.

Systematic review of perioperative outcomes following laparoscopic abdominal aortic aneurysm repair

Objective To collate information available in the literature regarding perioperative outcomes following elective laparoscopic abdominal aortic aneurysm repair. Materials and methods Electronic databases were searched and a systematic review was performed. In total, 1256 abstracts were screened, from which 10 studies were included for analysis. Perioperative and technical outcomes were analysed. Results In the totally laparoscopic repair of infra-renal aneurysms (n = 302), 30-day mortality ranged between 0% and 6% and in the laparoscopic-assisted cases (n = 547) ranged between 0% and 7%. Of the former group, 5–30% of cases were converted to open repair, with 6% reintervention rate, whereas there was a 5–10% conversion and 3% reintervention rate in the latter group. Conclusions The outcomes from selected patients in selected centres demonstrate that elective laparoscopic repair of aortic aneurysms is feasible and comparable in safety to open repair; it remains unclear, however, whether there are substantial advantages of this method compared with open and endovascular repair.

Pharmacological adjuncts for chronic venous ulcer healing: a systematic review

Background The aim of this study was to systematically review the current evidence and determine whether there is a clinical benefit for using pharmacological agents as adjunctive treatment for chronic venous ulcers. Method A systematic review of the MEDLINE and EMBASE (from 1 January 1947 through 15 August 2013) and Cochrane databases (from inception through 15 August 2013) was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Inclusion criteria were all randomised controlled trials investigating pharmacological adjuncts for the treatment of venous ulcers with a minimum sample size of 20 patients for each treatment arm. Results Ten relevant articles were identified; one pilot randomised controlled trial and four Cochrane reviews were included. Pentoxifylline, aspirin, sulodexide, mesoglycan, flavonoids, thromboxane A2 antagonist (ifetroban), zinc, prostaglandin and prostacyclin analogues were the drugs reviewed. Pentoxifylline was found to be more effective than placebo in terms of complete ulcer healing or in causing a significant improvement (greater than 60% reduction in ulcer size) (RR 1.70, 95% CI 1.30 to 2.24). Aspirin and flavonoids show potential to be effective adjuncts but methodological shortcomings and issues with bias limit the validity of results from trials involving each of these drugs, respectively. There was no significant difference between placebo and Ifetroban and likewise pooled results from trials investigating sulodexide and zinc showed no benefit in comparison to placebo. Conclusion Many systemic pharmacological agents have been investigated as adjuncts to venous ulcer healing; however, pentoxifylline (400 mg, three times a day) is currently the only drug that has promising evidence to support its use. Other compounds are in early stage research.

History of Carotid Stroke

> [The] two branches which they call carotides or soporales, the sleepy arteries, because they being obstructed, or any way stopt we presently fall asleep. > > —Ambroise Pare (ca. AD 1510–1590)1 Current understanding of carotid artery disease begins in Ancient Greece. The term carotid is derived from the Ancient Greek karos (κάρος), meaning to stupefy. This first description is ascribed to Hippocrates (ca. 460–370 BC) but defined in the later accounts of Rufus of Ephesus (fl. ca. AD 100), who stated that the term was used because superficial compression of the vessels was known to induce stupefaction. The importance of the carotid arteries was even evident in the timeless art of the era. The 31st metope (a rectangular architectural element) from the south side of the Parthenon in Athens (Figure 1) depicts a centaur gripping the neck and compressing the left carotid artery of a Lapith (member of a mythological Thessalian people) during the legendary Centauromachy battle. Galen (ca. AD 131–201) attributed the loss of consciousness to compression not of the carotid arteries but of “sensitive nerves” located proximal to the vessels.2 Today cardiologists recognize a similar syndrome of carotid sinus syncope, tested for through carotid baroreceptor hypersensitivity. Figure 1. The 31st metope from the south side of the Parthenon in Athens. On display in the British Museum, the southern aspect metopes depict the battle between the centaurs (left) and the Lapiths (right) at the wedding of Peirithus, the king of the Lapiths. The left carotid artery of the Lapith is here being intentionally compressed to induce unconsciousness. Photograph courtesy of Colin Howley. Used with permission. The most devastating consequence of carotid artery disease is stroke, which was referred to during classical antiquity as apoplexy. Hippocrates and Galen were both aware that the hemiplegia often accompanying apoplexy resulted from a lesion in …

Author Correction: Abnormal contractility in human heart myofibrils from patients with dilated cardiomyopathy due to mutations in TTN and contractile protein genes

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