Genetic Testing in Unexplained Cardiac Arrest

Mellor et al (Circ Cardiovasc Genet. 2017;10:e001686. DOI: 10.1161/CIRCGENETICS.116.001686.) provide a very instructive paper on the value of genetic testing in evaluation of unexplained cardiac arrest. A significant proportion of survivors had a pathogenic variant identified.



Unexplained cardiac arrest may be because of an inherited arrhythmia syndrome. The role of genetic testing
in cardiac arrest survivors without a definite clinical phenotype is unclear.

Methods and Results

The CASPER (Cardiac Arrest Survivors with Preserved Ejection Fraction Registry) is a large
registry of cardiac arrest survivors where initial assessment reveals normal coronary arteries, left ventricular function,
and resting ECG. Of 375 cardiac arrest survivors in CASPER from 2006 to 2015, 174 underwent genetic testing. Patients
were classified as phenotype-positive (n=72) or phenotype-negative (n=102). Genetic testing was performed at treating
physicians’ discretion in line with contemporary guidelines and availability. All genetic variants identified from original
laboratory reports were reassessed by the investigators in line with modern criteria. Pathogenic variants were identified
in 29 (17%) patients (60% channelopathy-associated and 40% cardiomyopathy-associated genes) and 70 variants of
unknown significance were identified in 32 (18%) patients. Prior syncope (odds ratio, 4.0; 95% confidence interval,
1.6–9.7) and a family history of sudden death (odds ratio, 3.2; 95% confidence interval, 1.1–9.4) were independently
associated with the presence of a pathogenic variant. In phenotype-negative patients, broad multiphenotype genetic
testing led to higher yields (21% versus 8%; P=0.04) but was associated with more variants of unknown significance
(55% versus 5%; P<0.01).


Genetic testing identifies a pathogenic variant in a significant proportion of unexplained cardiac arrest
survivors. Prior syncope and family history of sudden death are predictors of a positive genetic test. Both arrhythmia
and cardiomyopathy genes are implicated. Broad, multiphenotype testing revealed the highest frequency of pathogenic
variants in phenotype-negative patients.

Mitral Valve Repair Review

Coutinho et al provide a review of mitral valve repair for degenerative mitral valve disease (Coutinho GF,
Antunes MJ. Heart Published Online doi:10.1136/heartjnl-2016-311031). Extracts from the paper:

Clonal Haematopoiesis of Indeterminate Potential and Atherosclerosis

Jaiswal et al report on a new risk factor for coronary heart disease: peripheral blood clonal haematopoiesis of indeterminate potential.



Clonal hematopoiesis of indeterminate potential (CHIP), which is defined as the
presence of an expanded somatic blood-cell clone in persons without other hematologic abnormalities, is common among older persons and is associated with an increased risk of hematologic cancer. We previously found preliminary evidence for an association between CHIP and atherosclerotic cardiovascular disease, but the nature of this association was unclear.


We used whole-exome sequencing to detect the presence of CHIP in peripheral blood cells and associated such presence with coronary heart disease using samples from four case–control studies that together enrolled 4726 participants with coronary heart disease and 3529 controls. To assess causality, we perturbed the function of Tet2, the second most commonly mutated gene linked to clonal hematopoiesis, in the hematopoietic cells of atherosclerosis-prone mice.


In nested case–control analyses from two prospective cohorts, carriers of CHIP
had a risk of coronary heart disease that was 1.9 times as great as in noncarriers (95% confidence interval [CI], 1.4 to 2.7). In two retrospective case–control cohorts for the evaluation of early-onset myocardial infarction, participants with CHIP had a risk of myocardial infarction that was 4.0 times as great as in noncarriers (95% CI, 2.4 to 6.7). Mutations in DNMT3A, TET2, ASXL1, and JAK2 were each individually associated with coronary heart disease. CHIP carriers with these mutations also had increased coronary-artery calcification, a marker of coronary atherosclerosis burden. Hypercholesterolemia-prone mice that were engrafted with bone marrow obtained from homozygous or heterozygous Tet2 knockout mice had larger atherosclerotic lesions in the aortic root and aorta than did mice that had received control bone marrow. Analyses of macrophages from Tet2 knockout mice showed elevated expression of several chemokine and cytokine genes that contribute to atherosclerosis.


The presence of CHIP in peripheral-blood cells was associated with nearly a doubling in the risk of coronary heart disease in humans and with accelerated atherosclerosis in mice.

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PCI in the Elderly with NSTEMI

Gnanenthiran et al (http:// dx. doi. org/ 10. 1136/heartjnl- 2017- 311233). report a meta-analysis of randomized clinical trials of percutaneous coronary intervention in the elderly presenting with non ST elevation myocardial infarction.  Reduction in myocardial infarction, repeat revascularization and a trend to reduction in mortality was noted. Bleeding was increased (compared with medical therapy) but appeared to decrease across time.



Whether revascularisation is superior to medical therapy in older populations presenting with non-ST-elevation acute coronary syndromes (NSTEACS) remains contentious, with inconclusive evidence from randomised trials. We aimed to compare routine invasive therapy with initial medical management in the elderly
presenting with NSTEACS.


MEDLINE, EMBASE and Cochrane Controlled Trial Register were searched for studies comparing routine invasive therapy with initial medical management
in patients ≥75 years old presenting with NSTEACS. Endpoints included long-term mortality, myocardial infarction (MI), revascularisation, rehospitalisation, stroke and major bleeding reported as ORs.


Four randomised trials and three observational studies met inclusion criteria, enrolling a total of 20 540 patients followed up from 6 months to 5 years. Routine invasive therapy reduced mortality (OR 0.67, CI 0.61 to 0.74), MI (OR 0.56, CI 0.45 to 0.70) and stroke (OR 0.53, CI 0.30 to 0.95). Analyses restricted to randomised controlled trials (RCTs) confirmed a reduction in MI (OR 0.51, CI 0.40 to 0.66), revascularisation (OR 0.27, CI 0.13 to 0.56) and a trend to reduced mortality (OR 0.84, CI 0.66 to 1.06) at the expense of major bleeding (OR 2.19, CI 1.12 to 4.28). Differences in major bleeding were unapparent in more recent studies.


Routine invasive therapy reduces MI and repeat revascularisation and may reduce mortality at the expense of major bleeding in elderly patients with NSTEACS. Our findings highlight the need for further RCTs to better determine the effect on mortality and contemporary bleeding risk.


Bioresorbable Vascular Scaffold Thrombosis

Wykrzykowska et al (N Engl J Med 2017;376:2319-28. DOI: 10.1056/NEJMoa1614954) report on a randomized clinical trial of bioresorbable vascular scaffold versus metallic drug eluting stent. The rates of target vessel failure were similar. However, scaffold thrombosis was significantly higher than stent thrombosis. There is an instructive accompanying editorial (DOI: 10.1056/NEJMe1703202).



Bioresorbable vascular scaffolds were developed to overcome the shortcomings of drugeluting stents in percutaneous coronary intervention (PCI). We performed an investigatorinitiated,randomized trial to compare an everolimus-eluting bioresorbable scaffold with an everolimus-eluting metallic stent in the context of routine clinical practice.


We randomly assigned 1845 patients undergoing PCI to receive either a bioresorbable vascular scaffold (924 patients) or a metallic stent (921 patients). The primary end point was target-vessel failure (a composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization). The data and safety monitoring board recommended early reporting of the study results because of safety concerns. This report provides descriptive information on end-point events.


The median follow-up was 707 days. Target-vessel failure occurred in 105 patients in the scaffold group and in 94 patients in the stent group (2-year cumulative event rates, 11.7% and 10.7%, respectively; hazard ratio, 1.12; 95% confidence interval [CI], 0.85 to 1.48; P = 0.43); event rates were based on Kaplan–Meier estimates in time-to-event analyses. Cardiac death occurred in 18 patients in the scaffold group and in 23 patients in the stent group (2-year cumulative event rates, 2.0% and 2.7%, respectively), target-vessel myocardial
infarction occurred in 48 patients in the scaffold group and in 30 patients in the stent group (2-year cumulative event rates, 5.5% and 3.2%), and target-vessel revascularization occurred in 76 patients in the scaffold group and in 65 patients in the stent group (2-year cumulative event rates, 8.7% and 7.5%). Definite or probable device thrombosis occurred in 31 patients in the scaffold group as compared with 8 patients in the stent group (2-year cumulative event rates, 3.5% vs. 0.9%; hazard ratio, 3.87; 95% CI, 1.78 to 8.42; P<0.001).


In this preliminary report of a trial involving patients undergoing PCI, there was no significant difference in the rate of target-vessel failure between the patients who received a bioresorbable scaffold and the patients who received a metallic stent. The bioresorbable scaffold was associated with a higher incidence of device thrombosis than the metallic stent through 2 years of follow-up.


Aortic Stenosis and Non-cardiac Surgery

A useful reference on assessment and management of aortic stenosis in the context of non-cardiac surgery is available here.

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Late Gadolinium Enhancement in Dilated Cardiomyopathy

Halliday et al (Circulation. 2017;135:2106–2115. DOI: 10.1161/CIRCULATIONAHA.116.026910) report on the relationship between late gadolinium enhancement on cardiac MRI and sudden cardiac death in patients with dilated cardiomyopathy. They identify a subgroup with LVEF \ge 40% at increased risk of sudden cardiac death.



Current guidelines only recommend the use of an implantable
cardioverter defibrillator in patients with dilated cardiomyopathy for the primary prevention of sudden cardiac death (SCD) in those with a left ventricular ejection fraction (LVEF) 35%. Patients with an LVEF >35% also have low competing risks of death from nonsudden causes. Therefore, those at high risk of SCD may gain longevity from successful implantable cardioverter defibrillator therapy. We investigated whether late gadolinium enhancement (LGE) cardiovascular magnetic resonance identified patients with dilated cardiomyopathy without severe LV systolic dysfunction at high risk of SCD.


We prospectively investigated the association between midwall LGE and the prespecified primary composite outcome of SCD or aborted SCD among consecutive referrals with dilated cardiomyopathy and an LVEF ≥40% to our center between January 2000 and December 2011 who did not have a preexisting indication for implantable cardioverter defibrillator implantation.


Of 399 patients (145 women, median age 50 years, median LVEF 50%, 25.3% with LGE) followed for a median of 4.6 years, 18 of 101 (17.8%) patients with LGE reached the prespecified end point, compared with 7 of 298 (2.3%) without (hazard ratio [HR], 9.2; 95% confidence interval [CI], 3.9–21.8; P<0.0001). Nine patients (8.9%) with LGE compared with 6 (2.0%) without (HR,4.9; 95% CI, 1.8–13.5; P=0.002) died suddenly, whereas 10 patients (9.9%) with LGE compared with 1 patient (0.3%) without (HR, 34.8; 95% CI, 4.6–266.6; P<0.001) had aborted SCD. After adjustment, LGE predicted the composite end point (HR, 9.3; 95% CI, 3.9–22.3; P<0.0001), SCD (HR, 4.8; 95% CI, 1.7–13.8; P=0.003), and aborted SCD (HR, 35.9; 95% CI, 4.8–271.4; P5% compared with those without LGE were 10.6 (95% CI, 3.9–29.4), 4.9 (95% CI, 1.3–18.9), and 11.8 (95% CI, 4.3–32.3), respectively.


Midwall LGE identifies a group of patients with dilated cardiomyopathy and an LVEF ≥40% at increased risk of SCD and low risk of nonsudden death who may benefit from implantable cardioverter defibrillator implantation.