Rare Variation in Drug Metabolism and Long QT Genes and the Genetic Susceptibility to Acquired Long QT Syndrome.

BACKGROUND: Acquired long QT syndrome (aLQTS) is a serious unpredictable adverse drug reaction. Pharmacogenomic markers may predict risk. METHODS: Among 153 aLQTS patients (mean age 58 years [range, 14-88], 98.7% White, 85.6% symptomatic), computational methods identified proteins interacting most significantly with 216 QT-prolonging drugs. All cases underwent sequencing of 31 candidate genes arising from this analysis or associating with congenital LQTS. Variants were filtered using a minor allele frequency <1% and classified for susceptibility for aLQTS. Gene-burden analyses were then performed comparing the primary cohort to control exomes (n=452) and an independent replication aLQTS exome sequencing cohort. RESULTS: In 25.5% of cases, at least one rare variant was identified: 22.2% of cases carried a rare variant in a gene associated with congenital LQTS, and in 4% of cases that variant was known to be pathogenic or likely pathogenic for congenital LQTS; 7.8% cases carried a cytochrome-P450 (CYP) gene variant. Of 12 identified CYP variants, 11 (92%) were in an enzyme known to metabolize at least one culprit drug to which the subject had been exposed. Drug-drug interactions that affected culprit drug metabolism were found in 19% of cases. More than one congenital LQTS variant, CYP gene variant, or drug interaction was present in 7.8% of cases. Gene-burden analyses of the primary cohort compared to control exomes (n=452), and an independent replication aLQTS exome sequencing cohort (n=67) and drug-tolerant controls (n=148) demonstrated an increased burden of rare (minor allele frequency<0.01) variants in CYP genes but not LQTS genes. CONCLUSIONS: Rare susceptibility variants in CYP genes are emerging as potentially important pharmacogenomic risk markers for aLQTS and could form part of personalized medicine approaches in the future.

An inherited sudden cardiac arrest syndrome may be based on primary myocardial and autonomic nervous system abnormalities.

BACKGROUND: A recently discovered sudden cardiac arrest (SCA) syndrome is linked to a risk haplotype that harbors the dipeptidyl-peptidase 6 (DPP6) gene as a plausible culprit. OBJECTIVE: Because DPP6 impacts both cardiomyocyte and neuronal function, we hypothesized that ventricular fibrillation (VF) in risk haplotype carriers arises from functional changes in both the heart and autonomic nervous system. METHODS: We studied 6 risk haplotype carriers with previous VF (symptomatic), 8 carriers without VF (asymptomatic), and 7 noncarriers (controls). We analyzed supine and standing heart rate variability, baroreflex sensitivity, pre-VF heart rate changes, and myocardial 123I-meta-iodobenzylguanide (123I-mIBG) scintigraphy. RESULTS: Carriers had longer interbeat intervals than controls (1.03 ± 0.11 seconds vs 0.81 ± 0.07 seconds; P <.001), lower low-frequency (LF) and higher high-frequency (HF) activity, and lower LF/HF ratio (0.68 ± 0.50 vs 2.11 ± 1.10; P = .013) in the supine position. Upon standing up, carriers had significantly larger decrease in interbeat interval and increase in LF than controls (standing-to-supine ratio: 0.78 ± 0.07 vs 0.90 ± 0.07; P = .002; and 1.94 ± 1.03 vs 1.17 ± 0.34; P = .022, respectively), and nonsignificantly larger decrease in HF (0.62 ± 0.36 vs 0.97 ± 0.42; P = .065) and increase in LF/HF ratio (5.55 ± 6.79 vs 1.62 ± 1.24; P = .054). Sixteen of 17 VF episodes occurred at rest. Heart rate immediately before VF was 110 ± 25 bpm. Symptomatic carriers had less heterogeneous 123I-mIBG distribution in the left ventricle than asymptomatic carriers (single-photon emission computed tomography score ≥3 in 7 asymptomatic and 1 symptomatic carrier; P = .008). CONCLUSION: It can be speculated that these data are consistent with more labile autonomic tone in carriers, suggesting that the primary abnormalities may reside in both the heart and the autonomic nervous system.

High haemoglobin A1c level is a possible risk factor for ventricular fibrillation in sudden cardiac arrest among non-diabetic individuals in the general population.

AIMS: This study aimed to establish whether higher levels of glycated haemoglobin (HbA1c) are associated with increased sudden cardiac arrest (SCA) risk in non-diabetic individuals. METHODS AND RESULTS: Case-control study in non-diabetic individuals (HbA1c < 6.5%) in the Netherlands. Cases were SCA patients with electrocardiogram (ECG)-documented ventricular fibrillation (VF, the predominant cause of SCA) and HbA1c measurements immediately after VF, prospectively included in September 2009-December 2012. Controls (up to 10 per case) were age/sex-matched non-SCA individuals, included in July 2006-November 2007. We studied 306 cases (56.4 ± 6.8 years, 79.1% male) and 1722 controls (54.0 ± 6.8 years, 64.8% male). HbA1c levels were higher in cases than in controls (5.8 ± 0.3% vs. 5.4 ± 0.3%, P < 0.001). The proportion of increased HbA1c (≥5.7%) was 63.1% in cases and 19.3% in controls (P < 0.001). Multivariate regression models indicated that increased HbA1c was associated with a > six-fold increased VF risk [adjusted odds ratio (ORadj) 6.74 (5.00-9.09)] and that 0.1% increase in HbA1c level was associated with 1.4-fold increase in VF risk, independent of concomitant cardiovascular risk factors. Increased VF risk at higher HbA1c is associated with acute myocardial infarction (MI) as cause of VF [OR 1.14 (1.04-1.24)], but the association between HbA1c and VF was similar in non-MI patients [OR 1.32 (1.21-1.44)] and MI patients [OR 1.47 (1.37-1.58)]. CONCLUSION: Among non-diabetic individuals, risk of VF increased with rising HbA1c levels, independent of concomitant cardiovascular disease. Future studies should establish whether HbA1c level may be used as biomarker to recognize individuals at risk for VF.

Women have lower chances than men to be resuscitated and survive out-of-hospital cardiac arrest.

AIMS: Previous studies on sex differences in out-of-hospital cardiac arrest (OHCA) had limited scope and yielded conflicting results. We aimed to provide a comprehensive overall view on sex differences in care utilization, and outcome of OHCA. METHODS AND RESULTS: We performed a population-based cohort-study, analysing all emergency medical service (EMS) treated resuscitation attempts in one province of the Netherlands (2006-2012). We calculated odds ratios (ORs) for the association of sex and chance of a resuscitation attempt by EMS, shockable initial rhythm (SIR), and in-hospital treatment using logistic regression analysis. Additionally, we provided an overview of sex differences in overall survival and survival at successive stages of care, in the entire study population and in patients with SIR. We identified 5717 EMS-treated OHCAs (28.0% female). Women with OHCA were less likely than men to receive a resuscitation attempt by a bystander (67.9% vs. 72.7%; P < 0.001), even when OHCA was witnessed (69.2% vs. 73.9%; P < 0.001). Women who were resuscitated had lower odds than men for overall survival to hospital discharge [OR 0.57; 95% confidence interval (CI) 0.48-0.67; 12.5% vs. 20.1%; P < 0.001], survival from OHCA to hospital admission (OR 0.88; 95% CI 0.78-0.99; 33.6% vs. 36.6%; P = 0.033), and survival from hospital admission to discharge (OR 0.49, 95% CI 0.40-0.60; 33.1% vs. 51.7%). This was explained by a lower rate of SIR in women (33.7% vs. 52.7%; P < 0.001). After adjustment for resuscitation parameters, female sex remained independently associated with lower SIR rate. CONCLUSION: In case of OHCA, women are less often resuscitated by bystanders than men. When resuscitation is attempted, women have lower survival rates at each successive stage of care. These sex gaps are likely explained by lower rate of SIR in women, which can only partly be explained by resuscitation characteristics.

Transaortic Aortic Valve Implantation in 100 Patients: Follow-up to 3 Years.

OBJECTIVE: Transaortic aortic valve implantation (TAo-AVI) through the ascending aorta is a novel technique and is used as an alternative in patients with poor femoral access. Although early results have been promising, no midterm data have been published yet. To determine whether this approach is an acceptable treatment option, we analyzed the first 100 cases performed at our institution with a follow-up to 3 years. METHODS: Between July 2011 and January 2015, a total of 100 patients with high-risk or inoperable aortic valve stenosis were treated with TAo-AVI. Preoperative patient data were collected and analyzed retrospectively. All surviving patients were seen for clinical and echocardiographic examination for follow-up. RESULTS: Median follow-up was 15 months. Device success was accomplished in 94 patients (94%). There were no access site complications. The 30-day mortality rate was 9%. Stroke occurred in a total of six patients (6%). Survival at 1-, 2-, and 3 years was 75%, 62%, and 58%, respectively. CONCLUSIONS: Our results show that TAo-AVI is a promising alternative to transapical implantation for treating severe inoperable aortic valve stenosis.

Implantable cardioverter-defibrillators have reduced the incidence of resuscitation for out-of-hospital cardiac arrest caused by lethal arrhythmias.

BACKGROUND: Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline. METHODS AND RESULTS: Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005-2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995-1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005-2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995-1997 to 17.4/100 000 in 2005-2008 (P<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (P<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005-2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence. CONCLUSIONS: The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.