Screening for Rare Coding Variants That Associate With the QTc Interval in Iceland.

Background Long-QT syndrome (LQTS) is a cardiac repolarization abnormality that can lead to sudden cardiac death. The most common causes are rare coding variants in the genes KCNQ1, KCNH2, and SCN5A. The data on LQTS epidemiology are limited, and information on expressivity and penetrance of pathogenic variants is sparse. Methods and Results We screened for rare coding variants associated with the corrected QT (QTc) interval in Iceland. We explored the frequency of the identified variants, their penetrance, and their association with severe events. Twelve variants were associated with the QTc interval. Five in KCNQ1, 3 in KCNH2, 2 in cardiomyopathy genes MYBPC3 and PKP2, and 2 in genes where coding variants have not been associated with the QTc interval, ISOC1 and MYOM2. The combined carrier frequency of the 8 variants in the previously known LQTS genes was 530 per 100 000 individuals (1:190). p.Tyr315Cys and p.Leu273Phe in KCNQ1 were associated with having a mean QTc interval longer than 500 ms (P=4.2×10-7; odds ratio [OR], 38.6; P=8.4×10-10, OR, 26.5; respectively), and p.Leu273Phe was associated with sudden cardiac death (P=0.0034; OR, 2.99). p.Val215Met in KCNQ1 was carried by 1 in 280 Icelanders, had a smaller effect on the QTc interval (P=1.8×10-44; effect, 22.8 ms), and did not associate with severe clinical events. Conclusions The carrier frequency of associating variants in LQTS genes was higher than previous estimates of the prevalence of LQTS. The variants have variable effects on the QTc interval, and carriers of p.Tyr315Cys and p.Leu273Phe have a more severe disease than carriers of p.Val215Met. These data could lead to improved identification, risk stratification, and a more precise clinical approach to those with QTc prolongation.

Identifying out-of-hospital cardiac arrest patients with no chance of survival: An independent validation of prediction rules.

BACKGROUND: The Basic life support (BLS) and Advanced life support (ALS) are known prediction rules for termination of resuscitation (TOR) in out-of-hospital cardiac arrest (OHCA). Recently, a new rule was developed by Jabre et al. We aimed to independently validate and compare the predictive accuracy of these rules. METHODS: OHCA cases in Iceland from 2008 to 2017 from a population-based, prospectively registered database. Primary outcome was survival to discharge among patients that met all conditions of abovementioned rules: BLS (not witnessed by EMS personnel, no defibrillation nor ROSC before transport), ALS (BLS criteria plus not witnessed nor CPR by bystander) and Jabre (not witnessed by EMS personnel, initial rhythm non-shockable, no sustainable ROSC before third dose of adrenaline). RESULTS: Overall, 568 OHCA patients were included in validation of TOR rules. Mean age 67, males 74%, witnessed by EMS 11%, by bystander 66% that attempted CPR in 50%, transported to hospital 60%, overall survival 20%. All rules had high specificity for mortality, 99.6-100% (95%CI 95-100). The Jabre and BLS rules had similar sensitivity 47% (43-52) vs. 44% (40-49), respectively, the sensitivity of ALS was lower, 8% (5-11). Combined use of positive BLS and Jabre rules performed the best, identifying 88/226 (39%) of futile cases transported to hospital, specificity 100% (97-100) and sensitivity 59% (55-64). CONCLUSIONS: The accuracy of the BLS and Jabre TOR rules to predict mortality after OHCA is very good and their combined use may be superior to the use of either one.