Genetic variants associated with cardiac hypertrophy-related sudden cardiac death and cardiovascular outcomes in a Finnish population.

BACKGROUND: Hypertrophic cardiomyopathy is a common cause of non-ischaemic sudden cardiac death (SCD). Left ventricular hypertrophy (LVH) without cardiomyopathy-related myocardial disarray is a common autopsy finding and is often associated with prior hypertension in SCD subjects. Our aim was to investigate novel rare gene variants among SCD subjects with presumably hypertension-related LVH and myocardial fibrosis at autopsy. METHODS: Whole exome sequencing was used to study rare variants (minor allele frequency<0.005) estimated to be deleterious in 96 non-ischaemic SCD subjects with presumably hypertension-related LVH and myocardial fibrosis. Associations of the identified variants with cardiac disease endpoints were replicated in the Finnish national genetic study (FinnGen) dataset. RESULTS: 18 variants were estimated likely to affect protein function and 14 of these were associated with cardiomyopathies, heart failure, conduction abnormalities, hypertension and/or cardiac arrest in Finnish population (FinnGen). Three of the variants were classified as pathogenic or likely pathogenic. These include the splice site variant NM_000449.3:c.234-1G>A in regulatory factor X5 and frameshift variants NM_000449.3:c.234-1G>A in dehydrogenase/reductase 7C and NM_015873.3:c.1164del in villin like. CONCLUSIONS: We identified rare deleterious variants associated with LVH in SCD subjects. Several of the identified rare variants associated with cardiovascular endpoints including heart failure, cardiomyopathies, cardiac arrest and hypertension in general population.

Incidentally Induced Atrial Fibrillation During Programmed Electrical Stimulation in Patients With Depressed Left Ventricular Systolic Function After an Acute Myocardial Infarction.

BACKGROUND: The aim of this study was to investigate the clinical implication of incidentally induced atrial fibrillation (AF) during programmed electrical stimulation (PES) in patients with left ventricular systolic dysfunction (≤40%) after an acute myocardial infarction (MI). METHODS: In this study, we included 231 patients from the Cardiac Arrhythmias and RIsk Stratification after Myocardial InfArction (CARISMA) study with left ventricular ejection fraction ≤40% and no prior history of AF. These patients underwent PES 6 weeks post-MI as part of the study protocol. Patients all received an implantable cardiac monitor (ICM) 3-21 days post-MI and were continuously monitored for cardiac arrhythmias for 2 years. Induction of AF was unwanted but reported if this incidentally occurred. RESULTS: A total of 61 patients (26%) developed AF within 2 years of follow-up, in which n = 10 (29%) had incidental AF during PES at baseline. The overall risk of AF was not significantly increased in patients with incidental AF (n = 34) during PES compared to patients without incidental AF (n = 197) (HR 1.6 [0.9-3.0], p = 0.14). The risk of bradyarrhythmia (HR = 0.2 [0.0-1.2], p = 0.07), ventricular arrhythmias (HR = 0.7 [0.1-5.8], p = 0.77), and major cardiovascular events (MACE) (HR 0.5 [0.2-1.7], p = 0.28) was not significantly different in patients with versus without incidental AF. CONCLUSIONS: Incidentally induced AF during PES in post-MI patients with reduced LVEF was not significantly associated with a higher risk of long-term atrial fibrillation, other cardiac arrhythmias, or major cardiac events. TRIAL REGISTRATION: NCT00145119.

Reproducibility of autonomic cardiovascular function and hemodynamics at rest and during recovery from exercise.

Smartwatches and home-based blood pressure (BP) devices have permitted easy use of heart rate variability (HRV) and BP to identify the recovery status of users after acute exercise training. The reproducibility of HRV and BP after exercise in healthy young participants is not well known. Eighteen participants (age 27 ± 6 years, female n = 8) performed test and retest aerobic exercises (cycling, 30 min, 60% of peak workload, W) and a control session in randomized order. RMSSD, high and low-frequency power of RR intervals, and BP were measured at rest and 30-60 min after interventions. The relative reproducibility was assessed by the intraclass correlation coefficient (ICC) and 95% confidence interval (95% CI). The absolute reproducibility was evaluated using the coefficient of variation (CV%). HRV indices revealed moderate-to-excellent reproducibility at rest (ICC 0.81-0.86; 95% CI 0.53-0.95) but not after exercise (ICC -0.06 to 0.60; 95% CI -1.85 to 0.85). Systolic BP had a good-to-excellent reproducibility before (ICC 0.93; 95% CI 0.81-0.98, CV% 4.2) and after exercise (ICC 0.93; 95% CI 0.81-0.97, CV% 4.2). The reproducibility of HRV indices is poor after exercise in young participants. However, the reproducibility of BP is excellent at rest and after aerobic exercise.

Novel Genetic Variants Associated with Primary Myocardial Fibrosis in Sudden Cardiac Death Victims.

Myocardial fibrosis is a common finding in victims of sudden cardiac death (SCD). Whole exome sequencing was performed in 127 victims of SCD with primary myocardial fibrosis as the only pathological finding. These cases are derived from the Fingesture study which has collected data from autopsy-verified SCD victims in Northern Finland. A computational approach was used to identify protein interactions in cardiomyocytes. Associations of the identified variants with cardiac disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset. We identified 21 missense and one nonsense variant. Four variants were estimated to affect protein function, significantly associated with SCD/primary myocardial fibrosis (Fingesture) and associated with cardiac diseases in Finnish population (FinnGen). These variants locate in cartilage acidic protein 1 (CRATC1), calpain 1 (CAPN1), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B). The variants identified contribute to function of extracellular matrix and cardiomyocytes.

Lack of Prognostic Value of T-Wave Alternans for Implantable Cardioverter-Defibrillator Benefit in Primary Prevention.

BACKGROUND: New methods to identify patients who benefit from a primary prophylactic implantable cardioverter-defibrillator (ICD) are needed. T-wave alternans (TWA) has been shown to associate with arrhythmogenesis of the heart and sudden cardiac death. We hypothesized that TWA might be associated with benefit from ICD implantation in primary prevention. METHODS AND RESULTS: In the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter-Defibrillators) study, we prospectively enrolled 2327 candidates for primary prophylactic ICD. A 24-hour Holter monitor reading was taken from all recruited patients at enrollment. TWA was assessed from Holter monitoring using the modified moving average method. Study outcomes were all-cause death, appropriate shock, and survival benefit. TWA was assessed both as a contiguous variable and as a dichotomized variable with cutoff points <47 µV and <60 µV. The final cohort included 1734 valid T-wave alternans samples, 1211 patients with ICD, and 523 control patients with conservative treatment, with a mean follow-up time of 2.3 years. TWA ≥60 µV was a predicter for a higher all-cause death in patients with an ICD on the basis of a univariate Cox regression model (hazard ratio, 1.484 [95% CI, 1.024-2.151]; P=0.0374; concordance statistic, 0.51). In multivariable models, TWA was not prognostic of death or appropriate shocks in patients with an ICD. In addition, TWA was not prognostic of death in control patients. In a propensity score-adjusted Cox regression model, TWA was not a predictor of ICD benefit. CONCLUSIONS: T-wave alternans is poorly prognostic in patients with a primary prophylactic ICD. Although it may be prognostic of life-threatening arrhythmias and sudden cardiac death in several patient populations, it does not seem to be useful in assessing benefit from ICD therapy in primary prevention among patients with an ejection fraction of ≤35%.

Prognostic significance of beat-to-beat variability of spatial heterogeneity of repolarization analyzed from a 5-minute resting electrocardiogram in coronary artery disease.

BACKGROUND: Data on the prognostic significance of temporal variability of spatial heterogeneity of electrocardiographic repolarization in coronary artery disease (CAD) are limited. OBJECTIVE: The purpose of this study was to evaluate the prognostic value of temporal variability of T-wave morphology analyzed from a 5-minute resting electrocardiogram in CAD. METHODS: The standard deviation (SD) of T-wave morphology dispersion (TMD-SD) and the SD of total cosine R-to-T were analyzed on a beat-to-beat basis from a 5-minute period of the standard resting 12-lead electrocardiogram obtained before the clinical stress test in 1702 patients with angiographically verified CAD and well-preserved left ventricular function. RESULTS: During an average of 8.7 ± 2.2 years of follow-up, 60 patients experienced sudden cardiac death/arrest (SCD/SCA) (3.5%), 69 patients nonsudden cardiac death (NSCD) (4.1%), and 161 patients noncardiac death (9.5%). TMD-SD was significantly higher in patients who experienced SCD/SCA than in other patients (1.72 ± 2.00 vs 1.12 ± 1.75; P = .01) and higher in patients who succumbed to NSCD than in other patients (1.57 ± 1.74 vs 1.12 ± 1.76; P = .04), but it did not differ significantly between patients who experienced noncardiac death and those without such an event (1.16 ± 1.42 vs 1.14 ± 1.79; P = .86). In the Cox multivariable hazards model, TMD-SD retained its significant association with the risk of SCD/SCA (hazard ratio 1.119; 95% confidence interval 1.015-1.233; P = .024) but not with the risk of NSCD (hazard ratio 1.089; 95% confidence interval 0.983-1.206; P = .103). CONCLUSION: TMD-SD is independently associated with the long-term risk of SCD/SCA in patients with CAD.

Day-of-the-week variation of sudden unexpected cardiac death.

Background: There has been some controversy about the day-of-the-week (septadian) variation of unexpected sudden cardiac death (SCD). Methods: We evaluated the incidence of unexpected SCD on different days of the week in a consecutive series of 5869 SCD victims from Northern Finland [the FINGESTURE study (Finnish Genetic Study of Arrhythmic Events)]. As it is mandatory in Finland, a medico-legal autopsy was performed on all unexpected sudden death victims. The autopsies were performed between the years 1998-2017. Results: The mean incidence of unexpected SCD was higher at weekends (during the days from Friday to Sunday, peaking on Saturday) than during the days from Monday to Thursday (8.54 ± 0.72 vs. 7.22 ± 0.19 SCDs per day of the week per 100,000 inhabitants per year, p < 0.001). Regardless of sex or ischemic versus non-ischemic etiology of SCD, the distribution of the occurrence of SCD among the days of the week was similar compared with the whole SCD cohort. Conclusion: The incidence of unexpected SCD was highest at weekends (during the days from Friday to Sunday, peaking on Saturday).

Liver X Receptor Agonist 4ß-Hydroxycholesterol as a Prognostic Factor in Coronary Artery Disease.

BACKGROUND: Regardless of progress in treatment of coronary artery disease (CAD), there is still a significant residual risk of death in patients with CAD, highlighting the need for additional risk stratification markers. Our previous study provided evidence for a novel blood pressure-regulating mechanism involving 4ß-hydroxycholesterol (4ßHC), an agonist for liver X receptors, as a hypotensive factor. The aim was to determine the role of 4ßHC as a prognostic factor in CAD. METHODS AND RESULTS: The ARTEMIS (Innovation to Reduce Cardiovascular Complications of Diabetes at the Intersection) cohort consists of 1946 patients with CAD. Men and women were analyzed separately in quartiles according to plasma 4ßHC. Basic characteristics, medications, ECG, and echocardiography parameters as well as mortality rate were analyzed. At baseline, subjects with a beneficial cardiovascular profile, as assessed with traditional markers such as body mass index, exercise capacity, prevalence of diabetes, and use of antihypertensives, had the highest plasma 4ßHC concentrations. However, in men, high plasma 4ßHC was associated with all-cause death, cardiac death, and especially sudden cardiac death (SCD) in a median follow-up of 8.8 years. Univariate and comprehensively adjusted hazard ratios for SCD in the highest quartile were 3.76 (95% CI, 1.6-8.7; P=0.002) and 4.18 (95% CI, 1.5-11.4; P=0.005), respectively. In contrast, the association of cardiac death and SCD in women showed the lowest risk in the highest 4ßHC quartile. CONCLUSIONS: High plasma 4ßHC concentration was associated with death and especially SCD in men, while an inverse association was detected in women. Our results suggest 4ßHC as a novel sex-specific risk marker of cardiac death and especially SCD in chronic CAD. REGISTRATION INFORMATION: clinicaltrials.gov. Identifier NCT01426685.

QRS complex and T wave planarity for the efficacy prediction of automatic implantable defibrillators.

OBJECTIVE: To test the hypothesis that in recipients of primary prophylactic implantable cardioverter-defibrillators (ICDs), the non-planarity of ECG vector loops predicts (a) deaths despite ICD protection and (b) appropriate ICD shocks. METHODS: Digital pre-implant ECGs were collected in 1948 ICD recipients: 21.4% females, median age 65 years, 61.5% ischaemic heart disease (IHD). QRS and T wave three-dimensional loops were constructed using singular value decomposition that allowed to measure the vector loop planarity. The non-planarity, that is, the twist of the three-dimensional loops out of a single plane, was related to all-cause mortality (n=294; 15.3% females; 68.7% IHD) and appropriate ICD shocks (n=162; 10.5% females; 87.7% IHD) during 5-year follow-up after device implantation. Using multivariable Cox regression, the predictive power of QRS and T wave non-planarity was compared with that of age, heart rate, left ventricular ejection fraction, QRS duration, spatial QRS-T angle, QTc interval and T-peak to T-end interval. RESULTS: QRS non-planarity was significantly (p<0.001) associated with follow-up deaths despite ICD protection with HR of 1.339 (95% CI 1.165 to 1.540) but was only univariably associated with appropriate ICD shocks. Non-planarity of the T wave loop was the only ECG-derived index significantly (p<0.001) associated with appropriate ICD shocks with multivariable Cox regression HR of 1.364 (1.180 to 1.576) but was not associated with follow-up mortality. CONCLUSIONS: The analysed data suggest that QRS and T wave non-planarity might offer distinction between patients who are at greater risk of death despite ICD protection and those who are likely to use the defibrillator protection.

Lifestyle and Cardiac Structure and Function in Healthy Midlife Population.

The association between lifestyle and cardiac structure and function measures, such as global longitudinal strain and diastolic function in a healthy midlife general population, is not well known. A subpopulation of the Northern Finland Birth Cohort 1966 took part in follow-up, including echocardiography (n = 1,155) at the age of 46. All antihypertensive medication users (n = 164), patients with diabetes (n = 70), subjects with any cardiac diseases (n = 24), and subjects with echocardiography abnormalities (n = 21) were excluded. Moderate to vigorous physical activity (MVPA) was recorded with a wrist-worn accelerometer over 14 days and categorized into high, moderate, and low MVPA groups. Similarly, alcohol consumption was categorized as low, moderate, and high-dose users of alcohol and smoking as nonsmokers, former, and current smokers. The total number of healthy subjects included in the study was 715 (44% males). Left ventricular mass index and left atrial end-systolic volume index were significantly higher in the high MVPA group compared with the low MVPA group (adjusted main effect p = 0.002 and p <0.001, respectively). Cardiac function did not differ among the physical activity groups. High alcohol consumption was associated with impaired global longitudinal strain and diastolic function (adjusted main effect p = 0.002 and p = 0.004, respectively) but not with any cardiac structure variables. Smoking was not associated with cardiac structure or function. In healthy middle-aged adults, MVPA was independently associated with structural changes in the heart but not with cardiac function. High alcohol consumption was associated with impaired modern cardiac function measures but not with cardiac structure.

Lower hemoglobin levels associate with higher baroreflex sensitivity and heart rate variability.

The aim of this study was to cross-sectionally examine whether hemoglobin (Hb) levels within the normal variation associate with heart rate variability (HRV) measures and baroreflex sensitivity (BRS). The study population included 733 Finnish subjects of the OPERA cohort (aged 41-59 yr, 53% males, 51.7% treated for hypertension) of whom HRV was measured from a standardized 45-min period and whose Hb levels were within the Finnish reference intervals. The low Hb tertile (mean Hb, 135 g/L) had an overall healthier metabolic profile compared with the high Hb tertile (mean Hb, 152 g/L). BRS was higher in the low Hb tertile compared with the high Hb tertile (P < 0.05). R-R interval (RRi) and standard deviation (SD) of the RRi (SDNN)index were the longest in the low Hb tertile regardless of posture. Of the spectral components of HRV, HF power was the highest in the low Hb tertile regardless of posture (P < 0.05). In a stepwise logistic regression model, BRS associated negatively with Hb levels after adjusting for covariates (B = -0.160 [-0.285; -0.035]). Similar associations were observed for SDNNindex when lying down (B = -0.105 [-0.207; -0.003]) and walking (B = -0.154 [-0.224; -0.083]). For HF power negative associations with Hb levels were observed when lying down (B = -0.110 [-0.180; -0.040]), sitting (B = -0.150 [-0.221; -0.079]), and in total analysis (B = -0.124 [-0.196; -0.053]). Overall, lower Hb levels associated independently with healthier cardiac autonomic function.NEW & NOTEWORTHY Heart rate variability (HRV) and baroreflex sensitivity (BRS), which can be measured noninvasively, can predict cardiac and metabolic diseases. Our findings show that within normal variation subjects with lower hemoglobin (Hb) levels have an overall healthier HRV profile and increased cardiac parasympathetic activity in middle age, independent of age, sex, smoking status, and key metabolic covariates. These findings support our previous findings that Hb levels can be used in assessing long-term risks for cardiometabolic diseases.

Causes and characteristics of unexpected sudden cardiac death in octogenarians/nonagenarians.

INTRODUCTION: The risk for sudden cardiac death (SCD) increases with ageing. METHODS: We evaluated causes and characteristics of unexpected SCD in SCD victims aged ≥ 80 years in a consecutive series of 5,869 SCD victims in Northern Finland. All the victims underwent medico-legal autopsy as medico-legal autopsy is mandatory in cases of unexpected sudden death in Finland. All the non-cardiac deaths such as pulmonary embolism and cerebral hemorrhage were excluded from the study, as were unnatural deaths such as intoxications. RESULTS: Among SCD victims ≥ 80 years, 91.0% of SCDs were due to ischemic heart disease (IHD) determined in autopsy and 9.0% due to non-ischemic heart disease (NIHD), whereas among those < 80 years, only 72.6% of SCDs were due to IHD and 27.4% due to NIHD (P < .001). Severe fibrosis in myocardium was more common whereas heart weight and liver weight, body mass index and abdominal fat thickness, were lower among SCD victims aged ≥ 80 years than among victims aged < 80 years. In those with IHD as etiology of SCD, at least 75% stenosis in one or more major coronary vessels was more common in SCD victims aged ≥ 80 years than among victims aged < 80 years (P = .001). SCD victims 80 years or older were less likely to die during physical activity than those under 80 years old (5.6% vs. 15.9%, P < .001). Dying in sauna was more common among those ≥ 80 years than among those < 80 years (5.5% vs. 2.6%, P < .001). CONCLUSION: In victims of unexpected SCD aged ≥ 80 years, the autopsy-based etiology of SCD was more commonly IHD than in those aged < 80 years. In SCD victims aged ≥ 80 years, severe fibrosis in myocardium, representing arrhythmic substrate, was more common than in the younger ones.

Use of Psychotropic Medication in Victims of Sudden Cardiac Death with Nonischemic Heart Disease.

BACKGROUND: Nonischemic heart disease (NIHD) is the underlying pathology in about 20% of sudden cardiac deaths (SCDs). Psychotropic medication has been reported as a risk factor for SCD among patients with coronary artery disease, but similar information concerning NIHD is scarce. OBJECTIVES: We evaluated the use of psychotropic medication in victims of SCD due to NIHD and compared it to the general medication use in Finland. METHOD: Study population was derived from the Finnish Genetic Study of Arrhythmic Events (Fingesture) (n = 5,869, mean age: 65 ± 12, 79% males; 1,404 victims of SCD due to NIHD, mean age: 57 ± 13, 77% males). All deaths occurred in Northern Finland during 1998-2017. All victims underwent a medicolegal autopsy. Data on use of medication were defined using postmortem toxicology results and patient records. Subjects with neither toxicological analysis nor information of medication use available were excluded. Information on general medication use was derived from Finnish Statistics on Medicines 2018 and presented as defined daily dose/1,000 inhabitants/day. RESULTS: Psychotropic medication was used by 579 (41%) subjects with NIHD, whereas in the general population, only 12% were estimated to use psychotropics. The results were similar in subgroups of psychotropic medication: 27% versus 2.3% for benzodiazepines, 19% versus 7.5% for antidepressants, and 18% versus 2.2% for antipsychotics. CONCLUSIONS: Use of psychotropic medication is common in victims of SCD due to NIHD compared to the general population.

Association of electrocardiographic spatial heterogeneity of repolarization and spatial heterogeneity of atrial depolarization with left ventricular fibrosis.

AIMS: To evaluate the relationship between spatial heterogeneity of electrocardiographic repolarization and spatial heterogeneity of atrial depolarization with arrhythmic substrate represented by left ventricular fibrosis. METHODS AND RESULTS: We assessed the associations of T- and P-wave morphology parameters analysed from the standard 12-lead electrocardiograms with left ventricular fibrosis in 378 victims of unexpected sudden cardiac death (SCD) who underwent medico-legal autopsy. Based on autopsy findings, the SCD victims were categorized into four different groups according to different stages of severity of left ventricular fibrosis (substantial fibrosis, moderate patchy fibrosis, scattered mild fibrosis, no fibrosis). T-wave and P-wave area dispersion (TWAd: 0.0841 ± 0.496, 0.170 ± 0.492, 0.302 ± 404, 0.296 ± 0.476, P = 0.008; PWAd: 0.574 ± 0.384, 0.561 ± 0.367, 0.654 ± 0.281, 0.717 ± 0.257, P = 0.011, respectively; low values abnormal), non-dipolar components of T-wave and P-wave morphology (T_NonDipolarABS: 0.0496 ± 0.0377, 0.0571 ± 0.0487, 0.0432 ± 0.0476, 0.0380 ± 0.0377, P = 0.027; P_NonDipolarABS: 0.0132 ± 0.0164, 0.0130 ± 0.0135, 0.0092 ± 0.0117, 0.0069 ± 0.00472, P = 0.005, respectively, high values abnormal), T-wave morphology dispersion (TMD: 45.9 ± 28.3, 40.5 ± 25.8, 35.5 ± 24.9, 33.0 ± 24.6, P = 0.030, respectively, high values abnormal), and P-wave heterogeneity (PWH: 20.0 ± 9.44, 19.7 ± 8.87, 17.9 ± 9.78, 15.4 ± 4.60, P = 0.019, respectively, high values abnormal) differed significantly between the groups with different stages of left ventricular fibrosis. After adjustment with heart weight, T_NonDipolarABS [standardized ß (sß) = 0.131, P = 0.014], PWAd (sß = -0.161, P = 0.003), P_NonDipolarABS (sß = 0.174, P = 0.001), and PWH (sß = 0.128, P = 0.015) retained independent association, and TWAd (sß = -0.091, P = 0.074) and TMD (sß = 0.097, P = 0.063) tended to retain their association with the degree of myocardial fibrosis. CONCLUSION: Our findings suggest that abnormal values of T- and P-wave morphology are associated with arrhythmic substrate represented by ventricular fibrosis partly explaining the mechanism behind their prognostic significance.

Prognostic value of P-wave morphology in general population.

AIMS: To evaluate the prognostic significance of novel P-wave morphology descriptors in general population. METHODS AND RESULTS: Novel P-wave morphology variables were analyzed from orthogonal X-, Y-, Z-leads of the digitized electrocardiogram using a custom-made software in 6906 middle-aged subjects of the Mini-Finland Health Survey. A total of 3747 (54.3%) participants died during the follow-up period of 24.3 ± 10.4 years; 379 (5.5%) of the study population succumbed to sudden cardiac death (SCD), 928 (13.4%) to non-SCD (NSCD) and 2440 (35.3%) patients to non-cardiac death (NCD). In univariate comparisons, most of the studied P-wave morphology parameters had a significant association with all modes of death (P from <0.05 to <0.001). After relevant adjustments in the Cox multivariate hazards model, P-wave morphology dispersion (PMD) still tended to predict SCD [hazard ratio (HR): 1.006, 95% confidence interval (CI): 1.000-1.012, P = 0.05) but not NSCD (HR: 0.999, 95% CI: 0.995-1.003, P = 0.68) or NCD (HR: 0.999, 95% CI: 0.997-1.001, P = 0.44). The P-wave maximum amplitude in the lead Z (P-MaxAmp-Z) predicted SCD even after multivariate adjustments (HR: 1.010, 95% CI: 1.005-1.015, P = 0.0002) but also NSCD (HR: 1.005, 95% CI: 1.002-1.009, P = 0.0005) and NCD (HR: 1.002, 95% CI: 1.000-1.005, P = 0.03). CONCLUSION: Abnormalities of P-wave morphology are associated with the risk of all modes of death in general population. After relevant adjustments, PMD was still closely associated with the risk of SCD but not with NSCD or NCD. P-MaxAmp-Z predicted SCD even after adjustments, however, it also retained its association with NSCD and NCD.

Association of atrial depolarization variability and cardiac autonomic regulation with sudden cardiac death in coronary artery disease.

AIMS: To evaluate the prognostic significance of the temporal variability of P-wave morphology, specifically in relation to cardiac autonomic regulation. METHODS AND RESULTS: We analyzed the standard deviation of P-wave residuum (PWRSD) from five consecutive beats of the standard 12-lead ECG in 1236 patients with angiographically verified coronary artery disease (CAD). We evaluated the prognostic value of PWRSD, of PWRSD and PWR in relation to the 24 h standard deviation of normal-to-normal intervals (PWRSD/SDNN and PWR/SDNN). After 8.7 ± 2.2 years of follow-up on average, 43 patients (3.5%) experienced sudden cardiac death (SCD) or were resuscitated from sudden cardiac arrest (SCA), 34 (2.8%) succumbed to non-sudden cardiac death (NSCD) and 113 (9.1%) to non-cardiac death (NCD). In the Cox regression analysis, PWRSD (≥0.002727) had a significant univariate (uv) [hazard ratio (HR): 4.27, 95% confidence interval (CI): 2.26-8.08, P = 0.000008] and multivariate (mv) (HR: 2.58, 95% CI: 1.31-5.08, P = 0.006) association with SCD/SCA but not with NSCD (uv P = 0.76, mv P = 0.33) or NCD (uv P = 0.57, mv P = 0.66). All the studied P-morphology parameters retained a significant association with the risk of SCD/SCA after relevant adjustment (mv P-values from 0.00003 to <0.05) but not with NSCD or NCD. When dichotomized PWRSD, PWR, PWRSD/SDNN, and PWR/SDNN were added to the clinical risk model for SCD/SCD, the C-index increased from 0.799 to 0.834 and integrated discrimination index and net reclassification index improved significantly (P < 0.001). CONCLUSION: Variability of P-morphology representing temporo-spatial heterogeneity of atrial depolarization, specifically when combined with cardiac autonomic regulation, independently predicts the risk of SCD in patients with CAD.

ECG T-Wave Morphologic Variations Predict Ventricular Arrhythmic Risk in Low- and Moderate-Risk Populations.

Background Early identification of individuals at risk of sudden cardiac death (SCD) remains a major challenge. The ECG is a simple, common test, with potential for large-scale application. We developed and tested the predictive value of a novel index quantifying T-wave morphologic variations with respect to a normal reference (TMV), which only requires one beat and a single-lead ECG. Methods and Results We obtained reference T-wave morphologies from 23 962 participants in the UK Biobank study. With Cox models, we determined the association between TMV and life-threatening ventricular arrhythmia in an independent data set from UK Biobank study without a history of cardiovascular events (N=51 794; median follow-up of 122 months) and SCD in patients with coronary artery disease from ARTEMIS (N=1872; median follow-up of 60 months). In UK Biobank study, 220 (0.4%) individuals developed life-threatening ventricular arrhythmias. TMV was significantly associated with life-threatening ventricular arrhythmias (hazard ratio [HR] of 1.13 per SD increase [95% CI, 1.03-1.24]; P=0.009). In ARTEMIS, 34 (1.8%) individuals reached the primary end point. Patients with TMV ≥5 had an HR for SCD of 2.86 (95% CI, 1.40-5.84; P=0.004) with respect to those with TMV <5, independently from QRS duration, corrected QT interval, and left ventricular ejection fraction. TMV was not significantly associated with death from a cause other than SCD. Conclusions TMV identifies individuals at life-threatening ventricular arrhythmia and SCD risk using a single-beat single-lead ECG, enabling inexpensive, quick, and safe risk assessment in large populations.