Clinical and molecular genetic risk determinants in adult long QT syndrome type 1 and 2 patients : Koponen et al. Follow-up of adult LQTS patients.

BACKGROUND: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving ß-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations. METHODS: A follow-up study covering a mean of 18.6 ± 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events. RESULTS: In mutation carriers, risk factors for cardiac events before initiation of ß-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p < 0.001), a cardiac event before the age of 18 years (HR = 5.9, p < 0.001), and QTc ≥500 ms (vs < 470 ms, HR = 2.7, p = 0.001). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR = 3.0-3.9, p < 0.001-0.03) compared to G589D, c.1129-2A > G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR = 0.11-0.23, p < 0.001) than other KCNH2 mutations. CONCLUSIONS: LQT2 (compared to LQT1), female gender, a cardiac event before age 18, and long QT interval increased the risk of cardiac events in LQTS patients aged 18 to 40 years. The nature of the underlying mutation may be associated with risk variation in both LQT1 and LQT2. The identification of high-risk and low-risk mutations may enhance risk stratification.

Fibrosis and wall thickness affect ventricular repolarization dynamics in hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is characterized by ventricular repolarization abnormalities and risk of ventricular arrhythmias. Our aim was to study the association between the phenotype and ventricular repolarization dynamics in HCM patients. METHODS: HCM patients with either the MYBPC3-Q1061X or TPM1-D175N mutation (n = 46) and control subjects without mutation and hypertrophy (n = 35) were studied with 24-hr ambulatory ECG recordings by measuring time intervals of rate-adapted QT (QTe), maximal QT, and T-wave apex to wave end (TPE) intervals and the QTe/RR slope. Findings were correlated to specified echocardiographic and cardiac magnetic resonance imaging (CMRI) findings. RESULTS: Rate-adapted QTe interval was progressively longer in HCM patients with decreasing heart rates compared to control subjects (p = 0.020). The degree of hypertrophy correlated with measured QTe values. HCM patients with maximal wall thickness higher than the mean (20.6 mm) had longer maximum QTe and median TPE intervals compared to control subjects and HCM patients with milder hypertrophy (p < 0.001 and p = 0.014, respectively). HCM patients with late gadolinium enhancement (LGE) on CMRI had steeper QTe/RR slopes compared to HCM patients without LGE and control subjects (p = 0.044 and p = 0.001, respectively). LGE was an independent predictor of QTe/RR slope (p = 0.023, B = 0.043). CONCLUSION: Dynamics of ventricular repolarization in HCM are affected by hypertrophy and fibrosis. LGE may confer an independent effect on QT dynamics which may increase the arrhythmogenic potential in HCM.

Slowed depolarization and irregular repolarization in catecholaminergic polymorphic ventricular tachycardia: a study from cellular Ca2+ transients and action potentials to clinical monophasic action potentials and electrocardiography.

AIMS: Spontaneous Ca2+ release leads to afterdepolarizations and triggered arrhythmia in catecholaminergic polymorphic ventricular tachycardia (CPVT). Irregular Ca2+ release is hypothesized to manifest as slowed depolarization and irregular repolarization. Our goal was to study depolarization and repolarization abnormalities in CPVT, as they remain largely uninvestigated. METHODS AND RESULTS: We studied intracellular Ca2+ handling and action potentials (APs) in an induced pluripotent stem cell (iPSC) model of CPVT. Induced pluripotent stem cell cardiomyocytes from a RyR2-P2328S patient showed increased non-alternating variability of Ca2+ transients in response to isoproterenol. ß-Agonists decreased AP upslope velocity in CPVT cells and in monophasic AP recordings of CPVT patients. We compared 24 h electrocardiograms (ECGs) of 19 CPVT patients carrying RyR2 mutations and 19 healthy controls. Short-term variability (STV) of the QT interval was 6.9 ± 0.5 ms in CPVT patients vs. 5.5 ± 0.4 ms in controls (P < 0.05) and associated with a history of arrhythmic events. Mean T-wave alternans (TWA) was 25 ± 1.4 µV in CPVT patients vs. 31 ± 2.0 µV in controls (P < 0.05). Older CPVT patients showed lower maximal upslope velocity of the ECG R-spike than control patients. CONCLUSION: Catecholaminergic polymorphic ventricular tachycardia patients show higher STV of repolarization but lower TWA on the 24 h ECG than control patients, which is likely to reflect increased non-alternating variability of Ca2+ release by mutant RyR2s as observed in vitro. ß-Agonists slow depolarization in RyR2-mutant cells and in CPVT patients. These findings may constitute a marker of arrhythmogenicity.

Sensitivity and specificity of automated detection of early repolarization in standard 12-lead electrocardiography.

BACKGROUND: Early repolarization (ER) is defined as an elevation of the QRS-ST junction in at least two inferior or lateral leads of the standard 12-lead electrocardiogram (ECG). Our purpose was to create an algorithm for the automated detection and classification of ER. METHODS: A total of 6,047 electrocardiograms were manually graded for ER by two experienced readers. The automated detection of ER was based on quantification of the characteristic slurring or notching in ER-positive leads. The ER detection algorithm was tested and its results were compared with manual grading, which served as the reference. RESULTS: Readers graded 183 ECGs (3.0%) as ER positive, of which the algorithm detected 176 recordings, resulting in sensitivity of 96.2%. Of the 5,864 ER-negative recordings, the algorithm classified 5,281 as negative, resulting in 90.1% specificity. Positive and negative predictive values for the algorithm were 23.2% and 99.9%, respectively, and its accuracy was 90.2%. Inferior ER was correctly detected in 84.6% and lateral ER in 98.6% of the cases. CONCLUSIONS: As the automatic algorithm has high sensitivity, it could be used as a prescreening tool for ER; only the electrocardiograms graded positive by the algorithm would be reviewed manually. This would reduce the need for manual labor by 90%.

Differences in ST-elevation and T-wave amplitudes do not reliably differentiate takotsubo cardiomyopathy from acute anterior myocardial infarction.

BACKGROUND: Previous efforts to distinguish acute anterior ST-elevation myocardial infarction (anterior-STEMI) from various forms of takotsubo cardiomyopathy (TTC) by electrocardiography (ECG) have produced differing results. METHODS: We performed a retrospective comparison of acute ECGs between 48 apical and 9 mid-ventricular TTC patients, with 96 anterior-STEMI patients. ECG was recorded in acute phase (<24h from onset of pain), and analyzed for ST-changes, negative T-waves, abnormal Q-waves and QT-interval duration. Time from onset of pain to ECG was gathered from patient records. RESULTS: Anterior-STEMI patients had ST-elevation in lead V1 more frequently than apical (70% vs 15%, p<0.0001) or mid-ventricular TTC patients (70% vs 0%, p<0.0001), and higher ST-elevation amplitudes in leads V2-V5 (p<0.02). Lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 distinguished TTC from anterior-STEMI patients with 63% sensitivity and 93% specificity, with 79% predictive value. CONCLUSIONS: In patients with anterior ST-elevation and acute chest pain, lack of ST-elevation in lead V1 and ST-elevation amplitude <2mm in lead V2 suggests a TTC diagnosis. However, this criterion is not reliable enough in clinical practice to distinguish between TTC and anterior-STEMI patients.

T-wave morphology after epinephrine bolus may reveal silent long QT syndrome mutation carriers.

BACKGROUND: Long QT syndrome (LQTS) gene mutation carriers with indeterminate electrocardiogram frequently escape clinical diagnosis. We assessed the use of epinephrine bolus injection in revealing T-wave abnormalities. METHODS: We recruited 30 genotyped asymptomatic LQTS gene carriers with nondiagnostic QT interval and 15 controls. Electrocardiogram was recorded with body surface potential mapping after an intravenous epinephrine bolus. T-wave morphology was determined as normal, biphasic, inverted, bifid, or combined pattern. RESULTS: Long QT syndrome carriers and healthy controls had different T-wave profiles (P = .027). Of controls, 12 (80%) of 15 had no change or biphasic appearance, whereas only 10 (33%) of 30 of LQTS carriers had so. Bifid or combined pattern occurred in 15 (50%) of 30 in LQTS and in 6 (60%) of 10 in the LQT3 subgroup but only in 1 (7%) of 15 of healthy. CONCLUSIONS: Modification of ventricular repolarization with low-dose epinephrine injection helps to distinguish silent LQTS mutation carriers. This concerns also the LQT3 subtype, which may escape tests.

Effects of ß-blockers on ventricular repolarization documented by 24-hour electrocardiography in long QT syndrome type 2.

BACKGROUND: Long QT syndrome (LQTS) is an inherited arrhythmia disorder characterized by ventricular repolarization abnormalities and a risk of sudden cardiac death. The electrophysiological components generating the high risk of arrhythmias in LQTS are prolonged repolarization, increased dispersion of repolarization, and early afterdepolarizations, which are clinically estimated as QT interval, T-wave peak to T-wave end (TPE) interval, and T2/T1-wave amplitude ratio, respectively. In experimental LQTS type 2 (LQT2) models, ß-blockers decrease dispersion of repolarization and prevent early afterdepolarizations. In clinical studies in patients with LQT2 , ß-blockers are more effective against exercise-induced than arousal-induced cardiac events. OBJECTIVES: The aim of the study was to investigate the effects of ß-blocker therapy on repolarization properties in LQT2. METHODS: QT and TPE intervals and maximal T2/T1-wave amplitude ratios recorded by 24-hour electrocardiograms before and during ß-blocker therapy were evaluated in 25 patients with LQT2. RESULTS: ß-Blocker therapy decreased the maximal T2/T1-wave amplitude ratio from 2.9 ± 1.1 to 1.8 ± 0.7 (P < .001), but did not change the pause-induced T2/T1-wave amplitude ratio. Under medication, abrupt maximal TPE intervals were shorter at heart rates of ≥75 beats/min and maximal QT intervals were shorter at a heart rate of 100 beats/min. CONCLUSION: ß-Blockers stabilize ventricular repolarization in LQT2 by reducing electrocardiographic early afterdepolarizations and by reducing abrupt prolongation of electrocardiographic dispersion of repolarization and ventricular repolarization duration at elevated heart rates. The effect of ß-blockers on pause-induced electrocardiographic early afterdepolarizations is weak. The findings provide electrocardiographic explanation for the protective effects of ß-blockers against exercise-induced cardiac events in LQT2.

Epinephrine bolus test in detecting long QT syndrome mutation carriers with indeterminable electrocardiographic phenotype.

BACKGROUND: In long QT syndrome (LQTS), prolonged and heterogeneous ventricular repolarization predisposes to serious arrhythmias. We examined how QT intervals are modified by epinephrine bolus in mutation carriers of three major LQTS subtypes with indefinite QT interval. METHODS: Genotyped, asymptomatic subjects with LQTS type 1 (LQT1; n = 10; four different KCNQ1 mutations), type 2 (LQT2; n = 10; three different HERG mutations), and type 3 (LQT3; n = 10; four different SCN5A mutations), and healthy volunteers (n = 15) were examined. Electrocardiogram was recorded with body surface potential mapping system. After an epinephrine 0.04 µg/kg bolus QT end, QT apex, and T-wave peak-to-end (Tpe) intervals were determined automatically as average of 12 precordial leads. Standard deviation (SD) of the 12 channels was calculated. RESULTS: Heart rate increased 26 ± 10 bpm with epinephrine bolus, and similarly in all groups. QT end interval lengthened, and QT apex interval shortened in LQTS and normals, leading to lengthening of Tpe interval. However, the lengthening in Tpe was larger in LQTS than in normals (mean 32 vs 18 ms; P < 0.05) and SD of QT apex increased more in LQTS than in normals (mean 23 vs 7 ms; P < 0.01). The increase in Tpe was most pronounced in LQT2, and in SD of QT apex in LQT1 and LQT2. CONCLUSIONS: Abrupt adrenergic stimulation with a moderate dose of exogenous epinephrine affects ventricular repolarization in genotype-specific fashion facilitating distinction from normals. This delicate modification may help in diagnosing electrocardiographically silent mutation carriers when screening LQTS family members.

Prognostic value of changes in the electrocardiographic strain pattern during antihypertensive treatment: the Losartan Intervention for End-Point Reduction in Hypertension Study (LIFE).

BACKGROUND: The presence of the ECG strain pattern of lateral ST depression and T-wave inversion at baseline has been associated with an increased risk of cardiovascular morbidity and mortality; however, the independent predictive value for cardiovascular outcomes of regression versus persistence versus development of new ECG strain during antihypertensive therapy is unclear. METHODS AND RESULTS: ECG strain was evaluated at baseline and after 1 year of therapy in 7409 hypertensive patients in the LIFE study (Losartan Intervention For End-point reduction in hypertension) treated in a blinded manner with atenolol- or losartan-based regimens. During 3.8+/-0.8 years of follow-up after the year 1 ECG, cardiovascular death occurred in 236 patients (3.2%), myocardial infarction in 198 (2.7%), stroke in 313 (4.2%), the LIFE composite end point of these 3 events in 600 (8.1%), sudden death in 92 (1.2%), and death due to any cause in 486 (6.6%). Strain was absent on both baseline and year 1 ECGs in 6323 patients (85.3%), regressed from baseline to year 1 in 245 (3.3%), persisted on both ECGs in 549 (7.4%), and was absent at baseline but developed by year 1 in 292 patients (3.9%). Compared with absence of strain on both ECGs, development of new ECG strain was associated with 2.8- to 4.7-fold higher event rates; patients with regression or persistence of strain had intermediate event rates. In Cox multivariable analyses with adjustment for the known predictive value of in-treatment ECG left ventricular hypertrophy by Cornell product and Sokolow-Lyon voltage, in-treatment systolic and diastolic pressure, randomized treatment, and standard cardiovascular risk factors, development of new ECG strain was independently associated with increased risks of cardiovascular death (hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.56 to 3.76), myocardial infarction (HR 1.95, 95% CI 1.11 to 3.44), stroke (HR 1.98, 95% CI 1.30 to 3.01), the LIFE composite end point (HR 2.05, 95% CI 1.51 to 2.78), sudden cardiac death (HR 2.19, 95% CI 1.06 to 4.53), and all-cause mortality (HR 1.92, 95% CI 1.37 to 2.69), whereas the risk associated with regression or persistence of strain was attenuated. CONCLUSIONS: Development of new ECG strain is associated with an increased risk of cardiovascular morbidity and mortality and of all-cause mortality in the setting of antihypertensive therapy and regression of ECG left ventricular hypertrophy.

Abnormal repolarization dynamics revealed in exercise test in long QT syndrome mutation carriers with normal resting QT interval.

AIMS: The identification of affected family members with long QT syndrome (LQTS) is often difficult due to their normal-or only marginally lengthened-QT interval duration. We examined whether physical exercise test could increase the ability to detect the mutation carrier status in phenotypically normal LQTS family members. METHODS AND RESULTS: Sixty-six subjects were included: 15 were carriers of KCNQ1 (LQT1); 15 of KCNH(2) (LQT2); and 9 of SCN5A (LQT3) gene mutations with no, or borderline, QT lengthening; and 27 were healthy controls. Multiple electrograms over the precordial area were recorded during workload and recovery phases of exercise test. QT intervals and T peak to T end intervals (Tpe intervals) were determined using an automatic algorithm at specified heart rates (HR).The LQT1 mutation carriers had QT interval most prolonged during exercise and recovery, whereas the LQT2 carriers had QT interval longest at low exercise HR. The LQT3 carriers had QT interval longest at rest. The Tpe interval remained nearly unchanged during exercise in LQT1, but shortened in LQT2 and in LQT3 carriers. The Tpe interval was longest in LQT2 carriers at the end of the recovery phase. Tentative dichotomizing values of QT and Tpe intervals improved sensitivity and specificity in distinguishing LQTS subtypes, compared with the QT interval duration alone. CONCLUSIONS: LQTS mutation carriers lacking diagnostic QT interval prolongation exhibit abnormal QT and Tpe interval adaptations during physical exercise test. Looking for subtype-specific adaptations might facilitate the identification of LQTS mutation carriers when molecular genetic analysis is not available.

Dynamic QT/RR relationship in post-myocardial infarction patients with and without cardiac arrest.

OBJECTIVES: Changes in QT interval dynamicity may be associated with susceptibility to ventricular fibrillation (VF) after myocardial infarction (MI). We tested the hypothesis that dynamic QT/RR relationship might differ between post-MI patients with and without a history of VF. We also evaluated the influence of negative T-waves on the assessment of QT/RR relationship. DESIGN: We reviewed Holter recordings from 37 post-MI patients resuscitated from VF not associated with new MI (VF group) and 30 patients after MI without known sustained ventricular arrhythmias (control group). With an automated computerized program, we measured QT interval dynamicity as the mean QT/RR slope and as the maximal QT/RR slope determined at stable heart rates. RESULTS: The mean QT/RR slope was 0.20 ± 0.08 in control group and 0.15 ± 0.09 in VF group (p=0.01) whereas corresponding maximal QT/RR slope values were 0.42 ± 0.20 and 0.33 ± 0.18 (p=0.01), respectively. Thirteen control patients (43%) and 22 VF patients (59%) showed only negative or both positive and negative T-waves (p=0.45). Mean QT/RR slope values were similar irrespective of T-wave polarity whereas maximal QT/RR slopes were steeper in cases with both positive and negative T-waves. Cases showing T-waves of both positive and negative polarity exhibited greatest intersubject variability of both QT/RR slope values. CONCLUSIONS: Lower mean QT/RR slope may be associated with a risk of VF after MI. A detailed assessment and definition of differing T-wave polarities is essential in evaluating the QT/RR relation in post-MI patients.

QRS duration predicts sudden cardiac death in hypertensive patients undergoing intensive medical therapy: the LIFE study.

AIMS: To determine whether QRS duration predicts sudden cardiac death (SCD) in patients with left ventricular hypertrophy and treated hypertension. METHODS AND RESULTS: Over 4.8 +/- 0.9 years follow-up of 9193 hypertensive patients with electrocardiographic evidence of LVH who were treated with atenolol- or losartan-based regimens, 178 patients (1.9%) suffered SCD. In multivariable analysis including randomized treatment, changing blood pressure over time, and baseline differences between patients with and without SCD, QRS duration was independently predictive of SCD (HR per 10 ms increase = 1.22, P < 0.001). Baseline QRS duration remained a significant predictor of SCD even after controlling for the presence or absence of left bundle branch block (HR = 1.17, P = 0.001) and for changes in ECG LVH severity over the course of the study (HR = 1.16, P = 0.017). CONCLUSION: In the setting of aggressive antihypertensive therapy, prolonged QRS duration identifies hypertensive patients at higher risk for SCD, even after controlling for left bundle branch block, other known risk factors for SCD, and changes in blood pressure and severity of left ventricular hypertrophy.

Genealogy and clinical course of catecholaminergic polymorphic ventricular tachycardia caused by the ryanodine receptor type 2 P2328S mutation.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited arrhythmic disease associated with a risk of syncope and sudden cardiac death (SCD). AIMS: We aimed at identifying RYR2 P2328S founder mutation carriers and describing the clinical course associated with the mutation. METHODS: The study population was drawn from the Finnish Inherited Cardiac Disorder Research Registry, and from the present genealogical study. Kaplan-Meier graphs, log-rank test and Cox regression model were used to evaluate the clinical course. RESULTS: Genealogical study revealed a common ancestor couple living in the late 17th century. A total of 1837 living descendants were tested for RYR2 P2328S mutation unveiling 62 mutation carriers aged mean 39±23 years old. No arrhythmic deaths were documented among genotyped subjects, but 11 SCDs were detected in non-genotyped family members since 1970. Three genotyped patients (5%) suffered an aborted cardiac arrest (ACA), and 15 (25%) had a syncope triggered by exercise or stress. Rate of cardiac events was higher among patients who in exercise stress test showed a maximum rate of premature ventricular contractions >30/min (68% vs 17%, p<0.01; hazard ratio = 7.1, p = 0.02), in comparison to patients without the respective finding. A cardioverter-defibrillator (ICD) was implanted to 13 (22%) patients, with an appropriate ICD shock in four (31%) subjects. All ICD shocks, one ACA, and one syncope occurred during ß-blocker medication. CONCLUSIONS: Previously undiagnosed CPVT patients may be identified by well-conducted genealogical studies. The RYR2 P2328S mutation causes a potentially severe phenotype, but its expression is variable, thus calling for additional studies on modifying factors.

Search for cardiac calcium cycling gene mutations in familial ventricular arrhythmias resembling catecholaminergic polymorphic ventricular tachycardia.

BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a severe inherited cardiac disorder caused by mutations predominantly in the ryanodine receptor (RyR2) gene. We sought to identify mutations in genes affecting cardiac calcium cycling in patients with CPVT and in less typical familial exercise-related ventricular arrhythmias. METHODS AND RESULTS: We recruited 33 consecutive patients with frequent ventricular premature complexes (VPCs) without structural heart disease and often history of syncope or sudden death in family. Sixteen of the patients featured a phenotype typical of CPVT. In 17 patients, VPCs emerged also at rest. Exercise stress test and echocardiography were performed to each patient and 232 family members. Familial background was evident in 42% of cases (n = 14). We sequenced all the coding exons of the RyR2, FKBP1B, ATP2A2 and SLC8A1 genes from the index patients. Single channel recordings of a mutant RyR2 were performed in planar lipid bilayers. Two novel RyR2 missense mutations (R1051P and S616L) and two RyR2 exon 3 deletions were identified, explaining 25% of the CPVT phenotypes. A rare variant (N3308S) with open probabilities similar to the wild type channels in vitro, was evident in a patient with resting VPCs. No disease-causing variants were detectable in the FKBP1B, ATP2A2 or SLC8A1 genes. CONCLUSION: We report two novel CPVT-causing RyR2 mutations and a novel RyR2 variant of uncertain clinical significance in a patient with abundant resting VPCs. Our data also strengthen the previous assumption that exon 3 deletions of RyR2 should screened for in CPVT and related phenotypes.

ECG left ventricular hypertrophy as a risk predictor of sudden cardiac death.

BACKGROUND: Electrocardiographic (ECG) left ventricular hypertrophy (LVH) is an established risk factor for cardiovascular events. However, limited data is available on the prognostic values of different ECG LVH criteria specifically to sudden cardiac death (SCD). Our goal was to assess relationships of different ECG LVH criteria to SCD. METHODS: Three traditional and clinically useful (Sokolow-Lyon, Cornell, RaVL) and a recently proposed (Peguero-Lo Presti) ECG LVH voltage criteria were measured in 5730 subjects in the Health 2000 Survey, a national general population cohort study. Relationships between LVH criteria, as well as their selected composites, to SCD were analyzed with Cox regression models. In addition, population-attributable fractions for LVH criteria were calculated. RESULTS: After a mean follow-up of 12.5 ±â€¯2.2 years, 134 SCDs had occurred. When used as continuous variables, all LVH criteria except for RaVL were associated with SCD in multivariable analyses. When single LVH criteria were used as dichotomous variables, only Cornell was significant after adjustments. The dichotomous composite of Sokolow-Lyon and Cornell was also significant after adjustments (hazard ratio for SCD 1.82, 95% confidence interval 1.20-2.70, P = 0.006) and was the only LVH measure that showed statistically significant population-attributable fraction (11.0%, 95% confidence interval 1.9-19.2%, P = 0.019). CONCLUSIONS: Sokolow-Lyon, Cornell, and Peguero-Lo Presti ECG, but not RaVL voltage, are associated with SCD risk as continuous ECG voltage LVH variables. When SCD risk assessment/adjustment is performed using a dichotomous ECG LVH measure, composite of Sokolow-Lyon and Cornell voltages is the preferred option.

Combination of the electrocardiographic strain pattern and albuminuria for the prediction of new-onset heart failure in hypertensive patients: the LIFE study.

BACKGROUND: Although albuminuria and the electrocardiographic (ECG) strain pattern each predict development of heart failure (HF), whether combining albuminuria and strain improves prediction of new HF is unclear. METHODS: The relation of ECG strain and albuminuria to new-onset HF was examined in 7,786 hypertensive patients with no history of HF, who were randomly assigned to treatment with losartan or atenolol. Albuminuria was defined by a urine albumin/creatinine ratio >30.94 mg/g. RESULTS: During a mean follow-up of 4.7 +/- 1.1 years, new-onset HF occurred in 231 patients (3.0%). Five-year HF rate was highest when both strain and albuminuria were present (10.4%), intermediate when only ECG strain (8.0%) or albuminuria (4.9%) was present, and lowest when neither strain nor albuminuria was present at baseline (1.8%, P < 0.0001). In Cox multivariable analyses, controlling for HF risk factors, treatment assignment and baseline severity of ECG left ventricular hypertrophy (LVH) by both Sokolow-Lyon voltage and Cornell product, ECG strain and albuminuria remained significant predictors of incident HF, with the presence of both strain and albuminuria associated with the highest risk (HR 2.8, 95% CI 1.8-4.4) and the presence of only strain (HR 2.6, 95% CI 1.7-4.0) or albuminuria (HR 2.1, 95% CI 1.5-2.8) with intermediate risk of new HF compared with the absence of both strain and albuminuria. CONCLUSIONS: The combination of albuminuria and ECG strain identifies hypertensive patients at an increased risk of developing HF in the setting of aggressive blood pressure lowering, independent of treatment modality and of other risk factors for HF.

Electrocardiographic ventricular repolarization during cardiovascular autonomic function testing in patients with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) experience exercise-related malignant arrhythmias possibly based on delayed repolarization in the diseased right ventricle (RV). Autonomic interventions might unveil repolarization abnormalities in RV. DESIGN: We recorded 25-lead electrocardiograms from nine symptomatic ARVC patients and nine controls during rest, Valsalva maneuver, mental stress, handgrip and supine exercise. Interventricular repolarization gradient was defined as difference of QT intervals between left ventricular (LV) and RV type leads. T-wave peak to T-wave end interval (TPE) was defined as the electrocardiographic (ECG) equivalent of transmural dispersion of repolarization. RESULTS: ARVC patients showed longer QT and TPE intervals in RV than in LV whereas control subjects showed the opposite. Valsalva strain reversed the interventricular repolarization gradient from -5+/-13 to 4+/-20 ms (p<0.02) and induced fluctuation of TPE in ARVC patients. CONCLUSIONS: ARVC patients show ECG interventricular repolarization gradient from RV to LV and increased ECG transmural dispersion of repolarization in RV. Valsalva strain induces fluctuation of interventricular repolarization gradient and of transmural dispersion of repolarization in RV possibly modifying the substrate for arrhythmias.

Electrocardiographic transmural dispersion of repolarization in patients with inherited short QT syndrome.

BACKGROUND: Short QT syndrome (SQTS) carries an increased risk for sudden cardiac death. However, only a short QT interval does not express the risk of ventricular arrhythmias. Thus, additional evaluation of the repolarization abnormality in SQTS patients is essential. In experimental models of SQTS, increased transmural dispersion of repolarization (TDR) and its electrocardiographic counterpart T-wave peak to T-wave end interval (TPE) appeared critical for induction of polymorphic ventricular tachycardia (PMVT). In a clinical study with acquired long QT syndrome patients, TPE/QT ratio > 0.28 indicated arrhythmia risk. We hypothesized that the TPE/QT ratio would be greater in SQTS patients than in control subjects. METHODS AND RESULTS: We compared the behavior of the electrocardiographic TDR in three seriously symptomatic SQTS patients of unknown genotype presenting baseline QTc values < 320 ms and in nine healthy age-matched control subjects. We determined QT and TPE intervals as well as TPE/QT ratio from 24-hour ECG recordings using a computer-assisted program. Diurnal average of TPE/QT ratio was 0.28 +/- 0.03 in SQTS patients and 0.21 +/- 0.02 in control subjects (P = 0.01). SQTS patients had also lesser capacity to change TPE intervals from steady-state conditions to abrupt maximal values than control subjects. CONCLUSION: SQTS patients have increased and autonomically uncontrolled electrocardiographic TDR. According to experimental SQTS models, the present results may in part explain increased vulnerability of SQTS patients to ventricular arrhythmias.

Waveform prototype-based feature learning for automatic detection of the early repolarization pattern in ECG signals.

OBJECTIVE: Our aim was to develop an automated detection method, for prescreening purposes, of early repolarization (ER) pattern with slur/notch configuration in electrocardiogram (ECG) signals using a waveform prototype-based feature vector for supervised classification. APPROACH: The feature vectors consist of fragments of the ECG signal where the ER pattern is located, instead of abstract descriptive variables of ECG waveforms. The tested classifiers included linear discriminant analysis, k-nearest neighbor algorithm, and support vector machine (SVM). MAIN RESULTS: SVM showed the best performance in Friedman tests in our test data including 5676 subjects representing 45 408 leads. Accuracies of the different classifiers showed results well over 90%, indicating that the waveform prototype-based feature vector is an effective representation of the differences between ECG signals with and without the ER pattern. The accuracy of inferior ER was 92.74% and 92.21% for lateral ER. The sensitivity achieved was 91.80% and specificity was 92.73%. SIGNIFICANCE: The algorithm presented here showed good performance results, indicating that it could be used as a prescreening tool of ER, and it provides an additional identification of critical cases based on the distances to the classifier decision boundary, which are close to the 0.1 mV threshold and are difficult to label.

The genetics underlying idiopathic ventricular fibrillation: A special role for catecholaminergic polymorphic ventricular tachycardia?

BACKGROUND: Ventricular fibrillation (VF) is a major cause of sudden cardiac death. In some cases clinical investigations fail to identify the underlying cause and the event is classified as idiopathic (IVF). Since mutations in arrhythmia-associated genes frequently determine arrhythmia susceptibility, screening for disease-predisposing variants could improve IVF diagnostics. METHODS AND RESULTS: The study included 76 Finnish and Italian patients with a mean age of 31.2years at the time of the VF event, collected between the years 1996-2016 and diagnosed with idiopathic, out-of-hospital VF. Using whole-exome sequencing (WES) and next-generation sequencing (NGS) approaches, we aimed to identify genetic variants potentially contributing to the life-threatening arrhythmias of these patients. Combining the results from the two study populations, we identified pathogenic or likely pathogenic variants residing in the RYR2, CACNA1C and DSP genes in 7 patients (9%). Most of them (5, 71%) were found in the RYR2 gene, associated with catecholaminergic polymorphic ventricular tachycardia (CPVT). These genetic findings prompted clinical investigations leading to disease reclassification. Additionally, in 9 patients (11.8%) we detected 10 novel or extremely rare (MAF<0.005%) variants that were classified as of unknown significance (VUS). CONCLUSION: The results of our study suggest that a subset of patients originally diagnosed with IVF may carry clinically-relevant variants in genes associated with cardiac channelopathies and cardiomyopathies. Although misclassification of other cardiac channelopathies as IVF appears rare, our findings indicate that the possibility of CPVT as the underlying disease entity should be carefully evaluated in IVF patients.