Genome-wide association study of nocturnal blood pressure dipping in hypertensive patients.

BACKGROUND: Reduced nocturnal fall (non-dipping) of blood pressure (BP) is a predictor of cardiovascular target organ damage. No genome-wide association studies (GWAS) on BP dipping have been previously reported. METHODS: To study genetic variation affecting BP dipping, we conducted a GWAS in Genetics of Drug Responsiveness in Essential Hypertension (GENRES) cohort (n = 204) using the mean night-to-day BP ratio from up to four ambulatory BP recordings conducted on placebo. Associations with P < 1 × 10- 5 were further tested in two independent cohorts: Haemodynamics in Primary and Secondary Hypertension (DYNAMIC) (n = 183) and Dietary, Lifestyle and Genetic determinants of Obesity and Metabolic Syndrome (DILGOM) (n = 180). We also tested the genome-wide significant single nucleotide polymorphism (SNP) for association with left ventricular hypertrophy in GENRES. RESULTS: In GENRES GWAS, rs4905794 near BCL11B achieved genome-wide significance (ß = - 4.8%, P = 9.6 × 10- 9 for systolic and ß = - 4.3%, P = 2.2 × 10- 6 for diastolic night-to-day BP ratio). Seven additional SNPs in five loci had P values < 1 × 10- 5. The association of rs4905794 did not significantly replicate, even though in DYNAMIC the effect was in the same direction (ß = - 0.8%, P = 0.4 for systolic and ß = - 1.6%, P = 0.13 for diastolic night-to-day BP ratio). In GENRES, the associations remained significant even during administration of four different antihypertensive drugs. In separate analysis in GENRES, rs4905794 was associated with echocardiographic left ventricular mass (ß = - 7.6 g/m2, P = 0.02). CONCLUSIONS: rs4905794 near BCL11B showed evidence for association with nocturnal BP dipping. It also associated with left ventricular mass in GENRES. Combined with earlier data, our results provide support to the idea that BCL11B could play a role in cardiovascular pathophysiology.

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%.

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.

Short-term implantation-related complications of cardiac rhythm management device therapy: a retrospective single-centre 1-year survey.

AIMS: The aim of this study was to evaluate the current short-term (<3 months) complication rate related to cardiac rhythm management (CRM) device implantations. METHODS AND RESULTS: We analysed data of the complications related to all CRM device implantations during 1 year (2006) in a tertiary referral university hospital. In 567 device implantations, pacing system upgrade procedures, or lead revisions, 78 complications occurred in 69 (12.2%) patients. Lead dislodgement, pocket haematoma or bleeding, pneumothorax, and infection were the most common accounting for >80% of all complications. The complication rate was more than twice as high in bradycardia pacemaker (PM) implantations performed by cardiology trainees (17.4%) than by experienced cardiologists (7.7%, P = 0.001). When performed by experienced cardiologists, the complication rate was not higher in implantations of more complex devices compared with that of bradycardia PMs. Fifty-two of the 69 patients needed additional surgical procedures. Altogether, the complications required 504 additional treatment days in hospital. CONCLUSION: In conclusion, our retrospective 1-year single-centre survey shows that short-term implantation-related complications of contemporary device therapy are still frequent, occur much more frequently by trainees than by cardiologists, require a large number of additional surgical procedures, and substantially prolong the hospital stay.

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.

Effect of four classes of antihypertensive drugs on cardiac repolarization heterogeneity: A double-blind rotational study.

BACKGROUND: T-wave area dispersion (TW-Ad) is a novel electrocardiographic (ECG) repolarization marker associated with sudden cardiac death. However, limited data is available on the clinical correlates of TW-Ad. In addition, there are no previous studies on cardiovascular drug effects on TW-Ad. In this study, we examined the relation between TW-Ad and left ventricular mass. We also studied the effects of four commonly used antihypertensive drugs on TW-Ad. METHODS: A total of 242 moderately hypertensive males (age, 51±6 years; office systolic/diastolic blood pressure during placebo, 153±14/100±8 mmHg), participating in the GENRES study, were included. Left ventricular mass index was determined by transthoracic echocardiography. Antihypertensive four-week monotherapies (a diuretic, a beta-blocker, a calcium channel blocker, and an angiotensin receptor antagonist) were administered in a randomized rotational fashion. Four-week placebo periods preceded all monotherapies. The average value of measurements (over 1700 ECGs in total) from all available placebo periods served as a reference to which measurements during each drug period were compared. RESULTS: Lower, i.e. risk-associated TW-Ad values correlated with a higher left ventricular mass index (r = -0.14, p = 0.03). Bisoprolol, a beta-blocker, elicited a positive change in TW-Ad (p = 1.9×10-5), but the three other drugs had no significant effect on TW-Ad. CONCLUSIONS: Our results show that TW-Ad is correlated with left ventricular mass and can be modified favorably by the use of bisoprolol, although demonstration of any effects on clinical endpoints requires long-term prospective studies. Altogether, our results suggest that TW-Ad is an ECG repolarization measure of left ventricular arrhythmogenic substrate.

Human essential hypertension: no significant association of polygenic risk scores with antihypertensive drug responses.

Polygenic risk scores (PRSs) for essential hypertension, calculated from > 900 genomic loci, were recently found to explain a significant fraction of hypertension heritability and complications. To investigate whether variation of hypertension PRS also captures variation of antihypertensive drug responsiveness, we calculated two different PRSs for both systolic and diastolic blood pressure: one based on the top 793 independent hypertension-associated single nucleotide polymorphisms and another based on over 1 million genome-wide variants. Using our pharmacogenomic GENRES study comprising four different antihypertensive monotherapies (n ~ 200 for all drugs), we identified a weak, but (after Bonferroni correction) statistically nonsignificant association of higher genome-wide PRSs with weaker response to a diuretic. In addition, we noticed a correlation between high genome-wide PRS and electrocardiographic left ventricular hypertrophy. Finally, using data of the Finnish arm of the LIFE study (n = 346), we found that PRSs for systolic blood pressure were slightly higher in patients with drug-resistant hypertension than in those with drug-controlled hypertension (p = 0.03, not significant after Bonferroni correction). In conclusion, our results indicate that patients with elevated hypertension PRSs may be predisposed to difficult-to-control hypertension and complications thereof. No general association between a high PRS and less efficient drug responsiveness was noticed.

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.

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.

Repolarization Heterogeneity Measured With T-Wave Area Dispersion in Standard 12-Lead ECG Predicts Sudden Cardiac Death in General Population.

BACKGROUND: We developed a novel electrocardiographic marker, T-wave area dispersion (TW-Ad), which measures repolarization heterogeneity by assessing interlead T-wave areas during a single cardiac cycle and tested whether it can identify patients at risk for sudden cardiac death (SCD) in the general population. METHODS AND RESULTS: TW-Ad was measured from standard digital 12-lead ECG in 5618 adults (46% men; age, 50.9±12.5 years) participating in the Health 2000 Study-an epidemiological survey representative of the Finnish adult population. Independent replication was performed in 3831 participants of the KORA S4 Study (Cooperative Health Research in the Region of Augsburg; 49% men; age, 48.7±13.7 years; mean follow-up, 8.8±1.1 years). During follow-up (7.7±1.4 years), 72 SCDs occurred in the Health 2000 Survey. Lower TW-Ad was univariately associated with SCD (0.32±0.36 versus 0.60±0.19; P<0.001); it had an area under the receiver operating characteristic curve of 0.809. TW-Ad (≤0.46) conferred a hazard ratio of 10.8 (95% confidence interval, 6.8-17.4; P<0.001) for SCD; it remained independently predictive of SCD after multivariable adjustment for clinical risk markers (hazard ratio, 4.6; 95% confidence interval, 2.7-7.4; P<0.001). Replication analyses performed in the KORA S4 Study confirmed an increased risk for cardiac death (unadjusted hazard ratio, 5.5; 95% confidence interval, 3.2-9.5; P<0.001; multivariable adjusted hazard ratio, 1.9; 95% confidence interval, 1.1-3.5; P<0.05). CONCLUSION: Low TW-Ad, reflecting increased heterogeneity of repolarization, in standard 12-lead resting ECGs is a powerful and independent predictor of SCD in the adult general population.

Electrocardiographic strain pattern and prediction of new-onset congestive heart failure in hypertensive patients: the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study.

BACKGROUND: The ECG strain pattern of ST depression and T-wave inversion is strongly associated with left ventricular hypertrophy (LVH) independently of coronary heart disease and with an increased risk of cardiovascular morbidity and mortality in hypertensive patients. However, whether ECG strain is an independent predictor of new-onset congestive heart failure (CHF) in the setting of aggressive antihypertensive therapy in unclear. METHODS AND RESULTS: The relationship of ECG strain at study baseline to the development of CHF was examined in 8696 patients with no history of CHF who were enrolled in the Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study. All patients had ECG LVH by Cornell product and/or Sokolow-Lyon voltage criteria on a screening ECG, were treated in a blinded manner with atenolol- or losartan-based regimens, and were followed up for a mean of 4.7+/-1.1 years. Strain was defined as a downsloping convex ST segment with inverted asymmetrical T-wave opposite the QRS axis in lead V5 or V6. ECG strain was present in 923 patients (10.6%), and new-onset CHF occurred in 265 patients (3.0%), 26 of whom had a CHF-related death. Compared with patients who did not develop CHF, hypertensive patients who developed CHF were older; were more likely to be black, current smokers, and diabetic; were more like to have a history of myocardial infarction, ischemic heart disease, stroke, or peripheral vascular disease; and had greater baseline severity of LVH by Cornell product and Sokolow-Lyon voltage, higher baseline body mass indexes, higher serum glucose levels and albuminuria, similar baseline systolic and diastolic pressures, and reductions in diastolic pressure with treatment but greater reductions in systolic pressure. In univariate Cox analyses, ECG strain was a significant predictor of new-onset CHF (hazard ratio [HR], 3.27; 95% CI, 2.49 to 4.29) and CHF mortality (HR, 4.74; 95% CI, 2.11 to 10.64). In Cox multivariable analyses adjusting for baseline differences between patients with and without new-onset CHF, in-treatment differences in systolic and diastolic pressures, Sokolow-Lyon voltage, and Cornell product, and the impact of treatment with losartan versus atenolol on outcomes, ECG strain remained a significant predictor of incident CHF (HR, 1.80; 95% CI, 1.30 to 2.48) and CHF-related death (HR, 2.78; 95% CI, 1.02 to 7.63). CONCLUSIONS: ECG strain identifies hypertensive patients at increased risk of developing CHF and dying as a result of CHF, even in the setting of aggressive blood pressure lowering.

Relationship of electrocardiographic repolarization measures to echocardiographic left ventricular mass in men with hypertension.

OBJECTIVE: Arterial hypertension often leads to an increase in left ventricular mass (LVM). Marked left ventricular hypertrophy (LVH) is associated with potentially arrhythmogenic ventricular repolarization abnormalities, which may contribute to the increased risk of sudden cardiac death in this disorder. We studied whether electrocardiographic repolarization changes are already detectable in mild LVM increase associated with hypertension. METHODS: In 220 men (mean age 51+/-6 years) attending the GENRES hypertension study, we measured QT intervals (QTend and QTpeak), T-wave peak to T-wave end (TPE) intervals, and novel T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, and T-wave residuum) from a digital standard 12-lead electrocardiogram, and related them to echocardiographically determined LVM. RESULTS: In this group of moderately hypertensive men, the mean LVM index (LVMI; LVM divided by body surface area) was 99+/-19 g/m2, with only 18% of the subjects showing evidence of echocardiographic LVH (LVMI>116 g/m2). LVMI correlated significantly with QT intervals (r=0.16-0.21, P=0.018-0.002), TPE intervals (r=0.23-0.27, P<0.001), and T-wave morphology parameters (r=0.22-0.39, P<0.001). Except for the QTpeak interval, the relationship between LVMI and electrocardiographic repolarization parameters was independent in multivariate analyses. CONCLUSION: Altered electrocardiographic ventricular repolarization, indicating reduced repolarization reserve and possibly increased repolarization heterogeneity, is already present in hypertensive men with only mild LVM increase. At a population level, this may carry important risk implications for the large group of hypertensive patients.

Changing capacity of electrocardiographic ventricular repolarization in post-myocardial infarction patients with and without nonfatal cardiac arrest.

Prolonged and labile ventricular repolarization and decreased heart rate variability may be associated with susceptibility to ventricular fibrillation (VF) after myocardial infarction (MI). The response of ventricular repolarization related to abrupt heart rate changes may also be associated with arrhythmia vulnerability. We investigated whether diurnal maximal values or changing capacities of QT and T-wave peak to T-wave end (TPE) intervals are different in patients after MI with and without a history of VF. With an automated computerized program, Holter recordings from 29 patients after MI resuscitated from VF not associated with new MI (VF group) and 27 patients after MI without clinical ventricular arrhythmias (control group) were analyzed. Maximal QT and maximal TPE intervals were shorter in the VF group than in the control group. Patients with VF exhibited smaller capacity to change QT and TPE intervals, with differences between study groups being greatest at heart rates from 60 to 75 beats/min (p = 0.002 and 0.01, respectively). Capacity to change QT and TPE intervals correlated with vagally mediated measurements of heart rate variability (r from 0.35 to 0.46, p from 0.01 to <0.001, respectively). In conclusion, long maximal QT interval may not be the key factor exposing patients after MI to VF. Impaired capacity to change QT and TPE intervals seems to be associated with risk of VF after MI.

Electrocardiographic strain pattern and left ventricular diastolic function in hypertensive patients with left ventricular hypertrophy: the LIFE study.

BACKGROUND: Whether the typical electrocardiographic (ECG) strain pattern (Strain, in leads V5 and/or V6), which is associated with left ventricular hypertrophy (LVH) and LV systolic dysfunction, is independently associated with LV diastolic dysfunction is unknown. METHODS: The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study enrolled hypertensive patients with ECG-LVH, of whom 10% underwent Doppler echocardiography. LV diastolic function measures included peak mitral E and A wave velocities and their ratio (E/A); E wave deceleration time (EDT); atrial filling fraction (AFF); and isovolumic relaxation time (IVRT). Normal filling pattern was defined by E/A < 1 with EDT >or= 150 and or=60 ms; abnormal relaxation by E/A < 1 with EDT > 250 ms or IVRT > 100 ms; pseudonormal filling pattern by E/A >or= 1 associated with IVRT > 100 ms or EDT > 250 ms; restrictive pattern by E/A >or= 1 with IVRT < 100 ms and EDT < 250 ms. A combined index of LV systolic-diastolic function was also computed (isovolumic time/ejection time, modified myocardial performance index). Of LIFE echo substudy participants with all needed ECG and Doppler data (n = 791), 110 (14%) had Strain. RESULTS: Strain was associated with male gender, African-American race, diabetes, history of coronary heart disease (CHD), higher systolic blood pressure (BP), LV mass and relative wall thickness, and higher prevalences of echo-LV hypertrophy and wall motion abnormalities, and with slower heart rate (all P < 0.05). Age, diastolic BP and LV ejection fraction were similar in patients with or without Strain. Diastolic parameters, and prevalences of different LV filling patterns, did not differ significantly between patients with versus those without Strain (all P > 0.1), but modified myocardial performance index was higher with Strain (P < 0.05). Findings were consistent in multivariate analyses. The association of Strain with higher modified myocardial performance index was no longer statistically significant after accounting for LV systolic function and wall motion abnormalities. CONCLUSIONS: In hypertensive patients with ECG-LVH, the ECG Strain pattern did not identify independently those with more severe LV diastolic abnormalities.

Reductions in albuminuria and in electrocardiographic left ventricular hypertrophy independently improve prognosis in hypertension: the LIFE study.

BACKGROUND: In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, reduced urine albumin/creatinine ratio (UACR) as well as regression of left ventricular hypertrophy have been associated with lower incidence of cardiovascular events. We wanted to investigate whether these prognostic improvements were independent. METHODS: In 6679 hypertensive patients included in the LIFE study, we measured UACR, left ventricular hypertrophy by electrocardiography, serum cholesterol, plasma glucose and blood pressure after 2 weeks of placebo treatment and again after 1 year of anti-hypertensive treatment with either an atenolol- or a losartan-based regimen. During this first year of treatment, 77 patients encountered a non-fatal stroke or myocardial infarction and were excluded to avoid bias. During the next 3-4 years, 610 composite endpoints [cardiovascular death (n = 228), fatal or non-fatal myocardial infarction or stroke] were recorded. RESULTS: In Cox regression analyses, the composite endpoint was after adjustment for treatment allocation predicted by baseline logUACR [hazard ratio (HR) = 1.16 per 10-fold increase, P < 0.05], 1-year logUACR (HR = 1.29 per 10-fold increase), baseline Sokolow-Lyon voltage (HR = 1.01 per mm, both P < 0.001) and 1-year Cornell product (HR = 1.01 per 100 mm x ms, P < 0.01). Cardiovascular death was predicted by 1-year logUACR (HR = 1.59, P < 0.001), baseline Sokolow-Lyon voltage (HR = 1.01, P = 0.06) and 1-year Cornell product (HR = 1.02, P < 0.001). Both were predicted independent of age, Framingham risk score, current smoking, history of cardiovascular disease and diabetes. Gender, serum cholesterol, plasma glucose and blood pressure did not enter the models. CONCLUSIONS: Baseline UACR and Sokolow-Lyon voltage, as well as in-treatment UACR and Cornell product, added to the risk prediction independent of traditional risk factors, indicating that albuminuria and left ventricular hypertrophy reflect different aspects of cardiovascular damage and are modifiable cardiovascular risk factors.

Prediction of sudden cardiac death with automated high-throughput analysis of heterogeneity in standard resting 12-lead electrocardiograms.

BACKGROUND: Heterogeneity of depolarization and repolarization underlies the development of lethal arrhythmias. OBJECTIVE: We investigated whether quantification of spatial depolarization and repolarization heterogeneity identifies individuals at risk for sudden cardiac death (SCD). METHODS: Spatial R-, J-, and T-wave heterogeneity (RWH, JWH, and TWH, respectively) was analyzed using automated second central moment analysis of standard digital 12-lead electrocardiograms in 5618 adults (2588, 46% men; mean ± SEM age 50.9 ± 0.2 years), who took part in the epidemiological Health 2000 Survey as representative of the entire Finnish adult population. RESULTS: During the follow-up period of 7.7 ± 0.2 years, a total of 72 SCDs occurred (1.3%), with an average yearly incidence rate of 0.17% per year. Increased RWH, JWH, and TWH in left precordial leads (V4-V6) were univariately associated with SCD (P < .001 for each). When adjusted with standard clinical risk markers, JWH and TWH remained independent predictors of SCD. Increased TWH (≥102 µV) was associated with a 1.7-fold adjusted relative risk for SCD (95% confidence interval [CI] 1.0-2.9; P = .048) and increased JWH (≥123 µV) with a 2.0-fold adjusted relative risk for SCD (95% CI 1.2-3.3; P = .006). When both TWH and JWH were above the threshold, the adjusted relative risk for SCD was 2.9-fold (95% CI 1.5-5.7; P = .002). When RWH (≥470 µV), JWH, and TWH were all above the threshold, the adjusted relative risk for SCD was 3.2-fold (95% CI 1.4-7.1; P = .009). CONCLUSION: Second central moment analysis of standard resting 12-lead electrocardiographic morphology provides an ultrarapid means for the automated measurement of spatial RWH, JWH, and TWH, enabling analysis of high subject volumes and screening for SCD risk in the general population.

Ambulatory electrocardiographic evidence of transmural dispersion of repolarization in patients with long-QT syndrome type 1 and 2.

BACKGROUND: Transmural dispersion of repolarization (TDR) may be related to the genesis of torsade de pointes (TdP) in patients with the long-QT (LQT) syndrome. Experimentally, LQT2 models show increased TDR compared with LQT1, and beta-adrenergic stimulation increases TDR in both models. Clinically, LQT1 patients experience symptoms at elevated heart rates, but LQT2 patients do so at lower rates. The interval from T-wave peak to T-wave end (TPE interval) is the clinical counterpart of TDR. We explored the relationship of TPE interval to heart rate and to the presence of symptoms in patients with LQT1 and LQT2. METHODS AND RESULTS: We reviewed Holter recordings from 90 genotyped subjects, 31 with LQT1, 28 with LQT2, and 31 from unaffected family members, to record TPE intervals by use of an automated computerized program. The median TPE interval was greater in LQT2 (112+/-5 ms) than LQT1 (91+/-2 ms) or unaffected (86+/-3 ms) patients (P<0.001 for all group comparisons), and the maximal TPE values differed as well. LQT1 patients showed abrupt increases in TPE values at RR intervals from 600 to 900 ms, but LQT2 patients did so at RR intervals from 600 to 1400 ms (longest RR studied). Asymptomatic and symptomatic patients showed similar TDRs. CONCLUSIONS: TDR is greater in LQT2 than in LQT1 patients. LQT1 patients showed a capacity to increase TDR at elevated heart rates, but LQT2 patients did so at a much wider rate range. The magnitude of TDR is not related to a history of TdP.