Kimmo Porthan

Helsinki University Central Hospital, Helsinki, Southern Finland Province, Finland

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Publications (23)148.9 Total impact

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    ABSTRACT: Left ventricular hypertrophy (LVH) is a strong risk factor for cardiovascular events. ECG is the most widely used method for LVH detection. Despite the abundance of ECG LVH criteria, their prognostic values have been compared in only a few studies, and little has been known about how sex modifies the prognostic value of LVH. We assessed the relationship between ECG LVH and incident cardiovascular events in the general population. Several ECG LVH criteria were measured in 3059 women and 2456 men participating in the Health 2000 Study - a national general population survey. Association between ECG LVH and cardiovascular events were analyzed with Cox proportional-hazards models. ECG LVH was more prevalent in women than in men when measured with Cornell-based criteria, but less prevalent or nondifferent when measured with other criteria. The association between ECG LVH and events showed higher hazard ratios for women than in men. Sex × LVH interaction terms were statistically significant in part of the LVH criteria. In adjusted Cox models, Sokolow-Lyon voltage performed the best. The composite of Sokolow-Lyon voltage and Cornell voltage was statistically significantly associated with events in both sexes. Sex affects both the prevalence rates and prognostic values of ECG LVH criteria in the general population, while showing higher prognostic value of ECG LVH in women than in men. For clinical use, the composite of the Sokolow-Lyon voltage and the Cornell voltage seems to be a good option.
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    ABSTRACT: The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD.
    Nature Genetics 12/2014; DOI:10.1038/ng.3014 · 29.65 Impact Factor
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    ABSTRACT: 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.MethodsA 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.ResultsReaders 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%.
    Annals of Noninvasive Electrocardiology 11/2014; DOI:10.1111/anec.12226 · 1.08 Impact Factor
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    ABSTRACT: QRS transition zone is related to the electrical axis of the heart in the horizontal plane, and is easily determined from the precordial leads of a standard 12-lead ECG. However, it is unclear whether delayed QRS transition, or clockwise rotation of the heart, carries prognostic implications and predicts sudden cardiac death (SCD).
    Heart rhythm: the official journal of the Heart Rhythm Society 08/2014; DOI:10.1016/j.hrthm.2014.08.014 · 4.56 Impact Factor
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    ABSTRACT: BACKGROUND Early repolarization (ER) in the inferior/lateral leads predicts mortality, but whether ER is a specific sign of increased risk for arrhythmic events is not known. OBJECTIVE The purpose of this study was to study the association of ER and arrhythmic events and nonarrhythmic morbidity and mortality. METHODS We assessed the prognostic significance of ER in a community-based general population of 10,846 middle-aged subjects (mean age 44 8 years). The end-points were sustained ventricular tachycardia or resuscitated ventricular fibrillation (VT-VF), arrhythmic death, nonarrhythmic cardiac death, new-onset atrial fibrillation (AF), hospitalization for congestive heart failure, or coronary artery disease during mean follow-up of 30 11 years. ER was defined as >0.1-mV elevation of 3 point in either inferior or lateral leads. RESULTS After including all risk factors of cardiac mortality and morbidity in Cox regression analysis, inferior ER (prevalence 3.5%) predicted VF-VT events (n = 108 [1.0%]) with a hazard ratio (HR) of 2,2 (95% confidence interval [CI] 1.1-4.5, P =.03) but not nonarrhythmic cardiac death (n = 1235 [12.2%]), AF (n = 1659 [15.2%]), congestive heart failure (n = 1752 [16.1%]), or coronary artery disease (n = 3592 [32.9%]) (P = NS for all). Inferior ER predicted arrhythmic death in cases without other QRS complex abnormalities (multivariate HR 1.68, 95 % CI 1.10-2.58, P =.02) but not in those with ER and other coexisting abnormalities in QRS morphology (HR 1.30, 95% CI 0.86-1.96, P =.22). CONCLUSION ER in the inferior leads, especially in cases without other QRS complex abnormalities, predicts the occurrence of VT-VF but not nonarrhythmic cardiac events, suggesting that ER is a specific sign of increased vulnerability to ventricular tachyarrhythmias.
    Heart rhythm: the official journal of the Heart Rhythm Society 05/2014; 11(10). DOI:10.1016/j.hrthm.2014.05.024 · 4.56 Impact Factor
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    ABSTRACT: Background Early repolarization (ER) in the inferior/lateral leads predicts mortality, but it is not known whether ER is a specific sign of increased risk for arrhythmic events. Objectives We studied the association of ER and arrhythmic events and non-arrhythmic morbidity and mortality. Methods We assessed the prognostic significance of ER in a community-based general population of 10,846 middle-aged subjects (mean age 44±8 years). The endpoints were sustained ventricular tachycardia or resuscitated ventricular fibrillation (VT-VF), arrhythmic death, non-arrhythmic cardiac death, new onset atrial fibrillation (AF), hospitalization for congestive heart failure (CHF) or coronary artery disease (CAD) during a mean follow-up of 30±11 years. ER was defined as ≥0.1 mV elevation of J-point in either inferior or lateral leads. Results After including all risk factors of cardiac mortality and morbidity in Cox regression analysis, inferior ER (prevalence 3.5%) predicted VF-VT events (n=108, 1.0%) with a hazard ratio (HR) of 2.2 (95% CI; 1.1-4.5, p=0.03), but not the non-arrhythmic cardiac death (n=1235, 12.2%), AF (n=1659,15.2%), CHF (n=1752, 16.1%) or CAD (n=3592, 32.9%) (NS for all). Inferior ER predicted arrhythmic death in cases without other QRS complex abnormalities (multivariate HR 1.68, 95 % CI; 1.10-2.58, p=0.02) but not in those with ER and other co-existing abnormalities in the QRS morphology (HR 1.30, 95% CI; 0.86-1.96, p=0.22) Conclusions ER in the inferior leads, especially in cases without other QRS complex abnormalities, predicts the occurrence of VT-VF but not non-arrhythmic cardiac events, suggesting that ER is a specific sign of increased vulnerability to ventricular tachyarrhythmias.
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    ABSTRACT: -Previous population studies have found an association between electrocardiographic (ECG) T-wave morphology parameters and cardiovascular mortality but their relationship to sudden cardiac death (SCD) is not clear. To our knowledge, there are no follow-up studies assessing the association between ECG T-wave peak to T-wave end interval (TPE) and SCD. We assessed the predictive value of ECG T-wave morphology parameters and TPE for SCD in an adult general population sample. -A total of four T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, T-wave residuum) as well as TPE were measured from digital standard 12-lead ECGs in 5,618 adults (46% men; mean age 50.9±12.5 years) participating in the Finnish population-based Health 2000 Study. After a mean follow-up time of 7.7±1.4 years, 72 SCDs had occurred. In univariable analyses, all T-wave morphology parameters were associated with an increased SCD risk. In multivariable Cox models, T-wave morphology dispersion and total cosine R-to-T remained as predictors of SCD, with T-wave morphology dispersion showing the highest SCD risk (hazard ratio of 1.4 [95% confidence interval 1.1-1.7, P=0.001] per 1-standard deviation increase in the loge TMD). In contrast, TPE was not associated with SCD in univariable or multivariable analyses. -ECG T-wave morphology parameters describing the three-dimensional shape of the T wave stratify SCD risk in the general population but we did not find an association between TPE and SCD.
    Circulation Arrhythmia and Electrophysiology 07/2013; 6(4). DOI:10.1161/CIRCEP.113.000356 · 5.95 Impact Factor
  • Journal of the American College of Cardiology 07/2013; 62(17). DOI:10.1016/j.jacc.2013.07.015 · 15.34 Impact Factor
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    ABSTRACT: Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10-8). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.The Pharmacogenomics Journal advance online publication, 5 March 2013; doi:10.1038/tpj.2013.4.
    The Pharmacogenomics Journal 03/2013; DOI:10.1038/tpj.2013.4 · 5.13 Impact Factor
  • Annals of Emergency Medicine 10/2012; 60(4):S8-S9. DOI:10.1016/j.annemergmed.2012.06.048 · 4.33 Impact Factor
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    ABSTRACT: The early repolarization pattern (ERP) is common and associated with risk of sudden cardiac death. ERP is heritable, and mutations have been described in syndromatic cases. To conduct a meta-analysis of genome-wide association studies to identify common genetic variants influencing ERP. We ascertained ERP on the basis of electrocardiograms in 3 large community-based cohorts from Europe and the United States: the Framingham Heart Study, the Health 2000 Study, and the KORA F4 Study. We analyzed genome-wide association studies in participants with and without ERP by logistic regression assuming an additive genetic model and meta-analyzed individual cohort results. We then sought to strengthen support for findings that reached P ≤ 1 × 10(-5) in independent individuals by direct genotyping or in-silico analysis of genome-wide data. We meta-analyzed the results from both stages. Of 7482 individuals in the discovery stage, 452 showed ERP (ERP positive: mean age 46.9 ± 8.9 years, 30.3% women; ERP negative: 47.5 ± 9.4 years, 54.2% women). After meta-analysis, 8 single nucleotide polymorphisms reached P ≤ 1 × 10(-5): The most significant finding was intergenic rs11653989 (odds ratio 0.47; 95% confidence interval 0.36-0.61; P = 6.9 × 10(-9)). The most biologically relevant finding was intronic to KCND3: rs17029069 (odds ratio 1.46; 95% confidence interval 1.25-1.69; P = 8.5 × 10(-7)). In the replication step (7151 individuals), none of the 8 variants replicated, and combined meta-analysis results failed to reach genome-wide significance. In a genome-wide association study, we were not able to reliably identify genetic variants predisposing to ERP, presumably due to insufficient statistical power and phenotype heterogeneity. The reported heritability of ERP warrants continued investigation in larger well-phenotyped populations.
    Heart rhythm: the official journal of the Heart Rhythm Society 06/2012; 9(10):1627-34. DOI:10.1016/j.hrthm.2012.06.008 · 4.56 Impact Factor
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    ABSTRACT: T-peak to T-end (TPE) interval on the electrocardiogram is a measure of myocardial dispersion of repolarization and is associated with an increased risk of ventricular arrhythmias. The genetic factors affecting the TPE interval are largely unknown. To identify common genetic variants that affect the duration of the TPE interval in the general population. We performed a genome-wide association study on 1870 individuals of Finnish origin participating in the Health 2000 Study. The TPE interval was measured from T-peak to T-wave end in leads II, V(2), and V(5) on resting electrocardiograms, and the mean of these TPE intervals was adjusted for age, sex, and Cornell voltage-duration product. We sought replication for a genome-wide significant result in the 3745 subjects from the Framingham Heart Study. We identified a locus on 17q24 that was associated with the TPE interval. The minor allele of the common variant rs7219669 was associated with a 1.8-ms shortening of the TPE interval (P = 1.1 × 10(-10)). The association was replicated in the Framingham Heart Study (-1.5 ms; P = 1.3 × 10(-4)). The overall effect estimate of rs7219669 in the 2 studies was -1.7 ms (P = 5.7 × 10(-14)). The common variant rs7219669 maps downstream of the KCNJ2 gene, in which rare mutations cause congenital long and short QT syndromes. The common variant rs7219669 is associated with the TPE interval and is thus a candidate to modify repolarization-related arrhythmia susceptibility in individuals carrying the major allele of this polymorphism.
    Heart rhythm: the official journal of the Heart Rhythm Society 02/2012; 9(7):1099-103. DOI:10.1016/j.hrthm.2012.02.019 · 4.56 Impact Factor
  • Article: Reply.
    Journal of the American College of Cardiology 10/2011; 58(17):1830-1. DOI:10.1016/j.jacc.2011.07.027 · 15.34 Impact Factor
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    ABSTRACT: Although sudden cardiac death (SCD) is heritable, its genetic underpinnings are poorly characterized. The QT interval appears to have a graded relationship to SCD, and 35% to 45% of its variation is heritable. We examined the relationship among recently reported common genetic variants, QT interval, and SCD. We genotyped 15 common (minor allele frequency >1%) candidate single nucleotide polymorphisms (SNPs), based on association with the QT interval in prior studies, in individuals in 2 cohort studies (Health 2000, n = 6597; Mini-Finland, n = 801). After exclusions, we identified 116 incident SCDs from the remaining sample (n = 6808). We constructed a QT genotype score (QT(score)) using the allele copy number and previously reported effect estimates for each SNP. Cox proportional hazards models adjusting for age, sex, and geographical area were used for time to SCD analyses. The QT(score) was a continuous independent predictor of the heart rate-corrected QT interval (P<10(-107)). Comparing the top with the bottom quintile of QT(score), there was a 15.6-ms higher group mean QT interval (P<10(-84)). A 10-ms increase in the observed QT interval was associated with an increased risk of SCD (hazard ratio, 1.19; 95% confidence interval, 1.07 to 1.32; P = 0.002). There was no linear relationship between QT(score) and SCD risk; although in post hoc secondary analysis there was increased risk in the top compared with the middle QT(score) quintile (hazard ratio, 1.92; 95% confidence interval, 1.05 to 3.58; P = 0.04). Our study strongly replicates the relationship between common genetic variants and the QT interval and confirms the relationship between the QT interval and SCD but does not show evidence for a linear relationship between QT(score) and SCD risk.
    Circulation Cardiovascular Genetics 06/2011; 4(3):305-11. DOI:10.1161/CIRCGENETICS.110.959049 · 5.34 Impact Factor
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    ABSTRACT: This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. There is growing recognition that ERP is associated with adverse outcomes. Participants of the Framingham Heart Study (FHS) (N = 3,995) and the Health 2000 Survey (H2K) (N = 5,489) were included. ERP was defined as a J-point elevation ≥0.1 mV in ≥2 leads in either the inferior (II, III, aVF) or lateral (I, aVL, V(4-6)) territory or both. We tested the association between clinical characteristics and ERP, and estimated sibling recurrence risk. ERP was present in 243 of 3,955 (6.1%) of FHS and 180 of 5,489 (3.3%) of H2K subjects. Male sex, younger age, lower systolic blood pressure, higher Sokolow-Lyon index, and lower Cornell voltage were independently associated with the presence of ERP. In the FHS sample, siblings of individuals with ERP had an ERP prevalence of 11.6% (recurrence risk ratio of 1.89). Siblings of individuals with ERP had an increased unadjusted odds of ERP (odds ratio: 2.22, 95% confidence interval: 1.01 to 4.85, p = 0.047). ERP has strong association with clinical factors and has evidence for a heritable basis in the general population. Further assessment of the genetic determinants of ERP is warranted.
    Journal of the American College of Cardiology 05/2011; 57(22):2284-9. DOI:10.1016/j.jacc.2011.04.003 · 15.34 Impact Factor
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    ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive myocardial disorder caused by mutations of desmosomal cell adhesion proteins. The prevalence of these variants in the general population is unknown. This study examined the spectrum and population prevalence of desmosomal mutations predisposing to ARVC in Finland. We screened 29 Finnish ARVC probands for mutations in the DSP, DSG2, and DSC2 genes. All Finnish-type ARVC-associated mutations, including those 3 previously identified in PKP2 in the same patient group, were analyzed in the population-based Health 2000 cohort of 6,334 individuals and tested for association with electrocardiographic variables. We detected 2 novel mutations: DSG2 3059_3062delAGAG and DSP T1373A. DSG2 3059_3062delAGAG was present in a family with 5 mutation carriers. The endomyocardial samples of the DSG2 deletion carrier showed reduced immunoreactive signal for desmoglein-2, plakophilin-2, plakoglobin, and desmoplakin. DSP T1373A was found in 1 proband with typical right ventricular disease and exercise-related ventricular tachycardia. In the population sample, the collective prevalence of all 5 mutations identified in the 29 ARVC patients (PKP2 Q62K, Q59L, N613K, DSG2 3059_3062delAGAG, and DSP T1373A) was 31 of 6,334 individuals, or 0.5%. The apparent founder mutation PKP2 Q59L is present in 0.3% of Finns and was previously shown to have an approximately 20% disease penetrance. One of 200 Finns carries a desmosomal mutation that may predispose to ARVC and its clinical sequelae. ARVC-associated mutations may thus be more prevalent in the population than expected based on the published ARVC prevalence data.
    Heart rhythm: the official journal of the Heart Rhythm Society 03/2011; 8(8):1214-21. DOI:10.1016/j.hrthm.2011.03.015 · 4.56 Impact Factor
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    ABSTRACT: Single-nucleotide polymorphisms (SNPs) in genes encoding cardiac ion channels and nitric oxide synthase-1 adaptor protein (NOS1AP) are associated with electrocardiographic (ECG) QT-interval duration, but the association of these SNPs with new, prognostically important ECG measures of ventricular repolarization is unknown. The purpose of this study was to examine the relationship of SNPs to ECG T-wave peak to T-wave end (TPE) interval and T-wave morphology parameters. We studied 5,890 adults attending the Health 2000 Study, a Finnish epidemiologic survey. TPE interval and four T-wave morphology parameters were measured from digital 12-lead ECGs and related to the seven SNPs showing a phenotypic effect on QT-interval duration in the Health 2000 Study population. In multivariable analyses, the KCNH2 K897T minor allele was associated with a 1.2-ms TPE-interval shortening (P = .00005) and the KCNH2 intronic rs3807375 minor allele was associated with a 0.8-ms TPE-interval prolongation (P = .001), whereas the KCNE1 D85N variant had no TPE-interval effect (P = .20). NOS1AP minor alleles (rs2880058, rs4657139, rs10918594, rs10494366) were associated with a shorter TPE interval (effects from 0.5 to 0.8 ms, P from .032 to .002), which resulted from their stronger effects on QT(peak) than QT(end) interval. None of the SNPs showed a consistent association with T-wave morphology parameters. KCNH2 K897T and rs3807375 as well as the four studied NOS1AP variants have modest effects on ECG TPE interval but are not related to T-wave morphology measures. The previously observed prognostic value of T-wave morphology parameters likely is not based on these SNPs.
    Heart rhythm: the official journal of the Heart Rhythm Society 03/2010; 7(7):898-903. DOI:10.1016/j.hrthm.2010.03.002 · 4.56 Impact Factor
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    ABSTRACT: The predictive value of ECG QT interval for mortality in the general population has been weak. Only a few population studies on the predictive value of ECG T-wave morphology parameters for mortality have been reported. The purpose of this study was to examine the predictive value of ECG QT interval and T-wave morphology parameters for all-cause and cardiovascular mortality in the general population. The prognostic values of ECG QT interval and four T-wave morphology parameters (principal component analysis ratio, T-wave morphology dispersion, total cosine R-to-T, T-wave residuum) were assessed in 5,917 adults (45% men; age 52 +/- 14 years) participating in the Finnish population-based Health 2000 Study. After a mean follow-up of 5.9 +/- 0.8 years, 335 deaths had occurred, including 131 cardiovascular deaths. QT interval and, with a few exceptions, all T-wave morphology parameters were significant univariate mortality predictors. In men, in Cox multivariate analyses, principal component analysis ratio and T-wave morphology dispersion remained as independent predictors of all-cause and cardiovascular mortality, with the above-median T-wave morphology dispersion group showing the highest risk of cardiovascular death (hazard ratio [HR] 4.4, 95% confidence interval [CI] 2.1-9.4). In women, independent mortality predictors were total cosine R-to-T (cardiovascular mortality) and T-wave residuum (all-cause and cardiovascular mortality), with the above-median T-wave residuum group showing the highest risk of cardiovascular death (HR 2.2, 95% CI 1.1-4.2). In the general population, T-wave morphology parameters, but not heart rate-corrected QT interval, provide independent prognostic information on mortality. The prognostic value of T-wave morphology parameters is specifically related to cardiovascular mortality and seems to be gender specific.
    Heart rhythm: the official journal of the Heart Rhythm Society 09/2009; 6(8):1202-8, 1208.e1. DOI:10.1016/j.hrthm.2009.05.006 · 4.56 Impact Factor
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    ABSTRACT: Background and aim. Hypertension-induced left ventricular structural remodelling associates with repolarization abnormalities. We investigated if antihypertensive drugs can modulate ventricular repolarization. Methods. A total of 183 hypertensive men received for 4 weeks drugs (losartan 50 mg, bisoprolol 5 mg, amlodipine 5 mg, hydrochlorothiazide (HCTZ) 25 mg) in a randomized order, separated by 4-week placebo periods. Electrocardiograms (ECG) were recorded at the end of placebo and drug periods. Measurements of repolarization duration (QT intervals), repolarization heterogeneity (T-wave peak to T-wave end (TPE) intervals), and T-wave morphology (T-wave principal component analysis (PCA) ratio, T-wave morphology dispersion (TMD), and total cosine R-to-T (TCRT)) during each drug were compared to placebo measurements. Results. Losartan and bisoprolol shortened maximum and mean rate-adjusted QT intervals as well as mean TPE interval, decreased TMD, and increased TCRT. Losartan also shortened precordial maximum TPE interval and decreased PCA ratio. Amlodipine had no repolarization effects, whereas HCTZ prolonged precordial maximum TPE interval and mean TPE interval. Conclusion. Losartan and bisoprolol have beneficial short-term ECG repolarization effects. Amlodipine seems to have no repolarization effects. HCTZ seems to prolong the ECG TPE interval, potentially reflecting increased repolarization heterogeneity. These findings show that antihypertensive drugs may relatively rapidly and treatment-specifically modulate ECG markers of ventricular repolarization.
    Annals of Medicine 07/2009; 41(1):29-37. DOI:10.1080/07853890802195211 · 4.73 Impact Factor