Heikki Väänänen

Primary cilia of human endothelial cells disassemble under laminar shear stress

We identified primary cilia and centrosomes in cultured human umbilical vein endothelial cells (HUVEC) by antibodies to acetyl-α-tubulin and capillary morphogenesis gene-1 product (CMG-1), a human homologue of the intraflagellar transport (IFT) protein IFT-71 in Chlamydomonas. CMG-1 was present in particles along primary cilia of HUVEC at interphase and around the oldest basal body/centriole at interphase and mitosis. To study the response of primary cilia and centrosomes to mechanical stimuli, we exposed cultured HUVEC to laminar shear stress (LSS). Under LSS, all primary cilia disassembled, and centrosomes were deprived of CMG-1. We conclude that the exposure to LSS ends the IFT in cultured endothelial cells.

The early repolarization pattern in the general population: clinical correlates and heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS 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. RESULTS 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). CONCLUSIONS 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.

Expedited PublicationThe Early Repolarization Pattern in the General Population: Clinical Correlates and Heritability

OBJECTIVES This study sought to describe the clinical correlates and heritability of the early repolarization pattern (ERP) in 2 large, population-based cohorts. BACKGROUND There is growing recognition that ERP is associated with adverse outcomes. METHODS 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. RESULTS 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). CONCLUSIONS 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.

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 &bgr;-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.

High prevalence of four long QT syndrome founder mutations in the Finnish population

Aims. Long QT syndrome (LQTS) is an inherited arrhythmia disorder with an estimated prevalence of 0.01%–0.05%. In Finland, four founder mutations constitute up to 70% of the known genetic spectrum of LQTS. In the present survey, we sought to estimate the actual prevalence of the founder mutations and to determine their effect sizes in the general Finnish population. Methods and results. We genotyped 6334 subjects aged≥30 years from a population cohort (Health 2000 study) for the four Finnish founder mutations using Sequenom MALDI-TOF mass spectrometry. The electrocardiogram (ECG) parameters were measured from digital 12-lead ECGs, and QT intervals were adjusted for age, sex, and heart rate using linear regression. A total of 27 individuals carried one of the founder mutations resulting in their collective prevalence estimate of 0.4% (95% CI 0.3%–0.6%). The KCNQ1 G589D mutation (n=8) was associated with a 50 ms (SE 7.0) prolongation of the adjusted QT interval (P=9.0×10−13). The KCNH2 R176W variant (n=16) resulted in a 22 ms (SE 4.7) longer adjusted QT interval (P=2.1×10−6). Conclusion. In Finland 1 individual out of 250 carries a LQTS founder mutation, which is the highest documented prevalence of LQTS mutations that lead to a marked QT prolongation.

Common candidate gene variants are associated with QT interval duration in the general population

Objectives.  QT interval prolongation is associated with increased risk of sudden cardiac death at the population level. As 30–40% of the QT‐interval variability is heritable, we tested the association of common LQTS and NOS1AP gene variants with QT interval in a Finnish population‐based sample.

Fragmented QRS in Prediction of Cardiac Deaths and Heart Failure Hospitalizations after Myocardial Infarction

Background: Increased QRS fragmentation in visual inspection of 12‐lead ECG has shown association with cardiac events in postmyocardial infarction (MI) patients. We investigated user‐independent computerized intra‐QRS fragmentation analysis in prediction of cardiac deaths and heart failure (HF) hospitalizations after MI.

Predictive value of electrocardiographic QT interval and T-wave morphology parameters for all-cause and cardiovascular mortality in a general population sample

BACKGROUND 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. OBJECTIVE 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. METHODS 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. RESULTS 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). CONCLUSION 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.

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.

Predictive Value of Electrocardiographic T-Wave Morphology Parameters and T-Wave Peak to T-Wave End Interval for Sudden Cardiac Death in the General Population

Background—Previous population studies have found an association between electrocardiographic 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 electrocardiographic T-wave peak to T-wave end interval (TPE) and SCD. We assessed the predictive value of electrocardiographic T-wave morphology parameters and TPE for SCD in an adult general population sample. Methods and Results—A total of 4 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 5618 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 SD increase in the loge T-wave morphology dispersion). In contrast, TPE was not associated with SCD in univariable or multivariable analyses. Conclusions—Electrocardiographic T-wave morphology parameters describing the 3-dimensional shape of the T-wave stratify SCD risk in the general population, but we did not find an association between TPE and SCD.