Matti Viitasalo

Arrhythmic disorder mapped to chromosome 1q42–q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts

OBJECTIVES The purpose of this study was to provide clinical and anatomical characteristics as well as genetic background of a malignant arrhythmogenic disorder. BACKGROUND An inherited autosomally dominant cardiac syndrome causing stress-induced polymorphic ventricular tachycardia and syncope in the absence of structural myocardial changes was detected in two families. METHODS Two unrelated families with six victims of sudden death and 51 living members were evaluated. Resting and exercise electrocardiograms (ECG), echocardiography, magnetic resonance imaging (MRI), cineangiography, microscopic examination of endomyocardial biopsies and a drug testing with a class IC antiarrhythmic agent flecainide were performed. A genetic linkage analysis was carried out to map the gene locus. RESULTS Of the 24 affected individuals, 10 had succumbed with six cases of sudden death, and 14 survivors showed evidence of disease. Exercise stress test induced ventricular bigeminy or polymorphic ventricular tachycardia in affected individuals. Three children initially examined before 10 years of age developed arrhythmias during a four-year follow-up. Resting ECGs were normal in affected subjects except a slight prolongation of the QT intervals adjusted for heart rate (QTc) (430 +/- 18 vs. 409 +/- 19 ms, affected vs. nonaffected, p < 0.01). Administration of flecainide did not induce ECG abnormalities encountered in familial idiopathic ventricular fibrillation. Ventricular volumes, contractility and wall measurements were normal by echocardiography, right ventricular cineangiography and MRI. Histopathological examination showed no fibrosis or fatty infiltration. The cumulative cardiac mortality by the age of 30 years was 31%. The disease locus was assigned to chromosome 1q42-q43, with a maximal pairwise lod score of 4.74 in the two families combined. Only one heterozygous carrier was clinically unaffected suggesting high disease penetrance in adulthood. CONCLUSIONS A distinct cardiac disorder linked to chromosome 1q42-q43 causes exercise-induced polymorphic ventricular tachycardia in structurally normal hearts and is highly malignant. Delayed clinical manifestation necessitates repeated exercise electrocardiography to assure diagnosis in young individuals of the families.

Relation between QT intervals and heart rates from 40 to 120 beats/min in rest electrocardiograms of men and a simple method to adjust QT interval values

OBJECTIVES The aim of this study was to establish the relation between QT intervals and a wide range of rest heart rates in men. These data provided the basis of a simple method for adjusting the QT interval for heart rate. BACKGROUND Earlier correction equations give conflicting results, especially at low and high heart rates. METHODS The QT intervals were measured in 324 electrocardiograms of healthy young men. The sample was weighted for low and high heart rates. A curve relating QT intervals and heart rates from 40 to 120 beats/min was constructed. The QT interval at 60 beats/min was used as the reference value, and an adjusting nomogram for different heart rates was created. The reliabilities of the nomogram and three earlier QT correction equations were tested in the study group and in 396 middle-aged men. RESULTS The nomogram method presented (QTNc = QT + correcting number) adjusted the QT interval most accurately over the whole range of heart rates on the basis of smallest mean-squared residual values between measured and predicted QT intervals. The Fridericia formula (QTFc = QT/RR1/3) gave the best correction at low, but failed at high, heart rates. The linear regression equation (QTLc = QT + 0.154[1 - RR], Framingham Study) was reliable at normal, but failed at low and high, heart rates. The Bazett formula (QTc = QT/RR1/2) performed poorest at all heart rates. The relation between QT and RR intervals was determined by three linear regressions expressing the slopes 0.116 for heart rates < 60 beats/min, 0.156 for heart rates from 60 to 100 beats/min and 0.384 for heart rates > 100 beats/min. CONCLUSIONS The QT-RR relation over a wide range of heart rates does not permit the use of one simple adjustment equation. A nomogram providing, for every heart rate, the number of milliseconds that the QT interval must be corrected gives excellent adjustment.

Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KVLQT1 and HERG potassium channel defects

OBJECTIVES This study was performed to evaluate the QT interval and heart rate responses to exercise and recovery in gene and mutation type-specific subgroups of long QT syndrome (LQTS) patients. BACKGROUND Reduced heart rate and repolarization abnormalities are encountered among long QT syndrome (LQTS) patients. The most common types of LQTS are LQT1 and LQT2. METHODS An exercise stress test was performed in 23 patients with a pore region mutation and in 22 patients with a C-terminal end mutation of the cardiac potassium channel gene causing LQT1 type of long QT syndrome (KVLQT1 gene), as well as in 20 patients with mutations of the cardiac potassium channel gene causing LQT2 type of long QT syndrome (HERG gene) and in 33 healthy relatives. The QT intervals were measured on electrocardiograms at rest and during and after exercise. QT intervals were compared at similar heart rates, and rate adaptation of QT was studied as QT/heart rate slopes. RESULTS In contrast to the LQT2 patients, achieved maximum heart rate was decreased in both LQT1 patient groups, being only 76 +/- 5% of predicted in patients with pore region mutation of KvLQT1. The QT/heart rate slopes were significantly steeper in LQT2 patients than in controls during exercise. During recovery, the QT/heart rate slopes were steeper in all LQTS groups than in controls, signifying that QT intervals lengthened excessively when heart rate decreased. At heart rates of 110 or 100 beats/min during recovery, all LQT1 patients and 89% of LQT2 patients had QT intervals longer than any of the controls. CONCLUSIONS LQT1 is associated with diminished chronotropic response and exaggerated prolongation of QT interval after exercise. LQT2 patients differ from LQT1 patients by having marked QT interval shortening and normal heart rate response to exercise. Observing QT duration during recovery enhances the clinical diagnosis of these LQTS types.

Prevalence and Prognostic Significance of Short QT Interval in a Middle-Aged Finnish Population

Background— Short-QT syndrome is an inherited disorder characterized by a short QT interval and an increased risk of sudden cardiac death. The clinical significance of a short QT interval observed in a randomly recorded ECG is not known. Therefore, we assessed the prevalence and prognostic significance of a short QT interval in a general population. Methods and Results— QT intervals were measured from the 12-lead ECGs of 10 822 randomly selected middle-aged subjects (5658 males, mean age 44±8.4 years) enrolled in a population study and followed up for 29±10 years. The end points were all-cause and cardiovascular mortality. In addition to Bazett’s method (corrected QT interval, or QTc), the Fridericia (QTfc) and nomogram (QTnc) methods were used to correct the QT interval for heart rate. The cutoff values for short QT intervals were defined as 320 ms (very short) and 340 ms (short). The prevalence of QT interval <320 ms based on QTc, QTfc, and QTnc was 0.10%, 0.08%, and 0.06%, and the prevalence of QT interval <340 ms was 0.4%, 0.3%, and 0.3%, respectively. The majority of subjects with short QT intervals were males. All-cause or cardiovascular mortality did not differ between subjects with a very short or short QT interval and those with normal QT intervals (360 to 450 ms). There were no sudden cardiac deaths, aborted sudden cardiac deaths, or documented ventricular tachyarrhythmias among subjects with a QTfc <340 ms. Conclusion— A short QT interval does not appear to indicate an increased risk for all-cause or cardiovascular mortality in middle-aged nonreferral, community-based individuals.

Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes

OBJECTIVES We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND Adaptive left ventricular hypertrophy is a feature of the athletes heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.

A founder mutation of the potassium channel KCNQ1 in long QT syndrome ☆: Implications for estimation of disease prevalence and molecular diagnostics

OBJECTIVES We took advantage of the genetic isolate of Finns to characterize a common long QT syndrome (LQTS) mutation, and to estimate the prevalence of LQTS. BACKGROUND The LQTS is caused by mutations in different ion channel genes, which vary in their molecular nature from family to family. METHODS The potassium channel gene KCNQ1 was sequenced in two unrelated Finnish patients with Jervell and Lange-Nielsen syndrome (JLNS), followed by genotyping of 114 LQTS probands and their available family members. The functional properties of the mutation were studied using a whole-cell patch-damp technique. RESULTS We identified a novel missense mutation (G589D or KCNQ1-Fin) in the C-terminus of the KCNQ1 subunit. The voltage threshold of activation for the KCNQ1-Fin channel was markedly increased compared to the wild-type channel. This mutation was present in homozygous form in two siblings with JLNS, and in heterozygous form in 34 of 114 probands with Romano-Ward syndrome (RWS) and 282 family members. The mean (+/- SD) rate-corrected QT intervals of the heterozygous subjects (n = 316) and noncarriers (n = 423) were 460 +/- 40 ms and 410 +/- 20 ms (p < 0.001), respectively. CONCLUSIONS A single missense mutation of the KCNQ1 gene accounts for 30% of Finnish cases with LQTS, and it may be associated with both the RWS and JLNS phenotypes of the syndrome. The relative enrichment of this mutation most likely represents a founder gene effect. These circumstances provide an excellent opportunity to examine how genetic and nongenetic factors modify the LQTS phenotype.

Itraconazole prevents terfenadine metabolism and increases risk of torsades de pointes ventricular tachycardia

SummaryTerfenadine, a nonsedating H1-selective antihistamine, is widely used in many countries. We report pharmacokinetic results in a patient who developed a prolonged QT-interval in ECG and symptomatic torsades de pointes ventricular tachycardia as a consequence of the interaction of itraconazole and terfenadine. Both drugs were taken in the recommended doses: terfenadine 60 mg b.d. and itraconazole 100 mg b.d.Terfenadine metabolism was delayed by itraconazole, leading to an increased level of unmetabolised terfenadine. Seven weeks after the cessation of itraconazole treatment, terfenadine was rapidly metabolized to its active metabolite and did not prolong the QT-interval when given as a single provocation dose (120 mg).The findings suggest that intraconazole in therapeutic doses inhibits terfenadine metabolism. It is also possible that unmetabolised terfenadine alone, without an increased level of its active metabolite, may cause torsades de pointes. The concomitant use of terfenadine and itraconazole (and ketoconazole) should be avoided.

QRS Duration and QT Interval Predict Mortality in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention for Endpoint Reduction in Hypertension Study

Abstract—Left ventricular hypertrophy is a risk factor for cardiovascular mortality, including sudden cardiac death. Experimentally, left ventricular hypertrophy delays ventricular conduction and prolongs action potential duration. Electrocardiographic QRS duration and QT interval measures reflect these changes, but whether these measures can further stratify risk in patients with electrocardiographic left ventricular hypertrophy is unknown. We measured the QRS duration and QT intervals from the baseline 12-lead electrocardiograms in the Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) study, which included hypertensive patients with electrocardiographic evidence of left ventricular hypertrophy randomized to either losartan-based or atenolol-based treatment to lower blood pressure. In the present study, we related study baseline electrocardiographic measures to cardiovascular and all-cause mortality. There were 5429 patients (male 45.8%; mean age 66±7 years) included in the present analyses. After a mean follow-up of 4.9±0.8 years, there were 417 deaths from all causes, including 214 cardiovascular deaths. In separate univariate Cox regression analyses, QRS duration and several QT measures were significant predictors of cardiovascular mortality and all-cause mortality. However, in multivariate Cox analyses including all electrocardiographic measures and adjusting for other risk factors as well as treatment strategy, only QRS duration and maximum rate-adjusted QTapex interval remained as significant independent predictors of cardiovascular (P =0.022 and P =0.037, respectively) and all-cause mortality (P =0.038 and P =0.002, respectively). In conclusion, in a hypertensive risk population identified by electrocardiographic left ventricular hypertrophy, increased QRS duration and maximum QTapex interval can further stratify mortality risk even in the setting of effective blood pressure-lowering treatment.

Electrocardiographic Strain Pattern and Prediction of Cardiovascular Morbidity and Mortality in Hypertensive Patients

The ECG strain pattern of lateral ST depression and T-wave inversion is a marker for left ventricular hypertrophy (LVH) and adverse prognosis in population studies. However, whether ECG strain is an independent predictor of cardiovascular (CV) morbidity and mortality in the setting of aggressive antihypertensive therapy is unclear. ECGs were examined at study baseline in 8854 hypertensive patients with ECG LVH who were treated in a blinded manner with atenolol- or losartan-based regimens. Strain was defined by the presence of a downsloping convex ST segment with an inverted asymmetrical T wave opposite to the QRS axis in leads V5 and/or V6 and was present in 971 patients (11.0%). The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study composite end point of CV death or nonfatal myocardial infarction or stroke occurred in 1035 patients (11.7%). In Cox analyses adjusting only for treatment effect, ECG strain was a significant predictor of CV death (hazard ratio [HR] 2.26, 95% confidence interval [CI] 1.78 to 2.86), fatal/nonfatal myocardial infarction (HR 2.16, 95% CI 1.67 to 2.80), fatal/nonfatal stroke (HR 1.76, 95% CI 1.39 to 2.21), and the composite CV end point (HR 1.99, 95% CI 1.70 to 2.33). After further adjusting for standard CV risk factors, baseline blood pressure, and severity of ECG LVH, ECG strain remained a significant predictor of CV mortality (HR 1.53, 95% CI 1.18 to 2.00), myocardial infarction (HR 1.55, 95% CI 1.16 to 2.06), and the composite CV end point (HR 1.33, 95% CI 1.11 to 1.59). Thus, ECG strain is a marker of increased CV risk in hypertensive patients in the setting of aggressive blood pressure lowering, independent of baseline severity of ECG LVH.

Four potassium channel mutations account for 73% of the genetic spectrum underlying long-QT syndrome (LQTS) and provide evidence for a strong founder effect in Finland.

BACKGROUND. Mutations in five cardiac voltage‐gated ion channel genes, including KCNQ1, HERG, SCN5A, KCNE1 and KCNE2, constitute the principal cause of inherited long‐QT syndrome (LQTS). Typically, each family carries its own private mutation, and the disease manifests with varying phenotype and incomplete penetrance, even within particular families. We had previously identified 14 different LQTS‐causing mutations in 92 Finnish families. AIM. In order to complete the characterization of Finnish spectrum of LQTS genes, we conducted a systematic search for mutations in the five LQTS genes among 188 additional unrelated probands. METHODS. The screening was performed by denaturing high‐performance liquid chromatography (dHPLC) and DNA sequencing. RESULTS. Nineteen novel and 12 previously described mutations were identified. Collectively, these data extend the number of molecularly defined affected Finnish LQTS families and patients at present to 150 and 939, respectively. Four presumable founder mutations (KCNQ1 G589D and IVS7‐2A > G, HERG R176W and L552S) together account for as much as 73% of all established Finnish LQTS cases. CONCLUSIONS. The extent of genetic homogeneity underlying LQTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LQTS, and constituting an excellent basis to study the role of genetic and non‐genetic factors influencing phenotypic variability in this disease.