Biomedical subjects
Lauri Toivonen
Publications and source records attributed to Lauri Toivonen.
Increased QT dispersion and loss of sinus rhythm as risk factors for late sudden death after Mustard or Senning procedures for transposition of the great arteries.
Increased QT dispersion and loss of sinus rhythm were both associated with sudden cardiac death in patients with transposition of the great arteries after Mustard and Senning operations at the early and late postoperative periods. A combination of increased QT dispersion with loss of sinus rhythm increases the positive predictive value for sudden cardiac death in patients with transposition of the great arteries after Mustard and Senning procedures.
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.
Left cardiac sympathetic denervation in the management of high-risk patients affected by the long-QT syndrome.
BACKGROUND: The management of long-QT syndrome (LQTS) patients who continue to have cardiac events (CEs) despite beta-blockers is complex. We assessed the long-term efficacy of left cardiac sympathetic denervation (LCSD) in a group of high-risk patients. METHODS AND RESULTS: We identified 147 LQTS patients who underwent LCSD. Their QT interval was very prolonged (QTc, 543+/-65 ms); 99% were symptomatic; 48% had a cardiac arrest; and 75% of those treated with beta-blockers remained symptomatic. The average follow-up periods between first CE and LCSD and post-LCSD were 4.6 and 7.8 years, respectively. After LCSD, 46% remained asymptomatic. Syncope occurred in 31%, aborted cardiac arrest in 16%, and sudden death in 7%. The mean yearly number of CEs per patient dropped by 91% (P<0.001). Among 74 patients with only syncope before LCSD, all types of CEs decreased significantly as in the entire group, and a post-LCSD QTc <500 ms predicted very low risk. The percentage of patients with >5 CEs declined from 55% to 8% (P<0.001). In 5 patients with preoperative implantable defibrillator and multiple discharges, the post-LCSD count of shocks decreased by 95% (P=0.02) from a median number of 25 to 0 per patient. Among 51 genotyped patients, LCSD appeared more effective in LQT1 and LQT3 patients. CONCLUSIONS: LCSD is associated with a significant reduction in the incidence of aborted cardiac arrest and syncope in high-risk LQTS patients when compared with pre-LCSD events. However, LCSD is not entirely effective in preventing cardiac events including sudden cardiac death during long-term follow-up. LCSD should be considered in patients with recurrent syncope despite beta-blockade and in patients who experience arrhythmia storms with an implanted defibrillator.
QRS duration and QT interval predict mortality in hypertensive patients with left ventricular hypertrophy: the Losartan Intervention for Endpoint Reduction in Hypertension Study.
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 QT(apex) 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 QT(apex) interval can further stratify mortality risk even in the setting of effective blood pressure-lowering treatment.
A novel mutation, Ser143Pro, in the lamin A/C gene is common in finnish patients with familial dilated cardiomyopathy.
AIMS: The mutations most frequently associated with dilated cardiomyopathy (DCM) have been reported in the lamin A/C gene. The role of variants of the lamin A/C gene was investigated in patients with DCM from eastern and southern Finland. METHODS AND RESULTS: All 12 exons of the lamin A/C gene were screened in 18 well-characterised familial DCM patients from eastern and southern Finland and in 72 sporadic DCM patients from eastern Finland using the PCR-SSCP method. A novel mutation, Ser143Pro (S143P), was detected in the lamin A/C gene in 24 subjects from 5 unrelated families and in one sporadic case of DCM. Sinus or atrioventricular nodal dysfunction occurred in the majority of the affected subjects, many of which required pacemaker implantation. Seven patients (28%) with the S143P mutation died suddenly or from progressive heart failure, or underwent heart transplantation. The haplotypes 5-5-5-3, 5-5-5-2, and 5-5-5-1 co-segregated with the Ser143Pro mutation, suggesting a founder effect of this mutation. CONCLUSIONS: A novel mutation S143P in the lamin A/C gene was found to be common among Finnish DCM patients. Haplotype analysis strongly suggests a founder effect of this mutation. The phenotype is characterised by severe heart failure, progressive atrioventricular conduction defects, and sudden death. Screening for the lamin A/C gene and, particularly, the S143P mutation seems warranted when patients with DCM have conduction system disturbances.
Two novel mutations in the beta-myosin heavy chain gene associated with dilated cardiomyopathy.
BACKGROUND: Dilated cardiomyopathy (DCM) is familial in approximately 20-35% of cases of idiopathic DCM. Several mutations in the different sarcomere protein genes have been reported to cause DCM. AIMS: We wanted to investigate the role of sarcomere protein gene variants in Finnish DCM patients. METHODS AND RESULTS: We screened all coding exons of five sarcomere protein genes (beta-myosin heavy chain, alpha-tropomyosin, troponin C, troponin I and troponin T) in a well-characterized population of 52 DCM patients in Eastern Finland by the PCR-SSCP and sequencing method. Two novel mutations, Arg1053Gln and Arg1500Trp, in the beta-myosin heavy chain gene in two index patients were detected. The proband with the Arg1053Gln mutation had a dilated left ventricle and impaired systolic function, but other family members carrying this mutation presented with septal hypertrophy. It thus seems that the Arg1053Gln mutation is primarily a HCM mutation, which can also lead to DCM. The other mutation, Arg1500Trp, was associated with a typical DCM phenotype. The Arg1500Trp mutation carrier had only one family member alive, but she did not carry the mutation and, therefore, cosegregation of the mutation and the disease in this family could not be reliably verified. No disease-causing mutations were found in the other sarcomere protein genes. CONCLUSIONS: Two novel mutations in the beta-myosin heavy chain gene were detected in patients with DCM. Overall, mutations in the beta-myosin heavy chain gene seem to be relatively uncommon in Finnish DCM patients.
Genetics of hypertrophic cardiomyopathy in eastern Finland: few founder mutations with benign or intermediary phenotypes.
Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR-SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin-binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5-2A --> C, IVS14-13G --> A, and Ex25deltaLys) were found in one family each. A previously described alpha-tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3-Gln1061X and TPM1-Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the beta-myosin heavy chain gene (MYH7) was found in one family, and no disease-causing mutations were found in the genes encoding alpha-actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM-related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes.
The calcium sensitizer levosimendan and cardiac arrhythmias: an analysis of the safety database of heart failure treatment studies.
BACKGROUND: Levosimendan is a calcium sensitizer that increases the contractility of the myofilaments and is considered not to affect cardiac electrophysiology. We assessed its potential to generate cardiac arrhythmias by analysing ECG recordings from clinical studies on intravenously administered levosimendan in heart failure patients. METHODS AND RESULTS: The database consisted of continuous 1-day recordings, of which 366 were during levosimendan and 142 during placebo comparison. Supraventricular (SVT) and ventricular tachycardia (VT) were defined as > or =3 premature complexes at a rate > or = 120/min. No difference appeared between levosimendan and control groups in the occurrence of atrial fibrillation (12% vs 13%), SVT (28% vs 30%), or VT (41% vs 44% of all recordings; all p = NS). Also the frequency of VT was similar (0.55 +/- 3.89 vs 0.20 +/- 1.08 episodes/h; p = NS). No torsade de pointes or sustained VT occurred. CONCLUSION: Short-term levosimendan therapy of heart failure showed no tendency to increase cardiac arrhythmias. Although assessing only surrogates of prognostically significant arrhythmias, the findings together with previously observed reduction of mortality in heart failure therapy studies support the presumption that levosimendan has an electrophysiologically neutral profile.
Genes, exercise and sudden death: molecular basis of familial catecholaminergic polymorphic ventricular tachycardia.
Familial catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare arrhythmogenic disease manifesting with exercise- or stress-induced ventricular arrhythmias, syncope, and even sudden death. CPVT is inherited as an autosomal dominant or autosomal recessive trait, usually with high penetrance. We characterized in detail the clinical, structural and electrocardiographic findings in this disorder and by use of genome-wide linkage analysis, mapped the disease-causing gene to chromosome 1q42-q43. Thereafter, we and others demonstrated point mutations of the cardiac ryanodine receptor gene (RyR2) to underlie this life-threatening disease. In addition, RyR2 mutations were identified in patients affected with a variant form of arrhythmogenic right ventricular dysplasia (ARVD2), a phenotypically distinct disease entity. Identification of the causal mutations has enabled molecular diagnosis in the affected families, which is of major importance in identifying individuals at risk of an arrhythmia. Recently, several groups have delineated the functional effects of the RyR2 mutations associated with CPVT and ARVD2. The results are slightly contradictory, and further studies are thus needed to clarify the exact molecular mechanisms leading to arrhythmia induction.
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 LOTS-causing mutations in 92 Finnish families. AIM: In order to complete the characterization of Finnish spectrum of LOTS genes, we conducted a systematic search for mutations in the five LOTS 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 LOTS 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 LOTS in Finland is unique in the whole world, providing a major advantage for screening and presymptomatic diagnosis of LOTS, and constituting an excellent basis to study the role of genetic and non-genetic factors influencing phenotypic variability in this disease.
Atrial refractoriness and action potential duration after sudden reversal of atrioventricular sequence.
To address the potential of atrioventricular (AV) asynchrony to provoke cardiac arrhythmias, atrial electrophysiology was examined during normal and reversed AV interval in anesthetized pigs. A new automatic stimulation technique was adapted to monitor rapid changes in the effective refractory period (ERP), using continuous AV sequential pacing, incremental extrastimulus interval scanning, and automatic detection of capture. Right atrial ERP using 2-8 ms stimulus interval increments and right atrial and ventricular monophasic action potential (MAP) duration were determined simultaneously when the AV interval was changed from normal (+80 ms) to reversed (-40 ms) and back. During reversed AV interval the peak right atrial pressure increased from 8 +/- 3 to 14 +/- 4 mmHg (P < 0.001) and mean arterial pressure decreased from 86 +/- 18 to 65 +/- 21 mmHg (P < 0.001). At new steady state, atrial ERP and MAP duration at 90% level of repolarization were lengthened by 22 +/- 16 and 42 +/- 12 ms respectively (P < 0.001). Ventricular MAP duration did not change. A statistically significant lengthening in atrial ERP could be demonstrated in 5-10 seconds. After reversion of the AV sequence, the ratio of atrial ERP to MAP duration decreased from 1.27 to 0.94 (P < 0.001) on average for 15 seconds, the change being thought to favor reentry. Thus atrial wall stress from contraction during ventricular systole even for a short period of time modifies atrial electrophysiology. Deficient AV synchrony may immediately contribute to the development of atrial arrhythmias.
Temporal analysis of the depolarization wave of healed myocardial infarction in body surface potential mapping.
BACKGROUND: We studied the ability of different time segments of the depolarization wave recorded with body surface potential mapping (BSPM) to detect and localize myocardial infarction (MI). METHODS: BSPM was recorded in 24 patients with remote MI and in 24 healthy controls. Cine and contrast-enhanced magnetic resonance imaging (MRI) was used as a reference method. Patients were grouped according to anatomical location of their MI. The QRS complex was divided into six temporally equal segments, for which time integrals were calculated. RESULTS: The time segments of the QRS complex showed different MI detection capability depending on MI location. For anterior infarction the second segment of the QRS complex was the best in MI detection and the optimal area was on the right inferior quadrant of the thorax (time integral average -1.5 +/- 1.8 mVms patients, 1.0 +/- 1.6 mVms controls, P = 0.002). For lateral infarction the first segment of the QRS complex performed best and the optimal area for MI detection was the left fourth intercostal area (time integral average 1.8 +/- 1.0 mVms patients, 0.7 +/- 0.5 mVms controls, P = 0.024). For inferior and posterior MI the mid-phases of the QRS complex were the best and the optimal area was the mid-inferior area of the thorax (time integral average -6.2 +/- 8.3 mVms patients, 3.3 +/- 4.3 mVms controls, P = 0.002; -9.1 +/- 6.1 mVms patients, 0.6 +/- 7.1 mVms controls, P = 0.001, respectively). CONCLUSIONS: Time segment analysis of the depolarization wave offers potential for improving the detection and localization of healed MI.
Volatile anesthetics and succinylcholine in cardiac ryanodine receptor defects.
Familial polymorphic (catecholaminergic) ventricular tachycardia is an arrhythmogenic cardiac disorder caused by mutations of the myocardial isoform of the ryanodine receptor gene (RyR2). Mutations of the corresponding gene in the skeletal muscle (RyR1) predispose its carriers to malignant hyperthermia upon use of volatile anesthetics or succinylcholine, which further deteriorate the inherited intracellular calcium release disorder. We report a series of patients with cardiac RyR defects who underwent general anesthesia without complications. Succinylcholine and volatile anesthetics did not have a clinically significant effect on RyR2 defects.
A novel mutation, Arg71Thr, in the delta-sarcoglycan gene is associated with dilated cardiomyopathy.
Approximately 20-35% of cases of idiopathic dilated cardiomyopathy are familial. DCM-associated mutations have been reported in 13 genes including the desmin, delta-sarcoglycan, and metavinculin genes. This study screened for variants in these genes in Finnish patients with DCM. All coding regions of the desmin and delta-sarcoglycan genes and the metavinculin-specific exon of the vinculin gene were screened in 52 DCM patients from eastern Finland by PCR-SSCP. We detected a novel mutation, Arg71Thr, in the delta-sarcoglycan gene in two members of a small DCM family. One of the mutation carriers fulfills diagnostic criteria for DCM and is also symptomatic. The other mutation carrier has slightly dilated left ventricle and well preserved systolic function. Therefore carriers of the Arg71Thr mutation had a relatively mild phenotype and a late onset of the disease. Disease-associated mutations were not found in the desmin gene or the metavinculin-specific exon of the vinculin gene. We conclude that the desmin and delta-sarcoglycan genes are not predominant disease-causing genes in patients with DCM in eastern Finland.
Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG).
OBJECTIVE: To determine whether the amino acid 897 threonine (T) to lysine (K) polymorphism of the KCNH2 (HERG) potassium channel influences channel performance or patient phenotype. METHODS: The phenotypic effects of this polymorphism were investigated in vitro by electrophysiological experiments in HEK-293 cells and in vivo by exercise electrocardiography in a group of LQTS patients carrying the same genetically proven KCNQ1 mutation. RESULTS: When expressed in HEK-293 cells, the 897T isoform of the KCNH2 channel exhibited changes in inactivation and deactivation properties, and a smaller current density than the more common 897K isoform. Western blot experiments indicated that the decreased current density associated with 897T was caused by reduced channel expression. During a maximal exercise test in 39 LQT1 patients carrying an identical KCNQ1 mutation (G589D) and showing a prolonged QT interval (>440 ms), QT intervals were longer in patients carrying the 897T allele than in those homozygous for the 897K allele. CONCLUSIONS: The K897T variation has an effect on channel function and clinical phenotype. Our data warrant further investigations into the significance of this polymorphism in drug-induced and inherited LQTS.
Relation of QT interval and QT dispersion to regression of echocardiographic and electrocardiographic left ventricular hypertrophy in hypertensive patients: the Losartan Intervention For Endpoint Reduction (LIFE) study.
BACKGROUND: In hypertensive patients, both echocardiographic and electrocardiographic left ventricular hypertrophy (LVH) increase the risk of sudden death, possibly in part because of LVH-induced proarrhythmic repolarization changes. Experimentally, regression of LVH normalizes ventricular electrophysiology. METHODS: To assess the relation of regression of LVH to changes in electrocardiographic measures of ventricular repolarization, we studied 317 hypertensive (61.2% men, mean age 65 +/- 7 years) participants in the Losartan Intervention For Endpoint Reduction (LIFE) study with electrocardiographic evidence of LVH, at study baseline, and after 1 year of blood pressure-lowering treatment with losartan or atenolol and hydrochlorothiatzide as the first adjunct therapy if needed to reach target blood pressure of 140/90 mm Hg. As indexes of LVH, we used echocardiographically determined LV mass as well as the Sokolow-Lyon and Cornell voltages from the electrocardiogram. QT interval duration and QT dispersion from the 12-lead electrocardiogram were used as ventricular repolarization measures. RESULTS: By using tertiles of LV mass change and adjusting for the difference in treatment (losartan or atenolol), shortening of the rate-adjusted QT intervals as well as reduction in QT(apex) dispersion were observed in the tertile showing the greatest decrease in LV mass but not in the tertile without substantial changes in LV mass despite a significant reduction in blood pressure. Similar results were obtained with the use of Sokolow-Lyon and Cornell voltage change tertiles. CONCLUSIONS: In hypertensive patients with electrocardiographic evidence of LVH, regression of echocardiographically determined LV mass and electrocardiographic indexes of LVH may partially reverse the LVH-induced proarrhythmic repolarization changes. This may have a beneficial impact on the increased incidence of sudden death in these patients.
ST-T integral and T-wave amplitude in detection of exercise-induced myocardial ischemia evaluated with body surface potential mapping.
Body surface potential mapping is superior to 12-lead electrocardiogram in detection of acute and old myocardial infarctions. We examined the capability of the ST-T integral and T wave to detect exercise-induced ischemia in body surface potential mapping. Body surface potential mapping with 123 channels was recorded in 70 subjects: 45 coronary artery disease (CAD) patients and 25 healthy controls during supine bicycle exercise testing. Of the patients, 18 had anterior, 14 posterior, and 13 inferior ischemia documented by coronary angiography and thallium scintigraphy. The ST-T isointegral area, as well as the positive and negative ST-T area, and the T-wave apex amplitude were determined. Discriminant index analysis was used to find the sites that optimally separated patient subgroups from other patients and controls. In the pooled CAD group, the optimal sites for detecting the decrease in ST-T isointegral, in the positive ST-T area and in the T-wave amplitude were over the left side (ST-T isointegral area: CAD -3.8 +/- 14 microVs and controls 24 +/- 14 microVs; T-wave amplitude: CAD 3 +/- 110 microV and controls 190 +/- 90 microV; P <.001, both). The area under the receiver operating characteristic curve for the decrease in ST-T isointegral, in the positive ST-T area, and in the T-wave amplitude and for the ST depression were 94%, 95%, 92%, and 93%, respectively. T wave performed especially well in patients with multivessel disease. In stepwise logistic regression analysis, using the presence of CAD as the dependent parameter, the decrease in the positive ST-T area and ST depression were the only parameters that entered the model. ST-T area and T-wave amplitude are sensitive and specific markers of transient myocardial ischemia. ST-T area contains information additional to ST depression and has thus independent discriminative value in ischemia detection.