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Biomedical subjects

Kimmo Kontula

Publications and source records attributed to Kimmo Kontula.

At least 37 records · Page 2Linked to original sources
PubMed2005

Effects of epinephrine on right ventricular monophasic action potentials in the LQT1 versus LQT2 form of long QT syndrome: preferential enhancement of "triangulation" in LQT1.

AIMS: To explore effects of epinephrine and phenylephrine on the behavior of right ventricular monophasic action potentials (MAPs) in symptomatic LQT1 and LQT2 patients. METHODS AND RESULTS: We recorded endocardial MAPs from right interventricular septum at baseline and during epinephrine and phenylephrine infusions in six symptomatic DNA-verified LQT1 (QTc 528 +/- 83) and five LQT2 patients (QTc 527 +/- 72) and in five control patients (QTc 381 +/- 22). We measured MAP durations at 90% and at 50% levels of repolarization and their difference (MAP50 to MAP90, a measure of MAP morphologic "triangulation"), during atrial pacing to characterize rate dependence of MAPs and repolarization phase 3 durations, respectively. Restitution kinetics were determined during atrioventricular sequential pacing, using the approach of empirical restitution rate. Epinephrine prolonged MAP50-to-MAP90 duration and increased the rate dependence of MAP90 duration and increased restitution rate in type LQT1, but not in LQT2 patients nor in control subjects. Phenylephrine did not change MAP behavior. During epinephrine administration, both LQT1 and LQT2 patients had a ratio of the restitution rate of MAP to diastolic interval >1.0 at short diastolic intervals. CONCLUSION: Symptomatic LQT1 patients with prolonged baseline QTc intervals showed beta-adrenergic-induced changes in MAPs (triangulation) known to be arrhythmogenic, thus giving insight to the difference in clinical triggers of life-threatening arrhythmias between LQT1- and LQT2-affected individuals.

Action Potentials↗
PubMed2004

Temporal repolarization lability differences among genotyped patients with the long QT syndrome.

The investigators sought to test whether certain long QT syndrome (LQTS) mutations are associated with increased repolarization lability and whether repolarization lability (quantified by the QT variability index [QTVI]) is increased in patients with LQTS compared with controls. In 32 genotyped patients with LQTS type 1 (LQT1), 32 genotyped patients with LQTS type 2 (LQT2), and 32 controls, the QTVI was increased in patients with LQT2 (-0.973 +/- 0.394, p = 0.01 vs controls) and in patients with LQT1 with mutations other than KCNQ1-FIN (-0.942 +/- 0.264, p = 0.04 vs controls) but was similar between the KCNQ1-FIN group and controls.

Adult↗
PubMed2004

Sudden death in familial polymorphic ventricular tachycardia associated with calcium release channel (ryanodine receptor) leak.

BACKGROUND: Familial polymorphic ventricular tachycardia (FPVT) is characterized by exercise-induced arrhythmias and sudden cardiac death due to missense mutations in the cardiac ryanodine receptor (RyR2), an intracellular Ca2+ release channel required for excitation-contraction coupling in the heart. METHODS AND RESULTS: Three RyR2 missense mutations, P2328S, Q4201R, and V4653F, which occur in Finnish families, result in similar mortality rates of approximately 33% by age 35 years and a threshold heart rate of 130 bpm, above which exercise induces ventricular arrhythmias. Exercise activates the sympathetic nervous system, increasing cardiac performance as part of the fight-or-flight stress response. We simulated the effects of exercise on mutant RyR2 channels using protein kinase A (PKA) phosphorylation. All 3 RyR2 mutations exhibited decreased binding of calstabin2 (FKBP12.6), a subunit that stabilizes the closed state of the channel. After PKA phosphorylation, FPVT-mutant RyR2 channels showed a significant gain-of-function defect consistent with leaky Ca2+ release channels and a significant rightward shift in the half-maximal inhibitory Mg2+ concentration (IC50). Treatment with the experimental drug JTV519 enhanced binding of calstabin2 to RyR2 and normalized channel function. CONCLUSIONS: Sympathetic activation during exercise induces ventricular arrhythmias above a threshold heart rate in RyR2 mutation carriers. Simulating the downstream effects of the sympathetic activation by PKA phosphorylation of RyR2 channels containing these FPVT missense mutations produced a consistent gain-of-function defect. RyR2 function and calstabin2 depletion were rescued by JTV519, suggesting stabilization of the RyR2 channel complex may represent a molecular target for the treatment and prevention of exercise-induced arrhythmias and sudden death in these patients.

Adult↗
PubMed2004

Loss-of-function mutations of the K(+) channel gene KCNJ2 constitute a rare cause of long QT syndrome.

Mutations of the KCNJ2 gene encoding the potassium channel Kir2.1 were previously shown to cause Andersen's syndrome (AS), a multisystem disease manifesting with developmental abnormalities, cardiac arrhythmias and periodic paralyses. We conducted a search for KCNJ2 mutations among 188 unrelated patients suspected to have long QT syndrome (LQTS). The screening was performed by denaturing high-performance liquid chromatography (dHPLC) and DNA sequencing. Two novel mutations of the KCNJ2 gene were detected: a missense threonine to alanine mutation (T75A) in the N-terminal region (family 1) and an in-frame deletion of two amino acids (DeltaFQ163-164) in the M2 transmembrane region (family 2). In addition, a previously described silent polymorphism C1146T was detected. In family 1, some of the affected family members had a history of periodic muscle weakness characteristic of AS, but no dysmorphic features. The mean QTc interval of the affected members were 444 +/- 24 ms (family 1, n=7) and 456 +/- 8 ms (family 2, n=2). The mutations affect functionally important regions of the KCNJ2 channel protein: upon injection of the Xenopus oocytes with the wild type and mutant KCNJ2 constructs, the channel proteins were correctly synthesized and localized to the cell surface, but no measurable inward K(+) current could be detected for the mutant KCNJ2 constructs. In conclusion, we report two novel loss-of-function mutations of the KCNJ2 channel, affecting different domains of the channel protein. Mutations of the KCNJ2 gene should be considered in genetic subclassification of LQTS patients, even in the absence of overt manifestations of AS.

Amino Acid Sequence↗
PubMed2004

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.

Catecholamines↗
PubMed2004

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.

Cation Transport Proteins↗
PubMed2004

Identification and characterization of melanocortin-4 receptor gene mutations in morbidly obese finnish children and adults.

Two Finnish cohorts, comprising 56 children with severe early-onset obesity (relative weight for height greater than or equal to +70% before age 10) and 252 morbidly obese adults (body mass index, > or = 40 kg/m(2)), were screened for melanocortin-4 receptor (MC4R) mutations. We identified a pathogenic mutation (S127L) in one child, causing severe early-onset obesity. We describe the phenotype of this particular mutation for the first time. We also identified a novel (I226T) polymorphism in the coding and two new variations (-439delGC and 1059C>T) outside the coding region of the MC4R gene. Three previously described polymorphisms (V103I, T112M, and I125L) were identified. In vitro functional studies of variants T112M, S127L, and I226T supported a pathogenic role of the S127L mutation, because signaling properties of the receptor in response to the MC4R agonists alpha-MSH, beta-MSH, and gamma(1)-MSH were impaired. The S127L mutation did not affect receptor inhibition by the antagonist agouti-related protein. Localization of the three variant receptors was similar to that of wild type. In conclusion, a pathogenic MC4R mutation was found among subjects with severe early-onset obesity but not among morbidly obese adults. Impaired function of the S127L receptor was due to reduced activation, not a defect of protein transport to the cell membrane.

Adolescent↗
PubMed2003

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.

Adolescent↗
PubMed2003

Molecular screening of selected long QT syndrome (LQTS) mutations in 165 consecutive bodies found in water.

The association of the long QT-syndrome (LQTS) with single accidental drowning or near-drowning cases has been recently emphasised, but no data on the prevalence of LQTS among drowning victims are currently available. In this study, we have retrospectively screened specific founder mutations in KCNQ1 (KVLQT1) and KCNH2 (HERG) genes in 165 consecutive bodies found in water in Finland. We found a KCNH2-Fin mutation in a 44-year-old woman whose death was classified as suicidal drowning, whereas no other carriers of the two LQTS founder mutations were identified among the remaining 164 victims. This study provides the first estimate of the minimum prevalence of LQTS (0.61%, CI(95): 0.02-3.33) in such a setting and demonstrates the value of genetic analysis of LQTS in putative drownings. The detection of a LQTS founder mutation in a body found in water is a relatively rare event based on our study sample. This finding is, however, of utmost medico-legal importance, since it broadens the spectrum of potential causes and manners of death.

Adolescent↗
PubMed2003

Genome-wide search in Finnish families with inflammatory bowel disease provides evidence for novel susceptibility loci.

Epidemiological and genetic linkage studies have indicated a strong genetic basis for development of inflammatory bowel disease (IBD) which was recently supported by discovery of the Crohn's disease (CD) susceptibility gene termed NOD2/CARD15. We carried out a genome-wide linkage study in Finnish IBD families, providing a particular advantage to map susceptibility genes for ulcerative colitis (UC) within a genetic isolate. Initially, 92 IBD families with 138 affected sib-pairs (ASPs), were genotyped for 429 markers spaced at approximately 10 cM intervals. Next, the loci on chromosomes 2p13-11, 11p12-q13, and 12p13-12 were high-density mapped in the extended family cohort of 130 families with 173 ASPs. In this study, the most significant lod scores were observed for the UC families on chromosome 2p11 (D2S2333), in the vicinity of the REG gene cluster which is strikingly overexpressed in the IBD mucosa. The maximum two-point lod score was 3.34 (dominant model), and the corresponding NPL score 2.61. For UC, the second highest two-point NPL score of 2.00 was observed at proximal 12p13, where also some evidence for linkage disequilibrium emerged (P=0.07 and P=0.007 for the basic and extended IBD cohorts, respectively). The highest two-point NPL score for the CD families was 2.34 at D12S78 (12q23) with significant evidence for linkage disequilibrium (P=0.004), and for the mixed (MX) families 2.07 at D4S406 near the linkage peak reported previously. This study confirmed several of the IBD loci that have previously been reported and gives evidence for new IBD loci on chromosomes 2p11, 11p12-q13, 12p13-12, 12q23, and 19q13.

Female↗
PubMed2003

Molecular genetics of exercise-induced polymorphic ventricular tachycardia: identification of three novel cardiac ryanodine receptor mutations and two common calsequestrin 2 amino-acid polymorphisms.

Mutations of two myocardial calcium signaling molecules, ryanodine receptor 2 (RYR2) and calsequestrin 2 (CASQ2), may cause catecholaminergic polymorphic ventricular tachycardia (CPVT), a severe inherited arrhythmic disease manifesting with salvoes of exercise-induced bidirectional and polymorphic tachycardias. We screened 12 Finnish CPVT probands for mutations in these genes and identified three novel RYR2 mutations (V2306I, P4902L, R4959Q), which were absent in unaffected and control individuals. Although no obvious disease-causing mutations were identified in the CASQ2 gene, the molecular screening revealed two novel amino-acid polymorphisms (T66A and V76M). The frequencies of these polymorphisms in 185 unrelated probands with long QT syndrome and in 280 healthy blood donors were not significantly different. These data, combined with our previous findings, show that RYR2 mutations are present in at least 6/16 (38%) of the catecholaminergic polymorphic ventricular tachycardia families, while CASQ2 mutations must be a rare cause of CPVT.

Adult↗
PubMed2003

The SLC6A14 gene shows evidence of association with obesity.

In our previous genome-wide scan of Finnish nuclear families, obesity was linked to chromosome Xq24. Here we analyzed this 15-Mb region by genotyping 9 microsatellite markers and 36 single nucleotide polymorphisms (SNPs) for 11 positional and functional candidate genes in an extended sample of 218 obese Finnish sibling pairs (sibpairs) (BMI > 30 kg/m2). Evidence of linkage emerged mainly from the obese male sibpairs, suggesting a gender-specific effect for the underlying gene. By constructing haplotypes among the obese male sibpairs, we restricted the region from 15 Mb to 4 Mb, between markers DXS8088 and DXS8067. Regional functional candidate genes were tested for association in an initial sample of 117 cases and 182 controls. Significant evidence was observed for association for an SNP in the 3'-untranslated region of the solute carrier family 6 member 14 (SLC6A14) gene (P = 0.0002) and for SNP haplotypes of the SLC6A14 gene (P = 0.0007-0.006). Furthermore, an independent replication study sample of 837 cases and 968 controls from Finland and Sweden also showed significant differences in allele frequencies between obese and non-obese individuals (P = 0.003). The SLC6A14 gene is an interesting novel candidate for obesity because it encodes an amino acid transporter, which potentially regulates tryptophan availability for serotonin synthesis and thus possibly affects appetite control.

Adult↗
PubMed2002

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.

Adult↗
PubMed2002

Association between HERG K897T polymorphism and QT interval in middle-aged Finnish women.

OBJECTIVES: The aim of this study was to test whether a recently reported polymorphism in the HERG gene coding for the rapidly activating delayed rectifier K+ channel has influence on myocardial repolarization. BACKGROUND: The length of myocardial repolarization, measured as the QT interval, has a hereditary component, but no genes that would explain the variability of repolarization have been identified in healthy subjects. METHODS: QT intervals were measured from the 12-lead electrocardiogram in a random middle-aged population (226 men/187 women). The longest QT interval at any of the 12 leads (QTmax), QTV(2), and the Tpeak-Tend interval were used as measures of repolarization. Deoxyribonucleic acid samples were genotyped for the nucleotide 2690A>C variation of the HERG gene, corresponding to the HERG K(lysine)897T(threonine) amino acid polymorphism. RESULTS: The allele frequencies were 0.84 (A) and 0.16 (C). Females with the genotype AC or CC had longer QTcmax (477 +/- 99 ms) and Tpeak-Tend intervals (143 +/- 95 ms) than females with the genotype AA (441 +/- 69 ms and 116 +/- 65 ms, p = 0.005 and p = 0.025, respectively). In males, the QTcmax and the Tpeak-Tend intervals did not differ between the genotypes. After adjustment for echocardiographic and various laboratory variables, the HERG K897T polymorphism remained as an independent predictor of QTcmax (p = 0.009) and the Tpeak-Tend intervals (p = 0.026) in females. CONCLUSIONS; The common K897T polymorphism of the HERG channel is associated with the maximal duration and transmural dispersion of ventricular repolarization in middle-aged females.

Adult↗
PubMed2002

ApoE epsilon3-haplotype modulates Alzheimer beta-amyloid deposition in the brain.

ApoE epsilon4 allele increases the risk of late-onset Alzheimer disease (AD) as well as the amount of beta-amyloid deposition in the brain. Because half of AD patients do not have ApoE epsilon4, it is important to search for other determinants of ApoE that modify AD risk. We tested whether the haplotype background of the most common ApoE allele, epsilon3, influences brain amyloid deposition or the risk of neuropathologically verified AD in a population-based sample of elderly Finns. To exclude the effects of ApoE protein polymorphism we focused these analyses on subjects homozygous for epsilon3. Haplotypes were defined using polymorphisms at positions - 491 and -219 of the ApoE promoter and at position +113 of intron-1. We found that epsilon3-haplotypes containing the promoter allele -219T were associated with reduced amyloid deposition and reduced risk of neuropathologically verified AD as compared to epsilon3-haplotypes containing -219G. The functional polymorphism(s) responsible for the haplotypic difference remains to be identified. These results indicate that there is significant allelic variation in the ApoE gene region, which modulates brain amyloid deposition and AD risk, independent of the ApoE protein polymorphism.

Aged↗
PubMed2002

Differentiation between LQT1 and LQT2 patients and unaffected subjects using 24-hour electrocardiographic recordings.

This study assesses the use of 24-hour ambulatory electrocardiographic recordings in distinguishing patients with long-QT1 syndrome (LQT1) from those with LQT2, and for distinguishing affected from unaffected patients. The diagnoses of the congenital LQT syndrome and its most common types LQT1 and LQT2 are made difficult because of the limitations of the electrocardiogram as a diagnostic tool. With an automated computerized program, Holter recordings from 15 LQT1 and 15 LQT2 patients and 43 healthy subjects (training set) were reviewed to select the best criteria using QT duration and rate dependence as well as the difference between QT end and QT apex to separate the 3 groups. Fixed criteria were then applied in blinded fashion to separate a different group of 32 genotyped patients and 16 unaffected subjects (test set). In the training set, the RR interval (100 ms), a slope value for median QT/RR curves of -0.016 separated 25 of 30 (83%) and a minimal QT end - QT apex value of 80 ms, separated 26 of 30 (87%) LQT1 patients from LQT2 patients. When all selected criteria were applied to differentiate LQT1 from LQT2 versus unaffected genotypes in the test set, 38 of 48 cases (79%) were correctly identified, whereas using the electrocardiogram alone, 60% of patients were correctly classified into 3 genotypes (p = 0.03). Combining measures for QT duration, rate dependence, and QT end - QT apex interval, derived from Holter recordings, complements the clinical differentiation between LQT1 versus LQT2 patients and between affected and unaffected persons for genotype screening purposes.

Adolescent↗