30 results on '"Piippo K"'
Search Results
2. You may live to the age of more than 100 years even if you are homozygous for a haemochromatosis gene mutation
- Author
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Piippo, K., Louhija, J., Tilvis, R., and Kontula, K.
- Published
- 2003
3. Response of the QT interval to mental and physical stress in types LQT1 and LQT2 of the long QT syndrome
- Author
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Paavonen, K J, Swan, H, Piippo, K, Hokkanen, L, Laitinen, P, Viitasalo, M, Toivonen, L, and Kontula, K
- Published
- 2001
4. Sarcoplastic calcium channel mutations in inherited and acquired forms of human ventricular arrhythmias
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Laitinen, P.J., Fodstad, H., Swan, H., Paavonen, K., Piippo, K., Viitasalo, M., Toivonen, L., Rosemblit, N., Marks, A.R., and Kontula, K.
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Human genetics -- Research ,Ventricular tachycardia -- Genetic aspects ,Genetic disorders -- Research ,Biological sciences - Published
- 2001
5. Sound fields inside street canyons with inclined flanking building facades.
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Tang, S. K., primary and Piippo, K. E., additional
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- 2011
- Full Text
- View/download PDF
6. Sound fields inside street canyons with inclined flanking building façades
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Tang, SK, primary and Piippo, K. E., additional
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- 2011
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7. HFE Haemochromatosis Gene Mutations in Liver Transplant Patients
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Halme, L., primary, Heliö, T., additional, Mäkinen, J., additional, Höckerstedt, K., additional, Färkkilä, M., additional, Piippo, K., additional, Krusius, T., additional, and Kontula, K., additional
- Published
- 2001
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- View/download PDF
8. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia
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Laitinen, P.J, primary, Brown, K.M, additional, and Piippo, K, additional
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- 2001
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- View/download PDF
9. High efficacy of beta-blockers in long-QT syndrome type 1: contribution of noncompliance and QT-prolonging drugs to the occurrence of beta-blocker treatment 'failures'.
- Author
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Vincent GM, Schwartz PJ, Denjoy I, Swan H, Bithell C, Spazzolini C, Crotti L, Piippo K, Lupoglazoff JM, Villain E, Priori SG, Napolitano C, and Zhang L
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- 2009
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- View/download PDF
10. Mutations of the cardiac ryanodine receptor (RyR2) gene in familial polymorphic ventricular tachycardia.
- Author
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Laitinen, P J, Brown, K M, Piippo, K, Swan, H, Devaney, J M, Brahmbhatt, B, Donarum, E A, Marino, M, Tiso, N, Viitasalo, M, Toivonen, L, Stephan, D A, and Kontula, K
- Published
- 2001
11. Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension
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Krusius Tom, Virtamo Jarmo, Miettinen Helena E, Piippo Kirsi, Fodstad Heidi, Helin Karri, Fyhrquist Frej, Tikkanen Tuula, Tikkanen Ilkka, Kontula Kimmo, Hannila-Handelberg Tuula, Sarna Seppo, Gautschi Ivan, Schild Laurent, and Hiltunen Timo P
- Subjects
Internal medicine ,RC31-1245 ,Genetics ,QH426-470 - Abstract
Abstract Background Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC βand γ subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system. Methods Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests. Results Two commonly occurring βENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel γENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). βENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the βENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048). Conclusions At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of β and γENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.
- Published
- 2005
- Full Text
- View/download PDF
12. Effect of the antimalarial drug halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene SCN5A.
- Author
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Piippo, Kirsi, Holström, Sam, Swan, Heikki, Viitasalo, Matti, Raatikka, Marja, Toivonen, Lauri, Kontula, Kimmo, Piippo, K, Holmström, S, Swan, H, Viitasalo, M, Raatikka, M, Toivonen, L, and Kontula, K
- Subjects
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ANTIMALARIALS , *SODIUM channels , *AMINO acids , *COMPARATIVE studies , *DOCUMENTATION , *ELECTROCARDIOGRAPHY , *GENEALOGY , *GENETIC techniques , *HYDROCARBONS , *RESEARCH methodology , *MEDICAL cooperation , *MEMBRANE proteins , *GENETIC mutation , *RESEARCH , *VENTRICULAR tachycardia , *LONG QT syndrome , *EVALUATION research , *MEMBRANE transport proteins - Abstract
Studies the effect of the antimalarial drug, Halofantrine in the long QT syndrome due to a mutation of the cardiac sodium channel gene, SCN5A. Mutations of the SCN5A gene that caused long QT syndrome; Drugs implicated in provocation of ventricular tachyarrhythmias; Use of the Halofantrine against chloroquine-resistant Plasmodium falciparum malaria.
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- 2001
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13. High Efficacy of β-Blockers in Long-QT Syndrome Type 1
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Candice Bithell, Silvia G. Priori, Carlo Napolitano, Li Zhang, Heikki Swan, Carla Spazzolini, Peter J. Schwartz, Isabelle Denjoy, G. Michael Vincent, Kirsi Piippo, Villain E, Lia Crotti, Jean Marc Lupoglazoff, Vincent, G, Schwartz, P, Denjoy, I, Swan, H, Bithell, C, Spazzolini, C, Crotti, L, Piippo, K, Lupoglazoff, J, Villain, E, Priori, S, Napolitano, C, and Zhang, L
- Subjects
Adult ,Male ,medicine.medical_specialty ,Adolescent ,Drug-Related Side Effects and Adverse Reactions ,Romano-Ward Syndrome ,Long QT syndrome ,Adrenergic beta-Antagonists ,030204 cardiovascular system & hematology ,Treatment failure ,Young Adult ,03 medical and health sciences ,0302 clinical medicine ,Physiology (medical) ,Internal medicine ,medicine ,Humans ,Treatment Failure ,030212 general & internal medicine ,Patient compliance ,long qt syndrome, beta-blockers, drugs, long qt syndrome type 1 ,Retrospective Studies ,Syndrome type ,business.industry ,Follow up studies ,Retrospective cohort study ,MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE ,Middle Aged ,medicine.disease ,3. Good health ,Romano–Ward syndrome ,Pharmaceutical Preparations ,Anesthesia ,Mutation ,Cardiology ,Patient Compliance ,Female ,Cardiology and Cardiovascular Medicine ,business ,Follow-Up Studies - Abstract
Background— β-Blocker efficacy in long-QT syndrome type 1 is good but variably reported, and the causes of cardiac events despite β-blocker therapy have not been ascertained. Methods and Results— This was a retrospective study of the details surrounding cardiac events in 216 genotyped long-QT syndrome type 1 patients treated with β-blocker and followed up for a median time of 10 years. Before β-blocker, cardiac events occurred in 157 patients (73%) at a median age of 9 years, with cardiac arrest (CA) in 26 (12%). QT-prolonging drugs were used by 17 patients; 9 of 17 (53%) had CA compared with 17 of 199 nonusers (8.5%; odds ratio, 12.0; 95% confidence interval, 4.1 to 35.3; P P P =0.001). None of the 26 patients with CA before β-blocker had CA/sudden death on β-blockers. Conclusions— β-Blockers are extremely effective in long-QT syndrome type 1 and should be administered at diagnosis and ideally before the preteen years. β-Blocker noncompliance and use of QT-prolonging drug are responsible for almost all life-threatening “β-blocker failures.” β-Blockers are appropriate therapy for asymptomatic patients and those who have never had a CA or β-blocker therapy. Routine implantation of cardiac defibrillators in such patients does not appear justified.
- Published
- 2009
14. X-linked pyruvate dehydrogenase complex deficiency due to a novel PDHA1 variant associated with structural brain abnormalities in a fetus.
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Tanner LM, Tynninen O, Piippo K, and Puhakka AM
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- Pregnancy, Female, Humans, Male, Cerebellum, Fetus diagnostic imaging, Fetus pathology, Pyruvate Dehydrogenase Complex Deficiency Disease genetics, Pyruvate Dehydrogenase Complex Deficiency Disease pathology, Abnormalities, Multiple diagnostic imaging, Abnormalities, Multiple genetics, Abnormalities, Multiple pathology, Hydrocephalus
- Abstract
We report a case of pyruvate dehydrogenase E1 alpha subunit deficiency associated with a novel hemizygous PDHA1 variant presenting prenatally as multiple structural brain abnormalities in a male fetus. A healthy Finnish couple was initially referred to the Fetomaternal Medical Center because of suspected fetal choroid plexus cyst at 11 + 2 weeks of pregnancy. At 20 + 0 weeks, multiple abnormalities were observed with ultrasound including narrow thorax, slightly enlarged heart, hypoplastic cerebellum, absent cerebellar vermis and ventriculomegaly. Autopsy and genetic analyses were performed after the termination of pregnancy. The findings of macroscopic examination included cleft palate, abnormally overlapping position of fingers and toes and dysmorphic facial features. Neuropathological examination confirmed the absence of corpus callosum, cerebellar hypoplasia and ventriculomegaly. Nodular neuronal heterotopia was also observed. Trio exome sequencing revealed a novel hemizygous de novo variant c.1144C>T p.(Gln382*) in the PDHA1 gene, classified as likely pathogenic. We suggest that inherited metabolic disorders should be kept in mind as differential diagnoses in fetuses with structural brain abnormalities., (© 2023 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.)
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- 2023
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15. Clinical and molecular genetic risk determinants in adult long QT syndrome type 1 and 2 patients : Koponen et al. Follow-up of adult LQTS patients.
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Koponen M, Havulinna AS, Marjamaa A, Tuiskula AM, Salomaa V, Laitinen-Forsblom PJ, Piippo K, Toivonen L, Kontula K, Viitasalo M, and Swan H
- Subjects
- Adrenergic beta-Antagonists therapeutic use, Adult, Female, Follow-Up Studies, Genetic Predisposition to Disease, Humans, Long QT Syndrome drug therapy, Male, Prognosis, Regression Analysis, Risk Factors, Romano-Ward Syndrome drug therapy, Young Adult, ERG1 Potassium Channel genetics, KCNQ1 Potassium Channel genetics, Long QT Syndrome genetics, Mutation, Romano-Ward Syndrome genetics
- Abstract
Background: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving β-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations., Methods: A follow-up study covering a mean of 18.6 ± 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events., Results: In mutation carriers, risk factors for cardiac events before initiation of β-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p < 0.001), a cardiac event before the age of 18 years (HR = 5.9, p < 0.001), and QTc ≥500 ms (vs < 470 ms, HR = 2.7, p = 0.001). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR = 3.0-3.9, p < 0.001-0.03) compared to G589D, c.1129-2A > G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR = 0.11-0.23, p < 0.001) than other KCNH2 mutations., Conclusions: LQT2 (compared to LQT1), female gender, a cardiac event before age 18, and long QT interval increased the risk of cardiac events in LQTS patients aged 18 to 40 years. The nature of the underlying mutation may be associated with risk variation in both LQT1 and LQT2. The identification of high-risk and low-risk mutations may enhance risk stratification.
- Published
- 2018
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16. Prevalence of recurrent pathogenic microdeletions and microduplications in over 9500 pregnancies.
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Grati FR, Molina Gomes D, Ferreira JC, Dupont C, Alesi V, Gouas L, Horelli-Kuitunen N, Choy KW, García-Herrero S, de la Vega AG, Piotrowski K, Genesio R, Queipo G, Malvestiti B, Hervé B, Benzacken B, Novelli A, Vago P, Piippo K, Leung TY, Maggi F, Quibel T, Tabet AC, Simoni G, and Vialard F
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- Adult, Chromosome Disorders epidemiology, Chromosome Disorders genetics, Female, Follow-Up Studies, Humans, Incidence, Pregnancy, Prevalence, Retrospective Studies, Sensitivity and Specificity, Chromosome Deletion, Chromosome Disorders diagnosis, Chromosome Duplication, Karyotyping methods, Prenatal Diagnosis methods
- Abstract
Objectives: The implementation of chromosomal microarray analysis (CMA) in prenatal testing for all patients has not achieved a consensus. Technical alternatives such as Prenatal BACs-on-Beads(TM) (PNBoBs(TM) ) have thus been applied. The aim of this study was to provide the frequencies of the submicroscopic defects detectable by PNBoBs(TM) under different prenatal indications., Methods: A total of 9648 prenatal samples were prospectively analyzed by karyotyping plus PNBoBs(TM) and classified by prenatal indication. The frequencies of the genomic defects and their 95%CIs were calculated for each indication., Results: The overall incidence of cryptic imbalances was 0.7%. The majority involved the DiGeorge syndrome critical region (DGS). The additional diagnostic yield of PNBoBs(TM) in the population with a low a priori risk was 1/298. The prevalences of DGS microdeletion and microduplication in the low-risk population were 1/992 and 1/850, respectively., Conclusions: The constant a priori risk for common pathogenic cryptic imbalances detected by this technology is estimated to be ~0.3%. A prevalence higher than that previously estimated was found for the 22q11.2 microdeletion. Their frequencies were independent of maternal age. These data have implications for cell-free DNA screening tests design and justify prenatal screening for 22q11 deletion, as early recognition of DGS improves its prognosis., (© 2015 John Wiley & Sons, Ltd.)
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- 2015
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17. Licorice-induced hypertension and common variants of genes regulating renal sodium reabsorption.
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Miettinen HE, Piippo K, Hannila-Handelberg T, Paukku K, Hiltunen TP, Gautschi I, Schild L, and Kontula K
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- Adolescent, Adult, Aldosterone blood, Female, Genetic Variation, Humans, Hypertension blood, Hypertension genetics, Kidney metabolism, Male, Middle Aged, Mineralocorticoid Excess Syndrome, Apparent blood, Mineralocorticoid Excess Syndrome, Apparent genetics, Mutagenesis, Insertional, Potassium blood, Renin blood, Sodium metabolism, Young Adult, 11-beta-Hydroxysteroid Dehydrogenase Type 2 genetics, Epithelial Sodium Channels genetics, Glycyrrhiza adverse effects, Hypertension chemically induced, Mineralocorticoid Excess Syndrome, Apparent chemically induced
- Abstract
Aim: To study if gene alterations affecting renal sodium reabsorption associate with susceptibility to licorice-induced hypertension., Methods: Finnish subjects (n = 30) with a previously documented incident of licorice-induced hypertension were recruited for the study using a newspaper announcement. Their previous clinical and family histories as well as serum electrolyte levels were examined. DNA samples from all individuals were screened for variants of the genes encoding 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) and alpha-, beta-, and gamma-subunits of the epithelial sodium channel (ENaC)., Results: Upon licorice predisposition, the patients had a mean blood pressure of 201/118 mmHg. Circulating potassium, renin, and aldosterone levels were low. No significant DNA variations were identified in the 11betaHSD2 gene. Four subjects were heterozygous for beta- and gammaENaC variants previously shown to be associated with hypertension. Furthermore, a novel G insertion (2004-2005insG) in the SCNN1A gene encoding the alphaENaC was identified in two subjects. The frequency of these ENaC variants was significantly higher in subjects with licorice-induced hypertension (6/30 i.e. 20%) than in blood donors (11/301 i.e. 3.7%, P = 0.002)., Conclusions: Defects of the 11betaHSD2 gene do not constitute a likely cause for licorice-induced hypertension. Variants of the ENaC subunits may render some individuals sensitive to licorice-induced metabolic alterations and hypertension.
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- 2010
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18. Beta1-adrenergic receptor polymorphisms, QTc interval and occurrence of symptoms in type 1 of long QT syndrome.
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Paavonen KJ, Swan H, Piippo K, Laitinen P, Fodstad H, Sarna S, Toivonen L, Kontula K, and Viitasalo M
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- Adolescent, Adult, Aged, Aged, 80 and over, Electrocardiography, Exercise Test, Female, Finland epidemiology, Genotype, Humans, KCNQ1 Potassium Channel genetics, Long QT Syndrome diagnosis, Long QT Syndrome epidemiology, Male, Middle Aged, Mutation genetics, Odds Ratio, Reference Values, Regression Analysis, Long QT Syndrome genetics, Polymorphism, Genetic genetics, Receptors, Adrenergic, beta-1 genetics
- Abstract
Background: The most prevalent LQT1 form of inherited long QT syndrome is caused by mutations of the KCNQ1 gene resulting repolarizing I(Ks) potassium current to decrease and the QT interval to prolong. As abrupt sympathetic activation triggers ventricular arrhythmias that may cause syncopal attacks and sudden death in LQT1 patients, we investigated whether two known beta1-adrenergic receptor polymorphisms were associated with the duration of QT interval or history of symptoms in LQT1., Methods: We determined beta1-adrenergic receptor polymorphisms (Ser49Gly and Arg389Gly) in 168 LQT1 patients. We also reviewed each patient's clinical records on the history of long QT syndrome-related symptoms and measured QT intervals from baseline ECG in each subject and from an exercise test ECG in 55 LQT1 patients., Results: Patients with the homozygous Arg389Arg genotype tended to have shorter and those with the Ser49Ser genotype longer QT intervals than patients with other genotypes, but neither polymorphism studied alone affected the risk of symptoms. In contrast, adjusted odds ratio for the history of symptoms was 4.9 (95% CI 1.18 to 20.3) in patients homozygous for both Ser49 and Arg389. These double homozygous patients showed similar QT intervals as the rest of the LQT1 cohort., Conclusions: In this relatively small study, double homozygosity for Arg389 and Ser49 of the human beta1-adrenergic receptor associated with the risk of symptoms in LQT1. The association between these beta1-adrenergic receptor polymorphisms and the symptom history in LQT1 is not mediated via QT interval duration.
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- 2007
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19. The relation of the XbaI and PvuII polymorphisms of the estrogen receptor gene and the CAG repeat polymorphism of the androgen receptor gene to peak bone mass and bone turnover rate among young healthy men.
- Author
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Välimäki VV, Piippo K, Välimäki S, Löyttyniemi E, Kontula K, and Välimäki MJ
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- Acid Phosphatase blood, Adolescent, Adult, Biomarkers blood, Bone Density physiology, Collagen urine, Cross-Sectional Studies, Estradiol blood, Femur, Genotype, Humans, Isoenzymes blood, Life Style, Lumbar Vertebrae, Male, Military Personnel, Peptide Fragments blood, Polymorphism, Restriction Fragment Length, Procollagen blood, Retrospective Studies, Tartrate-Resistant Acid Phosphatase, Bone and Bones physiology, Polymorphism, Genetic genetics, Receptors, Androgen genetics, Receptors, Estrogen genetics
- Abstract
The genes coding for estrogen receptor-alpha (ER-alpha) and androgen receptors (AR) are potential candidates for the regulation of bone mass and turnover, which may contribute to both the achievement of peak bone mass and bone loss after completion of growth. The present study was aimed at elucidating the role of two restriction fragment lengths (XbaI and PvuII) polymorphisms of the ER gene and the CAG repeat polymorphism of the AR gene as determinants of peak bone mass in men; special attention was paid to the interaction between serum free estradiol (E2) levels and the XbaI and PvuII genotypes. A cross-sectional study, with data on lifestyle factors collected retrospectively, was performed in 234 young men, aged 18.3 to 20.6 years. Of the men, 184 were recruits of the Finnish Army and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD) and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). The bone turnover rate was assessed by measuring serum type I procollagen aminoterminal propeptide (PINP) and tartrate-resistant acid phosphatase 5b (TRACP5b) as well as urinary excretion of type I collagen aminoterminal telopeptide (NTX). After adjusting for age, height, weight, exercise, smoking, calcium and alcohol intake, BMC, scan area and BMD at all measurement sites were similar for the different XbaI and PvuII genotypes of the ER and independent of the number of the CAG repeats of the AR gene. No association was found between free E2 levels and bone parameters among any genotype group of the XbaI and PvuII polymorphisms. Except for urinary NTX, which showed a tendency to higher values for the xx (P=0.08) and pp (P=0.10) genotypes of the ER, bone turnover markers were not related to the genotypes studied. Our study does not support the view that the XbaI and PvuII polymorphisms of the ER gene and the CAG polymorphism of the AR gene would have a substantial impact on the development of peak bone mass in young Finnish men.
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- 2005
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20. Common variants of the beta and gamma subunits of the epithelial sodium channel and their relation to plasma renin and aldosterone levels in essential hypertension.
- Author
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Hannila-Handelberg T, Kontula K, Tikkanen I, Tikkanen T, Fyhrquist F, Helin K, Fodstad H, Piippo K, Miettinen HE, Virtamo J, Krusius T, Sarna S, Gautschi I, Schild L, and Hiltunen TP
- Subjects
- Adult, Aged, Alleles, Epithelial Sodium Channels, Female, Genetic Predisposition to Disease, Humans, Hypertension blood, Hypertension diagnosis, Male, Middle Aged, Protein Subunits genetics, Renin-Angiotensin System, Sequence Analysis, DNA, Aldosterone blood, Genetic Variation, Hypertension genetics, Renin blood, Sodium Channels genetics
- Abstract
Background: Rare mutations of the epithelial sodium channel (ENaC) result in the monogenic hypertension form of Liddle's syndrome. We decided to screen for common variants in the ENaC beta and gamma subunits in patients with essential hypertension and to relate their occurrence to the activity of circulating renin-angiotensin-aldosterone system., Methods: Initially, DNA samples from 27 patients with low renin/low aldosterone hypertension were examined. The DNA variants were subsequently screened for in 347 patients with treatment-resistant hypertension, 175 male subjects with documented long-lasting normotension and 301 healthy Plasma renin and aldosterone levels were measured under baseline conditions and during postural and captopril challenge tests., Results: Two commonly occurring betaENaC variants (G589S and a novel intronic i12-17CT substitution) and one novel gammaENaC variant (V546I) were detected. One of these variants occurred in a heterozygous form in 32 patients, a prevalence (9.2%) significantly higher than that in normotensive males (2.9%, p = 0.007) and blood donors (3.0%, p = 0.001). betaENaC i12-17CT was significantly more prevalent in the hypertension group than in the two control groups combined (4.6% vs. 1.1%, p = 0.001). When expressed in Xenopus oocytes, neither of the two ENaC amino acid-changing variants showed a significant difference in activity compared with ENaC wild-type. No direct evidence for a mRNA splicing defect could be obtained for the betaENaC intronic variant. The ratio of daily urinary potassium excretion to upright and mean (of supine and upright values) plasma renin activity was higher in variant allele carriers than in non-carriers (p = 0.034 and p = 0.048)., Conclusions: At least 9% of Finnish patients with hypertension admitted to a specialized center carry genetic variants of beta and gammaENaC, a three times higher prevalence than in the normotensive individuals or in random healthy controls. Patients with the variant alleles showed an increased urinary potassium excretion rate in relation to their renin levels.
- Published
- 2005
- Full Text
- View/download PDF
21. Genes, exercise and sudden death: molecular basis of familial catecholaminergic polymorphic ventricular tachycardia.
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Laitinen PJ, Swan H, Piippo K, Viitasalo M, Toivonen L, and Kontula K
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- Catecholamines metabolism, Chromosomes, Human, Pair 1 genetics, Humans, Polymorphism, Single Nucleotide, Ryanodine Receptor Calcium Release Channel genetics, Ryanodine Receptor Calcium Release Channel physiology, Tachycardia, Ventricular genetics, Tachycardia, Ventricular physiopathology, Death, Sudden, Cardiac, Exercise physiology, Genetic Predisposition to Disease genetics
- Abstract
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.
- Published
- 2004
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22. 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.
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Fodstad H, Swan H, Laitinen P, Piippo K, Paavonen K, Viitasalo M, Toivonen L, and Kontula K
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- Cation Transport Proteins genetics, Chromatography, High Pressure Liquid, DNA Mutational Analysis, Ether-A-Go-Go Potassium Channels, Female, Finland, Genetic Testing, Humans, KCNQ Potassium Channels, KCNQ1 Potassium Channel, Long QT Syndrome diagnosis, Male, Middle Aged, NAV1.5 Voltage-Gated Sodium Channel, Phenotype, Polymorphism, Genetic, Sodium Channels genetics, Founder Effect, Long QT Syndrome genetics, Mutation, Potassium Channels genetics, Potassium Channels, Voltage-Gated
- Abstract
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.
- Published
- 2004
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23. Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG).
- Author
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Paavonen KJ, Chapman H, Laitinen PJ, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, Kontula K, and Pasternack M
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- Adolescent, Adult, Aged, Aged, 80 and over, Analysis of Variance, Animals, COS Cells, Cell Line, Child, Child, Preschool, ERG1 Potassium Channel, Electrocardiography, Ether-A-Go-Go Potassium Channels, Exercise Test, Female, Gene Expression, Heterozygote, Humans, Kidney, Long QT Syndrome physiopathology, Male, Middle Aged, Patch-Clamp Techniques, Potassium Channels metabolism, Transcriptional Regulator ERG, Transfection, Cation Transport Proteins, DNA-Binding Proteins, Long QT Syndrome metabolism, Polymorphism, Genetic, Potassium Channels genetics, Potassium Channels, Voltage-Gated, Trans-Activators
- Abstract
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.
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- 2003
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24. Differentiation between LQT1 and LQT2 patients and unaffected subjects using 24-hour electrocardiographic recordings.
- Author
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Viitasalo M, Oikarinen L, Väänänen H, Swan H, Piippo K, Kontula K, Barron HV, Toivonen L, and Scheinman MM
- Subjects
- Adolescent, Adult, Aged, Child, Diagnosis, Differential, Female, Genotype, Heart Conduction System physiopathology, Humans, Long QT Syndrome genetics, Male, Middle Aged, Sensitivity and Specificity, Circadian Rhythm physiology, Electrocardiography, Ambulatory, Long QT Syndrome diagnosis
- Abstract
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.
- Published
- 2002
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25. A founder mutation of the potassium channel KCNQ1 in long QT syndrome: implications for estimation of disease prevalence and molecular diagnostics.
- Author
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Piippo K, Swan H, Pasternack M, Chapman H, Paavonen K, Viitasalo M, Toivonen L, and Kontula K
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Deafness genetics, Female, Finland, Gene Frequency genetics, Genetics, Population, Genotype, Humans, KCNQ Potassium Channels, KCNQ1 Potassium Channel, Long QT Syndrome diagnosis, Male, Middle Aged, Patch-Clamp Techniques, Pedigree, Phenotype, Syndrome, Founder Effect, Long QT Syndrome genetics, Mutation, Missense genetics, Potassium Channels genetics, Potassium Channels, Voltage-Gated
- Abstract
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.
- Published
- 2001
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26. Survey of the coding region of the HERG gene in long QT syndrome reveals six novel mutations and an amino acid polymorphism with possible phenotypic effects.
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Laitinen P, Fodstad H, Piippo K, Swan H, Toivonen L, Viitasalo M, Kaprio J, and Kontula K
- Subjects
- Adult, Aged, DNA Mutational Analysis, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Female, Humans, Middle Aged, Phenotype, Potassium Channels analysis, Sequence Deletion, Transcriptional Regulator ERG, Amino Acid Substitution genetics, Cation Transport Proteins, DNA-Binding Proteins, Long QT Syndrome genetics, Mutation genetics, Polymorphism, Single-Stranded Conformational, Potassium Channels genetics, Potassium Channels, Voltage-Gated, Trans-Activators
- Abstract
Analysis of the entire coding region of the HERG gene of 39 Finnish LQTS patients revealed eight mutations, six of which are hitherto unreported. All these mutations are located in the evolutionarily conserved regions of HERG, including the transmembrane domains (P451L, Y569H, 1631delAG, G584S, G601S, T613M) and the cytoplasmic N-terminus (453delC, R176W) of the channel. Our present and earlier results suggest that the LQT2 subtype accounts for approximately 20-30% of LQTS cases in Finland. We also report the first common amino acid polymorphism (K897T) of the HERG channel, with allele frequencies of 0.84 and 0.16. Investigation of 170 genetically homogenous LQT1 patients suggests that this polymorphism may influence QT interval in female individuals., (Copyright 2000 Wiley-Liss, Inc.)
- Published
- 2000
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27. Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns.
- Author
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Piippo K, Laitinen P, Swan H, Toivonen L, Viitasalo M, Pasternack M, Paavonen K, Chapman H, Wann KT, Hirvelä E, Sajantila A, and Kontula K
- Subjects
- Adult, Child, ERG1 Potassium Channel, Ether-A-Go-Go Potassium Channels, Female, Finland, Homozygote, Humans, Male, Mutation, Pedigree, Phenotype, Severity of Illness Index, Transcriptional Regulator ERG, Cation Transport Proteins, DNA-Binding Proteins, Long QT Syndrome genetics, Potassium Channels genetics, Potassium Channels, Voltage-Gated, Trans-Activators
- Abstract
Objectives: We studied the clinical characteristics and molecular background underlying a severe phenotype of long QT syndrome (LQTS)., Background: Mutations of cardiac ion channel genes cause LQTS, manifesting as increased risk of ventricular tachycardia and sudden death., Methods: We studied two siblings showing prolonged QT intervals corrected for heart rate (QTc), their asymptomatic parents with only marginally prolonged QTc intervals and their family members. The potassium channel gene HERG was screened for mutations by deoxyribonucleic acid sequencing, and the electrophysiologic consequences of the mutation were studied in vitro using the whole-cell patch-clamp technique., Results: A novel missense mutation (L552S) in the HERG channel, present in the homozygous state in the affected siblings and in the heterozygous state in their parents, as well as in 38 additional subjects from six LQTS families, was identified. One of the homozygous siblings had 2:1 atrioventricular block immediately after birth, and died at the age of four years after experiencing unexplained hypoglycemia. The other sibling had an episode of torsade de pointes at the age of two years. The mean QTc interval differed significantly (p < 0.001) between heterozygous symptomatic mutation carriers (500 +/- 59 ms), asymptomatic mutation carriers (452 +/- 34 ms) and noncarriers (412 +/- 23 ms). When expressed in vitro, the HERG-L552S formed functional channels with increased activation and deactivation rates., Conclusions: Our data demonstrate that homozygosity for a HERG mutation can cause a severe cardiac repolarization disorder without other phenotypic abnormalities. Absence of functional HERG channels appears to be one cause for intrauterine and neonatal bradycardia and 2:1 atrioventricular block.
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- 2000
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28. [Hereditary polymorphic ventricular tachycardia as a cause of syncopes and sudden cardiac deaths].
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Swan H, Viitasalo M, Toivonen L, Piippo K, and Kontula K
- Subjects
- Death, Sudden, Cardiac epidemiology, Exercise, Exercise Test, Finland epidemiology, Genes, Dominant, Humans, Pedigree, Syncope epidemiology, Tachycardia, Ventricular genetics, Death, Sudden, Cardiac etiology, Syncope etiology, Tachycardia, Ventricular complications, Tachycardia, Ventricular diagnosis
- Published
- 2000
29. Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.
- Author
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Swan H, Piippo K, Viitasalo M, Heikkilä P, Paavonen T, Kainulainen K, Kere J, Keto P, Kontula K, and Toivonen L
- Subjects
- Adolescent, Adult, Anti-Arrhythmia Agents, Biopsy, Child, Chromosome Aberrations diagnosis, Chromosome Aberrations mortality, Chromosome Disorders, Cineangiography, Coronary Angiography, Death, Sudden, Cardiac pathology, Diagnosis, Differential, Echocardiography, Electrocardiography, Exercise Test, Female, Flecainide, Humans, Lod Score, Magnetic Resonance Imaging, Male, Middle Aged, Myocardial Contraction, Pedigree, Potassium Channels genetics, RNA analysis, Reverse Transcriptase Polymerase Chain Reaction, Survival Rate, Tachycardia, Ventricular diagnosis, Tachycardia, Ventricular mortality, Chromosome Aberrations genetics, Chromosome Mapping, Chromosomes, Human, Pair 1 genetics, Genetic Linkage genetics, Myocardium pathology, Potassium Channels, Tandem Pore Domain, Tachycardia, Ventricular genetics
- Abstract
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.
- Published
- 1999
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30. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects.
- Author
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Swan H, Viitasalo M, Piippo K, Laitinen P, Kontula K, and Toivonen L
- Subjects
- Adolescent, Adult, Aged, Child, ERG1 Potassium Channel, Electrocardiography methods, Electrocardiography statistics & numerical data, Ether-A-Go-Go Potassium Channels, Exercise Test methods, Exercise Test statistics & numerical data, Female, Heart Ventricles physiopathology, Humans, KCNQ Potassium Channels, KCNQ1 Potassium Channel, Long QT Syndrome diagnosis, Long QT Syndrome genetics, Male, Middle Aged, Mutation genetics, Mutation physiology, Potassium Channels genetics, Statistics, Nonparametric, Transcriptional Regulator ERG, Cation Transport Proteins, DNA-Binding Proteins, Exercise physiology, Long QT Syndrome physiopathology, Potassium Channels physiology, Potassium Channels, Voltage-Gated, Sinoatrial Node physiopathology, Trans-Activators
- Abstract
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.
- Published
- 1999
- Full Text
- View/download PDF
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