Arrhythmic disorder mapped to chromosome 1q42-q43 causes malignant polymorphic ventricular tachycardia in structurally normal hearts.
OBJECTIVE
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.
Swan
H
H
Department of Medicine, Helsinki University Hospital, Finland.
Piippo
K
K
Viitasalo
M
M
Heikkilä
P
P
Paavonen
T
T
Kainulainen
K
K
Kere
J
J
Keto
P
P
Kontula
K
K
Toivonen
L
L
D000293:Adolescent; D000328:Adult; D000889:Anti-Arrhythmia Agents; D001706:Biopsy; D002648:Child; D002869:Chromosome Aberrations / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D025063:Chromosome Disorders; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D002932:Cineangiography; D017023:Coronary Angiography; D016757:Death, Sudden, Cardiac / Q000473:pathology; D003937:Diagnosis, Differential; D004452:Echocardiography; D004562:Electrocardiography; D005080:Exercise Test; D005260:Female; D005424:Flecainide; D008040:Genetic Linkage / Q000235:genetics*; D006801:Humans; D008126:Lod Score; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction; D009206:Myocardium / Q000473:pathology*; D010375:Pedigree; D015221:Potassium Channels / Q000235:genetics; D024683:Potassium Channels, Tandem Pore Domain; D012313:RNA / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D017180:Tachycardia, Ventricular / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality
D000889:Anti-Arrhythmia Agents; C109137:KCNK1 protein, human; D015221:Potassium Channels; D024683:Potassium Channels, Tandem Pore Domain; D012313:RNA; D005424:Flecainide