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Relation between the electrocardiographic response to encainide administration and CYP2D6 phenotype and genotype in humans
J
Mel Cell Cardiol 24 (Supplement VI) (1992)
85
Effects of time in culture and l3-adrenergic stimulation on the expression of contractile protein genes in cultured adult rat cardiomyocytes lsabelle Dubus, Lydie Rappaport, Alice Barrieux, Ketty Schwartz and Jane-Lyse Samuel. U 127 INSERM, 41 5d Chapelle, 75010, Paris, France. A model of adult rat cardiomyocytes maintained in a serum-free medium for 3 days was used to study the effects of a B-adrenergic stimulation on cardiac genomic expression. Quantitative changes in MHC and actin gene expression were determined by dot-blot analysis using specific cDNA probes (Schiaffino et al., Crrc Res 1989, 64: 937). After 3 days in culture, the relative amounts of R-MHC and cc-skeletal actin mRNAs increased respectively by 64 % and 380 % while that of n-MHC mRNA decreased by 41%. Addition of lo-8M rsoproterenol in the culture medium: 1) had no effect on a-skeletal actin mRNA accumulation; 2) inhibited the R-MHC mRNA accumulation; 3) increased the relative amount of o(-MHC mRNA at day 1 but not at day 3. inese results demonstrate that in adult rat cardiac tnyocytes maintained in culiure the absence of any mechanical or growth factor provoked the reexpression of the fetal contractile protern program. A R-adrenergic agonist by itself can modulate the relative expression of the I?-MHC gene but not that of the a-MHC gene, which appears to depend on other factor(s) whose levels rapidly decreased with time in culture.
86
RELATION BETWEEN ADMINISTRATION AND
THE ELECTROCARDIOGRAPHIC CYP2D6 PHENOTYPE AND
GENOTYPE
RESPONSE TO IN HUMANS.
ENCAINIDE
C. Funck-Brentano, G. Thomas, E. Jacqz-Aigrain, J.-M. Poirier, T. Simon, P. Jaillon. Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, FRANCE. Encainide (E) biotransformation to 0-desmethyl-E (ODE) co-segregates with the genetically determined polymorphism of dextromethorphan metabolism and is related to cytochrome P-450 2D6 (CYPZD6) activity. ODE is more potent than E in its ability to prolong QRS and PR intervals. Extensive (EM) and poor (PM) metabolizers of E can be identified by calculating the dextromethorphan/dextrorphan metabolic ratio (MR) in urine and by genotyping. In order to examine the influence of CYP2D6 phenotype and genotype on E-induced ECG changes, the relations between dextromethorphan MR, genotypes and PR or QRS prolongation measured 2.5 h after oral administration of 50 mg of E, 110 normal volunteers were studied. 99 EMS and 11 PMs were identified. The % change in PR interval duration was 1718 % in EMS and 352 % in PM (pi 0.01). Corresponding values for QRS were 1858 % and 3-f-4 % (p< 0.01). However, the distribution of PR and QRS changes was not plurimodal and there was an overlap of PR and QRS variations in EMS and PMs. Dextromethorphan MR, PR and QRS changes were similar in heterozygotes and homozygotes EMS. Thus, CYP2D6 activity does not fully predict the ECG effects of E and genotype cannot replace the determination of MR in predicting CYP2D6 activity and E response in EMS.
87
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY (FHC): CLINICAL AND PEDIGREES ANALYSIS OF FRENCH FAMILIES. L. Faurc” L. F&x, D. Pulvcnis, A. Sacrez, M. Dcsnos, A. Hagege, M. Ferriere, J. Castaldo, JB. Bouhour, G., .l. Almange, A. Millairc, F. Guerin, JP. Bounhoure, JC. Daubert, D. Garello, *F. Cambien, **K. Schwartz, 0. Dubourg et M. Komajda. “C.E.P.H.B Paris. Groupe Cardiomyopathie de la S.F.C. H8pital Piti&Salp&ihe. Cardiologie Paris *INSERM SCN?? PARIS ; ** INSERM lJ 127. Hdpitai Lariboiskke, Pan-s. FHC is characterized by primary hypertrophy (H) of the left or both ventricles of unknown origin. H involves predominantly the interventricular septum but a concentric pattern may occur. The degree and the extent of H may vary in a affected members of the same family and H is not always fully exprcsscd in infants. The genetic transmission is most often autosomal dominant. We collected 34 unrelated families including 421 subjects (146 presumably affcctcd) in order to perform linkage analysis for chromosomal localization and, after localization, to correlate phenotypic subgroups with different gene localizations. Diagnosis was based on blindly reviewed echo-doppler. Preliminary results show that transmission is autosomal dominant in the 34 families with ;1variable penetrancc according to age classes : O-18 years = 0,17, 18-40 years = O,G7, 40-70 years = 0,82. Echocardiographic analysis showed that 95% (61/64) of FHC are asymmetric, 3% (Z/Cd) are concentric and 2% (l/64) apical. There is a systolic anterior motion in 50% of cases and a milral insufficiency in 45%. Conclusion : In our panel of families : 1) Phcnotypic expression is predominantly asymmetric. 2) FHC is predominantly autosomal dominant. 3) Penetrancc is not full and varies according to age classes. s.33
Mel Cell Cardiol 24 (Supplement VI) (1992)
85
Effects of time in culture and l3-adrenergic stimulation on the expression of contractile protein genes in cultured adult rat cardiomyocytes lsabelle Dubus, Lydie Rappaport, Alice Barrieux, Ketty Schwartz and Jane-Lyse Samuel. U 127 INSERM, 41 5d Chapelle, 75010, Paris, France. A model of adult rat cardiomyocytes maintained in a serum-free medium for 3 days was used to study the effects of a B-adrenergic stimulation on cardiac genomic expression. Quantitative changes in MHC and actin gene expression were determined by dot-blot analysis using specific cDNA probes (Schiaffino et al., Crrc Res 1989, 64: 937). After 3 days in culture, the relative amounts of R-MHC and cc-skeletal actin mRNAs increased respectively by 64 % and 380 % while that of n-MHC mRNA decreased by 41%. Addition of lo-8M rsoproterenol in the culture medium: 1) had no effect on a-skeletal actin mRNA accumulation; 2) inhibited the R-MHC mRNA accumulation; 3) increased the relative amount of o(-MHC mRNA at day 1 but not at day 3. inese results demonstrate that in adult rat cardiac tnyocytes maintained in culiure the absence of any mechanical or growth factor provoked the reexpression of the fetal contractile protern program. A R-adrenergic agonist by itself can modulate the relative expression of the I?-MHC gene but not that of the a-MHC gene, which appears to depend on other factor(s) whose levels rapidly decreased with time in culture.
86
RELATION BETWEEN ADMINISTRATION AND
THE ELECTROCARDIOGRAPHIC CYP2D6 PHENOTYPE AND
GENOTYPE
RESPONSE TO IN HUMANS.
ENCAINIDE
C. Funck-Brentano, G. Thomas, E. Jacqz-Aigrain, J.-M. Poirier, T. Simon, P. Jaillon. Clinical Pharmacology Unit, Saint-Antoine University Hospital, Paris, FRANCE. Encainide (E) biotransformation to 0-desmethyl-E (ODE) co-segregates with the genetically determined polymorphism of dextromethorphan metabolism and is related to cytochrome P-450 2D6 (CYPZD6) activity. ODE is more potent than E in its ability to prolong QRS and PR intervals. Extensive (EM) and poor (PM) metabolizers of E can be identified by calculating the dextromethorphan/dextrorphan metabolic ratio (MR) in urine and by genotyping. In order to examine the influence of CYP2D6 phenotype and genotype on E-induced ECG changes, the relations between dextromethorphan MR, genotypes and PR or QRS prolongation measured 2.5 h after oral administration of 50 mg of E, 110 normal volunteers were studied. 99 EMS and 11 PMs were identified. The % change in PR interval duration was 1718 % in EMS and 352 % in PM (pi 0.01). Corresponding values for QRS were 1858 % and 3-f-4 % (p< 0.01). However, the distribution of PR and QRS changes was not plurimodal and there was an overlap of PR and QRS variations in EMS and PMs. Dextromethorphan MR, PR and QRS changes were similar in heterozygotes and homozygotes EMS. Thus, CYP2D6 activity does not fully predict the ECG effects of E and genotype cannot replace the determination of MR in predicting CYP2D6 activity and E response in EMS.
87
FAMILIAL HYPERTROPHIC CARDIOMYOPATHY (FHC): CLINICAL AND PEDIGREES ANALYSIS OF FRENCH FAMILIES. L. Faurc” L. F&x, D. Pulvcnis, A. Sacrez, M. Dcsnos, A. Hagege, M. Ferriere, J. Castaldo, JB. Bouhour, G., .l. Almange, A. Millairc, F. Guerin, JP. Bounhoure, JC. Daubert, D. Garello, *F. Cambien, **K. Schwartz, 0. Dubourg et M. Komajda. “C.E.P.H.B Paris. Groupe Cardiomyopathie de la S.F.C. H8pital Piti&Salp&ihe. Cardiologie Paris *INSERM SCN?? PARIS ; ** INSERM lJ 127. Hdpitai Lariboiskke, Pan-s. FHC is characterized by primary hypertrophy (H) of the left or both ventricles of unknown origin. H involves predominantly the interventricular septum but a concentric pattern may occur. The degree and the extent of H may vary in a affected members of the same family and H is not always fully exprcsscd in infants. The genetic transmission is most often autosomal dominant. We collected 34 unrelated families including 421 subjects (146 presumably affcctcd) in order to perform linkage analysis for chromosomal localization and, after localization, to correlate phenotypic subgroups with different gene localizations. Diagnosis was based on blindly reviewed echo-doppler. Preliminary results show that transmission is autosomal dominant in the 34 families with ;1variable penetrancc according to age classes : O-18 years = 0,17, 18-40 years = O,G7, 40-70 years = 0,82. Echocardiographic analysis showed that 95% (61/64) of FHC are asymmetric, 3% (Z/Cd) are concentric and 2% (l/64) apical. There is a systolic anterior motion in 50% of cases and a milral insufficiency in 45%. Conclusion : In our panel of families : 1) Phcnotypic expression is predominantly asymmetric. 2) FHC is predominantly autosomal dominant. 3) Penetrancc is not full and varies according to age classes. s.33