title: Polymorphisms in CYP2D6 may predict methamphetamine related heart failure.
abstract: BACKGROUND
  Methamphetamine (METH) has been associated with a dilated cardiomyopathy. The first and rate-limiting step of metabolism is dependent on the polymorphic enzyme CYP2D6.
  
  
  OBJECTIVE
  To evaluate if polymorphisms in CYP2D6 can be associated with the development of a methamphetamine-induced cardiomyopathy.
  
  
  METHODS
  We performed a prospective case-control pilot study. Cases were defined by a urinary drug screen positive for amphetamine and evidence of heart failure by beta natriuretic peptide (BNP) greater than 300 pg/ml and symptoms of heart failure. Controls were defined with urinary drug screens positive for amphetamines but without evidence of heart failure defined by a BNP lesser than 300 pg/ml or symptoms of heart failure. Exclusion criteria were less than 18 years or greater than 60 years of age, urinary toxicology screen positive for additional stimulants, known coronary artery disease (CAD) defined by greater than 50% stenosis on catheterization or previous myocardial infarction, known cardiomyopathy of alternative etiology or inability to provide consent. Patients underwent gas chromatography confirmation-mass spectroscopy for methamphetamine, genotyping of CYP2D6, limited echocardiography, and participated in a modified 2007 National Survey of Drug Use and Health Stimulant Survey. Genotype results were analyzed with traditional classifications and "Activity Scores".
  
  
  RESULTS
  Fifty-six patients completed the study with 19 cases and 37 controls. There was no statistically significant difference in days of use in a month, age, gender, or ethnicity between cases and controls. While not statistically significant, age and days of use did trend higher in cases. CYP2D6 genotype demonstrated that the lower the activity score/poor metabolizer group had less heart failure than extensive metabolizers/higher activity score. However, it did not reach statistical significance. When adjusting for higher days of use, extensive metabolizers had the highest odds of developing a dilated cardiomyopathy. (OR: 2.33, 95% CI: 0.54-10.13). Echo findings in all cases showed reduced ejection fractions with a mean of 18.6% (range: 10-35%) and 70% had a dilated cardiomyopathy. No cardiomyopathies were seen in the controls. Mean ejection fraction was 56.75% (range: 45-70%). The odds ratio of having a dilated cardiomyopathy in extensive metabolizers was 1.62 (95% CI: 0.47-5.5).
  
  
  CONCLUSIONS
  Our study demonstrates a trend that individuals with decreased metabolic activity were less likely to develop heart failure. While not statistically significant, a signal is present that extensive metabolizers may be at increased risk for the development of a cardiomyopathy.
authors.affiliation: Department of Emergency Medicine, University of California, Davis Medical Center, Sacramento, CA, USA. Mark.sutter@ucdmc.ucdavis.edu
authors.forename: M E
authors.initials: ME
authors.lastname: Sutter
authors.forename: A
authors.initials: A
authors.lastname: Gaedigk
authors.forename: T E
authors.initials: TE
authors.lastname: Albertson
authors.forename: J
authors.initials: J
authors.lastname: Southard
authors.forename: K P
authors.initials: KP
authors.lastname: Owen
authors.forename: L D
authors.initials: LD
authors.lastname: Mills
authors.forename: D B
authors.initials: DB
authors.lastname: Diercks
mesh_terms: D000328:Adult; D019969:Amphetamine-Related Disorders / Q000150:complications* / Q000175:diagnosis; D015415:Biomarkers / Q000097:blood; D002311:Cardiomyopathy, Dilated / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000378:metabolism; D016009:Chi-Square Distribution; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D020022:Genetic Predisposition to Disease; D006333:Heart Failure / Q000097:blood / Q000139:chemically induced / Q000175:diagnosis / Q000201:enzymology / Q000235:genetics*; D006801:Humans; D016015:Logistic Models; D008297:Male; D008694:Methamphetamine / Q000009:adverse effects* / Q000378:metabolism; D008875:Middle Aged; D020097:Natriuretic Peptide, Brain / Q000097:blood; D016017:Odds Ratio; D010641:Phenotype; D010865:Pilot Projects; D011110:Polymorphism, Genetic; D011237:Predictive Value of Tests; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D015813:Substance Abuse Detection
chemical_list: D015415:Biomarkers; D000697:Central Nervous System Stimulants; D020097:Natriuretic Peptide, Brain; D008694:Methamphetamine; D019389:Cytochrome P-450 CYP2D6