Interaction between PPARA genotype and beta-blocker treatment influences clinical outcomes following acute coronary syndromes.
OBJECTIVE
beta-blockers (BB) are strongly recommended after an acute coronary syndrome (ACS), although all patients may not benefit. Causes for variable patient responses to BB are unknown. Given that myocardial ischemia and BB influence metabolic processes regulated by peroxisome proliferator-activated receptor alpha (PPARalpha), we hypothesized that interactions between polymorphisms of the PPARalpha gene (PPARA) and BB treatment would influence clinical outcome following ACS.


METHODS
Patients were prospectively enrolled into an ACS registry. A total of 735 ACS patients were genotyped. Mortality and cardiac rehospitalization through 1 year were analyzed in relation to PPARA genotype and BB prescription (597 BB; 138 no BB) at discharge.


RESULTS
Significantly different outcomes associated with BB therapy were observed according to PPARA IVS7 2498 genotype (p = 0.002 for interaction). PPARA IVS7 2498 GG homozygous patients discharged on BB had decreased cardiac rehospitalization (hazard ratio [HR]: 0.52; 95% CI: 0.32-0.86; p = 0.011), while C allele carriers discharged on BB had nearly threefold increased cardiac rehospitalization (HR: 2.92; 95% CI: 1.32-6.92; p = 0.015; genotype interaction p = 0.0005) compared with patients not on BB. PPARA genotype was also associated with differences in PPARalpha expression, with significantly increased mRNA levels in myocardial samples from normal hearts among GC heterozygotes compared with GG homozygotes (p = 0.04). Transgenic mice with cardiac-specific overexpression of PPARalpha showed significantly reduced myocardial contractile and chronotropic responses to the beta-sympathomimetic dobutamine (p < 0.05) compared with wild-type littermates, supporting the hypothesis that increased PPARalpha levels result in a blunted beta-adrenergic response.


CONCLUSIONS
PPARA IVS7 2498 genotype is associated with heterogeneity in 1-year outcome in response to BB among patients following ACS, and may predict which patients benefit from BB therapy, putatively related to the effect of myocardial PPARalpha expression on beta-adrenergic responsiveness.
Department of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Campus Box 8086, Saint Louis, MO 63110-1093, USA. scresci@dom.wustl.edu
Sharon
S
Cresci
Philip G
PG
Jones
Carmen C
CC
Sucharov
Sharon
S
Marsh
David E
DE
Lanfear
Adam
A
Garsa
Michael
M
Courtois
Carla J
CJ
Weinheimer
Jun
J
Wu
Michael A
MA
Province
Daniel P
DP
Kelly
Howard L
HL
McLeod
John A
JA
Spertus
D054058:Acute Coronary Syndrome / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000368:Aged; D015331:Cohort Studies; D004347:Drug Interactions / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005796:Genes; D008040:Genetic Linkage; D005838:Genotype; D006239:Haplotypes; D006579:Heterozygote; D006720:Homozygote; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics* / Q000627:therapeutic use; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012333:RNA, Messenger / Q000378:metabolism; D012042:Registries / Q000706:statistics & numerical data; D013997:Time Factors; D016896:Treatment Outcome
D000319:Adrenergic beta-Antagonists; D047493:PPAR alpha; D012333:RNA, Messenger