Carl Pepine

Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil.

In the CYP3A5 gene, the A>G (*3) and G>A (*6) polymorphisms result in severely decreased expression of CYP3A5 enzyme relative to a normal functional allele (*1). We sought to determine if the CYP3A5 genetic polymorphisms were associated with level of blood pressure (BP), risk of hypertension (HTN), and the antihypertensive response to verapamil. A total of 676 normotensive and hypertensive participants (mean age 49±8.2 years) from the Hypertension Genes study and 722 patients (mean age 66±9 years) from the International Verapamil/Trandolapril Study Genetic Substudy (INVEST‐GENES) were genotyped for CYP3A5 to test for associations with BP, HTN, and in the latter cohort, antihypertensive response to verapamil. CYP3A5 haplotypes were determined using PHASE 2, with any allele containing either (*3) or (*6) designated as non functional. In the HTN genes population, there were no significant differences based on the number of functional CYP3A5 alleles, in systolic blood pressure (SBP) or diastolic blood pressure (DBP) among the normotensive whites or blacks (all P⩾0.70) or in allele frequency between normotensives and hypertensives. In INVEST‐GENES, when controlled for baseline BP, race, age, and gender, untreated BP in carriers versus non carriers of a CYP3A5 functional allele was 158.2±13.7 and 154.8±13.7 (P=0.061), respectively. CYP3A5 functional allele status was marginally associated with the SBP response to verapamil in blacks (P=0.075) and Hispanics (P=0.056), but not in whites (P=0.40), with the effect being largely driven by higher SBP in the carriers of two functional alleles. There was no association with DBP response and CYP3A5 allele status. CYP3A5 genotype does not contribute importantly to BP or risk of HTN, but may influence response to calcium channel blockers in populations in which carrier status of two functional alleles is common.

Association between beta-adrenergic receptor polymorphisms and their G-protein-coupled receptors with body mass index and obesity in women: a report from the NHLBI-sponsored WISE study.

OBJECTIVES:The β-adrenergic receptor (βAR) genes are candidate genes for obesity because of their roles in energy homeostasis and promotion of lipolysis in human adipose tissue. Objective is to determine the association between obesity and polymorphisms in genes of the β1AR (ADRB1), β2AR (ADRB2), β3AR (ADRB3), Gs protein alpha (GNAS1), to which all three β-receptors couple and the G protein β3 subunit (GNB3), to which β3ARs couple.DESIGN:A case–control genetic association study.SUBJECTS:A total of 643 black or white women enrolled in Womens Ischemia Syndrome Evaluation (WISE) study.MEASUREMENTS:Genotypes were determined by PCR with single primer extension. Associations between genotype and body mass index (BMI), waist-to-hip ratio (WHR), waist circumference, and obesity were made.RESULTS:Polymorphisms in the three βAR genes, GNAS1, and GNB3 were not associated with BMI, WHR, waist circumference, or obesity. Linear and logistic regression analyses found no contribution of either genotype or haplotype with anthropometric measurements or obesity.CONCLUSIONS:Our study suggests that among American women with suspected coronary heart disease, polymorphisms in the βARs and their G-protein-coupled receptors do not contribute to increased BMI, WHR, waist circumference, or obesity. Given that 50% of all women die from coronary heart disease, and a higher percentage have heart disease during their lifetime, our results are likely generalizable to many American women.

Syndrome X and Microvascular Coronary Dysfunction

C ase presentation: A 44-year-old woman is referred for worsening chest pain since 2007, with abnormal stress testing in May 2008, followed by coronary angiography in June 2008. She had several prior hospitalizations to evaluate possible myocardial infarction, and 1 with an elevated troponin level in 2001. She has a history of breast cancer in 2007. She currently reports daily exertional substernal chest pain that radiates to her left arm and hand that is relieved with rest. She works as an undercover police officer, frequently has to chase suspects, and is concerned about being able to do her job. A review of cardiac risk factors is negative. She takes tamoxifen with vitamins, and her physical examination and resting ECG are normal. Review of the prior coronary angiography confirms absence of obstructive coronary artery disease and normal left ventricular function. To further evaluate the basis for her symptoms, she underwent coronary reactivity testing (CRT), which demonstrated a limited coronary flow reserve (CFR) to adenosine and coronary blood flow reserve (Figure 1) as well as coronary artery constriction with acetylcholine, indicative of endothelial dysfunction (Figure 2). Adenosine stress cardiac magnetic resonance imaging was consistent with microvascular coronary dysfunction (MCD; Figure 3). Figure 1. Intracoronary Doppler blood flow velocity waveforms in response to intracoronary adenosine and acetylcholine. Coronary flow reserve (CFR) is the ratio of average peak velocities before and after adenosine. Coronary blood flow (CBF) reserve is the ratio of average peak CBF before and after acetylcholine. Figure 2. Intracoronary acetylcholine (ACH) demonstrating constriction of the coronary arteries (arrow) and intracoronary nitroglycerin (NTG) coronary angiography demonstrating dilation. Figure 3. Adenosine stress perfusion base-ventricle cardiac magnetic resonance imaging (left) and rest perfusion base-ventricle cardiac magnetic resonance imaging (right). Arrows indicate areas of reduced myocardial perfusion, worsened during stress (left). Management of patients with angina and evidence of myocardial …

LATE GADOLINIUM ENHANCEMENT AND ADVERSE CARDIAC EVENTS AT 1 YEAR FOLLOW-UP IN WOMEN WITH SIGNS AND SYMPTOMS OF ISCHEMIA AND NO OBSTRUCTIVE CORONARY DISEASE: A REPORT FROM THE WOMEN’S ISCHEMIA SYNDROME EVALUATION

methods: We identified a subgroup of 173 women who underwent 1.5T CMRI at baseline and one year in the Women’s Ischemia Syndrome Evaluation. LGE was determined by blinded visual scores and quantified with CAAS MRV software (Pie Medical Imaging, Netherlands). Ischemic LGE pattern was defined as subendocardial or transmural in a coronary distribution, while nonischemic LGE pattern was midmyocardial or epicardial. Interval myocardial infarction (MI), stroke, and hospitalization for angina or heart failure were recorded.

PREVALENCE OF MYOCARDIAL SCAR IN WOMEN WITH SIGNS AND SYMPTOMS OF ISCHEMIA BUT NO OBSTRUCTIVE CORONARY ARTERY DISEASE: A REPORT FROM THE WOMEN’S ISCHEMIA SYNDROME EVALUATION

Moderated Poster ContributionsStable Ischemic Heart Disease Moderated Poster Theater, Poster Hall B1Sunday, March 15, 2015, 10:00 a.m.-10:10 a.m.Session Title: Ischemia in Women without Obstructive Coronary Artery DiseaseAbstract Category: 26. Stable Ischemic Heart Disease: ClinicalPresentation Number: 1205M-05Authors: May Bakir, Janet Wei, Louise Thomson, John Petersen, Quanlin Li, Erika Jones, Puja Mehta, Chrisandra Shufelt, Daniel Berman, Eileen Handberg, Sheryl Kelsey, George Sopko, Carl Pepine, C. Noel Bairey Merz, Cedars-Sinai Medical Center, Los Angeles, CA, USABackground: Women with signs and symptoms of ischemia and no obstructive coronary artery disease (CAD) have an elevated major adverse cardiac event rate. We evaluated the presence, extent and distribution of scar using cardiac magnetic resonance imaging (CMRI) late gadolinium enhancement (LGE) in the Women’s Ischemia Syndrome Evaluation.methods: Women (n=344) with signs and symptoms of ischemia and no obstructive CAD underwent 1.5T CMRI LGE. Scans were read blindly for presence and segmental distribution of LGE. Scar size was quantified using Pie Medical Imaging software. LGE type was defined as ischemic when subendocardial or transmural and localized to a coronary artery distribution, and non-ischemic when mid-myocardial or epicardial. Fisher’s exact and two sample t-tests were used for statistical analysis.results: LGE was present in 20 (5.8%) women, including 15 (75%) with ischemic LGE. Women with non-ischemic LGE (n=5) had larger scar size compared to women with ischemic LGE (Table). There were no significant differences in cardiac risk factors among women with no LGE, ischemic LGE, or non-ischemic LGE, and there was no significant correlation between LGE presence and cardiac risk factors.Conclusion: Women with signs and symptoms of ischemia and no obstructive CAD have a 5.8% prevalence of myocardial scar detected by CMRI, with a predominant ischemic LGE pattern. These findings demonstrate that these women can develop irreversible myocardial injury, which may be clinically under-diagnosed.No LGE(n=324)Ischemic LGE(n=15)Non-ischemic LGE(n=5)Age 54 ± 11 years 55 ± 8 years 37 ± 15 yearsBody Mass Index 30 ± 8 32 ± 11 35 ± 7Hypertension 40% 31% 75%Diabetes 11% 14% 50%Dyslipidemia 20% 10% 33%Family History of Coronary Artery Disease 48% 21% 50%Scar pattern n/a4 LAD6 LCX4 RCA1 LAD and RCA3 patchy epicardial1 midmyocardial ASH1 RV insertion pointsScar size n/a 4.83 ± 3.12g* 9.57 ± 6.10g*ASH= asymmetric septal hypertrophy, LAD= left anterior descending artery, LCX= left circumflex artery, LGE= late gadolinium enhancement, RCA= right coronary artery, RV= right ventricular*p=0.0034

B-TYPE NATRIURETIC PEPTIDE DOES NOT CORRELATE WITH INVASIVE OR NONINVASIVE MEASURES OF CORONARY MICROVASCULAR DYSFUNCTION IN WOMEN WITH PRESERVED EJECTION FRACTION: A REPORT FROM THE WOMEN'S ISCHEMIA SYNDROME EVALUATION- CORONARY VASCULAR DYSFUNCTION (WISE-CVD) STUDY

Women with symptoms/signs of ischemia and no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD), diagnosed by invasive coronary reactivity testing (CRT). CMD has recently been proposed to be a precursor to heart failure with preserved ejection fraction. The

CORONARY MICROVASCULAR DYSFUNCTION IS RELATED TO LEFT VENTRICULAR CONCENTRIC REMODELING AND DIASTOLIC DYSFUNCTION: FROM THE WISE-CVD STUDY

Background: Women with signs and symptoms of ischemia but no obstructive coronary artery disease often have coronary microvascular dysfunction (CMD). However, mechanistic contributors of CMD remain poorly understood. We investigated relations between CMD, LV geometry and diastolic function in women

DIFFERENCES IN ADENOSINE AND REGADENOSON ON MYOCARDIAL PERFUSION RESERVE INDEX: A REPORT FROM THE WOMEN'S ISCHEMIA SYNDROME EVALUATION-CORONARY VASCULAR DYSFUNCTION (WISE-CVD) STUDY

Cardiac magnetic resonance imaging (CMRI) quantitative myocardial perfusion reserve index (MPRI) has been shown to predict prognosis in women with persistent chest pain and no obstructive coronary artery disease. A prior study of healthy men revealed that regadenoson produces higher MPRI than

MICROVASCULAR CORONARY DYSFUNCTION, LEFT VENTRICULAR VOLUMES AND MASS: RESULTS FROM THE WOMEN'S ISCHEMIA SYNDROME EVALUATION-CORONARY VASCULAR DYSFUNCTION STUDY

Women with signs and symptoms of ischemia and no obstructive coronary artery disease (CAD) often have microvascular coronary dysfunction (MCD). This has been associated with adverse outcomes including hospitalization for heart failure with preserved ejection fraction (EF). We sought to explore how

PI-26Association of angiotensin II type I receptor (AGTR1) 1166A>C polymorphism with blood pressure response to ACE inhibitor in a subgroup of patients of the international verapamil SR/trandolapril study (INVEST)

The AGTR1 1166A>C gene polymorphism (SNP) has been associated with hypertension. We investigated whether this SNP affects blood pressure (BP) response to ACE inhibitor (ACEI) therapy in an ethnically diverse group of hypertensive coronary artery disease patients who had an ACEI (trandolapril) added to verapamil SR 240 mg monotherapy to achieve BP goals during INVEST.