Publications

CONTEXT

A common haplotype of the glucocorticoid receptor (GR) gene has been associated with increased susceptibility to coronary heart disease (CHD). Whether this haplotype predisposes to heart failure (HF) is unknown.

OBJECTIVE

The objective of the study was to determine whether GR haplotype 3 is associated with HF and whether this association is explained by low-grade inflammation (C-reactive protein).

DESIGN

In a prospective cohort study, participants were genotyped for common GR gene polymorphisms (ER22/23EK, BclI C/G, N363S, 9beta A/G). Haplotype analyses were conducted.

SETTING

The study was conducted at one university medical center, two Veterans Affairs medical centers, and nine public health clinics.

PATIENTS

Patients included 526 white outpatients with stable CHD.

MAIN OUTCOME MEASURES

Echocardiographic evidence of ventricular dysfunction, self-reported heart failure, and subsequent hospitalization for heart failure were measured.

RESULTS

After adjusting for age, sex, smoking, and body mass index, participants with two copies of haplotype 3 were more likely than those with 0 or 1 copy to report heart failure [hazard ratio (HR) 4.15, 95% confidence interval (CI) 1.5-11.3, P < 0.01], have systolic dysfunction (left ventricular ejection fraction <50%) (HR 3.0, 95% CI 0.9-9.9, P = 0.07), and be hospitalized for HF during a mean follow-up of 6 yr (HR 3.0, 95% CI 1.3-7.0, P = 0.01). These associations were attenuated after adjustment for higher C-reactive protein levels in patients with two copies of haplotype 3.

CONCLUSIONS

We found that the GR gene haplotype 3 was associated with prevalent HF, systolic dysfunction, and subsequent HF hospitalization in patients with CHD. This association was partly mediated by low-grade inflammation.

BACKGROUND

Erythropoietin (EPO) has generated interest as a novel therapy after myocardial infarction (MI), but the safety and efficacy of prolonged therapy have not been studied in a large animal model of reperfused MI.

METHODS AND RESULTS

MI was induced in pigs by a 90-minute balloon occlusion of the left anterior descending coronary artery. Sixteen animals were randomized to either EPO or saline (control group). Inflammatory markers, bone marrow cell mobilization, and left ventricular function (by both echocardiography and pressure-volume measurements) were assessed at baseline, 1 and 6 weeks post-MI. EPO therapy was associated with a significant increase in hemoglobin and mononuclear counts. D-dimer and C-reactive protein levels did not differ between groups. At week 6, EPO therapy prevented further deterioration of left ventricular ejection fraction (39 +/- 2% vs. 33 +/- 1%, P < .01) and improved wall motion score index (P < .02). Histopathology revealed increased areas of viable myocardium, vascular density, and capillary-to-myocyte ratio in the EPO therapy compared with the control (all P < .05).

CONCLUSION

Prolonged EPO therapy after MI in a large animal model is safe and leads to an increase in viable myocardium, increased vascular density, and prevents further deterioration of left ventricular function. These results support future clinical studies in post-MI patients.