Histamine H2 Receptor Antagonists, Left Ventricular Morphology, and Heart Failure Risk: The MESA Study.

BACKGROUND: Myocardial H2 receptor activation may promote cardiac fibrosis and apoptosis in pre-clinical models and histamine H2 receptor antagonist (H2RA) use may improve symptoms in participants with heart failure (HF); however, relationships between H2RA use, incident HF, and longitudinal change in left ventricular (LV) morphology are not known. OBJECTIVES: This study sought to determine whether H2RA use is associated with incident HF and change in LV morphology over time. METHODS: We included 6,378 men and women from MESA (Multi-Ethnic Study of Atherosclerosis), a multicenter prospective observational cohort of participants without cardiovascular disease at baseline. Cox proportional hazards were used to estimate the association between H2RA use and incident HF in adjusted models. In participants with cardiac magnetic resonance imaging, associations between H2RA use, baseline LV morphology (n = 4,691), and longitudinal change in the LV (n = 2,806) were estimated using linear regression. RESULTS: H2RAs were used by 313 participants but not by the other 6,065 individuals. During a median follow-up of 11.2 years, 236 participants developed HF. In adjusted models, baseline H2RA use relative to nonuse was associated with 62% lower risk for incident HF (p = 0.02). H2RA use was associated with preserved stroke volume, LV end-diastolic volume, and mass/volume ratio as measured by cardiac magnetic resonance imaging over approximately 10 years (all p < 0.05). There were no associations between H2RA use and LV mass or ejection fraction. CONCLUSIONS: H2RA use was associated with reduced risk for incident HF. Left heart morphology over time suggests less age-related change in H2RA users. These associations suggest histamine signaling may be important in the pathogenesis of HF. (Multi-Ethnic Study of Atherosclerosis [MESA]; NCT00005487).

The role of vitronectin receptor (alphavbeta3) and tissue factor in the pathogenesis of transplant coronary vasculopathy.

OBJECTIVES: This study was undertaken to test the hypothesis that transplant coronary vasculopathy (CV) is associated with increased myocardial protein expression of both tissue factor (TF) and integrin alphavbeta3. BACKGROUND: The vitronectin receptor (integrin alphavbeta3) and TF have recently been found to play a key role in apoptotic cell death and vascular endothelial cell injury. METHODS: A total of 77 heart transplant recipients underwent simultaneous endomyocardial biopsy and intravascular ultrasound (IVUS) at one year of transplant. Patients with pre-existing donor coronary atherosclerosis (n = 35) or with acute rejection (grade >1A, n = 10) at the time of the IVUS were excluded from the analysis. The remaining 32 patients constitute the cohort of the present study. A computerized biopsy score was derived based on the duration and severity of cellular rejection. Both TF and alphavbeta3 expression in the heart biopsy specimens were evaluated by immunoperoxidase histochemistry and Western blot analysis. RESULTS: Patients with CV (n = 24) had increased expression of alphavbeta3 (2.7-fold, p = 0.003) and TF (7.9-fold, p = 0.04) compared with patients without evidence of vasculopathy (n = 8). In the absence of myocardial fibrosis, alphavbeta3 expression correlated significantly with the cellular rejection score (r = 0.58, p = 0.02). CONCLUSIONS: Transplant vasculopathy is associated with increased expression of both TF and alphavbeta3. The significant correlation of alphavbeta3 with cellular rejection suggests an important role for this integrin in serving as a mechanistic link between cellular rejection and vasculopathy.