Histamine H2 Receptor Antagonists, LV Morphology, and Heart Failure Risk

Study Questions:

Does the use of histamine H2 receptor blockers reduce the risk of heart failure (HF)?


Participants in the MESA (Multi-Ethnic Study of Atherosclerosis) study were evaluated for the relationship between use of histamine H2 receptor antagonists (H2RAs), and risk of incident HF and changes in left ventricular (LV) morphology. Per the MESA protocol (http://www.mesa-nhlbi.org/manuals.aspx), clinical outcomes were assessed at study examinations and by telephone interview every 9-12 months. The diagnosis of incident HF required a physician diagnosis of HF, symptoms of HF, and another objective feature of HF. The full details have been described in the MESA Manual of Operations. Kaplan-Meier analysis was performed to assess unadjusted associations and Cox proportional hazards to assess adjusted associations of H2RA use with incident HF. Two restricted cohorts were considered to address the possibility of confounding by indication and confounding related to participant’s likelihood to use H2RA. Exploratory analyses were performed to assess the relationship between H2RA and HF in patients with differing predicted risk of HF.


Of the 6,814 participants enrolled in MESA, 6,378 had follow-up information regarding incident HF and complete covariates. Of these, 4,691 completed a baseline cardiac magnetic resonance and were included in the cohort describing associations between H2RA use and LV morphology. The mean age of the study sample was 62.3 years, 52.7% were women, and 37.9% were white. A total of 313 of the participants in the cohort used H2RA at baseline. The median follow-up was 11.2 years, and total follow-up was 65,082 person-years. In unadjusted analyses, the incidence of HF was 1.9 events/1,000 patient-years in H2RA users and 3.7 events/1,000 person-years in nonusers (p = 0.11) However, the adjusted hazard ratio for H2RA use was 0.38 (95% confidence interval, 0.17-0.86; p = 0.02). After adjusting for N-terminal pro–B-type natriuretic peptide and troponin T, there was an 82% lower risk of HF in H2RA users. H2RA users with higher HF risk had the greatest reduction in incident HF and experienced 5.3 fewer episodes of HF/1,000 person-years than nonusers. There was no relationship between H2RA use and LV ejection fraction or mass; however, H2RA users had smaller LV end-diastolic volume (LVEDV), smaller stroke volume, and higher mass/volume ratio.


H2RA use was associated with lower risk of incident HF and less reduction in LVEDV, stroke volume, and mass/volume ratio, suggesting that histamine signaling may play an important role in the pathogenesis of HF.


In preclinical studies, H2 receptor activation contributes to cardiac fibrosis and alterations in cardiac function. Blockade of histamine receptors or its release is associated with protection from HF. This retrospective analysis examines the relationship of H2RA use in humans and incident HF in a large community cohort. This study demonstrates an association between H2RA use and reduction in the incidence of HF, particularly in those at highest risk of HF. This compelling association warrants prospective evaluation.

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