May 19, 2016
Interestingly, histamine is an abundant neurotransmitter in the heart acting through a similar mechanism to stimulate G-proteins as is seen with norepinephrine.1-2 Research in animal models has shown a decrease in left ventricular size and improvement in symptoms of heart failure with histamine receptor antagonists (H2RAs). So, can H2RAs be beneficial in human heart failure?
The Multi-Ethnic Study of Atherosclerosis (MESA Study) had magnetic resonance imaging of the right ventricle performed in a cohort of 4122 patients, without evidence of clinical cardiovascular disease, aged 45 to 84 years from six U.S. communities.3 Multivariate linear regression estimated the association between H2RA use (313 patients) and right ventricle morphology. If a patient recorded use of H2RA drug by prescription or over-the-counter, they were included in H2RA user group. H2RA use was associated with lower right ventricular mass (-0.7 g; 95% CI, -1.2 g to 2.0 g) and smaller right ventricle end-diastolic volume (-4.2 mL; 95% CI, -7.2 mL to 1.2 mL). Six H2RA (1.9/1000 person-years) users developed heart failure compared with 230 non-users (3.9/1000 person-years), P=0.11. H2RA use at baseline was associated with a 62% reduction of heart failure relative to non-use (HR: 0.38; 95% CI, 0.17-0.86). The association was stronger when considering NT-proBNP and troponin T at baseline (HR: 0.18; 95% CI, 0.05-0.62). These findings are independent of cardiovascular risk factors including diabetes, hypertension, or obesity.
Several mechanisms may explain these results. The first is that H2 receptors are the predominant histamine receptor subtype in the heart and histamine is rich in the myocardium.2 Second, H2RAs may therefore act directly on the heart to influence growth of cardiac cells or myocardial remodeling.4-5 Smaller hearts may lower pulmonary pressures and resistance. Gastroesophageal reflux disease (GERD) may contribute to higher pulmonary pressures as well.6 A reduction in pulmonary vascular remodeling may factor into these findings.
These findings suggest that lower histamine levels may have benefit in preventing the development of heart failure. Because of the retrospective nature of this evaluation, further conformational studies will need to be undertaken to confirm these findings. But to these findings, H2RAs in patients with heart failure should be considered for patients with co-morbid GERD.
Mark A. Munger, PharmD, FCCP, FACC, is a Professor of Pharmacotherapy and Adjunct Professor of Internal Medicine, at the University of Utah, where he also serves as the Associate Dean, Academic Affairs for the College of Pharmacy.
1. Bristow MR, Ginsburg R, Harrison DC. Histamine and the human heart: the other receptor system. Am J Cardiol. 1982;49(1):249-251.
2. Matsuda N, Jesmin SK, Takahashi Y, et al. Histamine H1 and H2 receptor gene and protein levels are differentially expressed in the hearts of rodents and humans. J Pharmacol Exp Ther. 2004;309(2):786-795.
3. Leary PJ, Tedford RJ, Bluemke DA, et al. Histamine H2receptor antagonists, left ventricular morphology, and heart failure risk: The MESA Study. J Am Coll Cardiol. 2016;67(13):1544-1552.
4. Kim J, Ogai A, Nakatani S, et al. Impact of blockade of histamine H2 receptors on chronic heart failure revealed by retrospective and prospective randomized studies. J Am Coll Cardiol. 2006;48(7):1378-1384.
5. Takahama H, Asanuma H, Sanada S, et al. A histamine H2receptor blocker ameliorates development of heart failure in dogs independently of β-adrenergic receptor blockade. Basic Res Cardiol. 2010;105(6):787-794.
6. Russell PC, Wright CE, Barer GR, Howard P. Histamine induced pulmonary vasodilation in the rate: site of action and changes in chronic hypoxia. Eur Respir J. 1994;7:1138-1144.