Hypocretin/Orexin Receptor-2 May Play a Role in the Treatment of Heart Failure

Hypocretin (orexin) receptor-2, a new genetic contribution to heart failure may have promising treatment effects.

A recent study identified a new therapeutic target called hypocretin (orexin) receptor-2  (HCRTR2) to treat heart failure (HF), regulate cardiac function, and possibly contribute to effects on myocardial remodeling, according to research published in the Journal of the American College of Cardiology.

Systems approaches that study the genetics of complex traits have helped to determine gene targets and disease patterns. While genetic determinants of HF remain unknown, identifying the associated genetic variations could help improve therapy.

“Starting from a clinical observation of a dramatic response to heart failure medical therapy in a subset of patients, we categorized dramatic responders then studied the extremes of response using a customized gene array,” the authors wrote.

“Allele-specific reporter assays at [HCRTR2] further suggested a role for this variant in regulating nearby gene transcription, and functional characterization of mice with HCRTR2 transcription deficiency demonstrated that HCRTR2 itself plays an important role in the regulation of cardiac function.”

Researchers compared the response to medical therapy in 866 patients with HF using a single nucleotide variant array. They used allele-specific luciferase reporter assays to measure the effect of genotype on gene expression.

A group of mice with gene transcription deficiencies were evaluated by an echocardiography and treadmill exercise. The target genes that could save the mice from a chemically-induced HF were examined with the echocardiography.

An ejection fraction improvement of ≥20% was found in 136 patients. Additionally, 83 patients (61%) had improvements via resynchronization therapy, 7 (5.1%) via  revascularization therapy, 2 (1.5%) from  tachycardia resolution, 1 (0.7%) from alcohol cessation, and 43 (32%) from standard HF medical therapy.

The participants with the minor allele upstream of HCRTR2 were less likely to have improved left ventricular function (odds ratio [OR] 0.4 per minor allele). In a replication cohort, the participants with the same allele had a lower prevalence rate of ejection fraction >35% (OR 0.769 per minor allele).

Mice with lower levels of HCRTR2 experienced poorer cardiac function, worsened treadmill exercise capacity, and increased myocardial scarring, but orexin—an HCRTR2 agonist rescued cardiac function for this cohort.

The results demonstrated that myocardial fibrosis was more pronounced in the HCRTR2-deficient mice, which suggests that HCRTR2 may potentially help regulate myocardial remodeling.

Diseased myocardial tissue in the human left ventricle from the myocardial gene expression arrays had a higher degree of HCRTR2 gene expression, which also suggests that HCRTR2 may have an additional role in the protection against HF.


  1. Perez MV, Pavlovic A, Shang C, et al. Systems genomics identifies a key role for hypocretin/orexin receptor-2 in human heart failure. J Am Coll Cardiol. 2015;66(22):2522-2533. doi: 10.1016/j.jacc.2015.09.061.