Author + information
- Walter J. Koch, PhD∗ ( and )
- Alessandro Cannavo, PhD
- Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
- ↵∗Reprint requests and correspondence:
Dr. Walter J. Koch, Department of Pharmacology, Center for Translational Medicine, Temple University School of Medicine, 3500 North Broad Street, MERB 941, Philadelphia, Pennsylvania 19140.
Heart failure (HF) remains one of the leading causes of morbidity and mortality worldwide, and outcomes remain poor despite improvements in therapy (1). In this regard, it has been shown that not all patients respond favorably to some of the more effective therapies, such as β-adrenergic receptor (βAR) antagonists (2). This response variability is dependent not only on clinical features, but also on genetic variation (3,4). Importantly, technology continues to advance to identify genetic alterations that may influence disease development as well as therapeutic responses. Indeed, next-generation sequencing (NGS) has advanced the study of human genome variation and discrimination of patients that may respond to specific therapies (5). This area of pharmacogenomics is powerful and several interesting candidate single nucleotide polymorphisms (SNPs) recently have appeared to alter the response to treatment for people with HF. The current study by Perez et al. (6) used GWAS to identify a new gene variant candidate that is strongly associated with altering the response to conventional HF therapy, which could lead to novel drug treatments because the candidate gene is a G protein–coupled receptor (GPCR), a member of a family of proteins that remains the largest drug-target system (6,7).
This new finding from Perez et al. (6) in this issue of the Journal is especially exciting because the GPCR gene found to be variant, HCRTR2, is a receptor not previously linked directly to heart function or cardiac biology. GPCRs have been the focus of previous studies dealing with the pharmacogenomics of SNPs and their relatedness to HF therapeutic responses. The primary GPCR with this relationship was the β1-adrenergic receptor (β1AR), and a gene variant has been found to alter responsiveness to β-blocker therapy in HF patients (8,9). Of note, the Arg389Gly β1AR variant is common in the general population, but with racial differences in its frequency, has been shown to possess greater ejection fraction improvement in patients carrying the Arg allele (9).
In addition to these single pharmacogenomics studies showing SNP association with HF responses, GWAS has been used to robustly find gene associations to the disease itself. Of note, in the current study by Perez et al. (6), the combination between a customized SNP array and GWAS led to the discovery of this new HCRTR2 gene variant that appears highly associated with therapeutic responsiveness in HF. Specifically in this study, the investigators analyzed 866 HF patients. Patients who were found to have a low functional response to therapy presented with a variation in the regulatory region of the HCRTR2 gene (6). Patients without this mutation generally responded to therapy with a ≥20% improvement in ejection fraction. The HCRTR2 gene encodes for a GPCR that is the receptor for the endogenous neuropeptides Orexin A or B (also known as hypocretins) (10). The variant found in the nonresponders generally results in less expression of the hypocretin receptor (6). Orexins are produced by neurons of the lateral hypothalamic area and are well known for their effects on eating behaviors and sleep patterns (6,10). Accordingly, any cardiovascular effects of orexins or the hypocretin receptor was viewed as indirect due to changes in eating or sleeping. As an example of this, the global or neuronal-specific knockout in mice of the orexin gene locus resulted in mice with lower resting blood pressure compared with wild-type controls (10). Moreover, the administration of orexin peptides have been associated with increases in circulating catecholamines and increased heart rate (10). Thus, no direct effect on cardiac function has been demonstrated. This Perez et al. (6) study adds significant new knowledge to the cardiovascular impact of this receptor system and orexins because it appears to be cardioprotective. Low receptor levels are associated with decreased therapeutic improvement in HF patients (6).
Interestingly, in addition to the association with this HCRTR2 gene variant to response to HF treatment, Perez et al. (6) found a consistent increase of total cardiac hypocretin receptor levels in both ischemic and dilated cardiomyopathy patients compared with samples in controls. This suggests a response to disease progression that may be an adaptive or compensatory response that may be protective (6). To directly test this hypothesis, the investigators created a mouse model with disruptive transcription of the hyocretin receptor (HCRTR2-TD) and exposed them to HF models. Although the model used to induce HF is limited in value because it was based only on massive neurohormonal treatment (angiotensin II and isoproterenol), the authors were able to find a significant difference in the fibrotic response and diastolic function in the HCRTR2-TD mice compared with control mice, strongly suggesting that loss of receptor worsens HF, and normal levels or increases with injury are protective (6). Importantly, the most significant support for the hypocretin GPCR system having positive effects on the heart was from the beneficial effects of orexin feeding to HF mice. Stimulation of the hypocretin receptor is an interesting target. Downstream effectors should be studied for mechanistic insights into potential novel cardioprotective strategies.
Overall, the study by Perez et al. (6) is powerful and provides a translational analysis in humans and mice for the involvement of the HCRTR2 gene in HF treatment response. These findings may have broader implications for the development of a new treatment that may “eat away” at the epidemic of HF.
↵∗ Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Both authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- American College of Cardiology Foundation
- ↵Cannavo A, Liccardo D, Koch WJ. Targeting cardiac β-adrenergic signaling via GRK2 inhibition for heart failure therapy. Front Physiol 2013;4:264.
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