The recent discovery of renalase has elucidated a novel pathway for the homeostatic control of circulating catecholamines. Data from the International HapMap Consortium has identified a single common non-synonymous single-nucleotide polymorphism in the human renalase gene that results in an aspartic acid to glutamic acid substitution at codon 37 (Glu37Asp) in the flavin-adenine dinucleotide-binding site. In the present study of 590 persons with stable coronary artery disease, we report an association of CC (Asp/Asp) homozygosity at codon 37 with cardiac hypertrophy, dysfunction, and ischemia. Although this is a conservative substitution (Glu37Asp), it does occur in a critical region of the protein, namely the FAD binding domain, And it is, therefore, not surprising that compared to Glu37, Asp37 has a significantly lower affinity for NADH and a reduced maximal velocity. These findings raise the intriguing possibility that decreased activity of the enzyme renalase may contribute to cardiovascular disease.
At baseline, renalase activity in blood mirrors sympathetic tone 
. Brief surges in catecholamine levels increase the activity, secretion, and synthesis of renalase resulting in accelerated degradation of catecholamines via a negative feedback mechanism. In animal models, catecholamine regulation by renalase demonstrates significant hemodynamic effects that mimic nonselective beta-adrenoceptor blockade: reduced heart rate, blood pressure, and cardiac contractility 
. However, studies examining the in vivo
relevance of renalase in humans are lacking. In a large case-control study of a northern Han Chinese population, Zhao et al found an association of the (Glu37Asp) polymorphism with essential hypertension (odds ratio 1.61; 95% CI 1.26–2.04; p
. By contrast we found no significant association of the (Glu37Asp) polymorphism with either systolic or diastolic blood pressure, possibly because of more aggressive blood pressure control in patients with coronary artery disease. This discrepancy may reflect differences in study populations (essential hypertension versus stable coronary artery disease) and commensurate differences in medication use.
Accumulating evidence implicates excessive circulating catecholamines in the pathogenesis of left ventricular hypertrophy, a powerful independent risk factor for cardiovascular death and morbidity 
. The observation that left ventricular hypertrophy is common in patients with end-stage renal disease has suggested a link between kidney function and cardiac hypertrophy 
. Ghosh et al recently demonstrated that neonatal nephrectomy in rats results in cardiac hypertrophy associated with decreased norepinephrine metabolism 
. Notably, renalase protein expression in cardiac tissue from nephrectomized rats was significantly lower than in controls. In the present study, we found an association of Asp/Asp homozygosity at codon 37 with increased left ventricular mass index (multivariable adjusted effect size
). This supports a mechanistic link between the renalase-catecholamine axis and left ventricular hypertrophy, and extends this finding to humans. Further studies in animal models are warranted to investigate the relative contributions of renalase secreted from the kidney and the heart to the inhibition of cardiac hypertrophy.
The association of the Glu37Asp polymorphism with cardiac dysfunction has not previously been reported. Renalase infusion in rats results in an increase in stroke volume, which may reflect a compensatory response to decreased heart rate. However, since renalase also reduces cardiac contractility, an alternative explanation is that renalase-induced metabolism of circulating catecholamines increases cardiac lusitropy and optimizes diastolic-systolic coupling. We found essentially similar odds ratios for both systolic and diastolic dysfunction associated with Asp/Asp homozygosity in multivariable adjusted models further suggesting an influence of the renalase-catecholamine axis on both aspects of cardiac function. Detailed hemodynamic studies examining the effects of renalase administration on diastolic function would be of interest in this regard.
Cardiac ischemia, whether acute or chronic, is associated with a significant elevation in circulating catecholamines that promote and exacerbate myocardial infarction 
. Pharmacologic blockade of beta adrenoceptors has therefore become an essential component of medical therapy for acute coronary syndromes and chronic stable angina 
. Since renalase specifically metabolizes circulating catecholamines, we sought to determine whether common variation in the renalase gene is associated with inducible ischemia in persons with stable coronary artery disease. Homozygosity for Asp/Asp at codon 37 was associated with inducible wall motion abnormalities during stress echocardiography (OR 1.5) as well as reduced exercise tolerance (multivariable adjusted effect size
−1.0 METS). These findings extend the observation that, in rats, recombinant renalase reduced myocardial infarction size by 54% 
. Taken together, these data suggest that renalase deficiency or loss of function may contribute to the ischemic cascade in myocardium. Whether renalase replacement therapy can reduce myocardial ischemia in persons with coronary artery disease is not known. We speculate that experimental studies addressing this question may have therapeutic implications in this population.
The main strength of the present study is the collection of detailed phenotypic data derived from comprehensive resting and stress echocardiography in all participants. Combined with the a priori
selection of the only known common coding polymorphism in renalase, the genotype-phenotype associations reported are biologically plausible and unlikely to represent false positive associations 
. In addition, confounding by renal impairment is unlikely given the normal mean estimated GFR of study participants. However, several important limitations should be considered in the interpretation of our results. First, our study population was restricted to Caucasian individuals, predominantly men. Therefore, our results may not be generalized to women or to other racial groups, and should be replicated in other populations. Second, we did not measure serum renalase levels or activity as an intermediate phenotype. Finally, our analysis of diastolic dysfunction did not incorporate newer echocardiographic techniques such as tissue Doppler imaging, which would offer further refinement and resolution of phenotype 
In conclusion, we found an association of the renalase Glu37Asp polymorphism (C allele) with cardiac hypertrophy, dysfunction, and ischemia in a cross-sectional study of individuals with stable coronary artery disease and normal renal function. The renalase pathway is a novel regulator of circulating catecholamine levels. Future studies should be aimed at determining whether there is a potential therapeutic role for renalase replacement in persons at high risk of cardiovascular morbidity and mortality.