Role of ANP gene on cardiac hypertrophy in essential hypertension

Abstract

The atrial natriuretic peptide (ANP) exerts an important role in cardiovascular functions and remodeling. In particular, experimental evidence support a critical role for ANP in the regulation of cardiac hypertrophy. In fact, lack of ANP favours the hypertrophic process, whereas higher ANP levels reduce it in animal models. No evidence of an involvement of ANP in the hypertrophic response in the human disease was yet available. In the present study we investigated the influence of the ANP gene on dimensions of cardiac chambers in never treated mild to moderate essential hypertensives. Two-hundreds and thirteen individuals were studied by mono-bidimensional echocardiography and three markers of the ANP gene were characterized (a promoter variant, an exon 1 and exon 3 mutations). We found that subjects carrying the ANP gene promoter variant had an increased cardiac mass (117±11.8 g/m2 vs 95±1.6 g/m2, P<0.001), left posterior wall thickness (11.4±0.7 mm vs 9.7±0.1 mm, P<0.0002), septal wall thickness (12.0±1.0 mm vs 10.5±0.1 mm, P<0.02), independently from the blood pressure levels. In order to assess the effect of the promoter gene variant on circulating proANP levels, we characterized the peptide levels in a subgroup of wild type and heterozygous hypertensives, as well as in a cohort of healthy wild type and heterozygous individuals. Plasma proANP levels were 3110±547 and 1395±228 fmol/L in wild type and heterozygous hypertensives, respectively (P<0.01); 2319±223 and 1165±150 fmol/L in wild type and heterozygous healthy subjects, respectively (P<0.001). In summary, a promoter ANP gene variant, responsible of a significant reduction of plasma proANP levels, is strongly associated with cardiac hypertrophy development in untreated essential hypertensives. Therefore, lower levels of atrial natriuretic peptide favours the hypertrophic process in human hypertension, as well as in animal models. Moreover, our results, that demonstrate a direct contribution of ANP to left ventricular hypertrophy (as an intermediate phenotype) further support the role of ANP as an independent predictor of cardiovascular events.