ANP and cardiovascular risk ANP and left ventricular hypertrophy ANP has long been known as a marker of left ventric- ular hypertrophy, simply as a consequence of a signifi- cant induction of ANP gene transcription during the hy- pertrophic process of cardiac myocytes (23). However, we have recently learned that ANP plays an indepen- dent, direct role on cardiac mass regulation in both ani- mal models and in humans (18-20, 24). In fact, ablation of ANP gene was associated with a greater ratio of heart weight/body weight, independently from hypertension (18), whereas the overexpression of ANP was associat- ed with presence of smaller hearts (19). Moreover, mice lacking the NPR-A gene had a marked cardiac hypertro- phy (20). In this regard, studies from our group have recently demonstrated for the first time a direct modulatory role of both ANP and NPR-A genes on cardiac mass devel- opment in humans. In fact, an ANP promoter gene vari- ant, associated with significantly lower levels of circu- lating ANP, was found to associate with increased LVMI, left ventricular posterior wall thickness, left ventricular septum thickness, and relative wall thickening in human essential hypertension. On the other hand, an allelic variant of NPR-A gene was associated with increased LVMI and left ventricular septum thickness in the same human sample (24). Taken together, these findings support the ANP- NPRA system as a relevant regulatory mechanism an- tagonizing hypertrophic growth responses within the heart. Thus, the increase of ANP that generally accom- panies cardiac hypertrophy should not be interpreted as a marker of a contributory role of ANP to cardiac REFERENCES 1. Levis ER, Gardner DG, Samson WK. Natriuretic peptides. N Engl J Med 1998; 339: 321-8. 2. De Bold AJ, Borestein HB, Veress AT, et al. A rapid and potent natriuretic response to intravenous injec- tion of atrial myocardial extract in rats. Life Sci 1981; 28: 89-94. 3. Rubattu S, Volpe M. The atrial natriuretic peptide: A changing view. J Hypertens 2001; 19: 1923-31. 4. Burnett JC, Kao PC, Hu DC, et al. Atrial natriuretic pep- tide elevation in congestive heart failure in the human. 80 growth, but rather as the response of an intrinsic “friendly” mechanism that protects myocardiocytes against hypertrophic stimuli (25). Perspectives The traditional view of atrial natriuretic peptide as a key regulator of blood pressure and electrolyte homeo- stasis, as well as a marker of ventricular hypertrophy and cardiac failure has been overcome by the new con- cept of ANP as a cardiovascular risk factor. In fact, both experimental and clinical evidence show a role for ANP in the development of all major cardio- vascular diseases (Fig. 1). Therefore, measurement of ANP plasma levels, and, furthermore, assessment of the ANP genotype for the known mutations can be proposed as important ele- ments when assessing the cardiovascular risk profile of an individual subject. The future research in this exciting field will certainly provide us with more information which, hopefully, we will also be able to apply in better therapeutical strate- gies. Address for correspondence: Speranza Rubattu, MD IRCCS Neuromed Località Camerelle-Zona Industriale 86077 Pozzilli (IS) - Italy rubattu.speranza@neuromed.it Science 1986; 231: 1145-7. 5. Montorsi P, Tonolo GC, Polonia J, et al. Correlate of plas- ma atrial natriuretic factor in health and hypertension. Hy- pertension 1987; 10: 570-6. 6. Takayanagi R, Imada T, Grammer RT, et al. Atrial natri- uretic factor in spontaneously hypertensive rats: Concen- tration changes with the progression of hypertension and elevated formation of cyclic GMP. J Hypertens 1986; 4: S303-S7. 7. Rubattu S, Volpe M, Kreutz R, Ganten U, Ganten D, Lind- paintner K. Chromosomal mapping of a quantitative trait locus for stroke in an animal model of complex human