Clinical Diagnosis and Heart Weights in Patients with and without CHF Time to autopsy Ventricular Patient Age Sex Diagnosis from death Heart weight Atrial weight weight h g g g Patients without CHF

Introduction To elucidate the expression of the atrial natriuretic polypeptide (ANP) gene in the ventricle of the human failing heart, we have measured ANP and ANP messenger RNA (ANPmRNA) levels in left ventricular aneurysm obtained at operation, biopsy specimens of left ventricles from dilated cardiomyopathy (DCM) and autopsy samples of old myocardial infarction (OMI) and DCM hearts, and compared the levels with those in the normal ventricle. The ANP level (mean±SE) was 17.5±6.9 ng/g in the normal ventricle, and increased to 6603±122.2 ng/g in the left ventricular aneurysm tissues and to 3,138.6±1,642.1 ng/g in the biopsy specimens of the DCM ventricle. These levels were 40 and 200 times higher than in the normal ventricle. The increase ofANP levels was observed in both infarcted and noninfarcted regions of the OMI heart, and in the entire ventricle of the DCM heart. A significant positive correlation was found between the ANP level in aneurysm tissues and pulmonary capillary wedge pressure (r = 0.85). The ANPmRNA level in the left ventricular aneurysm showed about a 10-fold increase compared with that in the normal heart and reached 23% of that in the atrium of the same heart. A similar increase in the ANPmRNA level was observed in the entire ventricle ofDCM. These data clearly indicate that the expression of the ANP gene in the ventricle is augmented in the failing heart in accordance with the severity of heart failure. In the atrium of the failing heart, ANP and ANPmRNA levels were only two times higher than those in the normal atrium. Thus, the augmentation in the expression of the ANP gene was more prominent in the ventricle than in the atrium. Taking tissue weight into account, the total content of ANPmRNA in the ventricle of the failing heart is much the same as that in the normal atrium. The ratio of the ANP level to the ANPmRNA level in the ventricle is much smaller than that in the atrium. These results suggest more rapid secretion ofANP after synthesis in the ventricle. These findings demonstrate that the expression of the ANP gene is augmented in the human ventricle of the failing heart and suggest that the ventricle becomes a substantial source of circulating ANP in congestive heart failure. Address reprint requests to Dr. Nakao, Second Division, Department of Medicine, Kyoto University School of Medicine, 54 Shogoin Kawahara-cho, Sakyo-ku, Kyoto 606, Japan. Receivedfor publication 13 May 1987 and in revisedform 12 July 1988. Atrial natriuretic polypeptide (ANP)l is a cardiac hormone secreted through the coronary sinus from the heart and is involved in fluid, electrolyte, and vascular homeostasis (1-7). The plasma ANP concentration is increased in patients with congestive heart failure (CHF) in relation to its severity (8-10), and this elevation of the plasma ANP concentration is mainly due to increased secretion ofANP from the heart (7, 1 1). It is ofgreat importance, therefore, to investigate ANP synthesis in the human failing heart in order to elucidate the clinical implication ofANP in CHF. We have recently reported that ANP synthesis is augmented in the atrium in accordance with the severity of CHF (12). Since ANP was first discovered from atrial tissues, the atrium had been thought to be the sole source of circulating ANP (4, 13-16). There is growing evidence, however, indicating that ANP is also synthesized in the ventricle of normal animals (17-19) and that ANP synthesis in the ventricle is increased under certain pathological conditions, such as spontaneously hypertensive rats (SHR) (20, 21), SHR stroke-prone (20), cardiomyopathic hamsters (22), experimentally volume or pressure overloaded rats (23-25), and myocarditis mice (26). In evaluating ANP synthesis in the human failing heart, it is, therefore, necessary to investigate ANP synthesis not only in the atrium but also in the ventricle. To date, however, there has been only a few preliminary reports on human ventricular ANP. We reported that the ANP gene is expressed in the normal ventricle as well as in the atrium and that the expression is augmented in the ventricle in a patient with dilated cardiomyopathy (DCM) (27). Immunohistochemical studies performed by us and others have also confirmed the increased ANP immunostaining in diseased ventricular cardiocytes (28, 29). Specimens obtained at operation and biopsy have a great advantage for the precise analysis of ANP and ANPmRNA levels, because of minimal postmortem nonspecific degradation. On the other hand, the autopsy sample is useful to evaluate ANP synthesis in the whole heart. To further elucidate ANP synthesis in the ventricle of the human failing heart, we investigated in the present study ANPmRNA and ANP in ventricles of old myocardial infarction (OMI) and DCM hearts, using samples obtained at operation, biopsy, and autopsy. 1. Abbreviations used in this paper: ANP, atrial natriuretic polypeptide; CAD, coronary artery disease; CHF, congestive heart failure; DCM, dilated cardiomyopathy; OMI, old myocardial infarction; PCWP, pulmonary capillary wedge pressure; SHR, spontaneously hypertensive rats. 298 Saito et al. J. Clin. Invest. © The American Society for Clinical Investigation, Inc. 0021-9738/89/01/0298/08 $2.00 Volume 83, January 1989, 298-305