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Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients with Cardiac Amyloidosis

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Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients with Cardiac Amyloidosis View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector 754 JACC Vol. 31, No. 4 March 15, 1998:254–65 Expression of Atrial and Brain Natriuretic Peptides and Their Genes in Hearts of Patients With Cardiac Amyloidosis GENZOU TAKEMURA, MD,*† YOSHIKI TAKATSU, MD,* KIYOSHI DOYAMA, MD,‡ HIROSHI ITOH, MD,‡ YOSHIHIKO SAITO, MD,‡ MASATOSHI KOSHIJI, MD,† FUMITAKA ANDO, MD,* TAKAKO FUJIWARA, MD,§ KAZUWA NAKAO, MD,‡ HISAYOSHI FUJIWARA, MD† Hyogo, Gifu and Kyoto, Japan Objectives. We investigated the expression of atrial natriuretic secretory granules in ventricular myoctyes of the patients with peptide (ANP) and brain natriuretic peptide (BNP) and their cardiac amyloidosis, but not in ventricular myocytes from the genes in the hearts of patients with cardiac amyloidosis and those normal control subjects. Double immunocytochemical analysis with isolated atrial amyloidosis. revealed the co-localization of ANP and BNP in the same granules Background. The expression of ANP and BNP is augmented in and that isolated atrial amyloid fibrils were immunoreactive for the ventricles of failing or hypertrophied hearts, or both. The ANP and BNP, whereas ventricular amyloid fibrils were negative expression of ANP and BNP in the ventricles of hearts with for both peptides. Both ANP mRNA and BNP mRNA were cardiac amyloidosis, which is hemodynamically similar to restric- expressed in the ventricles of the patients with cardiac amyloid- tive cardiomyopathy, is not yet known. ANP is the precursor osis but not in the normal ventricles. The autopsy study of four protein of isolated atrial amyloid. patients with cardiac amyloidosis revealed an almost transmural Methods. We analyzed the immunohistocytochemical localiza- distribution of ANP and BNP, with predominance in the endocar- tions of ANP and BNP as well as the expression of their mRNAs dial side. Plasma BNP levels in the patients were markedly by in situ hybridization in the myocardium and measured the elevated ([mean 6 SD] 1,165.1 6 561.2 pg/ml) compared with plasma levels of ANP and BNP in patients with cardiac amyloid- those in the control subjects (8.9 6 6.0 pg/ml, p < 0.05). osis. Conclusions. Expression of ANP and BNP and their genes was Results. Four of the five right and all six left ventricular augmented in the ventricular myocytes of the patients with endomyocardial biopsy specimens obtained from six patients with cardiac amyloidosis. Both regional mechanical stress by amyloid cardiac amyloidosis were immunohistochemically positive for deposits and hemodynamic stress by diastolic dysfunction may be both ANP and BNP; none of the biopsy specimens from eight responsible for the expression of the peptides in patients with normal subjects were positive for ANP or BNP. All four of the cardiac amyloidosis. right atria obtained at operation showed positive immunoreac- (J Am Coll Cardiol 1998;31:254–65) tions for both peptides. Electron microscopy identified specific ©1998 by the American College of Cardiology Atrial natriuretic peptide (ANP) is a cardiac hormone secreted regard to both its amino acid sequence and pharmacologic mainly from the atria and is involved in fluid, electrolyte and spectrum (10–12). Patients with congestive heart failure have vascular homeostasis (1,2). ANP is synthesized not only in the extremely high plasma levels of BNP, and the secretion of this atria but also in the ventricles of normal animals (3,4), and peptide from the ventricles is greatly augmented in these ventricular ANP synthesis is increased in various pathologic patients (12,13). These studies suggest a pathophysiologic role conditions, causing hemodynamic overload (5–9). Brain natri- for ANP and BNP in cardiovascular disease as endogeneous uretic peptide (BNP) has a striking similarity to ANP with vasodilator and diuretic agents, and the finding that ANP or BNP administration produces clinical improvement in patients with congestive heart failure supports this hypothesis (14,15). From the *Department of Internal Medicine and Department of Cardiovas- Dilated cardiomyopathy is one of the myocardial diseases cular Surgery, Hyogo Prefectural Amagasaki Hospital, Hyogo; †Second Depart- that cause heart failure, and thus augmented ANP and BNP in ment of Internal Medicine, Gifu University School of Medicine, Gifu; ‡Third ventricles afflicted with this disease have been well studied Department and Second Department of Internal Medicine, Kyoto University School of Medicine and §Kyoto Women’s University, Kyoto, Japan. (7–9,13). We found (16,17) that in the ventricles of hearts with Manuscript received January 21, 1997; revised manuscript received Decem- hypertrophic cardiomyopathy, the expression of ANP and BNP ber 3, 1997, accepted December 12, 1997. was augmented despite the absence of heart failure. ANP or Address for correspondence: Dr. Hisayoshi Fujiwara, Second Department of Internal Medicine, Gifu University School of Medicine, 40 Tsukasa-Machi, Gifu BNP, or both, was found to be overexpressed in the myocytes 500, Japan. E-mail: [email protected]. surrounding myocardial lesions, such as myocardial infarction ©1998 by the American College of Cardiology 0735-1097/98/$19.00 Published by Elsevier Science Inc. PII S0735-1097(98)00045-X JACC Vol. 31, No. 4 TAKEMURA ET AL. 755 March 15, 1998:254–65 NATRIURETIC PEPTIDES IN CARDIAC AMYLOIDOSIS Endomyocardial biopsy. Six patients who met the clinical Abbreviations and Acronyms and histologic criteria for the diagnosis of restrictive cardio- ANP 5 atrial natriuretic peptide myopathy on the basis of cardiac involvement of AL amyloid- BNP 5 brain natriuretic peptide osis (systemic amyloidosis with light chain deposition) were ELISA 5 enzyme-linked immunosorbent assay 5 enrolled in the study (five men, one woman; 46 to 71 years old, ET-1 endothelin-1 6 6 LVEDP 5 left ventricular end-diastolic pressure mean [ SD] 57 8). Clinical findings included the presence LVMI 5 left ventricular mass index of monoclonal protein in serum or urine, the involvement of PBS 5 phosphate-buffered saline other organs with amyloidosis, the absence of underlying PRA 5 plasma renin activity diseases other than myeloma and clinical syndromes, such as 5 SSC standard saline citrate nephrotic and carpal tunnel syndrome. The classification of restrictive heart disease was based on the presence of classical restrictive hemodynamic features at catheterization or by Doppler echocardiographic examination. The histologic diag- and myocarditis (18–20). These findings suggest that focal as nosis was confirmed at biopsy by the presence of amyloid well as hemodynamic stress is responsible for the ventricular deposits identified by a positive staining reaction with alkaline augmentation of these peptides. Cardiac amyloidosis presents Congo red with dichronic birefringence that was not attenu- a hemodynamically restrictive pattern and is sometimes cate- ated after treatment with KMnO4 (27). No patient had coro- gorized as restrictive cardiomyopathy (21). In general, hearts nary artery disease, myocardial infarction, valvular heart dis- with cardiac amyloidosis preserve systolic function until the ease or any heart disease other than cardiac amyloidosis. terminal stage, but diastolic function is damaged, mainly as a Control endomyocardial biopsy specimens were taken from result of the mechanical disturbance of myocyte movement by eight patients with clinically suspected cardiac disease because the diffuse deposition of amyloid. A previous study (22) of chest pain, syncope, slight electrocardiographic changes or reported immunohistochemical ANP expression in the ventri- arrhythmia. Noninvasive and invasive examinations, including cles of patients with restrictive cardiomyopathies, mainly idio- biopsy, revealed no organic heart disease in these patients. pathic restrictive cardiomyopathy. However, ANP and BNP Two-dimensional echocardiographic examination was per- have not yet been studied in detail in cardiac amyloidosis. formed in all 14 patients. The left ventricular mass index was Another interesting relation between amyloidosis and na- calculated by the method of Feneley et al. (28). All patients triuretic peptides is that in isolated atrial amyloidosis, amyloid underwent biventricular cardiac catheterization, biplane left fibrils themselves show antigenicity against both ANP and ventriculography and selective coronary angiography by stan- BNP, and thus ANP is regarded as the precursor protein of dard techniques. During the procedure, endomyocardial bi- isolated atrial amyloid (23–25). Amyloid in cardiac amyloidosis opsy samples were taken from both the right and left ventricles is indeed derived from monoclonal immunoglobulin light chain in five of the six patients with cardiac amyloidosis and all eight (26), but it is of interest as to whether it also contains the control patients and from only the right ventricle in one patient immunogenicity of natriuretic peptides, in light of the above- with cardiac amyloidosis. Two to five pieces of tissue were mentioned isolated atrial amyloidosis case. obtained from each site. The largest specimens were immedi- In the present study, we investigated the expression and ately immersed in 10% buffered formalin solution, and other tissue localization of ANP and BNP and their genes in the pieces were fixed with 2.5% glutaraldehyde solution. Some myocardium of patients with cardiac amyloidosis by means of specimens from two patients with cardiac amyloidosis and immunohistochemical analysis at both the light and electron
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