BACKGROUND:Aldosterone (ALD) has been shown to stimulate cardiac collagen synthesis and fibroblast proliferation via activation of local mineralocorticoid receptors. In patients with acute myocardial infarction, we demonstrated that ALD was extracted through the infarct heart and extracting ALD-stimulated post-infarct left ventricular (LV) remodeling. METHODS AND RESULTS:To evaluate the effect of mineralocorticoid receptor antagonist (MRA) spironolactone on post-infarct LV remodeling, 134 patients with first anterior acute myocardial infarction were randomly divided into the MRA (n=65) or non-MRA (n=69) groups after revascularization. All patients were administered angiotensin-converting enzyme (ACE) inhibitor and study drug just after revascularization. Left ventriculography with contrast medium was performed at the acute stage and after 1 month to evaluate LV remodeling. ALD was measured at aortic root and coronary sinus. There was no difference in the baseline characteristics including infarct size and LV performance between the two groups. However, LV ejection fraction was significantly improved in the MRA group compared with that in the non-MRA group (46.0+/-0.6% to 53.2+/-0.8% versus 46.5+/-0.8% to 51.0+/-0.8%, Pinteraction=0.012). LV end-diastolic volume index was significantly suppressed in the MRA group compared with that in non-MRA group (86.5+/-1.0 to 90.6+/-2.4 versus 87.5+/-1.3 to 106.8+/-3.5 mL/m2, Pinteraction=0.002). Transcardiac extraction of ALD through the heart was significantly suppressed in the MRA group (Pinteraction=0.001), and plasma procollagen type III aminoterminal peptide level, a biochemical marker of fibrosis, was significant lower in the MRA group compared with the non-MRA group (Pinteraction=0.002). CONCLUSIONS:These findings indicate that MRA combined with ACE inhibitor can prevent post-infarct LV remodeling better than ACE inhibitor alone in association with the suppression of a marker of collagen synthesis.

In order to obtain information about the developmental mechanisms of restenosis after angioplasty, we investigated an association between the expression of platelet-derived growth factors (PDGFs) and neointimal cell accumulation in rabbit femoral arteries subjected to balloon angioplasty. Northern analysis demonstrated that mRNA expression of PDGF B-chain (PDGF-B) increased markedly in the injured arteries, peaking at day 7 (sevenfold), and the transcripts remained augmented until day 21. Also transcripts of PDGF beta-receptor (PDGFR-beta) and alpha-receptor increased by 3- and 2.5-fold, respectively, but those of PDGF A-chain showed only a slight increase (1.5-fold). In situ hybridization and immunohistochemistry demonstrated the concordant expression of mRNA and protein for PDGF-B in the smooth muscle cells (SMCs) of injured vessels throughout the experiment. PDGF-B expression peaked in neointimal SMCs at day 7. In accordance with PDGF-B expression, cellular proliferation in neointima peaked at day 7, being followed by a dramatic increase of neointimal areas thereafter. Further, we demonstrated PDGFR-beta immunoreactivity in these neointimal cells with PDGF-B expression. Our data provide evidence that PDGF-B may stimulate vascular SMC proliferation and contribute to neointimal formation after angioplasty.

Background. High levels of endogenous atrial natriuretic peptide (ANP) are thought to compensate the condition of patients with heart failure by reducing preload and afterload. However, recent reports have indicated that a high plasma ANP level is a prognostic predictor in patients with heart failure. Therefore, the role of endogenous ANP has not been clearly established in patients with heart failure.Methods and Results. The plasma ANP and cGMP levels were determined in the femoral artery and the femoral vein of 97 patients with chronic congestive heart failure (CHF). The plasma ANP level decreased significantly, whereas the plasma cGMP levels increased significantly from the femoral artery to the femoral vein. Among patients with mild CHF (n = 52), the plasma cGMP level correlated with the ANP level, and the calculated ANP extraction level also correlated with the calculated cGMP production in the peripheral circulation (r = 0.70, p < 0.001). In contrast, these correlations were not found in patients with severe CHF (n = 45). Among these patients, the plasma cGMP levels seemed to reach a plateau despite high levels of plasma ANP, and the molar ratio of cGMP production to ANP extraction in the peripheral circulation was significantly lower than in patients with mild CHF (36.7 +/- 9.5 versus 183 +/- 17,p < 0.001). In patients with acute severe CHF (n=9) and those with mild CHF, patients who were administered exogenous ANP, plasma cGMP levels increased in proportion to those of plasma ANP without saturation.Conclusions. These results indicate that downregulation of ANP receptors coupled to guanylate cyclase may occur in the peripheral vascular beds of patients with chronic severe CHF.

Corrective surgeries for TOF (Tetralogy of Fallot) were performed in 350 patients from 1967 to 1983 by Okamura's method under simple deep hypothermia. Radical operations were done in all patients, including very young children. The operative techniques had several differences from the standard procedure. Patients were operated on without any extracorporeal perfusion, the VSD was closed by a patch which was attached firmly to the margin of VSD using cross mattress sutures and the right ventricular outflow tract was dilated by infundibular myectomy only, with no use of outflow-patch-plasty. One hundred ten out of 350 patients were investigated by questionnaire and their responses showed that they had few long-term problems. ECG, X-ray, echocardiography and stress test by treadmill were performed in 26 cases. They were divided into two groups by the presence or absence of pulmonary regurgitation (PR). The CTR of the PR (+) group was larger than the PR (-) group (p less than 0.05). There was no statistical difference in cardiac function between the two groups. Few arrhythmias were observed during the exercise test. No residual shunts were found in any of the cases. The occurrence of PR was relatively rare in those who were operated on before their second birthdays. These results suggest that our surgical techniques under simple deep hypothermia are adequate to correct TOF.