Kazunobu Nishimura

Clinical application of atrial natriuretic polypeptide in patients with congestive heart failure: beneficial effects on left ventricular function.

Synthetic alpha-human atrial natriuretic polypeptide was infused in patients with congestive heart failure (CHF) (New York Heart Association class III or IV) and in those without CHF. The infusion of atrial natriuretic polypeptide (ANP) at a rate of 0.1 microgram/kg/min significantly decreased pulmonary capillary wedge pressure and increased stroke volume index in all of the patients with CHF, whereas it decreased pulmonary capillary wedge pressure but caused no significant change in stroke volume index in the patients without CHF. Concomitant significant reductions in total systemic resistance were observed in both groups of patients. The ANP infusion significantly increased the urine volume, the excretion of sodium, and endogenous creatinine clearance in the patients without CHF. In the patients with CHF, it also showed a tendency to increase all these variables, but the urine volume did not correlate with the reduction in pulmonary capillary wedge pressure. The ANP infusion also decreased plasma aldosterone concentrations in these patients, although no significant difference was observed in the decrement of the plasma aldosterone concentration in the patients with and those without CHF. These findings indicate that the ANP infusion improves left ventricular function in patients with CHF, and suggest that this improvement results mainly from the vasodilating activity of ANP.

α-Human atrial natriuretic polypeptide is released from the heart and circulates in the body

In order to clarify whether or not atrial natriuretic polypeptides are hormones in man, we have measured plasma alpha-human atrial natriuretic polypeptide (alpha-hANP)-like immunoreactivity (alpha-hANP-LI) with or without extraction procedure. alpha-hANP-LI was detected in plasma extracts from all 5 normal subjects and 7 patients with heart diseases. The alpha-hANP-LI concentration in normal peripheral plasma was 37.7 +/- 7.0 pg/ml (mean +/- SE). Plasma concentrations of alpha-hANP-LI in the coronary sinus obtained by cardiac catheterization were 3 to 10 times higher than those in the peripheral vein, inferior vena cava, right atrium, pulmonary artery and aorta. High performance gel permeation chromatography coupled with a radioimmunoassay (RIA) for alpha-hANP revealed that alpha-hANP-LI in normal peripheral plasma eluted at the position corresponding to that of authentic alpha-hANP without detectable amounts of high molecular weight forms. alpha-hANP-LI extracted from plasma taken from the coronary sinus of two patients also showed a single peak of alpha-hANP-LI co-eluting with alpha-hANP. In contrast, not only alpha-hANP but gamma-hANP and beta-hANP, high molecular weight forms, were present in the human atrial tissue. These results indicate that alpha-hANP is the predominant form of alpha-hANP-LI in human plasma and that this form generated in the atrial cardiocytes is preferentially released from these cells and circulates in the body.

Augmented expression of atrial natriuretic polypeptide gene in ventricle of human failing heart.

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 660.3 +/- 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 approximately 40 and 200 times higher than in the normal ventricle. The increase of ANP 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 of DCM. 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 of ANP 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.

Prediction of reversible ischemia after revascularization: perfusion and metabolic studies with positron emission tomography

BACKGROUND Accurate noninvasive determination of myocardial viability is of paramount importance for the clinical identification of patients who will benefit most from revascularization. The preserved metabolic activity in the myocardium, as studied with positron emission tomography (PET), has been considered a gold standard for this purpose. However, recent reports show that moderate hypoperfusion or stress-induced ischemia may represent reversible ischemia. The present study was undertaken to compare the value of perfusion and metabolic studies with PET for predicting improvement in wall motion after revascularization. METHODS AND RESULTS Of 61 patients who had regional asynergy and underwent PET before revascularization, 43 patients who had successful revascularization were included in the study. Each patient underwent rest-stress 13N-ammonia perfusion scans and 18F-fluorodeoxyglucose (FDG) scan at rest while in a fasting state. Reversible ischemia was considered to be present when the resting perfusion was > or = 50% of the peak value, stress-induced hypoperfusion was present, or an increase in FDG uptake was observed. Of 130 asynergy segments, 51 segments had improved wall motion after revascularization. The positive and negative predictive values for improvement in asynergy were 48% and 87% by the rest perfusion study, 63% (P = .05 versus the rest value) and 87% by the rest-stress perfusion study, and 76% (P < .01 versus the rest value) and 92% by the FDG study. CONCLUSIONS FDG PET provided the best predictive value for improvement in wall motion after revascularization. On the other hand, 13N-ammonia PET is useful for predicting nonreversible myocardial scarring when it shows severe hypoperfusion at rest or hypoperfusion without stress-induced ischemia.

Transplanted Skeletal Myoblasts Can Fully Replace the Infarcted Myocardium When They Survive in the Host in Large Numbers

Background—It is not clear how many skeletal myoblsts (SM) can survive and exert beneficial effects in the host myocardial infarction (MI) area. We assessed the hypothesis that a large number of SM can replace the MI area with reverse left ventricular (LV) remodeling. Methods and Results—MI was created by left coronary artery ligation in male Lewis rats. Four weeks after ligation, 45 rats had skeletal myoblast transplantation in the MI area. They were randomized into 3 groups according to the number of SM: group I (n=15), 5×107; group II (n=15), 5×106; and group III (n=15), 5×105 cells. Donor SM were obtained from neonatal Lewis rats and directly used without expansion. Another four weeks later, all rats were sacrificed following hemodynamic assessment. All heart sections were stained with anti-fast skeletal myosin heavy chain (FSMHC) antibody to determine the spacial extent of donor myocytes. Results—Four weeks after transplantation, LV diastolic dimension was decreased, fractional area change was increased, and MI size was decreased maximally in group I. Histological study showed that donor cells positive for FSMHC occupied the MI area with nearly normal wall thickness in group I, in which estimated volume of donor-derived muscle tissue was 40 mm3. In the other groups, FSMHC-positive cells were found only partly in the MI area. Conclusions—A large number of freshly isolated neonatal SM can survive in the host and fully replace the infarcted myocardium with reverse LV remodeling in rats with MI.

Assessment of regional and global left ventricular function by reinjection Tl-201 and rest Tc-99m sestamibi ECG-gated SPECT: Comparison with three-dimensional magnetic resonance imaging

OBJECTIVES The purpose of this study was to test the ability of reinjection thallium-201 and rest technetium-99m sestamibi ECG (electrocardiographic)-gated SPECT (i.e., reinjection-g-SPECT [single-photon emission computed tomography] and MIBI-g-SPECT) to determine regional and global functional parameters. BACKGROUND The ECG-gated perfusion SPECT was reported to provide accurate left ventricular ejection fraction (LVEF) using an automated algorithm. We hypothesized that other various functional data may be obtained using reinjection-g-SPECT and MIBI-g-SPECT. METHODS Reinjection-g-SPECT, MIBI-g-SPECT, and three-dimensional magnetic resonance imaging (3DMRI) were conducted in 20 patients with coronary artery disease. Regional wall motion (RWM) and wall thickening (RWT) were analyzed using semiquantitative visual scoring by each g-SPECT and 3DMRI. The left ventricular end-systolic and end-diastolic volumes (EDV, ESV) and LVEF estimated by reinjection- and MIBI-g-SPECT were compared with the results of 3DMRI. RESULTS A high degree of agreement in RWM and RWT assessment was observed between each g-SPECT and 3DMRI (kappa >.70, p < .001). The LVEF values by reinjection- and MIBI-g-SPECT correlated and agreed well with those by 3DMRI (reinjection: r = .92, SEE = 5.9%, SD of differences = 5.7%; sestamibi: r = .94, SEE = 4.4%, SD of differences = 5.1%). The same also pertained to EDV (reinjection: r = .85, SEE = 18.7 ml, SD of differences = 18.4 ml; sestamibi: r = .92, SEE = 13.1 ml, SD of differences = 13.0 ml) and ESV (reinjection: r = .94, SEE = 10.3 ml, SD of differences = 10.3 ml; sestamibi: r = .97, SEE = 6.7 ml [p < .05 vs. reinjection by F test], SD of differences = 6.6 ml [p < .05 vs. reinjection by F test]). CONCLUSIONS Reinjection- and MIBI-g-SPECT provide clinically satisfactory various functional data. These functional data in combination with the perfusion information will improve diagnostic and prognostic accuracy without an increase in cost or the radiation dose to the patients.

Toward surgical angiogenesis using slow-released basic fibroblast growth factor

OBJECTIVE Therapeutic angiogenesis using basic fibroblast growth factor (bFGF) in coronary artery disease has been documented in a number of papers. However, the effectiveness is discrepant among documents. In this study, we evaluated the distribution of bFGF in the rat heart by different administration methods, and investigated the efficacy of slow-released administration of bFGF using biodegradable hydrogel microspheres (bFGF microspheres) in a pig infarction model toward an enhanced coronary bypass surgery. METHODS Heart failure due to myocardial infarction was induced in rats and pigs. In the rat study, free form of bFGF (central venous injection, intracoronary injection, and intramyocardial administration) and bFGF microspheres (intramyocardial administration) were given 4 weeks later. The remaining radioactivity of bFGF in the hearts was estimated 1, 24, and 72 h later. On the other hand, the pigs were randomized into two groups 4 weeks after myocardial infarction. While the control group (n=8) had gelatin hydrogel microspheres with saline, the FGF group (n=8) received bFGF microspheres in the left ventricular (LV) wall. RESULTS In the rat study, after intramyocardial administration of bFGF microspheres, more bFGF remained in the rat heart 72 h later compared with the other methods (P<0.0001). In the pig study, 4 weeks after the treatment, the FGF group had smaller LV diastolic diameter (48.7+/-5.3 vs. 56.7+/-5.2 mm, P<0.01) than the control group. LV end-systolic elastance was higher in the FGF group (2.96+/-1.2 vs. 1.06+/-0.3 mmHg/ml, P<0.01). In microscopic examinations, many neovessels were found in and around the scar tissue, and the vascular density in the FGF group was significantly higher (61.5+/-18.3 vs. 153.0+/-29.0/mm2, P<0.01). In addition, the infarcted LV walls were less expanded and more thickened in the FGF group. CONCLUSIONS Biodegradable hydrogel microspheres with bFGF improved LV function and inhibited LV remodeling by angiogenesis in pigs with chronic myocardial infarction. bFGF microspheres into ischemic myocardium may revascularize small ungraftable vessels and may potentially increase distal run-off when applied in coronary bypass surgery.

The pharmacokinetics of α-human atrial natriuretic polypeptide in healthy subjects

SummaryWe have analysed the pharmacokinetics ofα-human atrial natriuretic polypeptide (α-hANP) in healthy subjects, using a two-compartment open model following bolus intravenous injection. The plasma half-times for the fast and slow components were 1.7±0.07 min and 13.3±1.69 min respectively. V1 (the volume of the central compartment), Vz (volume of distribution) and Vss (volume of distribution at steady-state) were 5370±855 ml (89.5±14.3 ml·kg−1), 32000±4620 ml (533±77.0 ml·kg−1), and 11900±1530 ml (198±25.5 ml·kg−1) respectively. The mean plasma clearance was 1520±121 ml·min−1 (25.4±2.0 ml·min−1·kg−1.

Assessment of transesophageal Doppler echography in dissecting aortic aneurysm.

To assess the clinical value of transesophageal Doppler echography in the diagnosis of dissecting aortic aneurysm, both transesophageal and conventional echograms were performed in 22 cases of dissecting aortic aneurysm. Of the 22 patients, 17 underwent angiography; 8, X-ray computed tomography; 4, both; and 12, surgery. The performance of each method was assessed in the following four segments: A, ascending aorta; B, aortic arch; C, thoracic descending aorta; and D, upper abdominal aorta. The results by angiography were presumed to be correct. In the group of 17 patients who underwent angiography, the rate of correct detection of an intimal flap using the transesophageal approach was 100% in all four segments, significantly better than detection by the conventional approach (segment A, 65%; segment B, 47%; segment C, 35%; segment D, 53%) (p less than 0.01), and the rate of correct detection of the entry sites using the transesophageal approach was 100%, significantly better than that by conventional approach (42%) (p less than 0.05). X-ray computed tomography was not capable of detecting the site of entry in all cases. The presence of thrombus, aortic regurgitation and pericardial hemorrhage were all revealed clearly by the transesophageal approach, and the results were partly proved by other methods. In conclusion, transesophageal Doppler echography provides a rapid and accurate method of diagnosing and evaluating dissecting aortic aneurysm and permits prompt initiation of appropriate treatment.

Composite arterial Y graft has less coronary flow reserve than independent grafts.

BACKGROUND It is not known whether a composite Y graft of the left internal thoracic artery can provide sufficient blood flow to the whole left coronary system. The aim of this study was to compare regional myocardial blood flow (MBF) and coronary flow reserve after coronary artery bypass grafting using arterial composite Y graft or independent arterial grafts. METHODS Positron emission tomography was performed at rest and after dipyridamole infusion using oxygen-15-labeled water 2 weeks after coronary artery bypass grafting. Regional MBF was calculated in seven segments of the left ventricle. Coronary flow reserve was defined as the ratio of MBF after dipyridamole infusion to MBF at rest. In the Y graft group (n = 22), a free arterial graft to obtuse marginal arteries was anastomosed to the proximal side of in situ left internal thoracic artery, which was anastomosed to the left anterior descending artery. In the independent graft group (n = 13), left anterior descending and obtuse marginal arteries were independently revascularized using in situ left internal thoracic artery and a free arterial graft. RESULTS There was no difference between the groups in MBF at rest. Coronary flow reserve in the Y graft group was lower than that in the independent group in the anterobasal (1.43 +/- 0.07 versus 1.90 +/- 0.13, p = 0.038), apical (1.24 +/- 0.06 versus 1.64 +/- 0.12, p = 0.003), septal (1.34 +/- 0.05 versus 1.75 +/- 0.13, p = 0.023), and lateral regions (1.19 +/- 0.04 versus 1.66 +/- 0.09, p = 0.001). CONCLUSIONS Although arterial composite Y graft improved MBF at rest, it was not as effective as independent grafts for improving coronary flow reserve soon after coronary artery bypass grafting.