In order to determine whether or not late potentials indicate either a degree of myocardial fibrosis or necrosis, the relationship between late potentials and thallium-201 myocardial perfusion images was studied in 13 patients with idiopathic dilated cardiomyopathy. Late potentials were defined as low-amplitude waveforms having duration of over 20 msec after the end of the QRS complex using a high-resolution ECG (Marquette electronics, MAC 1). In the Tl-201 myocardial perfusion image, the segmental perfusion state was assessed by use of a parameter called the uptake index (= normalized sector counts/maximal normalized sector counts) of each of 6 different segments. Segments which showed an uptake index of -2SD less than the normal value were judged to be abnormal. Late potentials were detected in 8 (61.5%) of the 13 patients. All of the patients showing late potentials also had ventricular tachycardia. Among the patients showing no late potential, ventricular tachycardia was observed in only one patient. Seven of the 8 patients showing late potentials and 3 of 5 patients not showing late potentials had abnormal perfusion images. The patients showing late potentials, however, had both a higher degree and a greater extent of abnormal perfusion images than the patients not showing late potentials. Therefore, late potentials may reflect a degree of myocardial fibrosis or necrosis in patients with idiopathic cardiomyopathy. It is indicated that among patients with dilated cardiomyopathy, those showing abnormal thallium images are apt to show late potentials, and these patients seem to be also at a high risk of suffering from ventricular tachycardia.

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To characterize slow conduction of the common type of atrial flutter (common AF), in which excitation wave propagated in a counterclockwise fashion, transient entrainment during the distal high lateral right atrium (HRAd) pacing and during the proximal coronary sinus (CSp) pacing was studied in 7 patients with common AF. In transient entrainment of common AF, conduction time from stimulus to CSp during HRAd pacing was always longer than that from stimulus to HRAd during CSp pacing. It was also longer than that from stimulus to CSp during HRAd pacing in 5 control patients without common AF in sinus rhythm. Return cycles at HRA and CS after cessation of rapid pacing during transient entrainment were studied. In HRAd pacing, return cycle at the proximal high lateral right atrium was almost equal to the pacing cycle length, or almost equal to or slightly shorter than the flutter cycle length (AFCL). Return cycle at CSp was almost equal to AFCL. In CSp pacing, return cycle at the distal coronary sinus was much longer than AFCL and increased at progressively shorter pacing cycle lengths. In conclusion, slow conduction was demonstrated in the lateral limb (from HRA laterally to CS) of the reentrant circuit in common AF, but it did not exhibit decremental conduction property. Return cycle at an endocardial recording site after transient entrainment in common AF does not always exhibit an uniform pattern, affected by the relative location of and the distance between the recording site, the pacing site, the reentrant circuit and the area of slow conduction.

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To determine left ventricular diastolic properties in patients with familial amyloid polyneuropathy, 23 patients were studied by digitized M-mode echocardiography and were compared with 15 age-matched normal subjects. None of the patients had restrictive ventricular physiology and all but two showed normal left ventricular fractional shortening. Both the normalized peak rate of diastolic increase in left ventricular internal dimension and the normalized peak rate of diastolic thinning of posterior wall were significantly lower in patients than in normal subjects (2.0 ± 0.8 vs 3.0 ± 0.4 sec^-1 ; p<0.001, and 2.5 ± 1.2 vs 5.8 ± 1.0 sec^-1 ; p<0.001, respectively). The left ventricular isovolumic relaxation time in patients was 91.5 ± 22.2 msec, compared with 64.0 ± 2.6 msec in normal subjects (p<0.001). Of the 18 patients without clinical evidence of overt heart disease, 12 had normal ventricular wall thickness and normal fractional shortening, but 10 of the 12 exhibited some abnormalities in diastolic properties. In addition, indexes of diastolic function were significantly related to ventricular wall thickness alone. These findings indicate that left ventricular diastolic abnormalities precede the development of clinically overt heart disease, ventricular wall thickening, and systolic dysfunction and may be related to intramyocardial amyloid infiltration with resultant fibrosis in patients with familial amyloid polyneuropathy.

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Restenosis was studied histopathologically by serial step sectioning of 22 coronary arteries from 21 patients in whom percutaneous transluminal coronary angioplasty (PTCA) had been performed (9 arteries from patients who had died shortly after PTCA and 1 3 from those who had died considerably later). Nine of the 13 arteries from the patients who had died long after PTCA were immunohistochemically stained using anti-actin antibody for examination of spindle-shaped cells proliferating in the intima. In the patients who had died shortly after PTCA, all 9 arteries showed fresh thrombus formation. In the patients who had died considerably later after PTCA, however, there was fragmentation of the internal elastic lamina (IEL) in 9 arteries. In each of these 9 arteries, a remarkable proliferation of intimal cells was observed on the intimal side, mainly at the site of the IEL fragmentation. These spindle-shaped cells were identified as smooth muscle cells (SMC) because they stained reddish-brown with Masson's trichrome, and because immunohistochemical staining with anti-actin antibody was also positive. In 2 arteries, proliferation of SMC and elastic fibers was observed on the luminal side of the intima, despite absence of fragmentation in the IEL. Proliferation of SMC in false lumens was identified in 2 patients with medial dissection . From the above findings, the following 4 forms of restenosis after PTCA have been identified: l. thrombus formation; 2. proliferation of SMC on the intimal side, mainly around fragmentation in the IEL; 3. proliferation of SMC on the luminal side of the intima where there was no fragmentation of the IEL ; and 4. proliferation of SMC in dissected false lumen. The proliferation of SMC on the intimal side of the disrupted IEL was thought to have been a result of migration of SMC from the media to the intima, because SMC proliferation was seen around the disrupted region.

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Factors determining prognosis in 100 patients with recent onset of congestive heart failure (CHF) were evaluated. The 1 year, 3 year, 5 year, and 10 year survival rates in the entire CHF group were 78.5%, 59 8% 50 4% and 14.7%, respectively. No correlations between age, sex, heart rate and cardiothoracic ratio, and the cumulative survival rate were found. The prognosis of patients with CHF due to underlying coronary artery disease or primary cardiomyopathy was poor compared with that of patients with other types of heart disease. Patients whose NYHA classification was class III or VI had a significantly lower survival rate than those in class II. Patients with lower left ventricular stroke work and consecutive ventricular premature deporalization also had a significantly lower survival rate. These results suggest that functional status, underlying heart disease, left ventricular stroke work, and the presence of ventricular tachycardia provide important information regarding the long-term prognosis in patients with congestive heart failure.

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To assess the relationship between left ventricular functional reserve and prognosis in patients with idiopathic mitral valve prolapse, ergometer exercise echocardiography was performed in 10 normal subjects and 30 patients with mitral valve prolapse having either mild, or no mitral regurgitation. These 30 patients with mitral prolapse were followed for 2 to 8 (mean 4.5) years. Increment of % fractional shortening during maximum exercise at the initial study in patients with mitral valve prolaspe and normal subjects were 7 ± 7 and 11 ± 3%, respectively. Based on increment of % fractional shortening, patients with mitral valve prolapse were divided into 2 groups; Group I: 13 cases with Δ% fractional shortening < 5%, Group II: 17 cases with Δ% fractional shortening &ges;5%. The incidence of cardiac symptoms was higher in Group I than in Group II (85 vs 41%, P<0.05). ST-T changes and life-threatening arrhythmias were more frequently observed in Group I. During the follow-up period, M-mode echocardiographic measurements did not vary in Group II, but left ventricular and left atrial dimensions increased significantly (p<0.05, p<0.01, respectively) and % fractional shortening decreased significantly (p<0.01) in Group I without any change in mitral regurgitation severity. Thus, some patients with mitral valve prolapse not having significant mitral regurgitation may develop progressive deterioration of the cardiac function, which may be predicted by exercise echocardiography.

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The efficacy and safety of intravenous infusion of human tissue-type plasminogen activator (rt-PA), developed in Japan (TD-2061), were investigated in 205 patients (154 men and 51 women) with evolving myocardial infarction (EMI). TD-2061 was given at a rate of 3.2 to 50 mg over 1h after angiographic documentation of complete or subtotal (99%) occlusion. Nineteen patients were excluded as they did not meet the inclusion criteria. A total of 186 patients were divided into 6 groups according to the total dose given: Group I, 3.2 mg, 10 patients (pts); Group II, 6.4 mg, 15 pts; Group III, 12 8 mg, 15 pts; Group IV, 25.6 mg, 38 pts; Group V, 33.3 mg, 70 pts; Group VI, 50.0 mg, 38 pts. Ages ranged from 30 to 70 years (mean 60±l). Coronary angiography was done at 30 min and 1h. In patients with TIMI grades 0 and 1, reperfusion was accomplished after 1h in 22% of Group I, 50% of Group II, 64% of Group III, 70% of Group IV, 67% of Group V, and 74% of Group VI patients. Complications were hypotension, nausea and vomiting, bradycardia and bleeding at the puncture site. These findings suggest that clot-selective coronary thrombolysis can be induced in patients with EMI by means of human tissue-type plasminogen activator without concomitant induction of a severe systemic lytic state. The optimal dose for Japanese patients is considered to be 33.350.0 mg from the standpoint of reperfusion.

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It has been demonstrated that the adenylate cyclase activity of vascular smooth muscle regulates its tonus. The present study was undertaken to examine adenylate cyclase activity in early and established deoxycorticosterone acetate (DOCA)/salt hypertensive rats. Early and established DOCA/salt hypertensive rats were prepared by injecting 30 mg of DOCA weekly for 3 and 10 weeks, respectively, into male Wistar rats given drinking water with l% saline. The membrane protein fraction of the aorta was obtained by centrifugation at 37, 000 g. To the incubation medium containing the protein, 50μM isoproterenol, 100μM GTP, 50μM forskolin or 25μM calmodulin was applied. The adenylate cyclase activity was determined by a modified method developed in our laboratory using double. isotope counting. The adenylate cyclase activity in the early DOCA/salt hypertensive rats was significantly higher (p < 0.05) than that in the control rats in the basal condition, which was unaffected by additions of isoproterenol, GTP or forskolin. There was no significant difference in basal adenylate cyclase activity between the established DOCA/salt hypertensive and control rats. The adenylate cyclase activities in the established DOCA/salt hypertensive rats were significantly lower with GTP (p < 0.02) and forskolin (p < 0.01) as compared with the control rats. Calmodulin elevated the adenylate cyclase activity significantly (p < 0.05) in the established DOCA/salt hypertensive rats as well as in the control rats. However, enzyme activity with calmodulin in the established DOCA/salt hypertensive rats was significantly lower (p < 0.05) than that in the control rats. These results suggest that the adenylate cyclase activity of vascular smooth muscle in early DOCA/salt hypertension was fully stimulated in the basal condition, and that there was an abnormality distal to the β-adrenoceptor, especially the catalytic subunit of the adenylate cyclase in established DOCA/ salt hypertension. Accordingly, it is thought that reduction of the enzyme activity may be attributable in part, to biochemical events involved in the pathogenesis of DOCA/salt hypertension.

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The effects of long-term treatment with diltiazem on the heart in normotensive (WKY) and spontaneously hypertensive rats (SHR) were studied. Diltiazem was added to the drinking fluid (900 mg/liter) and given ad libitum from 19 to 26 weeks of age, whereas tap water was given to the control animals. Although diltiazem did not decrease blood pressure in SHR, it decelerated the increase in their left ventricular weight (p <0.01 ). Hearts were removed and perfused by the working heart technique for 15 min, and then global ischemia was induced for either 10 or 30 min. The ischemic heart was reperfused for 30 min. The extent of recovery of coronary flow after reperfusion, following 30 min of ischemia in the diltiazem-treated SHR, was higher than that in the control SHR (p<0.01). The levels of adenosine triphosphate (ATP), creatine phosphate (CrP), and energy charge potential in the SHR heart reperfused after 30 min of ischemia were lower than those in the reperfused WKY heart (p<0.01, respectively). Diltiazem improved the restoration of ATP and CrP and prevented the decrease in energy charge potential in SHR after reperfusion following 30 min of ischemia (p<0.01, respectively). In conclusion, long-term treatment of SHR with diltiazem may protect the myocardium when myocardial ischemia occurs.

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Nine adult mongrel dogs were subjected to cardiopulmonary bypass and both right and left atria were surgically isolated, exclusive of the sinoatrial (SA) node, crista terminalis, and interatrial septum. Thus, the SA node remained in continuity with the ventricles despite biatrial isolation. Moreover, of the right and left SA node arteries, the predominant one (right in 7 dogs, left in 2 dogs) was spared. Postoperatively, normal SA node function was preserved in 8 out of 9 dogs, with no difference in sinus rhythm cycle length (preop: 446±25, postop: 434±22 sec, p = NS) or sinus node recovery time (preop: 488±28, postop: 487±32 msec, p = NS). Simulated supraventricular tachycardia was confined in the isoloated right or left atria did not affect sinus rhythm in the remainder of the heart. One out of 9 dogs developed junctional rhythm postoperatively, indicating exclusion of the SA node or a fast atrial pacemaker. In the 8 dogs with postoperative sinus rhythm, the spared SA node artery was occluded at the end of each study. All dogs developed rhythm deterioration including sinus rhythm slowing with prolonged sinus node recovery time (4 dogs), sinus bradyarrhythmia (2 dogs) and atrioventricular nodal rhythm (2 dogs). Thus, biatrial isolation is feasible for the treatment of supraventricular tachycardia, but it is essential to preserve SA node blood supply in order to maintain normal sinus rhythm in the remainder of the heart.

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Many clinical clues suggest a link between abnormal catecholamine function during a phase of rapid cardiac development and hypertrophic cardiomyopathy. However, experimental investigation focusing on abnormal catecholamine function during the fetal period as the pathogenesis of hypertrophic cardiomyopathy has not yet been carried out. In this study. isoproterenol (ISO) was administered to pregnant female rats and the effects of the drug on the hearts of their offspring were studied morphologically. Fifty /μg/kg/day of ISO was administered subcutaneously to 15 pregnant female rats 5 days a week for 3 weeks and the offspring were killed at 2 days, 4 weeks or 7 weeks after birth. Isotonic saline was administered to 15 pregnant female rats as control. The hearts of the offspring were removed and weighed immediately. The ventricles were cut in two, parallel to the atrio-ventricular groove. Left and right ventricular free wall thickness and interventricular septal thickness were measured. Under light-microscope, myocardial fiber diameter was measured and myocardial fiber disarray was assessed. Fine structural alterations of the cardiac muscle cells were observed by an electron microscope. The hearts of newborn offspring from pregnant rats treated with ISO showed disproportionate septal hypertrophy and frequent inter- and intracellular disarray in the interventricular septum. However, these changes were not prominent at 7 weeks after birth. These results suggest that abnormal catecholamine function during the fetal period may result in disproportionate septal hypertrophy.

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This investigation was undertaken to define the mechanism by which diltiazem protects against life-thereatening, reperfusion-induced arrhythmias. Using an isolated retrogressively perfused rat heart preparation with transient coronary artery occlusion, we compared the effects of diltiazem in its active form (d-cis) to its stereo-isomer (1-cis). Pre-ischemic administration of d-diltiazem (5 × 10^-8, 5 × 10^-7, 5 × 10^-6 M) caused a dose-dependent reduction in ventricular arrhythmias upon reperfusion following 10 min of regional ischemia. The incidence of reperfusion-induced ventricular fibrillation (RVF) was 50%, 0% (P<0.05) and 0% (P<0.05) with 5 × 10^-8, 5 × 10^-7, 5 × 10^-6 M diltiazem, respectively, compared with 60% in the control group. Pre-ischemic administration of the 1-isomer caused different dose-dependent reduction in RVF. With 5 × 10^-6M, the l-isomer also reduced the incidence of RVF to 0% (P<0.05). However below this concentration it was ineffective (67%). D-diltiazem (5 × 10^-7 and 5 × 10^-6M) increased coronary flow from 11.5 ± 1.9 ml/min to 15.3 ± 1.6 ml/min (p<0.05) and 15.2 ± 1.0 ml/min (p<0.05) respectively, prior to ischemia. In contrast. the same dose of the 1-isomer did not alter coronary flow. The highest dose (5 × 10^-6M) of d-diltiazem decreased heart rate by approximately 30% during the reperfusion phase, but all other concentrations had no significant effects. The high-energy phosphate content of the ischemic myocardium was significantly elevated after treatment with diltiazem. ATP content was increased from 11.1 ± 3.7 μmol/g dry weight to 18.0 ± 1.8 μmol/g dry weight (p<0.05), 17.2 ± 2.9 μmol/g dry weight (p<0.05) and 17.9 ± 3.4 μmol/g dry weight (p<0.05) with 5 × 10^-8, 5 × 10^-7 and 5 × 10^-6M diltiazem. The 1-isomer, at 5 × 10^-7M, preserved ischemic myocardial creatine phosphate content (16.9 ± 5.6 μmol/g dry weight: p<0.05 compared to 6.2 ± 1.8 μmol/g dry, wt in the control group) however the ATP content was not significantly higher. Thus, effects of the drugs on coronary flow, heart rate and high-energy phosphate content failed to explain the anti-arrhythmic properties of diltiazem. We conclude that the protective effect of diltiazem against reperfusion-induced arrhythmias is mediated mainly by its specific effect on the slow calcium channel, although a sodium channel blocking effect may also play an additional role.

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