Search

Background: Angiotensin-converting enzyme inhibitors (ACEI) reduce the mortality in the chronic phase of myocardial infarction (MI), and similar effects of angiotensin receptor blockers (ARB) have been reported. However, these effects of ARB have not yet been established in Japanese patients. A multicenter randomized study was designed for the present study to examine the effect of valsartan as compared to that of ACEI against left ventricular dysfunction after MI., Methods and Results: Patients with acute MI were randomly allocated to either the valsartan group (n=120; mean age 63 +/-1.0) or the ACEI group (n=121; mean age 62.9 +/-1.0) and followed up until 6 months. Left ventriculography was performed during hospital admission and at 6 months. The blood pressure was similar in the 2 groups throughout the study. The incidences of cardiovascular events and target vessel revascularization were similar, although that of adverse events was significantly higher in the ACEI (12.4%) than in the valsartan group (3.3%; P<0.05). There were no differences in left ventricular ejection fraction and left ventricular end-diastolic volume index between the groups., Conclusions: Valsartan exhibits similar efficacy effective to that of ACEI in preventing left ventricular dysfunction in Japanese patients with acute MI, and is, in addition, better tolerated than ACEI.

Background: Granulocyte-colony stimulating factor (G-CSF) affects injured arteries through early endothelialization. Some reports, however, have cautioned that the restenosis rate may increase after G-CSF injection. In the present study, high-dose G-CSF was administered to mice with vascular injury to clarify its effect., Methods and Results: Mice were received daily subcutaneous injections of saline or a high dose (300 microg/kg) of G-CSF for 5 days after vascular injury. In the FACS analysis, CD34-/Sca-1-positive progenitor cells were more abundant in the G-CSF group (p<0.05). Neointimal hyperplasia was more evident in the G-CSF group at 1 week (p<0.05), whereas at 4 weeks it was more evident in the control group (p<0.01). TUNEL-positive cells in the arterial wall were more numerous in the G-CSF group at day 1 (p<0.01). CD34-positive cells were observed in the G-CSF group at 1 week. Re-endothelialization appeared earlier in the G-CSF group (at 4 weeks; p<0.01). An increased number of 1A4-positive smooth muscle cells were found in bone marrow cell culture treated with G-CSF., Conclusion: High-dose G-CSF induced neointimal proliferation through excessive inflammation and bone marrow cell mobilization in the early phase. In the late phase, however, it induced early re-endothelialization and thereby inhibited neointimal hyperplasia.

Background: Tumor necrosis factor (TNF)-alpha is linked to the pathogenesis of cardiovascular diseases, but how it affects myocardial infarction (MI), so the present study examined the effects of TNF-alpha and the involvement of intercellular adhesion molecule (ICAM)-1 on MI., Methods and Results: Left coronary arteries of C57BL/6 wild type (WT) and TNF-alpha knockout (KO) mice were ligated and the mice were killed 1, 3, and 7 days later. Fractional shortening on echocardiography of the KO mice was significantly higher than that of the WT mice from day 1 to 7 (p<0.01). The ICAM-1 mRNA in the infarcted area of the KO mice was significantly lower than that of the WT from day 1 (p<0.01) to 7. In immunohistochemistry, the expression of ICAM-1 was weaker in the KO than in the WT mice. The number of neutrophils in the KO mice peaked at day 1, but even this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT. The number of macrophages in the KO mice peaked at day 7, but this peak level failed to reach the levels in the infarcted (p<0.01) and peri-infarcted areas (p<0.05) in the WT., Conclusion: In a permanent occlusion model of MI TNF-alpha decreased cardiac function and ameliorated myocardial remodeling through the induction of ICAM-1.

Background: Transthoracic epicardial ablation can be an alternative to conventional treatment for critical pathways of ventricular tachycardia located in the epicardium. However, the usefulness and safety of epicardial ablation close to the coronary arteries (CA) is not clear. The purpose of the present experimental animal study was to analyze the efficacy and safety of epicardial radiofrequency (RF) ablation close to the CA., Methods and Results: Of the left ventricle-epicardium ablated sites, 35 lesions (20 with cooling and 15 without cooling) were close to the CA (left anterior descending artery < or = 15 mm) and 33 lesions (23 with cooling and 10 without cooling) were further from the CA. For sites close to the CA, epicardial ablation was effective in 77% (15/20) with cooling and in 40% (6/15) without cooling. There was a significant difference of effective ablation between with cooling and without cooling (p < 0.05). For cooling, epicardial lesion size could be predicted by the change of endocardial ventricular potential using a basket catheter. No damage to major epicardial arteries was detected when the catheter tip was positioned 5 mm away from the CA., Conclusions: Close to the CA, RF ablation with cooling is more effective than RF without cooling and is safe if the ablation sites are located 5 mm away from the major CA.

Background: Although small dense low-density lipoprotein (sd-LDL) has an established association with diabetic dyslipidemia, previous studies have failed to show an association between sd-LDL and diabetes among coronary heart disease patients. This study investigated the prevalence of sd-LDL and abnormal glucose regulation in acute coronary syndrome (ACS)., Methods and Results: LDL size at the onset of ACS was measured by nondenatured gradient gel electrophoresis in 314 of 429 consecutive patients. Sd-LDL was prevalent in 54% of the patients, irrespective of the presence of previously known diabetes (50% vs 60% in nondiabetes and diabetes, respectively). Diabetes was present in 122 (28%) of the patients, and 110 patients without diabetes underwent an oral glucose tolerance test. Impaired glucose tolerance (IGT) and newly detected diabetes were found in as many as 44% and 22% of the patients tested, even though their hemoglobinA1c levels were in the normal range (5.3+/-0.5%). The prevalence of sd-LDL was significantly higher in patients with glucose intolerance than in those with normal glucose tolerance (61% vs 42%)., Conclusion: IGT and diabetes were far more common than normal glucose regulation in ACS patients, and the abnormal glycometabolism was closely associated with highly atherogenic sd-LDL.

Background: We investigated the mechanism of in-stent restenosis in radius stents in comparison to balloon-expandable stent (NIR stent) in pigs, with a focus on extracellular matrix (ECM)., Methods and Results: Radius (n = 4) or NIR (n = 4) stents were implanted in the left coronary arteries of miniature pigs. Quantitative coronary ultrasound (QCU) was performed before, immediately after, and at 1 and 4 weeks after the implantation. The stented-coronary arteries were harvested at 4 weeks after the implantation followed by immunohistochemical, histological, reverse transcription-polymerase chain reaction (RT-PCR) and real-time PCR studies. In QCU, mean luminal areas at 4 weeks did not differ between both groups, whereas the mean stent area and neointimal area were significantly greater in the radius (p < 0.01). The immunohistochemical study revealed a significantly decreased number of neointimal macrophages and neovascularizations (p < 0.05, p < 0.01, respectively), and a stronger expression of tenascin-C in the radius. The histological study showed a larger ECM area and less neointimal cell density in the radius than in the NIR. The RT-PCR and real-time PCR analysis revealed an enhanced expression of tanascin-C mRNA in the radius than in the NIR., Conclusions: Increased production of ECM, especially tenascin-C, played a greater role in the neointimal formation in the radius stent than inflammation.

Background: The Multicenter Automatic Defibrillator Implantation Trial (MADIT) II investigators concluded that prophylactic use of an implantable cardioverter defibrillator (ICD) improved survival in patients with prior myocardial infarction (MI) and reduced the left ventricular ejection fraction (LVEF). However, it is unclear whether MADIT II criteria for ICD implantation are appropriate for Japanese patients., Methods and Results: During the period 1997 to 2001 90 (M/F: 75/15; mean age: 65+/-9 years) of the 3,258 patients who underwent elective cardiac catheterization met MADIT II criteria (Q-wave MI more than 4 weeks prior; LVEF 21 years of age; electrophysiologic testing not required) and were selected in this retrospective study of patient prognosis after catheterization. During the 37+/-12-month follow-up period, 15 patients died of congestive heart failure (n=9), sudden cardiac death (n=2), acute MI (n=1), or noncardiac causes (n=3). The survival rate in the present series was comparable with that in the MADIT II defibrillator group, but higher than that in the MADIT II conventional therapy group. A significantly greater percentage of the present patients were found to be in New York Heart Association class I and have undergone percutaneous coronary intervention than in MADIT II., Conclusion: These results suggest that it may be inappropriate to apply MADIT II criteria to Japanese patients.

Background: Although the small dense low-density lipoprotein (sd-LDL) is associated with hypertriglyceridemia, more than 60% of myocardial infarction (MI) patients are normotriglyceridemic in the fasting state. This study was aimed to investigate the relationship between the low-density lipoprotein (LDL) phenotype and postprandial hyperlipemia (PPL) in MI patients., Methods and Results: Oral fat tolerance tests were performed in 71 patients with acute MI and fasting triglyceride concentrations below 200 mg/dl. Postprandial changes in the LDL particle diameter (LDL-PD) and lipids over a 6-h period after a meal were compared among 4 groups of patients classified according to fasting triglyceride levels (A, B as <150, and C, D as > or =150) and postprandial triglyceride levels (A, C as <230 and B, D as > or =230). Although fasting concentrations of triglyceride and remnant-like particle (RLP)-triglyceride were significantly higher in group C than in group B, the areas under the curves of the RLPs were significantly higher in group B. The triglyceride-to-cholesterol ratio in the RLPs was significantly higher in the PPL group than in the nonPPL group postprandially. The prevalence of sd-LDL (LDL-PD < or =25.5 nm) was significantly higher in group D but similar between groups B and C (23%, 42%, 50% and 83% in groups A, B, C and D, respectively)., Conclusion: These results suggest that postprandial accumulation of triglyceride-rich lipoproteins is strongly associated with sd-LDL in MI patients without hypertriglyceridemia.

A single nucleotide polymorphism of mitochondrial 5178A/C, causing a Met to Leu replacement within the NADH dehydrogenase subunit, is reported to be associated with longevity. The purpose of the present study was to assess the contribution of mitochondrial polymorphisms, particularly the 5178A/C genotype, to the susceptibility to acute myocardial infarction (AMI) in a Japanese study population. There were 4 groups: 150 patients with AMI, 150 with essential hypertension, 100 with diabetes mellitus, and 150 subjects matched for age and sex who served as the control group. Mitochondrial 5178A/C was detected by the polymerase chain reaction restriction fragment length polymorphism method. The allelic frequency of 5178C was significantly higher in the AMI group than in the control group, and this difference was more marked in younger patients. There were differences in allelic frequencies among the essential hypertension group, diabetes mellitus group and control group, but a higher frequency of the C allele was seen in the AMI group compared with the essential hypertension and diabetes mellitus groups. This particular polymorphism was found to be associated with development of AMI, especially in younger patients and constitutes a new risk factor for AMI.

Arteriosclerosis of the small arteries is one of the main causes of microvascular angina, and although some reports have shown favorable prognoses, there is progressive reduction in left ventricular function. The present study evaluated the prognosis of microvascular angina in 86 Japanese patients (51 women, 35 men; average age, 59+/-9 years) who had ischemic ST segment depression, normal coronary angiograms and small artery sclerosis confirmed by endomyocardial biopsies. The mean follow-up period was 7.2+/-3.4 years. Questionnaires regarding their symptoms, cardiac medication, and new events were sent to all patients. Eighty-five patients (98.9%) were still alive at the end of the follow-up period. Chest pain remained in 35.3%; the degree of pain was unchanged in 18.8%, and had lessened in 11.8%. None of the patients died of cardiac events or suffered from a myocardial infarction. At the end of the follow-up period, calcium antagonist was used in 63.5% of patients. Seventeen patients (20.0%) were free of antianginal medication. The prognosis of microvascular angina diagnosed by strict criteria was favorable.

This study assessed the contribution of polymorphisms of angiotensin II (AngII) receptors and bradykinin B2 (BK-B2) receptor to hypertension and acute myocardial infarction (AMI) in a Japanese population: 150 subjects with essential hypertension, 150 subjects with AMI with/without hypertension, and 150 healthy, age- and sex-matched controls. Polymorphisms of the AngII type 1 receptor (1166 A/C) and type 2 receptor (3123 C/A), and the BK-B2 receptor (-58T/C, exon 1) were analyzed and significant differences of genotypes and allelic frequencies in the AngII type 2 receptor C/A and BK-B2 receptor -58T/C were found between the essential hypertension and control subjects. Further, a significantly higher incidence of the C allele of the BK-B2 receptor was seen in AMI subjects with hypertension compared with those without hypertension. Genetic variations in the AngII and BK-B2 receptors could prove to be significant pathophysiological mechanisms affecting essential hypertension and AMI, and genetic differences appear to be a new risk factor for these conditions.

An implantable cardioverter defibrillator (ICD) was used in a 62-year-old man with dilated cardiomyopathy (DCM) because of hemodynamically intolerable ventricular tachycardia (VT). Amiodarone was administered after a second episode of ICD discharge. Three weeks later, incessant VT appeared, and DC discharge failed to terminate it. Microvolt T wave alternans (TWA), measured by a spectral method, was observed in this patient with and without amiodarone administration. The onset heart rate with TWA was lower and the alternans voltage was higher with amiodarone than without it. The effects of amiodarone appeared to be related to the exacerbation of VT and an increased defibrillation threshold. TWA might be useful in predicting the proarrhythmic effects of amiodarone in similar cases.

The present study investigated the mechanism of ventricular arrhythmias showing left bundle branch block (LBBB) pattern with an inferior axis. The effects of 3 drugs, adenosine triphosphate (ATP), nicorandil and verapamil, were evaluated in 17 patients. ATP suppressed the arrhythmias in 14 patients and nicorandil suppressed them in 8 of those 14. Verapamil suppressed 5 of the 6 ATP-nicorandil-sensitive arrhythmias. Four patients with ATP- or nicorandil-sensitive arrhythmias were not sensitive to verapamil. On the other hand, 3 of the ATP-insensitive arrhythmias were sensitive to neither nicorandil nor verapamil. The QT intervals and QTc were shortened by nicorandil in 5 of the 6 patients who were sensitive to all 3 drugs. One mechanism of suppression by nicorandil could be related to less Ca++ entering the myocardium, which would decrease the duration of the action potential as indicated by the shortened QT intervals. The results suggest that the mechanism of some ventricular arrhythmias is related to triggered activity. Arrhythmias that are sensitive to ATP or nicorandil, but not to verapamil, may be caused by abnormal automaticity. On the other hand, arrhythmias that are insensitive to all 3 drugs might be related to reentry. The features of ventricular arrhythmias with LBBB pattern and inferior axis differ and therefore the causative mechanisms are not the same.

Analysis of heart rate variability (HRV) can identify patients at risk of sudden cardiac death after myocardial infarction. The present study examined the effect of 2 weeks of supervised aerobic exercise training on the recovery of the autonomic nervous activity, exercise capacity, and cardiac output (CO) after coronary artery bypass grafting (CABG). Twenty-eight patients were randomly divided into the training group or the control group and performed exercise tests at 1 week, 3 weeks, 3 months, 6 months and 1 year after CABG. The HRV was measured, and the high-frequency component of HRV was used as an index of parasympathetic nerve activity (PNA); the plasma norepinephrine concentration (NE) was used as an index of sympathetic nervous activity. Cardiac output was also measured. In the training group, peak VO2, peak CO and PNA during exercise had improved at 3 weeks, but there was no improvement in these indices in the control group. NE decreased 1 week after CABG in both groups. These results indicate that physical training soon after CABG improves not only the exercise capacity, but also PNA.

The present study examined the genetic contribution of the human beta2 bradykinin receptor gene in Japanese subjects with essential hypertension, and identified a -58T/C polymorphism of the core promoter that might be responsible for essential hypertension in Japanese. The study consisted of 100 hypertensive subjects and 100 age- and sex-matched controls. The allelic frequencies were 0.575 for the C allele and 0.425 for the T allele in hypertensive subjects, and 0.465 for the C allele and 0.535 for the T allele in normotensive subjects. The allelic frequencies were in Hardy-Weinberg equilibrium. Significant differences between hypertensive and normotensive subjects were seen in the genotypes distribution (p=0.049) and allelic frequencies (p=0.028), and the beta2 bradykinin receptor gene variant was associated with human essential hypertension in this Japanese population. This new marker may provide a valuable tool for assessing the risk for putative bradykinin-associated common diseases, such as hypertension, and cardiovascular diseases with genetic determinism. These results suggest that the -58 polymorphism of the human beta2 bradykinin receptor gene is an independent risk factor for essential hypertension in the Japanese population.

The purpose of this study was to establish the safest way to bathe patients with myocardial infarction (MI) through measuring the hemodynamics during and after bathing. Seventy patients with MI were bathed supine in a Hubbard tank filled with 42 degrees C tap water for 5 min. The subjects were divided into 2 groups depending on their hemodynamic values 10 min after bathing: pulmonary capillary wedge pressure unchanged even after bathing (group A), and decreased pressure after bathing (group B). The left ventricular ejection fraction of group B was significantly higher than that of group A: 53.6% vs. 39.7%, respectively (p<0.01). The physical work capacity of group B was significantly higher at 5.6 METs, than that of group A with 4.5 METs (p<0.05). During the average of their 37-month follow-up period, there were 3 cardiac events in group B and 6 in group A. There were 2 cardiac events during bathing, both of which occurred in group A. When patients with MI take a bath, it is essential to closely monitor them, especially to those patients with lower cardiac function, because they have a higher possibility of a cardiac event.

Understanding the causes of syncope in patients with arrhythmia is important in determining the therapeutic interventions. Neurally mediated syncope (NMS) was evaluated in 55 patients with various arrhythmias. The head-up tilt test with or without isoproterenol infusion induced NMS in 41 (74%) patients. When these patients was categorized into 3 types, depending on the development of syncope, vasodilatation was significant in a majority of patients. In 46% of patients with tachyarrythmias, NMS was accompanied by an increase in extrasystole. It was concluded that the evaluation of vasodilatation is important for the preventive strategy of NMS in patients with arrhythmias and that NMS may induce arrhythmias.

Free radical generation was studied by the electron spin resonance (ESR) technique using alpha-phenyl N tert butyl nitrone (PBN) in a brief ischemia-reperfusion model of the canine heart, and correlated with biochemical changes of the sarcoplasmic reticulum (SR). ESR spectra (aH=0.3-0.4mT, aN=1.43-1.58mT) were observed as PBN spin adducts, which peaked at levels 5-fold above the control levels at 5 min after reperfusion. The simulated coupling constants of PBN spin adducts suggested that the sample should contain at least 2 carbon-centered radicals at 5 min after reperfusion (radical A: aH=0.350mT, aN=1.485mT; radical B: aH=0.370mT, aN=1.615 mT). At this time point, a significant reduction in Ca-ATPase activity of the SR was found without degradation of the major ATPase protein. Superoxide dismutase (SOD) significantly reduced the intensity of the PBN spin adduct signals and preserved the Ca-ATPase activity of the SR to 80% of the control level. Reperfusion injury after brief ischemia may be the result of inactivation of intracellular Ca-ATPase by free radicals generated during reperfusion, and SOD contributes to the protective effect by scavenging the radicals.

Left ventricular hypertrophy (LVH) is an adaptive change in response to hypertensive pressure overload. Some evidence indicates that the decrease in sarcoplasmic reticulum (SR) Ca2+-ATPase mRNA expression, which may contribute to a diastolic dysfunction of the heart, occurs in the experimental pressure overload model. Also, recent studies have demonstrated that angiotensin II (Ang II) and angiotensin II receptor type 1 (AT1) play important roles in LVH. The purpose of this study was to investigate the function of the SR and the role of AT1 in genetic hypertension in spontaneously hypertensive rats (SHR) at ages 10 and 18 weeks. In SHR, cardiac hypertrophy has already developed at 10 weeks of age. SR Ca2+-ATPase activity and mRNA expression were significantly lower in SHR than in Wistar-Kyoto rats (WKY). Plasma renin activity in SHR was unchanged compared with WKY, whereas the Ang II concentration in SHR was significantly higher than that in WKY. AT1 mRNA expression in SHR was similar to that in WKY. These results suggest that in the early stage of hypertension in SHR Ang II may stimulate hypertrophy in the cardiomyocytes through the AT1, which is not downregulated by a high concentration of Ang II.

The aim of this study was to clarify the role of the adenosine triphosphate (ATP)-sensitive potassium channel on the mechanism of ischemic preconditioning (IP). Thirty-five anesthetized dogs were divided into 5 groups: (1) Control (C), (2) IP, (3) intravenous infusion of nicorandil (Ni) prior to IP, (4) glibenclamide (G1) pretreated with IP (G1+IP), and (5) G1 pretreated with Ni (G1+Ni). All groups had 60 min ischemia followed by 60 min reperfusion, and were analyzed by biochemical and morphological procedures. At the end of the 60-min reperfusion, %segment shortening in C indicated paradoxical bulging. This value had significantly recovered in IP and Ni groups, but it was still negative in the G1+IP and G1+Ni groups. Ca++-ATPase activity of the sarcoplasmic reticulum (SR) was significantly decreased in C. In the IP and Ni groups, this activity was significantly maintained; however, in the G1+IP and G1+Ni groups it was similar to that in C. State 3 respiration of mitochondria showed similar changes in the SR. In the ultrastructural observations, severely damaged cells were not observed in the IP and Ni groups. These results indicated that an ATP-sensitive potassium channel opener enhanced the effects of IP and its blockade abolished these phenomena. It was conclude that the ATP-sensitive potassium channel may play a key role in the mechanism of IP.

A 31-year-old male with slow ventricular tachycardia (VT) developed a nonsustained VT with prolongation of the JT intervals after injection of contrast medium and saline into the marginal vein of the coronary sinus. The earliest activation site of the VT existed in the epicardium of the left ventricular base. Adenosine triphosphate prevented induction of VT and prolongation of JT intervals. Ventricular premature contractions showing the same morphology as the VT were also inhibited by nicorandil and verapamil. The mechanism of the VT was suggested to be abnormal automaticity due to an increase in the Ca++ current into cells after prolongation of the action potential duration induced by hypothermia.

Holter ECG was used to evaluate changes in heart rate variability (HRV), indicators of the autonomic nervous system, and arrhythmia before and after radiofrequency (RF) catheter ablation in patients with symptomatic supraventricular tachycardia. Ablation targets in 43 patients included the atrioventricular (AV) nodal pathway (AVNRT, n = 17), a right free wall accessory pathway (n = 10), a septal accessory pathway (n = 6), and a left free wall accessory pathway (n = 10). The High frequency component (0.15 - 0.40 Hz) or pNN50 of HRV analysis, indicating parasympathetic activity, significantly decreased immediately after RF ablation in the AVNRT and septal accessory pathway groups, but not in the right or left wall groups. In contrast, in all four groups, ventricular premature contractions (VPCs) significantly increased in most of the patients, and ventricular tachycardia occurred in a few of the patients immediately after RF ablation. There was no serious arrhythmia. These alterations in HRV analysis and arrhythmia returned to the control level after 1 week or more. VPCs after RF ablation did not consistently increase as a result of the reduced parasympathetic tone activity, but at the lesion near the conduction system, the increase in VPCs was inhibited by higher parasympathetic tone activity, because the parasympathetic nerve fibers and receptors were distributed in these lesions.

The purpose of this study was to determine the efficacy of long-term pharmacological therapy selected on the basis of a head-up tilt test (HUT) in patients in whom reproducibility of the HUT response was demonstrable in the initial study. The HUT (80 degrees upright) was performed for 15 min with or without an infusion of isoproterenol (0.01-0.03 microgram/kg per min) in 54 patients with recurrent unexplained syncope. When vasovagal syncope was induced (positive response), the HUT was repeated to examine the test reproducibility. Vasovagal syncope was induced in 24 patients during HUT alone, and in 30 patients during the HUT with isoproterenol. Acute reproducibility was observed in 49/54 (91%) patients. In the tilt-positive patients, HUT was repeated after an intravenous administration of propranolol (0.1 mg/kg) or disopyramide (1 mg/kg) (acute test). Propranolol proved effective in 21 (80%) of 26 patients, and disopyramide in 13 (56%) of 23 patients. Thereafter, evaluation was done on the long-term clinical follow-up of the pharmacological intervention selected on the basis of the acute test in the 34 patients in whom the HUT could not induce vasovagal syncope after the oral administration of the pharmacological agent (propranolol 60 mg/day, disopyramide 300 mg/day). Thirty-two of 34 patients (94%) did not develop syncopal attacks during a 44 +/- 12-month period. Thus, in patients with unexplained syncope, HUT appears to have a high degree of acute reproducibility, and the acute drug response guided by HUT may be used to develop an effective long-term pharmacological therapy.

The purpose of this study was to investigate the function of sarcoplasmic reticulum (SR) and the role of angiotensin II type 1 receptor (AT1) in ventricular remodeling in non-infarcted areas after myocardial infarction (MI). MI was produced in anesthetized Sprague-Dawley rats (10-12-weeks old) by ligation of the left anterior descending coronary artery. Four weeks after MI, hemodynamic measurements were performed. SR Ca2+-ATPase activity and mRNA (SERCA2a) and AT1 mRNA (AT1a, AT1b) were analyzed. Left ventricular end-diastolic pressure was higher and left ventricular dp/dt was significantly lower in the MI group. In non-infarcted areas in the MI group, myocardial transverse diameter was significantly greater and both Ca2+-ATPase activity in the SR and SERCA2a level decreased. The AT1a level was higher in non-infarcted areas than in controls, whereas the AT1b mRNA expression level was unchanged. These results suggest that, in the ventricular remodeling after MI, alterations in SR protein and its mRNA in non-infarcted myocardium help initiate heart failure and that Ca overload caused by the up-regulation of AT1a mRNA is an important cause of alteration in SR function.

We report a case of hypertrophic cardiomyopathy (HCM) with apical left ventricular aneurysm, which is difficult to review because cases are so rare. A 54-year-old Japanese man was first found to have an electrocardiographic abnormality (T-wave inversion at rest) 19 years ago, and non-obstructive apical HCM without identifiable cause was diagnosed by echocardiography, left ventriculography, and clinical findings. After 19 years, he was admitted because of repeated episodes of palpitation and chest oppression at rest. Widespread left ventricular hypertrophy from the anteroseptal wall to the apex with an apical left ventricular aneurysm was detected by echocardiography, left ventriculography, and cardiac magnetic resonance imaging. Histologic examination of the hypertrophic apical myocardium surrounding the aneurysm showed that the myocardial tissue had been extensively replaced by fibrous tissue containing hypertrophic myocardial fibers, and uptakes of [123I]-metaiodobenzyl guanidine (MIBG) and [123I-] beta-methyliodophenyl pentadecanoic acid (BMIPP) in single-photon emission photography images were reduced despite high myocardial perfusion. On the other hand, histologic examination of the hypertrophic anterior wall revealed myocardial hypertrophy with disorganization; myocardial perfusion and the uptakes of MIBG and BMIPP were preserved. Abnormalities of myocardial fatty acid metabolism and sympathetic neuron activity with preserved perfusion flow and histologic changes such as fibrosis in the apical wall are indicative of apical myocardial injury or ischemia (infarction) without coronary artery stenosis; apical aneurysm may have occurred in severe apical HCM with cavity obliteration up to the midventricular level.

We evaluated quantitatively the correlations between resting wall motion and regional myocardial blood flow (RMBF; at rest and during exercise) in infarct-related myocardium. The study was performed in 28 subjects: 21 patients who had previously suffered myocardial infarction of the anteroseptal wall, and 7 normal individuals. Positron emission tomography (PET) with [13N]ammonia was performed at rest and during low-grade exercise (bicycle ergometer fixed at 25 W for 6.5 min), and RMBF was measured quantitatively from the radioactivity in myocardial tissue and arterial blood. Resting regional wall motion was calculated using the centerline method on left ventriculographic findings. Resting regional wall motion was correlated with RMBF both at rest and during exercise in the infarct areas (anterior walls; y = 2.74 +/- 4.25 x 10(-2)x, r = 0.43, at rest; and y = -2.48 + 3.04 x 10(-2)x, r = 0.48, during exercise, p < 0.05; septal walls; y = -3.61 + 5.64 x 10(-2)x, r = 0.62, at rest; and y = -3.46 + 4.31 x 10(-2)x, r = 0.62, during exercise, p < 0.01). In each infarct-related wall, the coefficient (the slope) during exercise was smaller than that at rest (3.04 vs 4.25 and 4.31 vs 5.64 in each), and the infarct areas with preserved wall motion showed higher RMBF during exercise than those with reduced wall motion. Our results may show that wall motion depends on viable but ischemic myocardium in infarct-related walls.

The effects of adenosine triphosphate (ATP) on ventriculoatrial (VA) conduction were examined before and after accessory pathway (AP) ablation, with emphasis on assessment of the complication of dual atrioventricular (AV) node pathway. By evaluating the differences in the response to ATP of APs and other pathways, we assessed the usefulness and problems of this method. Of 59 patients who underwent AP ablation, 31 showed pre-excitation and 28 had concealed APs. A dual AV node pathway was found in 9 patients (15.3%) before ablation. After ablation, a dual AV node pathway was newly found in 9 patients. Thus, the total number of patients with a dual AV node pathway was 18 (30.5%). VA conduction over APs was not blocked in 26 of 29 patients, but the remaining 3 APs were blocked transiently by ATP. ATP caused VA block over the AV node in 15 of 16 patients and a dual AV node pathway in all 11 patients. In contrast, VA conduction over the retrograde fast pathway was blocked in 9 of 14 patients with AV node re-entrant tachycardia. ATP has little effect on APs, so observation of the response to ATP provides a more reliable and useful means of evaluating successful ablation. With this method, however, it is important to consider the possibility of the presence of ATP-sensitive APs and ATP-resistant retrograde fast pathways. The influence of ablation-induced injury has not been fully clarified. It is therefore essential to take into account various data, including the comparison between data obtained before and after ablation.

The protective effect and mechanism of action of the angiotensin-converting enzyme inhibitor (ACE-I) captopril was investigated in organelles from ischemic myocardial cells in a canine coronary ligation model. Sarcoplasmic reticulum (SR) and mitochondrial fractions were extracted from ischemic and nonischemic myocardial cells from captopril- and saline-treated (control) hearts. Heart rate, cardiac output, and right ventricular systolic blood pressure were similar in the captopril-treated and control groups. Left ventricular systolic blood pressure (LVPs) decreased gradually to 89% of the baseline value after captopril administration, and to 78% of the baseline value after ligation. Ca-ATPase activity in the SR, the respiratory control ratio (RCR) in the mitochondria, and dinitrophenol (DNP)-stimulated ATPase activity were significantly higher in ischemic myocardium from the captopril-treated group than from the saline-treated (control) group. The SH group content of both organelles was higher in the captopril-treated group. Our results suggest that, in addition to their hemodynamic effects, ACE-I agents containing SH groups protect the myocardium from ischemic damage by preventing enzyme oxidation.

Changes in myocardial lactate metabolism during ramp exercise were investigated through great cardiac vein catheterization in 15 patients with effort angina (EA) and 7 patients with microvascular angina (MVA). The exercise test was performed using a supine bicycle ergometer. Blood samples were obtained from the great cardiac vein (GCV) and the radial artery each minute during exercise. Patients in the EA group showed a point at which the lactate extraction ratio (LER) and the ST level decreased rapidly during exercise. This point was clearly recognized in 12 of 13 patients, and may represent the ischemic threshold. Both the LER and ST level showed similar changes during exercise, and these values were significantly different between the ischemic threshold and peak exercise (p < 0.01). Both the LER and ST level were strongly correlated with the duration of exercise until the threshold (r = 0.703). In the MVA group, both the LER and ST level during exercise continuously decreased throughout exercise without an ischemic threshold in all of the subjects. Endomyocardial biopsy revealed sclerosis of small arteries in the myocardium in all of the patients. In both effort angina and microvascular angina, a close correlation was noted between the change in ST and that in the myocardial lactate extraction ratio.

The optimum potential of the slow pathway (SP) was investigated by determining the effectiveness and safety of high-radiofrequency catheter ablation to treat atrioventricular nodal reentrant tachycardia (AVNRT). The subjects consisted of 29 patients with AVNRT (11 men, with a mean age of 54 +/- 15 years). Three ablation methods were used: a) Method A used the earliest atrial activation site, which is retrograde to the slow pathway, b) Method SP used the SP potential, and c) Method SW, in which ablation was performed stepwise starting from the coronary sinus and moving toward the recording site of the His bundle potential. Five, 20, and 4 patients underwent Methods A, SP, and SW, respectively. The fewest number of applications was needed with Method SP (11 +/- 9, 6 +/- 4, and 13 +/- 9), and the delivered energy was also lowest with Method SP (9151 +/- 6119, 3712 +/- 2168, and 12183 +/- 4090 J, with Methods A, SP, and SW, respectively). In Method SP, the interval between the atrium and SP was significantly longer at sites which cured tachycardia, than at sites at which ablation was ineffective (88 +/- 26 vs 66 +/- 22 msec, p < 0.05). The SP potential showed a humped shape in 18 of 20 patients. Method SP was the most efficient ablation method for treating AVNRT.

To study the mechanism of ventricular arrhythmias, the effect of dipyridamole (DIP; 300 mg/day), an adenosine transport inhibitor, on ventricular premature contractions (VPCs) was assessed in 12 patients who showed VPCs (21312 +/- 12314/day) on Holter ECG in a controlled setting. The effects were compared with those of verapamil (240 mg/day) and bisoprolol (5 mg/day). DIP suppressed more than one-half the VPCs in 5 patients. The mean degree of reduction in these DIP-responders was 75 +/- 18%. Both verapamil and bisoprolol inhibited VPCs in all of the DIP-responders (verapamil: 71 +/- 15%, bisoprolol: 88 +/- 16%). Two of the 5 DIP-responders had sustained ventricular tachycardias (VT) that were terminated by intravenous DIP, ATP, acetylcholine, verapamil, and propranolol. In contrast, verapamil did not inhibit VPCs in any of the DIP-nonresponders. Bisoprolol also did not suppress VPCs in 3 of 6 DIP-non responders. heart rate was unaffected by DIP, but was suppressed by both verapamil and bisoprolol. In addition, DIP increased the serum concentration of adenosine (control 16.3 +/- 17.1 vs 22.3 +/- 19.0 pmol/ml after DIP, p < 0.05). The inhibitory effect of DIP may involve suppression of Ca+2 current through an extracellular increase in adenosine.

The purpose of this study was to examine mitochondrial respiratory impairment in the diabetic heart. Diabetes mellitus was induced in male Wistar rats by intravenous injection of streptozotocin (STZ) for 2 to 16 weeks (Group D). In some of the diabetic rats, insulin was injected for 2 or 3 weeks prior to sacrifice (Group I). Fasting blood glucose was markedly elevated to greater than 300 mg/dl in Group D and was similar to normal glucose levels in Group I. At 2 weeks after STZ injection, state 3 was only 59.1% of that in the control. Complex I and complex V activities were also significantly reduced to 43.4% and 71.7% of those in the control, respectively. These reductions recovered with insulin treatment. This phenomenon persisted for 16 weeks. Morphological studies revealed swelling of the mitochondria and an increase in lipid droplets in diabetic cardiomyocytes, and these were also improved with insulin treatment. We conclude that in the diabetic heart, disturbance of energy production in cardiac mitochondria is generated by the impairment of oxidative phosphorylation due to depression of complex I and complex V. These changes may contribute the cardiac dysfunction that is a complication of diabetes mellitus.

We measured regional myocardial blood flow (RMBF) by positron emission tomography (PET) with 13N-ammonia at rest and during low-grade exercise using a bicycle ergometer fixed at 25 watts for 6.5 min. The ischemic area with severe coronary artery stenosis was evaluated in terms of quantitative RMBF. The study was performed in 46 subjects consisting of 19 patients with old myocardial infarction, 20 with effort angina pectoris, and 7 normal individuals. RMBF was calculated using the radioactivity in myocardial tissue measured by PET and the radioactivity in arterial blood. The PET data were compared with coronary arteriographic findings and ECG findings. When the analysis was restricted to the anterior wall of the myocardium, it was found that exercise caused RMBF to increase by 44.9% (n = 28) in normal area, to increase by 23.3% (n = 37) in severely stenotic area (stenosis > or = 90%), and to decrease by 17.4% (n = 20) in infarcted area. When we considered only the infarcted area of the entire heart, exercise caused RMBF to decrease by 26.6% (n = 30) in the area of angiographically positive collaterals, and to increase by 0.8% (n = 31) in the area of negative collaterals. Thus, we were able to quantitate the degree of ischemia in myocardium that was associated with severe coronary artery stenosis. By application of low-grade exercise, RMBF in normal myocardium increased, while RMBF in myocardium perfused by collaterals decreased.

To investigate the pathologic changes of the myocardium and the adverse effects of radiofrequency (RF) catheter ablation, we observed canine hearts that had been ablated by RF energy. Catheter ablation was administered to three sites of the hearts of 46 dogs: endomyocardium, coronary sinus, and atrioventricular junction. The dogs were sacrificed 0-12 weeks after ablation and the lesions were stained with hematoxylin-eosin and Azan stain. Each ablated lesion was well demarcated from the adjacent normal tissue. The margin between the ablated lesion and normal tissue became clearer with time. The lesions were hemispherical and measured about 2 to 10 mm in diameter and 1 to 6 mm in depth. Histologic examination in the acute phase demonstrated the presence of coagulation necrosis of the myocardium, interstitial hemorrhage and edema, followed by infiltration of inflammatory cells. Granulation tissue replaced the normal myocardium. In the chronic phase, the lesions became fibrotic and fatty. A mural thrombus was found in 30% of the cases of endomyocardial ablation and 50% of the right ventricular lesions were transmural. Ablated lesions in the coronary sinus extended to the left atrium and left ventricle. Obstruction of the coronary sinus was observed in 8% of the ablated dogs. Most of the lesions with complete atrioventricular block were ablated at the His penetrating region of the conduction system. Thus, since the ablated lesions were clearly delineated, catheter ablation using RF energy appears to eliminate only the target area.

We studied the relative synthetic phase (S-phase) ratio of cardiac myocytes of spontaneously hypertensive rats (SHR) utilizing monoclonal antibody to 5-bromo 2'-deoxyuridine (BrdU), a halogen derivative of thymidine. BrdU was administered intraperitoneally to SHR and Wistar Kyoto rats at 66.7 mg/kg/day for 3 consecutive days. The rats were sacrificed 1 week after the first injection of BrdU. Using anti-BrdU antibody, myocardial tissue was stained by the avidin biotinylated peroxidase complex method. We assessed the ability of the nuclei to synthesize DNA. The percentage of BrdU-labeled myocytes was higher in SHR than in control rats at 9 weeks. The hyperplastic phase of heart growth in rats was presumed to occur about 3 weeks after birth. From these results, the ability of the myocardial cell to synthesize DNA is probably enhanced under the load of high blood pressure in the early hypertrophic phase following hyperplasia.

Impairment of sarcolemmal permeability after the initiation of acute ischemic myocardial injury was studied using an ionic lanthanum (La3+) probe in electron microscopy. Acute ischemic myocardium was induced by ligation of the left anterior descending coronary artery in dogs. In normal cardiac myocytes La is localized exclusively in the extracellular space. i.e. on the glycocalyx, in the T-system and in intercalated discs, with normal fine structures. In ischemic myocardial cells, La deposits were found in the cytosolic space in 22% of subendocardial cells with mild to moderate, but non-necrotic, fine structural changes as early as 30 min. The number of myocytes with La deposition increased with advancing ischemic injury, and necrotic fine structural changes were recognized following ischemia for 60 min. These results indicate that deposition of La occurs before the appearance of irreversible morphologic alterations in ischemic myocardial cells, and suggest an increased permeability of the sarcolemma for Ca2+ and the development of degradation of plasma membrane integrity.

Reperfusion injury in early myocardial ischemia was studied in the dog with special reference to sarcoplasmic reticulum (SR) and contraction bands. Acute myocardial ischemia (I) was induced by occlusion of the left anterior descending coronary artery (LAD) for 10, 20 and 30 min followed by reperfusion for 15 min (R). Ca(++)-ATPase activity of SR in 10-min-R-Group was significantly reduced to 60% of control activity, but activity of 10-min-I-Group remained near the control level in subendomyocardium (Endo). ATPase activity in 30-min-I-Group diminished to 60% of control activity in Endo and it was similar for 30-min-R-Group. In ischemic myocardium, composition of major ATPase protein decreased significantly in 30-min-I-Group and similar reduction was observed in 20-min-R-Group in Endo. In morphology proportion of appearance of contraction bands in Endo was significantly increased in 20-min or longer-R-Groups. These results suggest that reperfusion injury is likely to occur when coronary artery is reflowed after 10 min of ischemia. This may be caused by increased intracellular Ca++ at a very early stage of reperfusion period, and reperfusion injury may be induced due to acceleration in the necrotic process of the membrane system in the myocytes during ischemia.

We studied alterations in respiratory activity of mitochondria (Mt) in non-infarcted myocardium (NIZ) under severe pump failure complicated by acute myocardial infarction (AMI). Dogs in which AMI was induced were divided into two groups; one in which left ventricular systolic pressure (LVPs) was maintained higher than 70% of preligation level (ND group); and one in which LVPs was diminished to less than 70% (D group). Regional myocardial blood flow (MBF) in NIZ reduced significantly in proportion to decreases in LVPs and cardiac output (CO). State -III activity and RCR decreased in proportion to reductions in MBF, LVPs, and CO in Mt from NIZ of D group. Complex-I and DNP-stimulated ATPase activities were also reduced in NIZ of D group. Morphologic studies revealed slight swelling and fusion of mitochondria in NIZ cells of D group, but no changes such as the appearance of a dense deposit indicating ischemic damage were seen. Pump failure in AMI is likely to be caused partly by impaired function of Mt in NIZ induced by hypoperfusion. Improvement of metabolic impairment in NIZ is important in the treatment of pump failure.

Activities and subcellular distributions of acid hydrolases, cathepsin D, acid phosphatase and beta-glucuronidase in myocardial subfractions were determined serially with reference to the initiation of myocardial necrosis in dog hearts with acute ischemia. The following results were obtained: 1) In the normal myocardium, respectable activities of three enzymes were obtained either in the sarcoplasmic reticulum or in the lysosome-containing fraction. 2) Thirty min after coronary ligation, an increase in the activities was observed in both lysosome and sarcoplasmic reticulum fractions of the ischemic heart muscle. After 60 to 90 min these activities were decreased rapidly in both fractions to about 70% of those of the normal myocardium with an increase in the cytosolic activity. Two to 3 hours after ligation, the reduction in the cytosolic activity was noted, indicating an escape of the enzymes from the necrotic myocardium. The subcellular distribution of these enzymes was further altered in the ischemic heart muscle for 12 to 14 hours reflecting an infiltration of the interstitial cells. These findings suggest that activation and release of acid hydrolases not only in lysosomes but also in the sarcoplasmic reticulum are one of the primary and the earliest factors for the evolution of ischemic myocardial injury which leads to necrosis.

Alterations in the phospholipid component of membranes were studied in acute myocardial ischemia with respect to sarcoplasmic reticulum (SR) and mitochondria (Mt) in the canine heart and compared with changes in the phospholipid composition of intact membrane treated with exogenous phospholipases (PLases) A2 and C, in order to examine the mechanism of ischemic degradation. As early as 30 min after coronary ligation, the total phospholipid content of SR and Mt decreased significantly, 16.0% and 5.6%, respectively. The patterns of SR and Mt phospholipids from the ischemic myocardia did not differ on the chromatograms from those of the non-ischemic myocardia, and no significant increases in lysophospholipids were found for up to 3 hrs. Among the components of phospholipids, phosphatidylcholine (PC) and phosphatidylethanolamine (PE) decreased mainly during ischemia, and depletion of PC exceeded that of PE in SR. PLase C hydrolysed phospholipids yielded no lysophospholipids, compared to the production of a large amount of lysophospholipids by PLase A2. It was concluded that degradation of membrane phospholipids occurs in the early stage of myocardial ischemia mainly in PC and PE, which are the major components of membrane phospholipids. This may be an expression of irreversible changes, and the activation of PLase C was considered to play an important role in their degradation.

1. Quantitative analysis of structural proteins from a minute amount of myocardial tissue was performed from 10 mu thick cardiac tissue slices weighing 2 to 5 mg by the extraction in glycerol solution and by sodium dodecylsulfate (SDS) gel electrophoresis, and these changes were compared with the histologic alterations in the striated structure of the adjacent cardiac slices in the experimental myocardial infarction in the dog. 2. Approximately 69 micrograms of structural proteins were obtained from 1 mg of the normal heart muscle. In the central portions of the myocardial infarction, reductions in myosin heavy chain (HC), light chain (LC) 1 and alpha-actinin were observed at 12 to 24 hours after the coronary occlusion followed by the decrease in myosin LC 2 at 48 hours. Those changes became intense at 72 hours to 7 days, but restored gradually at 14 to 28 days. 3. Alterations in the striated structure of cardiac muscle fibers of the adjacent tissues slices were found simultaneously with the changes in structural proteins. At 12 to 24 hours after the coronary ligation increase in eosinophilia and overstretch of cross-striation were observed. The findings of coagulation necrosis, loss of striation, fragmentation, swelling of A-band, etc. of the infarcted fibers were markedly observed at 48 hours to 7 days, but the histologic restoration of cardiac fibers was found with the recovery of the infarcted tissue at 14 to 28 days after the coronary ligation. 4. Changes in the compositions of structural proteins corresponded well to the alterations in the striated structure in chronology and in quantity.

1. Morphologic as well as biochemical alterations in chronic ischemic myocardial tissue without infarction were studied in dogs utilizing the Ameroid constrictor. 2. Serum creatine kinase activity elevated at around three weeks after placing the Ameroid constrictor around the circumflex branch of the left coronary artery suggestive of myocardial tissue injury followed by the initial activation caused by surgery. 3. Subendocardial proliferation of connective tissue was observed in about 60% of the experiments, but the middle and the subepicardial muscles were morphologically intact. 4. The marked increase in glycogen particles was observed in the subendocardial muscle cells in most of the experiments, and mild features of myocardial cellular necrosis were found in approximately 60% of the experiments. 5. ATPase activities of the structural proteins as well as sarcoplasmic reticulum in the ischemic myocardium shoed relatively higher values than those in the non-ischemic myocardium. However, no substructural changes were observed in SDS gel electrophoresis in both the fractions. 6. The alterations in the chronic myocardial ischemia are supposed to be essentially the same as those in myocardial necrosis followed by acute coronary occlusion.

The degradation of the sarcoplasmic reticulum (SR) in acute myocardial ischemia was studied with references to the regional irreversibility and to the mechanism of ischemic degradation by the measurements of Ca++-stimulated ATPase activity and composition of the major ATPase protein of the SR and activity of cathepsin B of the SR and lysosome (Ly) fractions. Ca++-stimulated ATPase activity decreased to 66% of that of the nonischemic portion at 20 min after coronary ligation in the subendocardium (Endo) and to 44% at 30 min in the subepicardium (Epi). Composition of the major ATPase protein decreased to 55% and 73% at 30 min in Endo and Epi, respectively. In both SR and Ly fractions cathepsin B exhibited the maximal activity at 6.0-6.5, and pH dependent. And incubation of the SR at pH 6.0 induced the degradation of the ATPase protein quite similarly to that in vivo ischemia. These results suggest that the degradation of the SR membrane of ischemic myocardial cells begins earlier in Endo 20 to 30 min after the cease of the coronary blood flow, and extends to Epi later. Cathepsin B is strongly conceivable to play an initial role of necrotic process of the ischemic myocardial cells by activation inside of the SR in ischemic acidic state.

We investigated the morphologic changes in the sarcoplasmic reticulum (SR) in acute myocardial ischemia, induced by occlusion of the coronary artery in the canine heart, by freeze-fracture of SR in situ and in vitro, and they were compared to the alterations in Ca++-stimulated ATPase activity and protein composition of the isolated SR. Both SR in situ and the isolated SR exhibited typical intramembranous particles with diameters of 70 to 90 A in freeze-fracture replicas. The intramembranous particle density of the P face in SR in situ was 3,319 +/- 75 (mean +/- SE) per micrometer2 and that in the isolated SR was 2,667 +/- 60; particles were more numerous on the concave (P) face than on the convex (E) face. In ischemia for 30 to 60 min a significant decrease in the number of particles was found in SR in situ, and the corresponding change was noted in the isolated SR. Simultaneous decreases in Ca++-stimulated ATPase activity and the major ATPase protein of the SR were recognized. The close correlation of the changing pattern between the reduction in Ca++-ATPase and that in intramembranous particle density during ischemia supports the suggestion that a large part of the intramembranous particles represent ATPase protein itself. Decrease in the SR membrane particles strongly suggests the degradation of ATPase protein in the process of ischemic myocardial injury.

Pharmacological protection of acute ischemic myocardial injury was studied using diltiazem, bunazosin, coenzyme-Q10 (Co-Q), and nicorandil, in dogs of which the left anterior descending coronary artery was ligated for 60 min. Drugs were given intravenously prior to and/or during coronary ligation. Co-Q, bunazosin and diltiazem suppressed degradation of sarcoplasmic reticulum (SR) expressed as inhibitions of reduction in Ca++-dependent ATPase activity and degradation of major ATPase protein. Fine structures of ischemic myocardial cells were simultaneously retained as well. On the contrary, the effects of nicorandil on ischemic myocardial injury were few. It is likely that protection of ischemic myocardial injury could be expected with drugs which react with ischemic myocardium directly and inhibit excess inflow of extracellular Ca++ in ischemic myocardium.

Ultracytochemical changes in ATPase activity of ischemic myocardial cells were studied in the dog heart by electron microscopy in the early stage of myocardial infarction and compared to the fine structural alterations in the ischemic myocardium. 1) In the normal myocardial cell, ATPase activity was observed intensely in the terminal cisternae (TC) of the sarcoplasmic reticulum (SR), and moderately in the myofilaments in the longitudinal SR and around the gap junctions of the intercalated discs. 2) The most striking change in the ischemic myocardial cells was the reduction in the ATPase reaction product in the TC of the SR and along the gap junctions 60 min after coronary ligation, simultaneously with swelling of the TC and the appearance of mitochondrial dense deposits. The reaction product began to decrease at 30 min on the myofilaments, and for 3 to 12 hours no reaction product was observed except irreversible morphologic changes in 60 to 70% of the longitudinal SR in the ischemic subendocardial cells. 3) A decrease in ATPase activity was recognized in the early stage of myocardial ischemia simultaneously with the fine structural changes of myocardial cells and it is considered to be one of the signs of ischemic irreversibility.

Ultrastructural and biochemical alterations in myofibrils (Mf) were studied in biopsied myocardial tissues in 11 patients with dilated cardiomyopathy (DCM) and compared with those in non-hypertrophic control and secondary hypertrophic (SHT) heart muscles. Transverse diameters of biopsied cardiac myocytes increased significantly in both of SHT and DCM, and ultrastructural changes were similar in quality in both of them. Volume densities of Mf were 61.1 and 59.9% on average in control and SHT myocardial cells, respectively, and they were not significantly different. But in DCM volume density was significantly less (49.8% in left ventricular myocytes), and inverse relation between that and diameter of cardiac myocytes was observed (p less than 0.01). Electrophoretic pattern and relative composition of major structural proteins from control and SHT heart muscles were similar and statistically insignificant. In DCM, relative contents of myosin heavy chain and alpha-actinin decreased significantly and distinctively in all of cases suggesting primary degradation of myofibrils.

Changes in the cardiac sarcolemma in myocardial infarction were studied by both determination of Na+-K+-ATPase activity and SDS gel electrophoretic analysis of sarcolemmal proteins in the canine heart. Ninety minutes after coronary ligation, Na+-K+-ATPase activity in ischemic myocardium was decreased significantly to approximately 36% of that of non-ischemic myocardium, and it remained at the lower level for 28 days. By SDS gel electrophoresis, reduction of the protein band with molecular weight of 111,000, which is suggestive of the main component of ATPase, was observed simultaneously with the reduction of Na+-K+-ATPase activity. These results indicate that ischemia for 90 minutes produces substructural changes in the sarcolemma indicating irreversible myocardial changes.