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The present study investigated whether regional ventricular dyskinesia (ie, systolic bulging) is a direct cause of ST-segment elevation in canine hearts in vivo. Regional ventricular dyskinesia was induced in 33 anesthetized open-chest dogs by injection of negative inotropic agents into the left anterior descending coronary artery (LAD) without disruption of coronary blood flow. Regional myocardial contraction was assessed in terms of the percent systolic shortening (%SS) and percent systolic bulging (%bulging), which were measured using ultrasonic crystals. The ST-segment elevation of the LAD-perfused area was measured with a unipolar electrode. Lidocaine, a sodium channel blocker, nicorandil, a potassium channel opener, propranolol, a beta-adrenergic blocker, or verapamil, a calcium channel blocker, was administered by intracoronary injection during maximal vasodilation induced by adenosine. All drugs induced dose-dependent ST-segment elevation in association with a parallel reduction in %SS and a parallel increase in %bulging. The absence of myocardial ischemia was confirmed by the absence of NADH fluorescence. It was concluded that regional ventricular dyskinesia had an important role in ST-segment elevation not associated with myocardial ischemia.

Iodine-123-labeled 15-(p-iodophenyl)-3-(R,S)-methyl pentadecanoic acid (123I-BMIPP) is widely used to detect myocardial metabolic changes, but the preferred energy substrates in the myocardium would be expected to be altered in the presence of metabolic disorders such as diabetes mellitus (DM). We investigated the metabolism of branched-chain fatty acids in the myocardium of rats with DM. Streptozotocin-induced DM rats were examined 48 h (acute; AD) and 6 weeks (chronic; CD) after injection of streptozotocin. Hearts were excised 15 min or 60 min after injection of 0.185 MBq of 125I-BMIPP, followed by homogenization in an EDTA-Tris buffer. The homogenates were subjected to differential centrifugation to obtain the mitochondrial (MF) and cytoplasmic (CF) fractions. Myocardial 125I uptake tended to increase in the AD group, but the change was not significant. Myocardial 125I uptake at 15 min was significantly lower in the CD group than in the control group, even in the insulin-treated rats [control (CC), 4.4±0.4; not treated (CDN), 3.3±0.5; insulin-treated (CDI), 3.4±0.4×104 cpm/g, p

Background Although both clinical and animal studies have shown that ischemic tolerance is reduced in the senescent myocardium, it has not been clarified when myocardium becomes more vulnerable to ischemia. Preconditioning protects the hearts of young adult animals of various species, but its effects are not identical in human studies. We investigated whether ischemic tolerance and the effect of preconditioning decreased in isolated hearts of middle-aged rats. Methods and Results The hearts of young adult rats (12 weeks old: group Y, n=44) and middle-aged rats (50 weeks old: group M, n=44) were subjected to global ischemia for 15, 20, or 25 minutes followed by reperfusion. Hearts were also subjected to preconditioning and then to 20 (group Y, n=22) or 15 (group M, n=22) minutes of ischemia followed by reperfusion. Left ventricular developed pressure (LVDP) was decreased by 40% to 60%, and the level of ATP was decreased by 60% to 70% in group M compared with group Y. Preconditioning increased LVDP (% LVDP, 40.5% to 72.4%) and levels of high-energy phosphates (ATP, 11.8 to 14.1; creatine phosphate, 17.0 to 23.1 μmol/g dry wt) and reduced left ventricular end-diastolic pressure (LVEDP, 32.8 to 10.3 mm Hg), creatine kinase release (257 to 132 U/g dry wt), and ryanodine-sensitive sarcoplasmic reticulum Ca 2+ release after ischemia in group Y. Preconditioning exerted opposite effects in group M (% LVDP, 45.9% to 15.8%; LVEDP, 21.0 to 28.5 mm Hg; ATP, 14.1 to 8.5 μmol/g dry wt; and CK release, 176 to 332 U/g dry wt). Preconditioning was associated with increases in the incidence of reperfusion-induced ventricular fibrillation (0% to 62.5%) and the rate of sarcoplasmic reticulum Ca 2+ release in group M. Conclusions These results indicate that hearts became more vulnerable to ischemia with age and that the beneficial effects of preconditioning were reversed in middle-aged rat hearts.

To clarify the roles of subclasses of alpha 1-adrenoreceptors in ischemic-reperfused myocardium, we compared the effect of the nonselective alpha 1-blocker bunazosin with that of the alpha 1A-blocker WB4101 and the alpha 1B-blocker chlorethylclonidine (CEC) in isolated rat hearts. After 30 min of preperfusion, Langendorff-perfused hearts were subjected to 25 min of global ischemia followed by 30 min of reperfusion. Hearts were randomly divided into 4 groups, with one of the following substances being added to the perfusate: buffer alone (control), 10(-6) mol/L bunazosin, 10(-7) mol/L WB4101, or 10(-7) mol/L CEC. Bunazosin had a negative inotropic effect and preserved the postischemic ATP content, reduced the postischemic increase in intracellular Na+ content and then enhanced postreperfusion recovery of creatine phosphate. Bunazosin also reduced myocardial 45Ca2+ uptake during reperfusion (control 5.2 vs bunazosin 2.5 mumol/g dry weight of tissue (dwt), p < 0.01). However, the recovery of left ventricular developed pressure (DP) was not improved when bunazosin was added to the perfusate during reperfusion. WB4101 had neither a negative inotropic nor an energy-sparing effect, but it improved the recovery of DP (control 43% vs WB4101 56% of preischemic value, p < 0.05) with no reduction in myocardial 45Ca2+ uptake. CEC had a negative inotropic and energy-sparing effect and then reduced myocardial 45Ca2+ uptake (CEC 3.1 mumol/g dwt, p < 0.05), but it did not improve the recovery of DP. These results suggest that the preischemic administration of an alpha 1B-adrenoreceptor subtype blocker protected ischemic-reperfused myocardium via reduction of Ca2+ overload, whereas the selective blockade of the alpha 1A-adrenoreceptor subtype reduced myocardial damage via mechanism(s) other than Ca2+ metabolism.

The purpose of this study was to evaluate ST-segment elevation induced by regional myocardial stretch without myocardial ischemia in canine hearts. A strain gauge arch (TH-601T) was sutured to the left ventricular epicardium, parallel to the short axis, to shorten the end-diastolic length of the myocardium beneath the arch (stretch zone; SZ) and to produce regional myocardial stretch in each of 6 dogs. An increase in preload caused by altering the height of a saline-filled reservoir affected prolongation or shortening of the myocardium both in the SZ and outside the arch (normal zone; NZ) to increase myocardial stretch. An epicardial electrocardiogam was recorded in both the SZ and the NZ. After suture of the strain gauge arch, the ST segment was elevated in the SZ. An increase in preload augmented stretch during systole in the SZ, resulting in additional ST-segment elevation. These results suggest that regional myocardial stretch itself plays an important role in ST-segment elevation. (Jpn Circ J 1997; 61: 921 - 926)

The effect of varying the number of preconditioning (PC) episodes on the recovery of cardiac function and on the function of the sarcoplasmic reticulum (SR) was investigated to determine the correlation between the effect of PC and SR function. Isolated rat hearts were subjected to zero to three 5-min episodes of global ischemia with intermittent perfusion (PC0-PC3) followed by 25 min of ischemia (I) and 30 min of reperfusion. The left ventricular (LV) pressure and SR 45Ca2+ uptake in the absence or presence of ryanodine were then measured. The increase in LV end-diastolic pressure and the incidence and duration of ventricular tachyarrhythmias during reperfusion decreased. The recovery of LV developed pressure, LV dP/dtmax and dP/dtmin, increased as the number of episodes of PC increased. The rates of SR 45Ca2+ uptake after PC and after reperfusion were lower in PC3 than in PC0. Conversely, the rate of 45Ca2+ uptake after I did not differ between PC0 and PC3. The ryanodine-sensitive Ca2+ release increased after I, and additional increases were observed during reperfusion in PC0, whereas the release after I and reperfusion decreased progressively in PC3. These observations show that the beneficial effects of PC are associated with a decrease in ryanodine-sensitive SR Ca2+ release.

With 2 μM methylisobutyl amiloride (MIA), an inhibitor of Na + /H + exchange, we tested the hypothesis that ion imbalance due to H + /Na + /Ca 2+ exchange exacerbates reperfusion injury and arrhythmias. Isolated rat hearts were subjected to 25-min global ischemia and 30-min reperfusion. In the MIA-treated group, MIA was added throughout the perfusion protocol. Left ventricular pressure (LVP), arrhythmias, myocardial Na + and K + content, 45 Ca 2+ uptake, and the levels of energy metabolites were analyzed. The recovery of LV developed pressure (LVDP) and + dP/dt and - dP/dt were improved in the MIA group (53 vs. 80, 71 vs. 86, 77 vs. 94% : each p < 0.05). MIA inhibited the increase in Na + content and the decrease in K + content that occurred at the end of the ischemic phase and reduced 45 Ca 2+ uptake after reperfusion (28.6 vs. 17.1, 248 vs. 296, 2.79 vs. 1.36 μM/g dry weight of tissue ; each p < 0.05). The incidence of ventricular tachycardia (VT) or ventricular fibrillation (VF) was lower in the MIA group [VT 11 of 20 (55%) vs. 4 of 20 (20%), p < 0.05 ; VF 13 of 20, (65%) vs. 6 of 20 (30%), 0.05 < p < 0.1], although the incidence of VF just escaped statistical significance. ATP level was higher in the MIA group after the ischemic phase and reperfusion (5.3 vs. 9.9, 12.3 vs. 14.7 μM/g dry weight of tissue ; each p < 0.05). Our results suggest that MIA reduced reperfusion arrhythmias and improved functional recovery in isolated rat hearts subjected to global ischemia apparently by preserving high-energy phosphates during ischemia and by inhibiting Na + /H + exchange, with attenuated cellular imbalance between Na + and Ca 2+ .

Objectives: We previously reported that a brief period of hypoxic perfusion (BHP) prior to ischemia in rat hearts improved functional recovery upon reperfusion with reduced Ca2+ overload. The present study was designed to determine whether the effect of BHP would be associated with a reduction in reperfusion arrhythmias and a preservation of function of the sarcoplasmic reticulum (SR). Methods: Hearts were subjected to 40 min of global ischemia and 30 min of reperfusion after a 20 min period of oxygenated perfusion (oxygenated group: OG), or a 10 min period of oxygenation and 10 min of hypoxic perfusion (hypoxic group: HG). We evaluated the release of Ca2+ by SR blocked by ryanodine, the recovery of left ventricular function, and the reperfusion induced ventricular tachycardia/fibrillation (VT/VF). Results: Functional recovery improved and the incidence and duration of reperfusion VT/VF were reduced in HG. In HG the uptake of Ca2+ in SR decreased during ischemia, but this decrease was less than that in OG. However, recovery of Ca2+ uptake after reperfusion did not differ between groups. The release of Ca2+ by SR blocked by ryanodine was inhibited in HG throughout the ischemia-reperfusion sequence. Conclusions: Observations suggest that the benefits of BHP on recovery of function and reperfusion arrhythmias were associated with a decrease in release of Ca2+ by SR blocked by ryanodine.

The purpose of this study was to examine whether initial acidic reperfusion after ischemia followed by stepwise normalization of perfusate pH could improve functional recovery and to assess whether this is associated with a reduction in Ca2+ overload. Isolated rat hearts were subjected to global ischemia for 25 min, followed by 30 min of reperfusion. In the control group (Group C), the perfusate pH was 7.4 throughout reperfusion. In the acidic groups, the perfusate pH was 6.8 for the first 5 min, 7.1 for the second 5 min, and 7.4 for the remainder of reperfusion. Acidic buffer was produced either by adding HCl (metabolic acidosis, Group MA) or by bubbling with gas containing 12 to 24% CO2 (respiratory acidosis, Group RA). The recovery of ventricular function, Ca2+ uptake, and energy metabolites were analyzed. Thirteen of the 15 hearts in Group C, 14 of the 15 in MA and 8 of the 15 in RA recovered regular cardiac rhythm at the end of reperfusion. In these hearts which exhibited normal rhythm, the percent recovery in developed pressure was higher (MA: 73 +/- 8, RA: 68 +/- 6, C: 51 +/- 5%, p < 0.05) and left ventricular end-diastolic pressure was lower (MA: 5.1 +/- 1.4, RA: 5.9 +/- 1.3, C: 14.2 +/- 2.7 mmHg, p < 0.05) in the acidic groups. The improved recovery was associated with a significant reduction in Ca2+ uptake which persisted with the restoration of normal pH. These results demonstrate that early acidic reperfusion enhances contractile recovery and diminishes Ca2+ overload. Moreover, these salutary effects are maintained after stepwise normalization of the perfusate pH to physiological values.

The elevation of aortic pressure increases myocardial oxygen consumption and increases the blood supply to the myocardium. It is not obvious whether elevated systemic arterial pressure would enhance or diminish myocardial protection during acute myocardial ischemia. This report reviews previously published data on the effects of aortic pressure elevation on the coronary pressure-flow relationship, and on the ischemic myocardium in the dog. The shift of the maximally-dilated coronary pressure-flow line to the right on the pressure-flow diagram is an indication of the deterioration of the oxygen supply/demand ratio caused by aortic pressure elevation. The only maneuver recognized for protecting the ischemic myocardium is early reperfusion. In patients with de novo acute myocardial ischemia, we propose that myocardial protection can be enhanced by reduction of systemic blood pressure until coronary reperfusion therapy is initiated.

A number of studies have been published which have attempted to define the electrocardiographic (ECG) changes with aging, but most of them were obtained from cross-sectional studies. To distinguish ECG changes related to physiological aging from those associated with arteriosclerosis, we assessed the ECG changes of 500 apparently healthy subjects, aged 60 years and older in 1992, who had been followed at the Keio Health Consulting Center for over 15 years. All subjects had no overt cardiovascular diseases in 1992. We compared the ECG in 1992 with that taken over 15 years ago. Changes in ECG during that period were also reviewed. With aging, the mean axis deviated to the left, the mean QTc interval was shortened, and the mean PR interval was prolonged. ST segmental change, atrial overloading, bundle branch block developed newly in 16%, 8% and 7% of, respectively. There were no relationships among axis deviation, PR interval change, or QTc shortening and coronary risk factors. QTc prolongation and ST segmental change were strongly related to hypertension or impaired glucose tolerance. When ECG changes in those under 65 years old were compared with those over 80 years old, the incidence of ST segmental change in those over 80 years old was significant higher. This study was not a prospective study but suggested each type of ECG change related to aging was affected by physiological and/or pathological factors in a distinct way and had different phases of development and progression.

A left ventricular (LV) thrombus grew rapidly over chronic endocarditis 2 months after anterior myocardial infarction. Echocardiograms demonstrated a rapidly growing LV thrombus an eventual obstruction. Despite anticoagulant/thrombolytic therapy, the patient died of acute LV failure. Histopathologically, a fresh thrombus overlay thickened endocardium with massive T lymphocyte infiltration over healed infarction.

Angiodysplasia is one cause of chronic gastrointestinal tract bleeding that can not be difficult to detect. In particular, angiodysplasia in the small intestine is very rare and has seldom been reported. An 80-year-old man complained of hematochezia and was admitted to other hospital on October 1991. However, no bleeding sites in the gastrointestinal tract could be revealed by radiographic and endoscopic examinations. After 8 months, he was admitted to our hospital with the same symptom on June 1992. He suffered hemorrhagic shock due to continuous bleeding. Hypotension and anemia progressed in spite of immediate blood transfusion. Emergency angiography revealed extravasation from a peripheral branch of the jejunal artery, in addition tortuous and dilated ileal arteries. Embolization was performed with the catheter inserted superselectively into the nearest arcade of the segmental branch of the vasa recta. After embolization, no complications were occurred. He was discharged and is being followed up as an outpatient.

The purpose of this study was 1) to clarify whether augmented myocardial contraction after a brief coronary occlusion, i.e. post-ischemic hypercontraction, depends on a transient increase in coronary blood flow or preceding myocardial ischemia, and 2) to identify the role of catecholamines or calcium flux in this phenomenon. Sixteen mongrel dogs were examined in open-chest anesthetized condition. One-minute reperfusion after two-minute total coronary occlusion of the left anterior descending artery resulted in a transient increase in segment shortening. Intracoronary administration of adenosine caused hyperemia without any changes in segment shortening. Two minutes of total coronary occlusion with adenosine caused post-ischemic hypercontraction to the same degree, but without any additional hyperemia. Two minutes of partial occlusion with 75% flow reduction caused less post-ischemic hypercontraction. Post-ischemic hypercontraction did not occur after partial occlusion with 50% flow reduction, irrespective of hyperemia with adenosine during reperfusion. Propranolol or verapamil did not prevent this phenomenon. Thus, post-ischemic hypercontraction is not dependent on the transient increase in coronary blood flow, but is related to the preceding myocardial ischemia. Local release of catecholamines is not likely to be the cause. A calcium antagonist, verapamil, did not modify this phenomenon. The precise mechanism of this phenomenon is still uncertain, although some alterations in cellular hemeostasis, such as ionic changes, are likely to be the cause.

Hypokinetic myocardial segment motion is observed in various pathophysiologic conditions. The aim of this study was to clarify the mechanisms involved in differences in segment motion of hypokinesis. Nineteen open-chest dogs were studied with regard to myocardial segment length, left ventricular pressure, and internal minor-axis diameter. Sequential instantaneous myocardial elastance [alpha(t) curve] was calculated under 4 different hypoxic conditions: complete coronary occlusion and reperfusion, partial coronary occlusion, coronary microembolization, and anoxic perfusion. The alpha(t) curve peaked at end-systole in the case of normal contraction; but it was almost totally flat when complete bulging occurred. The hypokinesis which occurred during development of the complete systolic bulge immediately after complete coronary occlusion had an earlier alpha(t) peak curve than the hypokinesis resulting from partial coronary stenosis (209.5 +/- 35.6 ms after end-diastole vs. 261.9 +/- 18.2 ms; p less than 0.02), microsphere injection into the coronary artery (243.2 +/- 24.5 ms vs. 289.3 +/- 15.4 ms; p less than 0.05), or anoxic perfusion (213.4 +/- 40.2 vs. 275.6 +/- 28.3 ms; p less than 0.05). The early alpha(t) peak resulted in a late-systolic bulge in segment length motion. In conclusion, hypokinetic segment motion differed depending on whether the coronary blood flow was present or not. A late-systolic bulge only developed immediately after complete coronary occlusion, and resulted from an abrupt decrease in myocardial stiffness during the cardiac cycle, which is closely related to the abrupt cessation of coronary blood flow.

A patient with malignant lymphoma suddenly collapsed, and ST segment elevation with complete atrioventricular block was observed on his electrocardiogram during an episode resembling acute myocardial infarction. Cardiac cineangiography revealed posterobasal asynergy of the left ventricle with no significant obstruction in the coronary arterial tree. Autopsy revealed diffuse invasion of the myocardium by lymphoma cells. Left ventricular wall motion was preserved even in the area of massive invasion; there was no true necrosis. Myocardial biopsy may be indicated in patients in whom there is a discrepancy between coronary pathoanatomy and wall motion abnormalities.

The venous blood flow in the great cardiac vein (GCV) was meas-ured with an ultrasonic transit-time flowmeter during brief occlusion of major branches of the coronary arteries in open-chest dogs. Occlusion of the right coronary artery did not affect GCV outflow. GCV outflow vanished when the left anterior descending artery (LAD) was occluded proximal to the bifurcation of the septal artery. When the LAD was occluded distal to the septal artery, the GCV flow reduction averaged 70%. Occlusion of the left circumflex artery resulted in a slight but significant decrease, followed by an increase in GCV outflow. Partial occlusion of the coronary sinus or GCV by a catheter resulted in a decrease in outflow. This suggests that the absolute value of coronary venous flow obtained by the thermodilution technique should be evaluated carefully.

Prostaglandins play important roles for oocyte maturation and follicular rupture. Cyclooxygenase-2 (COX-2), an inducible isoform of a prostaglandin metabolic enzyme, is essential for the timed production of prostaglandins in the ovary. The aim of the present study is to examine expression and distribution of COX-2 in human ovarian follicles at each of the maturation stages. Immunohistochemical staining shows that COX-2 is expressed in the granulosa cell layer of secondary and developing follicles, but is not detected in primary and Graafian follicles. Western blotting analysis revealed the existence of COX-2 in periovulatory follicular fluid at a mean concentration of 5.6 +/- 0.6 ng/ml. COX-2 might begin to be produced at the secondary follicle stage, and once a follicle reaches the Graafian follicle stage, the production of this enzyme is stopped. After exposure to luteinizing hormone (LH) surge, follicles might resume production of COX-2, and this is secreted into the follicular fluid.

Timely indication of surgical correction of aortic regurgitation (AR) depends on precise evaluation of left ventricular (LV) function. However, it may still be difficult to accurately predict surgical outcome with only currently available indexes of LV function. We undertook this study to obtain a novel index of LV function from altered LV fluid dynamics in patients with AR. AR flow is expected to cause definitive changes in intraventricular flow distributions. The degree of such changes may be mainly determined by the severity of regurgitation but variously affected by chamber size, diastolic property and filling pressure of the left ventricle. Therefore, our hypothesis is that the changes in the intraventricular fluid dynamics reflect LV function in patients with similar degrees of AR. We tested this hypothesis in patients with severe AR using the Doppler ultrasound technique and obtained a novel index for estimating LV function.

Regional transmural ischemia causes both ST-segment elevation and systolic elongation (bulging) of the myocardium. Mechanical stretch might alter the transmembrane potentioal via stretch-activated ion channels (SAC); however, the role of SAC on ischemic ST-segment elevation has not yet fully studied. The present study investigated the role of SAC in the genesis of ischemic ST-segment elevation in the in-vivo canine heart. In 6 anesthetized dogs, an extracorporeal conduit connected to the left anterior descending coronary artery was occluded for 5 min before and after the intracoronary infusion of gadolinium (Gd, 500 μmol/min). To eliminate the effect of ischemic preconditioning, the bypass was occluded for 5 min before the experiment. Percent systolic shortening (%SS) and percent systolic elongation (%bulging) were measured using a pair of ultrasonic dimension crystals. A unipolar epicardial ECG was monitored at the center of the ischemic area for the measurement of the ST-segment level. At the end of coronary occlusion, there was no difference in the reduction of %SS or the increase of %bulging between before and after infusion of Gd. ST-segment elevation, however, was significantly attenuated by the infusion of Gd. These data demonstrated that the activation of SAC is one cause of ischemic ST-segment elevation. (Jpn Circ J 1999; 63: 624 - 628)

The delayed outward rectifier K+ channel has a role in the increase in automaticity of myocytes under pathophysiological conditions. The purpose of the present study was to clarify the effect of blockade of outward recitifier K+ channels by a class III antiarrhythmic drug, E4031, on ischemia- and reperfusion-induced arrhythmias. Ion fluxes, energy metabolites and cardiac function were measured and the epicardial electrocardiograms of Langendorffperfused rat hearts were recorded during initial perfusion, global or regional ischemia and reperfusion. 10-7M of E4031 administered during the initial perfusion did not prolong the QT interval, but slowed the heart rate (Control: 222, E4031: 183bpm, p

Apical hypertrophic cardiomyopathy (apical HCM) has been believed to be a special type of hypertrophic cardiomyopathy. It usually occurs in middle-aged or elderly men and the prognosis is thought to be good. However, recent reports suggest that approximately 10% of middle-aged patients with apical HCM have cardiac events and poor outcomes. We studied electrocardiograms and echocardiograms, the occurrence of cardiac events, and clinical characteristics in elderly patients with apical HCM (13 men and 7 women, 61 to 95 years old, mean age 74 +/- 7). Three of 20 patients (15%) had cardiac events (sudden death, 1; heart failure, 1; chest pain, 1), 2 had cerebral infarction with atrial fibrillation, and 2 died of non-cardiac causes. There were no differences in age, sex, medication, complications, or in initial values of electrocardiographic or echocardiographic variables between patients who had and did not have cardiac events. However, left ventricular end-systolic dimension (LVEDs) and left atrial diameter at the time of the last evaluation were larger in patients who had cardiac events than in those who did not (26 vs. 34 mm, p = 0.019, 33 vs. 38 mm, p = 0.1325, respectively). These results suggest that the prognosis for patients with apical HCM is not necessarily good, and that enlargement of the LVEDs might be used to predict cardiac events in elderly patients with apical HCM.

To examine the relationship between apolipoprotein E (apoE) phenotype and life span, we measured the frequently of the apoE phenotype and allele in 54 Japanese centenarians who lived in the Tokyo metropolitan area in 1994, 1995, and 1996. The control group consisted of 973 subjects, 883 healthy volunteers who were described previously and 90 healthy people who came to the Keio health consulting center. The apoE phenotypes in the centenarians was 2 E2/E2 (3.7%), 5 E2/E3 (9.3%), 38 E3/E3 (70.4%), and 9 3E/E4 (16.7%). No other phenotype was observed. In the control group, the phenotypes were 2 E2/E2 (0.2%), 57 E2/E3 (5.9%) 712 E3/E3 (73.2%), and 179 E3/E4 (18.4%). The frequency of E2 was higher in the centenarians. The frequencies of the apoE allele in the centenarians and the control subjects were epsilon 2 8.3% vs. 3.5%, epsilon 3 83.3% vs. 85.4%, and epsilon 4 8.3% vs. 10.9%. The frequency of the apoE allele differed significantly between centenarians and control subjects (chi 2 = 6.84, p = 0.033). Levels of serum cholesterol and apolipoprotein B were significantly lower in the E2/E2 + E2/E3 centenarians. Studies of the frequency of the apoE allele in Japanese, French, and Finnish subjects showed that epsilon 2 is more frequent and epsilon 4 is less frequent in centenarians. These data show the apoE phenotype may affect life span: epsilon 2 is positively and epsilon 4 is negatively associated with longevity.

To study the relationship between lipids and longevity, we examined the level of serum lipids and apolipoproteins, and the susceptibility of low density lipoprotein (LDL) to oxidation of 45 centenarians (15 men, 30 women, mean age 101.1 +/- 1.4) living in the Tokyo metropolitan area. The average levels of total cholesterol (TC), of LDL-C of high-density lipoprotein cholesterol (HDL-C), and of apolipoproteins A1 and B were significantly lower in centenarians than in healthy middle-aged controls. The frequency of hypobeta-lipoproteinemia (apoB < 60 mg/dl) in centenarians was almost ten times as high as in controls. The time course of copper-mediated LDL, oxidation (assessed by monitoring 234 nm diene absorption (lag time)) did not significantly differ between the two groups. Analysis of LDL subfractions by non-denaturated gradient-gel electrophoresis showed a predominance of large, buoyant LDL particles (pattern A) in 75%, and a predominance of small dense LDL particles (pattern B) in 25% of centenarians. We also assessed activities of daily living (ADL) and cognitive function in the centenarians. Centenarians were divided into two groups according to the median ADL score, and were classified into five groups with a scale clinical dementia. In subjects with good ADL scores, the mean concentration of HDL-3-C was significantly higher than in those with poor ADL scores. Average levels of HDL-C were also significantly lower in subjects with moderate or severe dementia than in those with normal cognitive function. These findings suggest that centenarians have protective phenotypes of lipids and lipoproteins that protect them from atheroscierosis.

We studied carotid intima-media thickness at non-plaque sites and the occurrence of plaque in 25 centenarians (8 men and 17 women) living in Tokyo. The studies were done by B-mode ultrasonography and the results were compared with those found in 126 healthy subjects (83 men and 43 women) aged 28 to 82 years. The intima-media complexes were diffusely thickened in the centenarians; average thickness at bifurcations and at three sites in each common carotid artery ranged from 0.91 to 1.12 mm. The thickness was not associated with blood pressure or with serum lipid concentration. The thickness in the control group correlated with age, and that relationship fit a second degree equation. The expected values of mean intima-media thickness of the common carotid arteries at age 100 were computed with these equations; the predicted values ranged from 0.92 to 0.98 mm, which are close to the mean values measured in the centenarians (0.95 to 1.05 mm). However, the variations in intima-media thickness were greater in the centenarians. The prevalence of plaque in the centenarians was 40% for the right carotid artery and 36% for the left, but the prevalence among those in the eighth decade of life was 9.5% for both sides; plaque was not found among subjects in the sixth decade of life or younger. These data suggest that the degree of carotid arteriosclerosis is one factor that limits human longevity.

Protection of the ischemic myocardium by pretreatment with a high dose of 2,3-butanedione monoxime (BDM) is attributed to the enhancement of glycolytic ATP production rather than to the inhibition of contracture during mild ischemia. Our objective was to investigate whether the inhibition of contracture would protect the arrested heart during prolonged ischemia. Isolated perfused rat hearts were subjected to 30 min of low-flow ischemia followed by reperfusion. Ischemic hearts were treated with BDM (5 mmol/l) after beating stopped. BDM ameliorated the increase in intraventricular pressure after ischemia without significant changes in ATP levels and with a decreased accumulation of lactate. BDM treatment accelerated the recovery of function and high-energy phosphates with reduced myocardial Ca2+ overload. The results of this study suggested that inhibition of contracture can protect the heart from ischemia-reperfusion injury.

This study was designed for the purpose of investigating the factors for longevity in the Tokyo metropolitan area. At first, we examined the social and physical background of centenarians by direct mail in 1992. A total of 398 questionnaires (from 81 males and 308 females) were returned. There was a significant gender difference in mobility, with 38% of males and 10% of females being able to take a walk. However 19% of male centenarians and 28% of female ones were bedridden. Hypertension, respiratory disease and heart disease were found in 22%, 16%, 16%, without any significant gender differences. On the contrary, there were more female centenarians with past histories of bone fracture (34%) than male (10%). This discrepancy suggest that bone fracture may be one of the factors causing the gender differences in mobility. Those who had a high level of education were more frequent in centenarians (27% of males and 8% of females) than in the general population of their contemporaries in Japan (less than 2%). The average age at death of the centenarians' parents was 69.6 +/- 15.7 y/o for their father and 71.2 +/- 17.2 y/o for their mother. These ages were significantly higher than the average life-span in the last decade of the 19th century, according to the First Life Tables in Japan. The possibility is suggested that longevity was inherited in these centenarians' families.

Objectives: Protons produced during ischemia may increase intracellular Na+ (Na+i) through Na+/H+ exchange, and may lead to Ca2+ overload through Na+/Ca2+ exchange to cause myocardial stunning. This study investigated whether an increase in the H+ buffering capacity of the perfusate or a reduction of H+ production by a brief hypoxic preperfusion before ischemia would reduce myocardial stunning. We also investigated whether the protective effect of these maneuvers depends on the free [Ca2+] of the perfusate. Methods: Isolated rat hearts were preperfused with oxygenated or hypoxic buffer (pH 7.4) containing 100 mM of either sucrose or HEPES for 10 min, followed by 15 min of total ischemia and 30 min of reperfusion. To investigate the dependence of the effects of HEPES or a brief hypoxic preperfusion, the free Ca2+ concentration in the buffer was changed from 1.25 mM to 2.5 mM in some hearts. Results: Oxygenated preperfusion with buffer containing HEPES and 1.25 or 2.5 mM Ca2+ improved the metabolic and functional recovery with a decrease in the accumulation of Na+ i during ischemia and in 45Ca2+ uptake during re-perfusion. A brief hypoxic preperfusion with 1.25 mM Ca2+ provided a similar protective effect whereas no protective effect was observed when the [Ca2+] was raised to 2.5 mM. Conclusions: An increase in the H+ buffering capacity or a brief hypoxic pre-perfusion reduced myocardial stunning with improved metabolic recovery, and reduced Ca2+ uptake. However, the effects of these interventions were affected differently by the free [Ca2+] of the perfusate, which suggests that they work, at least in part, through some different mechanism(s).

This study was designed to determine the sequential changes in sympatho-neuronal regulation and contractile function of hearts exposed to volume overloading. Aortic regurgitation was produced by perforation of the aortic valve in 20 rabbits. Another 20 rabbits underwent sham operation. They were randomly assigned to a 1-day group, a 1-week group, and a 4-week group. Haemodynamics, myocardial beta-adrenoceptor binding number and catecholamines were measured in each period after production of aortic regurgitation. Left ventricular end-diastolic pressure increased and cardiac output decreased progressively over the week following production of aortic regurgitation, but they returned towards normal during the subsequent 3 weeks. Left ventricular free wall thickness increased 4 weeks after production of aortic regurgitation, and plasma norepinephrine increased 1 day after the procedure. Maximal binding sites of myocardial beta-adrenoceptors (125I-iodocyanopindolol) were decreased 1 day and 1 week after production of aortic regurgitation. Myocardial norepinephrine was also reduced. After 4 weeks, both beta-adrenoceptor binding sites and myocardial norepinephrine content were restored. Alterations in sympatho-neuronal regulation are related to the compensatory processes in volume overloaded hearts.

BACKGROUND The purpose of this study was to clarify whether sympathetic denervation occurs in the infarcted heart and contributes to the dispersion of the effective refractory period (ERP) and arrhythmogenesis. METHODS ERP was measured at 47 epicardial sites in 13 dogs with 7-day-old infarctions after proximal ligation of the left anterior descending artery. To delineate the sympathetic innervation, the effects of ansae subclaviae stimulation (ASS), norepinephrine infusion, and prazosin infusion on ERP were tested. RESULTS The per cent change in ERP (delta ERP) induced by ASS was significantly lower at test sites where the surviving epicardial myocardial thickness (Th) was 2 mm or less than at those with a Th of more than 2 mm and the normal zone. Eleven out of 179 sites (6.1%) overlying the infarct showed no ERP change after ASS. ASS paradoxically prolonged ERP at 29 sites (16.2%). In contrast, norepinephrine infusion produced a greater delta ERP in the infarct zone than in the normal zone. Prazosin shortened ERP at sites where ASS prolonged it, but had no effect at sites where ASS shortened ERP. ASS increased both the degree of ERP dispersion and inducibility of ventricular tachycardias or ventricular fibrillation (VT/VF), whereas norepinephrine increased VT/VF inducibility despite a reduction in ERP dispersion. CONCLUSIONS We conclude that heterogeneous sympathetic denervation contributed to a prolongation and dispersion of ERP in the surviving epicardium overlying the infarct. Furthermore, a supersensitive response to norepinephrine with resultant ERP shortening and a paradoxical ERP prolongation during ASS caused by alpha-receptor mechanisms that may be related to increased electrical instability were observed.

The author assessed the physiological aging parameters of 38 apparently healthy subjects who were over 80 years old 1989, who were not on medication, and who had consulted with the Keio Health Counseling Center over 10 years. All subjects had no history of overt vascular disease and/or malignancy in 1989. In 17 of 38 subjects, physical, hematological and blood chemical parameters when they were in their 70s were analyzed. Many parameters were unchanged and remained within normal limits for ordinary adults. Cataract, atherosclerotic change of optic fundi and diagonal ear lobe creases were seen in all subjects during the study period. Concerning standard deviations, those of forced expiratory volume in one second/predicted vital capacity and pure tone average (acoustic ability) decreased with age, unlike those of other parameters. Furthermore, multiple regression analysis, revealed that serum albumin decreased but pure tone average, Scheie's atherosclerotic score, senile cataract, HDL-cholesterol blood urea nitrogen and forced expiratory volume in one second/predicted vital capacity increased with age. This study was not cohort study with selected subjects but shows very slight change of almost any parameter irrespective of age and abnormality can suggest the existence of disease.

The purpose of this study was to clarify the role of calcium flux in the pathogenesis of transient overshoot in regional myocardial contractile function after brief ischemia (post-ischemic hypercontraction). Six open-chest anesthetized dogs were examined. The left anterior descending coronary artery (LAD) was cannulated with a bypass system from the left carotid artery. Two minutes of total coronary occlusion of the LAD resulted in a post-ischemic hypercontraction 1 minute after reperfusion. Post-ischemic hypercontraction was abolished after reperfusion following 2 minutes of perfusion with anoxic Krebs-Henseleit solution containing 2.5 mM calcium. Post-ischemic hypercontraction occurred after calcium-free anoxic perfusion. The regional myocardial contractile function remained depressed 1 minute after reperfusion following anoxic perfusion with 5.0 mM calcium solution. Thus, post-ischemic hypercontraction was modified by the calcium concentration during anoxia. Alteration in transsarcolemmal calcium influx during reperfusion, which was modified by alterations in the calcium environment during anoxia, could be responsible for this phenomenon.

The effects of elevated aortic pressure on the pressure-flow (P/F) relationship below the pressure range of autoregulation were investigated. The effects of myocardial contraction dysfunction on coronary blood flow were also studied. In eight dogs, the left anterior descending coronary artery (LAD) was perfused by a bypass circuit from the subclavian artery. Coronary perfusion pressure (CPP) was reduced by mechanical stenosis of the bypass tube. Aortic pressure (AoP) was elevated by aortic banding. The heart rate was kept constant by SA block and pacing. Bypass flow (CoF), myocardial shortening (%SS) of the LAD region, and instantaneous diastolic P/F relation were obtained at each CPP and AoP level. When the stenosis was mild (CPP > 60 mmHg), CoF was increased by 1.2 ml/min by 10 mmHg elevation of AoP, but when the stenosis was severe (CPP < 50mmHg), CoF was reduced by 2.0ml/min by AoP elevation. The slope of P/F relation was reduced by the elevation of AoP in mild stenosis. In severe stenosis, AoP elevation increased the zero flow pressure (Pzf) and did not change the slope of the P/F relation. The %SS was significantly reduced with a rise of AoP only in severe stenosis. In five other dogs, phasic LAD flow was measured, using an ultrasonic transit time flowmeter just below the first diagonal branch. The branch was cannulated proximally to infuse adenosine (500μg/min) into the LAD to obtain maximal vasodilation. Lidocaine (0.5–4 mg) was injected into the LAD to alter the regional myocardial contraction.

Objective: The aim was to identify the role of calcium flux in the pathogenesis of transient overshoot of regional myocardial contraction after brief ischaemia, ie, postischaemic hypercontraction. Methods: Ten anaesthetised mongrel dogs were examined under open chest conditions. The left anterior descending coronary artery was initially occluded for 2 min and reperfused for 10 min. A further period of coronary occlusion of 15 min duration was followed by 15 min reperfusion to produce postischaemic regional dysfunction. A third occlusion of 2 min duration was followed by 10 min reperfusion to induce postischaemic hypercontraction. Coronary blood flow was measured using an ultrasonic transit time flow meter. Segment length was measured by ultrasonic microcrystals. Results: Postischaemic hypercontraction after 2 min coronary occlusion was exaggerated in ischaemically injured myocardium. The 10 dogs were divided into two groups, a control group (n=5) and a verapamil treated group (n=5), and were exposed to a final 2 min period of coronary occlusion with or without verapamil in the ischaemically injured myocardium. Postischaemic hypercontraction was attenuated in the verapamil treated group compared with the control group. Conclusions: Exaggeration of postischaemic hypercontraction in ischaemically injured myocardium may be mediated by a trans-sarcolemmal calcium flux. Changes in calcium flux may play a role in the pathogenesis of this phenomenon in the normal myocardium.

There is some controversy regarding the mechanisms of an upward shift in the left ventricular diastolic pressure-volume curve during ischemia. The effects of handgrip exercise on the pressure-volume curve were examined in 21 patients with coronary artery disease and in 6 control subjects. Pressure-volume curves were constructed from digitized left ventricular pressure and volume derived from biplane left ventriculogram. Diastolic pressure-volume curve shifted upward in 12 patients with coronary artery disease during handgrip exercise (Group 1), but not in the other 9 patients who were similarly afflicted (Group 2). The upward shift did not occur in any control subject. No difference was observed in rate-pressure product gain during exercise. In Group 1, left ventricular end-diastolic pressure increased (p less than 0.01) and ejection fraction was reduced (p less than 0.01), although it did not change in Group 2. In Group 1, the time constant was prolonged (p less than 0.01) with no change in the coefficient for elastic modulus. In Group 2, these parameters remained unchanged. Group 1 was accompanied by more extensive asynergy than Group 2. Thus, isometric handgrip exercise resulted in an upward shift in the diastolic pressure-volume curve in patients with coronary artery disease. Incomplete relaxation and/or the viscoelastic properties of the left ventricle associated with ischemia could be responsible for this phenomenon.

Study objective – To identify propensity to re-entry in a canine model of 7 day old myocardial infarction, the sensitivity and specificity of five indices of dispersion of refractoriness (ERP) were investigated. Design – With an epicardial patch electrode containing 47 electrodes, ERP was measured by S1-S2 method at each site overlying the infarct, ERP range, maximum adjacent dispersion, difference between mean ERPS of the infarct and normal zones, standard deviation (σ) of the mean ERP, and σ/mean ERP × 100 were calculated. Experimental material – 42 dogs were divided into three groups; 20 dogs with epicardial functional block on induction of sustained ventricular tachycardia or fibrillation, 10 dogs with inducible ventricular tachycardia or fibrillation but without epicardial functional block, and 12 control dogs without ventricular tachycardia, fibrillation or block. Measurements and main results – All five indices were significantly greater in the 20 dogs with ventricular tachycardia or fibrillation than in control dogs. A receiver operating characteristic curve analysis of the five indices showed that σ was the most sensitive and specific index for discriminating these 20 dogs. The sensitivity and specificity of a σ value greater than 14 ms (the mean value plus two SD of the control dogs) were 70% and 100%, respectively. Conclusions – The σ of the mean ERP at multiple sites could serve as a quantitative index for determining ERP dispersion.

The effects of endothelin-1 (ET-1), applied topically on the epicardium, on the coronary microcirculation of the beating canine heart were investigated in situ. ET-1 (1, 10, 100, and 1,000 pmol) induced a dose-dependent elevation of the ST segment in the epicardial ECG (n = 5). After application of ET-1 (100 pmol), the beating hearts were rapidly cross-sectioned and freeze-clamped in 120 ms using a specially developed device (n = 6). By NADH fluorescence photography of the cross-sectioned frozen sample, an increased fluorescent area in the subepicardium was clearly observable. The fluorescent dye injected from the left atrium was negative in the NADH fluorescent area. It can be concluded that ET-1, when administered extravascularly, induces severe vasoconstriction and myocardial ischemia in the microcirculation of the beating canine heart.

Study objective – The aim was to determine the site of coronary vasoconstriction induced by endothelin, by investigating the response in terms of retrograde pressure and reactive hyperaemia. Experimental material – Twelve anaesthetised mongrel dogs, 12-14 kg, were used for the studies. Design – The left anterior descending coronary artery was cannulated and perfused with blood through an extracorporeal bypass. The effects of intracoronary endothelin-l (1-500 pmol) on coronary blood flow, coronary flow reserve (the peak reactive flow and the repayment after 15 s coronary occlusion), and retrograde coronary pressure during coronary occlusion were studied (n=7). The retrograde coronary flow was collected from the bypass at each dose (n=5). Measurements and main results – At doses of greater than 20 pmol the coronary flow decreased dose dependently and reached almost zero flow at 500 pmol. The coronary flow reserve also decreased; however, the retrograde pressure was raised dose dependently at doses of greater than 10 pmol. At a dose of 500 pmol, the retrograde pressure was increased to 61 mm Hg [82(SEM 12)% of the coronary perfusion pressure]. Retrograde flow remained unchanged throughout the experiment. Conclusions – The endothelin-1 induced rise in retrograde pressure is in accordance with a dose dependent reduction in coronary flow reserve, and collateral flow was not augmented by endothelin. It is concluded that the effect of endothelin-1 on coronary circulation in situ was mainly due to the constriction of small resistant vessels.

A filtered QRS (fQRS) was recorded by signal averaging in 7-day-old myocardial infarction (MI) in dogs to detect late potential (LP). The criteria for the LP included a duration of fQRS (D) greater than or equal to 60 msec and a voltage in the last 15 msec (V15) less than or equal to 10 microV. These parameters were determined from the control data from 15 dogs without infarction (D: 45 to 60 msec and V15: 12.0 to 83.6 microV). On the seventh day of infarction, the D had increased from 53.5 +/- 4.7 to 62.2 +/- 9.6 msec (P less than 0.05) and the V15 decreased from 38.6 +/- 19.5 to 18.4 +/- 16.0 microV (P less than 0.01). Of 23 dogs, 14 met the LP criteria (group A) and 9 did not (group B). Sustained ventricular tachycardia (SVT) was induced in 12 group A dogs and in none of the group B dogs. The delayed epicardial activation (DEA) was recorded after the end of QRS at 5.1 +/- 4.7 sites in group A dogs and 1.3 +/- 1.8 sites in group B dogs (P less than 0.05). The maximum value of epicardial activation time was more prolonged in group A than in group B (70.0 +/- 28.3 vs 44.4 +/- 9.8 msec, P less than 0.01). The area of MI was more extensive in dogs with DEA than those without (24.9 +/- 5.8% vs 10.3 +/- 9.0% of the total left ventricular weight, P less than 0.01). In 72 of 90 sites with DEA, the thickness of the surviving epicardial muscle was less than or equal to 1 mm. The sensitivity and specificity of the criteria for LP in detecting DEA were 71.4% and 55.6%, and 100% and 81.8% for predicting inducibility of SVT. It was thus concluded that LP, reflected the DEA, was identified from infarct areas of slow conduction within a reentry circuit of SVT.