Mitsuo Matsuda

Quantitative analysis of narrowings of intramyocardial small arteries in normal hearts, hypertensive hearts, and hearts with hypertrophic cardiomyopathy.

To clarify the pathophysiologic role of intramyocardial small artery (IMSA) diseases in hypertrophied hearts, narrowings of the IMSA were quantitatively evaluated in 39 autopsied hearts, 10 from patients with typical hypertrophic cardiomyopathy (HCM), four from patients with HCM showing features mimicking dilated cardiomyopathy (DCM-like HCM), 10 from patients with hypertension, and 15 from normal adults. The relations of narrowings of the IMSA to myocytic hypertrophy, myocardial fiber disarray, and fibrosis were also examined. The external caliber and the ratio of the luminal area to the total vascular area (percent luminal area, % lumen) were calculated by an image analyzer in 85 to 203 IMSAs from each patient. The external calibers of the IMSAs were similar among groups of hearts with HCM, hypertensive hearts, and normal hearts but were greater in those with DCM-like HCM. The mean % lumen of the IMSAs was similarly reduced in the hearts with HCM (29 +/- 5% in the ventricular septum and 31 +/- 5% in the left ventricular free wall) and in hypertensive hearts (30 +/- 8% and 31 +/- 7%) compared with that in normal hearts (40 +/- 5% and 38 +/- 5%) and was the lowest in the ventricular septum of hearts with DCM-like HCM (17 +/- 3%). The mean % lumen of the IMSA was inversely correlated with heart weight (r = -.59), the mean size of myocytes (r = -.66 in the ventricular septum, r = -.63 in the free wall), and percent fibrotic area in the septum (r = -.68). The mean % lumen values of the IMSAs in the tissues with and without disarray in the hearts with HCM were similar. Thus IMSA disease is of pathophysiologic importance in patients with HCM, DCM-like HCM in particular, or with hypertension.

Effects of exercise training of 8 weeks and detraining on plasma levels of endothelium-derived factors, endothelin-1 and nitric oxide, in healthy young humans.

Vascular endothelial cells produce nitric oxide (NO), which is a potent vasodilator substance and has been proposed as having antiatherosclerotic property. Vascular endothelial cells also produce endothelin-1 (ET-1), which is a potent vasoconstrictor peptide and has potent proliferating activity on vascular smooth muscle cells. Therefore, ET-1 has been implicated in the progression of atheromatous vascular disease. Because exercise training has been reported to produce an alteration in the function of vascular endothelial cells in animals, we hypothesized that exercise training influences the production of NO and ET-1 in humans. The purpose of the present study was to examine whether chronic exercise could influence the plasma levels of NO (measured as the stable end product of NO, i.e., nitrite/nitrate [NOx]) and ET-1 in humans. Eight healthy young subjects (20.3 +/- 0.5 yr old) participated in the study and exercised by cycling on a leg ergometer (70% VO2max for 1 hour, 3-4 days/week) for 8 weeks. Venous plasma concentrations of NOx and ET-1 were measured before and after (immediately before the end of 8-week exercise training) the exercise training, and also after the 4th and 8th week after the cessation of training. The VO2max significantly increased after exercise training. After the exercise training, the plasma concentration of NOx significantly increased (30.69 +/- 3.20 vs. 48.64 +/- 8.16 micromol/L, p < 0.05), and the plasma concentration of ET-1 significantly decreased (1.65 +/- 0.14 vs. 1.23 +/- 0.12 pg/mL, p < 0.05). The increase in NOx level and the decrease in ET-1 level lasted to the 4th week after the cessation of exercise training and these levels (levels of NOx and ET-1) returned to the basal levels (the levels before the exercise training) in the 8th week after the cessation of exercise training. There was a significant negative correlation between plasma NOx concentration and plasma ET-1 concentration. The present study suggests that chronic exercise causes an increase in production of NO and a decrease in production of ET-1 in humans, which may produce beneficial effects (i.e., vasodilative and antiatherosclerotic) on the cardiovascular system.

Quantitative analysis of contraction band and coagulation necrosis after ischemia and reperfusion in the porcine heart.

To assess the importance of contraction band necrosis (CBN) in reperfusion, CBN, coagulation necrosis (CN), and infarct size, expressed as CBN + CN, were quantitatively analyzed in 25 porcine hearts without collateral circulation. The left anterior descending coronary artery was ligated for 20, 30, 60, and 120 min and then reperfused for 8 hr (groups 1 to 4, respectively). Five hearts were not reperfused (group 5). The areas of CBN and CN were traced at a magnification of X 100 under an inverted microscope and quantified with use of an image analyzer. There was no change in hemodynamics with either occlusion or reperfusion. Regional myocardial blood flow, measured by the generated hydrogen gas clearance method, decreased to almost zero after occlusion but recovered during reperfusion. Percent of risk area infarcted in groups 1 to 4 was 0 +/- 0%, 11 +/- 7%, 80 +/- 9%, and 96 +/- 2%, respectively, and the percent of risk area infarcted in group 4 was the same as that in hearts subjected to permanent occlusion (95 +/- 3%). The percent area of CBN was 100 +/- 0% in group 2, 68 +/- 11% in group 3, 2 +/- 1% in group 4, and 2 +/- 2% in group 5. In group 3, the inner third of the ischemic left ventricular wall showed CN and the middle and outer third CBN. These findings show that in pig hearts without collateral circulation, the transmural infarct, two-thirds of which is occupied by CBN, is evident even when reperfusion is achieved after 1 hr occlusion. Therefore, protection against CBN might reduce infarct size after reperfusion.

Dissociation between regional myocardial dysfunction and ECG changes during myocardial ischemia induced by exercise in patients with angina pectoris

In order to investigate the relation between regional myocardial function and electrical changes during myocardial ischemia in humans, left ventricular echocardiogram and ECG were recorded during supine ergometer exercise in 16 patients with coronary artery disease until angina or ischemic ECG appeared. During exercise in 13 patients a decrease of left ventricular posterior wall excursion or of interventricular septum excursion occurred earlier than the appearance of ST-T change on ECG. In two patients the excursion decreased at the same time as the ST-T change. Significant regional myocardial dysfunction occurred at 30 +/- 15 seconds and ECG changes occurred at 90 +/- 60 seconds (p less than 0.001). Percent systolic wall thickening occurred in similar fashion. Results support the hypothesis that regional contractile abnormalities may provide a more sensitive indicator of myocardial ischemia than ST-T changes in humans.

Effects of physical exercise on the elasticity and elastic components of the rat aorta

SummaryTo evaluate the effects of exercise on aortic wall elasticity and elastic components, young male rats underwent various exercise regimes for 16 weeks. In the exercised rats, the aortic incremental elastic modulus decreased significantly when under physiological strain. The aortic content of elastin increased significantly and the calcium content of elastin decreased significantly in the exercised group. The accumulated data from the exercised and sedentary groups revealed that the elastin calcium content was related positively to the incremental elastic modulus. We concluded that physical exercise from an early age decreases the calcium deposit in aortic wall elastin and that this effect probably produced in the exercised rats a distensible aorta.

Reliability of non-invasive estimates of pulmonary hypertension by pulsed Doppler echocardiography.

The duration of the acceleration phase of pulmonary systolic flow was measured by pulsed Doppler echocardiography in 39 normal subjects and 67 patients with heart disease to evaluate the reliability of this Doppler index as an estimate of pulmonary arterial pressure. The mean (SD) Doppler index in patients with abnormal mean pulmonary arterial pressure (greater than 15 mm Hg) was significantly shorter than that in normal subjects (110 (30) ms vs 150 (10) ms). The Doppler index was significantly related to the mean pulmonary arterial pressure (r = -0.75) the pulmonary blood flow (r = 0.46), and the total pulmonary vascular resistance (r = -0.68). Forty four of 45 patients with an abnormal index (less than or equal to 120 ms) showed abnormal mean pressure (greater than 15 mm Hg). Without exception patients with a low index (less than or equal to 90 ms) had distinct pulmonary hypertension (greater than or equal to 25 mm Hg). Twelve of 22 patients with a normal index (greater than or equal to 130 ms), however, also showed abnormal pressures. Nine of the 12 had an atrial septal defect and they had high pulmonary arterial pressure associated with high blood flow. Eighteen patients with valvar heart disease, whose mean pulmonary arterial pressure ranged from 16 mm Hg to 24 mm Hg, had a significantly shorter acceleration phase and a higher total vascular resistance than 11 patients with atrial septal defect in whom the pressure range was similar (120(20) ms vs 140 (20) ms, 3.8 (1.1) hybrid resistance unit vs 1.6 (0.5)). Thus although the acceleration time of the pulmonary systolic flow is useful for the evaluation of pulmonary hypertension, it is a complex index that is affected not only by pulmonary arterial pressure but also by pulmonary blood flow and pathological changes in the pulmonary vascular bed.

Polymorphism in Endothelin-Related Genes Limits Exercise-Induced Decreases in Arterial Stiffness in Older Subjects

Increase in arterial stiffness is associated with aging, which is improved by regular exercise. Endothelin (ET) system has crucial roles in regulating vascular tone and in the progression of atherosclerosis. We hypothesized that molecular variations (ie, gene polymorphisms) in ET-related gene might affect exercise-induced improvement in arterial stiffness with age in human subjects. The present study provides a cross-sectional investigation of 191 healthy middle-aged and older (65±1 years) human subjects to clarify the relationship between the regular exercise-induced improvement of arterial stiffness and the gene polymorphisms of ET converting enzyme (ECE)-1, ECE-2, ET-A receptor (ET-A), and ET-B receptor (ET-B). The study subjects were divided into active and inactive groups based on the median value (186 kcal/d) of energy expenditure. Brachial-ankle arterial pulse wave velocity (baPWV) was used to evaluate arterial stiffness. All individuals were genotyped for 4 different polymorphisms of the ET system: 2013(+289)A/G in intron 17 of ECE-1, 669(+17)T/C in intron 5 of ECE-2, 958A/G in exon 6 of ET-A, and 831A/G in exon 4 of ET-B. The baseline baPWV was significantly lower in the active group without any change in blood pressure. Polymorphisms in ECE-1 influenced basal blood pressure. Polymorphisms in ECE-1 and ECE-2 had no effect on baPWV between active and inactive groups. However, polymorphisms in both ET-A and ET-B affected baPWV in the 2 groups. The present results suggest that differences in ET-A and ET-B polymorphisms may influence the response of the vascular wall to exercise whereas ECE-1 polymorphisms may affect basal blood pressure.

Relationship between augmentation index obtained from carotid and radial artery pressure waveforms.

Objective Increased aortic and carotid arterial augmentation index (AI) has been directly linked with cardiovascular disease risk, mortality and morbidity. The aim of this study was to examine whether AI obtained directly from radial artery pressure waveforms (radial AI) can provide information comparable with carotid arterial AI measurements. Methods In a cross-sectional study of 204 apparently healthy subjects (88 men and 116 women) aged 19–76 years (51 ± 15 years, mean ± SD), carotid AI [(second peak carotid systolic pressure − first peak carotid systolic pressure)/carotid pulse pressure*100] and radial AI [(second peak radial systolic pressure − diastolic pressure)/(first peak radial systolic pressure − diastolic pressure)*100] were measured using applanation tonometry. Results Radial AI was strongly correlated with carotid AI (r = 0.86, P < 0.0001, SD of difference 10.0%), although radial AI was consistently approximately 66% higher than carotid AI. In 16 apparently healthy young adults (11 men and five women, aged 23 ± 3 years) handgrip exercise was immediately followed by post-exercise muscle ischaemia (PEMI) to compare changes in carotid and radial AI during increased sympathetic nervous activity. PEMI caused parallel increases in carotid and radial AI (26 and 19%). Accordingly, changes in radial AI with PEMI were strongly correlated with corresponding changes in carotid AI (r = 0.86, P < 0.0001, SD of difference 7.3%). Conclusion These results suggest that AI obtained directly from radial arterial pressure waveforms could provide equivalent information to carotid arterial AI, and has potential as a surrogate marker of cardiovascular disease.

Myocardial mechanics of athletic hearts in comparison with diseased hearts

Parameters of myocardial mechanics were measured by means of echocardiography in 31 competitive runners and 17 judo (Japanese wrestling) champions and were then compared with those in 25 normal control subjects, 15 patients with volume-overloaded (aortic regurgitation, AR) and 13 with pressure-overloaded (hypertension, HT) hearts, 14 patients with dilated cardiomyopathy (DCM), and 11 patients with hypertrophic cardiomyopathy (HCM). In runners, the ratio of left ventricular radius to wall thickness (R/Th) was maintained in the normal range, but fractional shortening (FS) and decreased slightly (p less than 0.01). Patients with decompensated DCM and AR had an increased R/Th (p less than 0.001) and a decreased FS (p less than 0.001). In judo champions, FS was maintained in the normal range, but R/Th had decreased (p less than 0.001). In patients with HT, R/Th had decreased slightly (p less than 0.05), but FS and peak systolic wall stress were maintained in the normal range. In patients with HCM, FS was maintained in the normal range, but R/Th had decreased (p less than 0.001). It is concluded that, at rest, hearts of runners are cardiomechanically similar to those of patients with compensated AR or DCM and probably have greater cardiac reserve, whereas hearts of judo champions are similar to those of HCM patients with inappropriate hypertrophy.

Effect of physical activity on the distensibility of the aortic wall in healthy males

To study the effect of physical activity level on the distensibility of the human aortic wall, aortic pulse wave velocity (APWV) was estimated in 139 healthy male subjects (19-67 years) and was related to the energy expenditure by habitual physical exercise (physical activity index: PAI), which was evaluated by a 7-day total activity recall. The subjects consisted of 56 fun runners (runner group) and 83 general subjects, who were divided into 25 active subjects (active group: PAI ≥ 1,500 kcal/week) and 58 sedentary subjects (sedentary group: PAI < 1,500 kcal/week). The APWV index (APWVI: standardized APWV by the diastolic blood pressure) was found to be positively correlated with age and was negatively correlated with PAI. The age-adjusted APWVI of the runner group was significantly lower than that of the active and sedentary groups. The age-adjusted APWVI was also significantly lower in the active group than in the sedentary group. These results suggest that increased physical activity may retard the age-dependent loss of arterial distensibility in humans, in proportion to the amount and/or intensity of exercise.