Hiroyuki Yoshio

Clinical Features of Hypertrophic Cardiomyopathy Caused by a Lys183 Deletion Mutation in the Cardiac Troponin I Gene

BACKGROUND Mutations that cause hypertrophic cardiomyopathy (HCM) have been identified in 9 genes that code proteins in the sarcomere. Previous reports have demonstrated that cardiac troponin I (cTnI) gene mutations may account for familial HCM; however, the clinical characteristics and prognosis of patients with HCM caused by cTnI gene mutations are not known. METHODS AND RESULTS We analyzed cTnI gene mutations in 130 unrelated probands with HCM and their families to clarify the genotype-phenotype correlations. We identified 25 individuals in 7 families with a Lys183 deletion (Lys183 del) mutation in exon 7 of the cTnI gene. The disease penetrance in subjects aged >20 years was 88% by echocardiography and 96% by ECG. Sudden death occurred in 7 individuals of 4 families at any age. Overall, 7 (43.8%) of 16 individuals aged >40 years had left ventricular systolic dysfunction, and 3 (18.8%) displayed dilated cardiomyopathy-like features. Of affected individuals, 4 of 5 individuals aged >40 years followed by echocardiography showed septal thinning and decreased fractional shortening during >5 years of follow-up. CONCLUSIONS The Lys183 del mutation in the cTnI gene in patients with HCM is associated with variable clinical features and outcomes. HCM caused by the Lys183 del mutation has a significant disease penetrance. This mutation is associated with sudden death at any age and dilated cardiomyopathy-like features in those aged >40 years. However, it remains unclear whether screening of families with HCM for this mutation will be useful in patient management and counseling.

Left ventricular systolic dysfunction during exercise and dobutamine stress in patients with hypertrophic cardiomyopathy.

OBJECTIVES We sought to characterize stress-induced left ventricular systolic dysfunction in patients with hypertrophic cardiomyopathy (HCM). BACKGROUND Myocardial ischemia and diastolic dysfunction occur in patients with HCM. We hypothesized that, in the setting of transient myocardial ischemia, left ventricular systolic dysfunction occurs during exercise and dobutamine stress. METHODS We studied 39 patients with HCM but without obstructive symptoms at rest or coronary artery disease. A continuous ventricular function monitor equipped with cadmium telluride detectors (VEST) was used to evaluate left ventricular function during supine bicycle ergometer exercise. Dobutamine stress echocardiography (DSE) was also performed. The left ventricular ejection fraction (LVEF) and regional wall motion were determined from echocardiographic images. RESULTS Changes in the LVEF correlated between exercise and dobutamine stress (r = 0.643, p < 0.0001). The LVEF decreased more than 5% at peak exercise in 17 of patients (group II), while the other patients had normal responses (group I). New regional wall motion abnormalities during dobutamine infusion were detected in 18 of 110 (16.4%) segments in group I and 42 of 85 (49.4%) segments in group II. Decreased or unchanged regional wall motion occurred more frequently in hypertrophied segments than in nonhypertrophied segments (p < 0.0001). There were significant inverse correlations between the LVEF responses during both stresses and the number of abnormal segments noted during dobutamine stress in all patients (VEST: p < 0.005; DSE: p < 0.0005). Signs of left ventricular obstruction were observed in 11 of 39 patients during DSE. However, there was no significant correlation between the LVEF response and the dobutamine-induced left ventricular pressure gradient. CONCLUSIONS Exercise-induced systolic dysfunction occurred in 50% of patients with HCM. In these patients, regional wall motion abnormalities were present in hypertrophied segments.

Assessment of autonomic nervous activity by heart rate spectral analysis in patients with variant angina

The purpose of this study was to assess the role of the autonomic nervous system in the pathogenesis of coronary artery spasm in patients with variant angina. We evaluated cardiac sympathetic and parasympathetic activity from the power (logarithmic scale) of the low-frequency (approximately 0.04 to 0.12 Hz) and the high-frequency (approximately 0.22 to 0.32 Hz) spectral components of heart rate variability with Holter monitoring in seven patients with nocturnal variant angina and in 11 healthy men who served as control subjects. None of the patients had organic coronary artery stenosis as determined by angiography. Low-frequency and high-frequency logarithmic values were calculated for each 5-minute period from 30 minutes before to immediately before each angina attack. The logarithmic low-frequency value during the 5-to-0-minute period was greater than the low-frequency values during most of the other periods (p < 0.05 - p < 0.01). The logarithmic high-frequency values during the 10-to-5-minute and 5-to-0-minute periods were greater than those during the 30-to-25-minute period (p < 0.05 and p < 0.01, respectively). These data indicate that parasympathetic activity increased during the 10 minutes before attacks of nocturnal variant angina, whereas sympathetic activity with vagal modulation increased during the 5 minutes before such attacks. The same pattern of changes in heart rate variability was found in the absence of ST-segment elevation in patients and in control subjects. So this phenomenon was not just associated with coronary spasm and variant angina. It is suggested that circadian variation in disease activity is also associated with spontaneous attacks.

Power spectral analysis of heart rate and arterial blood pressure oscillation in brain-dead patients

To clarify the mechanism of the slow arterial blood pressure oscillation seen in brain-dead patients, we investigated the frequency of fluctuations in arterial blood pressure and heart rate using power spectral analysis. The electrocardiogram, arterial blood pressure and respiration were recorded simultaneously from 9 brain-dead patients and 8 vegetative patients. Power spectral analysis of these data revealed a very slow fluctuation (0.002-0.01 Hz) in arterial blood pressure in brain-dead patients, the frequency of which was equal to that of the low-frequency spectrum of heart rate, indicating vasomotor sympathetic activity. Neuropathological examinations of the medulla and spinal cords of 4 autopsied brain-dead patients revealed that the spinal cord, ventral and dorsal nerve roots, and the nucleus intermediolateralis of the lateral horn below the level of C3/4 were virtually intact. These findings suggest strongly that the slow oscillation of arterial blood pressure in brain-dead patients originates from the vasomotor tone controlled by spinal sympathetic nerves.

Effects of short-term aminophylline administration on cardiac functional reserve in patients with syndrome X

OBJECTIVES This study sought to evaluate the effect of adenosine receptor blockade by aminophylline on cardiac functional reserve in patients with syndrome X. BACKGROUND Aminophylline may have a potentially antiischemic effect through the inhibition of adenosine and, thus, the coronary steal phenomenon in patients with syndrome X. METHODS A single-blind, placebo-controlled study of an intravenous infusion of aminophylline (6 mg/kg body weight over 15 min) or placebo (20 ml of saline solution over 15 min) was performed during continuous radionuclide monitoring of left ventricular ejection fraction in 12 patients performing supine bicycle ergometric exercise. RESULTS Aminophylline increased exercise time (aminophylline 400 s vs. placebo 355 s, p < 0.01), decreased degree of ST segment depression (aminophylline 1.6 mm vs. placebo 2.4 mm, p < 0.01) and either abolished (seven patients) or diminished (five patients) chest pain during exercise. Aminophylline also increased left ventricular ejection fraction at rest (aminophylline 66.5% vs. placebo 62.3%, p < 0.05) but did not improve its deterioration at peak exercise (aminophylline 60.1% vs. placebo 56.6%, p = NS) or shorten the abnormally prolonged interval between the end of exercise and the overshoot (aminophylline 115 s vs. placebo 130 s, p = NS). CONCLUSIONS Aminophylline infusion increases ischemic threshold and prolongs exercise duration in patients with syndrome X. It is hypothesized that aminophylline acts by inhibiting the coronary steal phenomenon through adenosine receptor blockade. It does not improve the deterioration in left ventricular function at peak exercise or the delayed response in ejection fraction in the recovery period, presumably because the beneficial effects of aminophylline that result from the redistribution of coronary blood flow are limited.

Correlation between histopathological changes and mechanical dysfunction in diabetic rat hearts

Recent clinical and experimental studies have suggested that diabetic patients may develop myocardial dysfunction in the absence of coronary heart disease and hypertension. In this study, the correlation between histopathological changes and myocardial dysfunction was studied in experimental diabetic rat hearts. Male Wistar rats were made diabetic at 9 weeks of age with a single intravenous injection of streptozotocin 50 mg/kg. The diabetic rats were studied along with age-matched control and insulin-treated rats at 4, 8, 12 and 24 weeks after the induction of diabetes to investigate isolated papillary muscle contraction and the histopathological picture simultaneously. In the isometric contractions, resting and developed tensions were similar. Time to peak tension and time to 1/2 relaxation were prolonged and the peak rate of tension rise and tension fall was depressed. On histological examination of left ventricular walls, diameters of myocytes were similar at all disease durations. Interstitial fibrosis and disarrangement of myocytes after 12 weeks were slightly increased in the diabetic hearts. Mechanical parameters did not worsen in parallel with the duration of diabetes and histological changes, but correlated with the blood glucose level. These data suggest that short-term mechanical defects in the experimental diabetic rat heart result from the metabolic disorder itself, with histopathological changes occurring later.

Usefulness of ultrasonography and Doppler color flow imaging in the diagnosis of internal jugular phlebectasia.

SummaryA 20-year-old woman presented to our hospital for investigation of a left neck mass. Ultrasonographic examination of the jugular mass demonstrated an echo-free space, the caliber of which markedly increased when the patient shifted from the sitting to the recumbent position or performed a Valsalva maneuver. On color Doppler flow imaging, a slow flow signal flowing in the direction opposite to that of the common carotid artery was found within this space. Ultrasonography and color Doppler flow imaging thus proved to be useful for correctly diagnosing internal jugular phlebectasia.

Myocardial scintigraphic study with 123I 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid in patients with hypertrophic cardiomyopathy

123I 15-(p-iodophenyl)-3(R,S)-methylpentadecanoic acid (BMIPP) myocardial scintigraphy and exercise stress thallium (TI)-201 myocardial scintigraphy were performed in 17 patients with hypertrophic cardiomyopathy (HCM) to evaluate the existence of abnormal fatty acid metabolism in the myocardium and the relationship between this abnormality and myocardial ischemia. On the BMIPP scintigraphy, abnormalities were found in 12 of 17 patients (71%). Five patients showing no abnormalities on the BMIPP scintigraphy had well preserved exercise tolerance and had longer exercise duration than the others showing BMIPP scintigraphic abnormalities (P < 0.001). On the evaluation of the segmental abnormalities, TI scintigraphic abnormalities were found in 15 (50%) of 30 segments showing decreased accumulation of BMIPP. On the other hand, BMIPP scintigraphic abnormalities were found in all segments showing decreased accumulation of TI. The sites of decreased accumulation of BMIPP and TI were in good agreement with the sites of wall hypertrophy. Four patients showing BMIPP scintigraphic abnormalities and no T1 scintigraphic abnormalities were in higher New York Heart Association functional classes, had shorter exercise duration (P < 0.05) than the 5 patients showing no abnormalities on either scintigraphy. It is concluded that abnormalities of fatty acid metabolism in the heart are detected at a high rate in patients with HCM, and may be due in part to factors other than myocardial perfusion disturbance.

Quantitative assessment of diffuse coronary artery disease using a three-dimensional reconstruction method compared with intravascular ultrasound images.

BackgroundIt can be difficult to estimate the degree of stenosis in patients with diffuse coronary artery disease (CAD), because of the lack of a normal reference segment. If the size of normal coronary lumen has a direct relation to size of distal myocardial bed, it could be used to estimate the ‘normal’ cross‐sectional area of coronary lumen. Accordingly, we could estimate the degree of stenosis of coronary arteries with diffuse disease by comparing them with calculated ‘normal’ areas of lumen. ObjectiveTo assess the validity of the above hypothesis. MethodFourteen subjects without coronary atherosclerosis (group A) and 16 patients with CAD (group B) underwent simultaneous bidirectional coronary arteriography. Using these coronary arteriograms, we determined the relationship between cross‐sectional area of coronary lumen measured by using a computerized edge‐detection system and summed distal branch length calculated by using our computerized three‐dimensional reconstruction method. ResultsFor group A, we found a close correlation between area of lumen and branch length (r  = 0.948). However, for group B, there were some segments for which the measured area of lumen was clearly smaller than that expected from the relationship for group A. From this relationship for group A, we calculated the stenosis ratios of 22 segments and, to confirm their accuracy, we compared the stenotic ratios with those measured on intravascular ultrasound images. The stenotic ratio of each segment of stenotic coronary artery calculated by our method agreed significantly well with the results obtained from the ultrasound measurements (r  = 0.980). ConclusionsThese observations validate a novel approach to quantifying diffuse CAD using clinical arteriograms.

Left ventricular dysfunction during exercise in patients with angina pectoris and angiographically normal coronary arteries (syndrome X)

Left ventricular function during exercise and recovery was investigated in patients with angina pectoris, ST segment depression during exercise and angiographically normal coronary arteries (syndrome X) using a continuous left ventricular function monitor with cadmium telluride detector (CdTe-VEST). Fourteen patients with syndrome X and 14 patients with atypical chest pain without ST segment depression during exercise and normal coronary arteries (control group) performed supine ergometric exercise after administration of 740–925 MBq of technetium-99m labelled red blood cells, and left ventricular function was monitored every 20 s using CdTe-VEST. Left ventricular ejection fraction (EF) response was impaired (≤55% increase from rest to peak exercise) in 11 or 14 patients with syndrome X but in none of the control patients. Resting EF was similar in the two groups (62.1%±6.7% in patients with syndrome X, 61.9%±6.2% in controls); however, EF increase from rest to peak exercise was lower in syndrome X (−3.1±9.5% vs 14.7%±7.4%, P <0.001). After cessation of exercise, all patients showed rapid EF increase over baseline and this EF overshoot was lower (19.3%±8.3% vs 26.4%±7.3%, P <0.001) with the time to EF overshoot longer (114±43 s vs 74±43 s, P<0.05) in patients with syndrome X. Thus, in patients with syndrome X, left ventricular dysfunction was frequently observed during exercise in spite of normal epicardial coronary arteries.