Hideo Kusuoka

Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure

OBJECTIVES Vagally mediated heart rate recovery after exercise was assessed in patients with chronic heart failure and in well trained athletes by analyzing the postexercise heart rate decay. BACKGROUND Vagal reactivation is an important cardiac deceleration mechanism after exercise. However, alterations of this mechanism under pathologic conditions have not been characterized because of the lack of a specific index. METHODS To find a vagally mediated component of heart rate recovery, the time constants of the beat-by-beat heart rate decay for the first 30 s (T30) and the first 120 s (T120) after exercise were obtained at six levels of exercise in eight normal volunteers: 1) at maximal exercise, 2) at anaerobic threshold, 3) at anaerobic threshold with propranolol administration, 4) at anaerobic threshold with atropine administration, 5) at anaerobic threshold with concomitant administration of both drugs, and 6) at 50% of anaerobic threshold. To investigate the effects of heart failure and endurance training on vagally mediated heart rate recovery, T30 and T120 at anaerobic threshold were obtained in 20 patients with chronic heart failure and in 9 cross-country skiers. RESULTS In normal volunteers, T30 and T120 were markedly prolonged by atropine administration, indicating that both time constants are mediated by vagal reactivation. Moreover, T30 was almost independent of the exercise intensity and sympathetic blockade, whereas T120 was affected by sympathetic nerve activity and exercise work load. These results indicate that T30 is mediated primarily by vagal reactivation, independent of sympathetic withdrawal, and is significantly smaller in athletes (p < 0.01) and significantly larger in patients with chronic heart failure (p < 0.01) than that in respective age-matched normal control subjects. CONCLUSIONS The T30 value could be a specific index for vagally mediated heart rate recovery. Vagally mediated heart rate recovery after exercise is accelerated in well trained athletes but blunted in patients with chronic heart failure.

A new approach for evaluation of left ventricular diastolic function: Spatial and temporal analysis of left ventricular filling flow propagation by color M-mode doppler echocardiography

OBJECTIVES To evaluate left ventricular diastolic function and differentiate the pseudonormalized transmitral flow pattern from the normal pattern, the propagation of left ventricular early filling flow was assessed quantitatively using color M-mode Doppler echocardiography. BACKGROUND Because the propagation of left ventricular early filling flow is disturbed in the left ventricle with impaired relaxation, quantification of such alterations should provide useful indexes for the evaluation of left ventricular diastolic function. METHODS Study subjects were classified into three groups according to the ratio of early to late transmitral flow velocity (E/A ratio) and left ventricular ejection fraction: 29 subjects with an ejection fraction > or = 60% (control group); 34 with an ejection fraction < 60% and E/A ratio < 1 (group I); and 25 with ejection fraction < 60% and E/A ratio > or = 1 (group II). The propagation of peak early filling flow was visualized by changing the first aliasing limit of the color Doppler signals. The rate of propagation of peak early filling flow velocity was defined as the distance/time ratio between two sampling points: the point of the maximal velocity around the mitral orifice and the point in the mid-left ventricle at which the velocity decreased to 70% of its initial value. High fidelity manometer-tipped measurement was performed in 40 randomly selected subjects. RESULTS The rate of propagation decreased in groups I and II compared with that in the control group (33.8 +/- 13.8 [mean +/- SD] and 30.0 +/- 8.6 vs. 74.3 +/- 17.4 cm/s, p < 0.001, respectively) and correlated inversely with the time constant of left ventricular isovolumetric relaxation and the minimal first derivative of left ventricular pressure (peak negative dP/dt) (r = 0.82 and r = 0.72, respectively). CONCLUSIONS Spatial and temporal analysis of filling flow propagation by color M-mode Doppler echocardiography was free of pseudonormalization and correlated well with the invasive variables of left ventricular relaxation.

Direct comparison of different stem cell types and subpopulations reveals superior paracrine potency and myocardial repair efficacy with cardiosphere-derived cells

OBJECTIVES The goal of this study was to conduct a direct head-to-head comparison of different stem cell types in vitro for various assays of potency and in vivo for functional myocardial repair in the same mouse model of myocardial infarction. BACKGROUND Adult stem cells of diverse origins (e.g., bone marrow, fat, heart) and antigenic identity have been studied for repair of the damaged heart, but the relative utility of the various cell types remains unclear. METHODS Human cardiosphere-derived cells (CDCs), bone marrow-derived mesenchymal stem cells, adipose tissue-derived mesenchymal stem cells, and bone marrow mononuclear cells were compared. RESULTS CDCs revealed a distinctive phenotype with uniform expression of CD105, partial expression of c-kit and CD90, and negligible expression of hematopoietic markers. In vitro, CDCs showed the greatest myogenic differentiation potency, highest angiogenic potential, and relatively high production of various angiogenic and antiapoptotic-secreted factors. In vivo, injection of CDCs into the infarcted mouse hearts resulted in superior improvement of cardiac function, the highest cell engraftment and myogenic differentiation rates, and the least-abnormal heart morphology 3 weeks after treatment. CDC-treated hearts also exhibited the lowest number of apoptotic cells. The c-kit(+) subpopulation purified from CDCs produced lower levels of paracrine factors and inferior functional benefit when compared with unsorted CDCs. To validate the comparison of cells from various human donors, selected results were confirmed in cells of different types derived from individual rats. CONCLUSIONS CDCs exhibited a balanced profile of paracrine factor production and, among various comparator cell types/subpopulations, provided the greatest functional benefit in experimental myocardial infarction.

Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial

BACKGROUND The antiplatelet drug cilostazol is efficacious for prevention of stroke recurrence compared with placebo. We designed the second Cilostazol Stroke Prevention Study (CSPS 2) to establish non-inferiority of cilostazol versus aspirin for prevention of stroke, and to compare the efficacy and safety of cilostazol and aspirin in patients with non-cardioembolic ischaemic stroke. METHODS Patients aged 20-79 years who had had a cerebral infarction within the previous 26 weeks were enrolled at 278 sites in Japan and allocated to receive 100 mg cilostazol twice daily or 81 mg aspirin once daily for 1-5 years. Patients were allocated according to a computer-generated randomisation sequence by means of a dynamic balancing method using patient information obtained at registration. All patients, study personnel, investigators, and the sponsor were masked to treatment allocation. The primary endpoint was the first occurrence of stroke (cerebral infarction, cerebral haemorrhage, or subarachnoid haemorrhage). The predefined margin of non-inferiority was an upper 95% CI limit for the hazard ratio of 1·33. Analyses were by full-analysis set. This trial is registered with ClinicalTrials.gov, number NCT00234065. FINDINGS Between December, 2003, and October, 2006, 2757 patients were enrolled and randomly allocated to receive cilostazol (n=1379) or aspirin (n=1378), of whom 1337 on cilostazol and 1335 on aspirin were included in analyses; mean follow-up was 29 months (SD 16). The primary endpoint occurred at yearly rates of 2·76% (n=82) in the cilostazol group and 3·71% (n=119) in the aspirin group (hazard ratio 0·743, 95% CI 0·564-0·981; p=0·0357). Haemorrhagic events (cerebral haemorrhage, subarachnoid haemorrhage, or haemorrhage requiring hospital admission) occurred in fewer patients on cilostazol (0·77%, n=23) than on aspirin (1·78%, n=57; 0·458, 0·296-0·711; p=0·0004), but headache, diarrhoea, palpitation, dizziness, and tachycardia were more frequent in the cilostazol group than in the aspirin group. INTERPRETATION Cilostazol seems to be non-inferior, and might be superior, to aspirin for prevention of stroke after an ischaemic stroke, and was associated with fewer haemorrhagic events. Therefore, cilostazol could be used for prevention of stroke in patients with non-cardioembolic stroke. FUNDING Otsuka Pharmaceutical.

Sign language ‘heard’ in the auditory cortex

The upper regions of the brains temporal lobe are important both for hearing and for comprehending spoken language. We have discovered that these regions can be activated by sign language in congenitally deaf subjects, even though the temporal lobe normally functions as an auditory area. This finding indicates that, in deaf people, the brain region usually reserved for hearing may be activated by other sensory modalities, providing striking evidence of neural plasticity.

The role of intracoronary thrombus in unstable angina: angiographic assessment and thrombolytic therapy during ongoing anginal attacks.

Intracoronary thrombus is regarded as a potentially important factor in the etiology of unstable angina, but the incidence of intracoronary thrombus in unstable angina has not been clearly defined. To determine the occurrence of intracoronary thrombus during ongoing angina pectoris, coronary angiography was performed during spontaneous ischemic attacks in 37 patients with prolonged rest angina. All patients exhibited significant (greater than 50%) stenoses of at least one major coronary artery. Of the 37 patients, 21 (57%) had intracoronary thrombus in major coronary arteries, whereas 14 (38%) had fixed narrowings without evidence of intracoronary thrombus and two exhibited coronary spasm. ST segment elevation was observed in 16 of 21 patients with thrombus and in all of the patients with coronary spasm, but all the patients with organic stable obstruction showed ST segment depression. Twenty of the 21 patients with thrombus improved after thrombolytic therapy with intracoronary injection of urokinase; obstructed arteries were reopened, or narrowings were attenuated, with relief of ischemic symptoms. In patients with fixed obstructions, the rate-pressure product during active symptoms was significantly higher than during an asymptomatic period, indicating that a transient increase in myocardial oxygen demand may contribute to the ischemic attack in these patients. A high incidence (71%) of recurrent symptoms was observed in patients with intracoronary thrombus even after successful thrombolysis, in contrast to a much lower incidence (36%) in those without intracoronary thrombus. Myocardial infarction within 4 weeks after catheterization was observed more frequently in patients with intracoronary thrombus (24%) than in those without thrombus (7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Intracellular Sodium Accumulation During Ischemia as the Substrate for Reperfusion Injury

To elucidate the role of intracellular Na+ kinetics during ischemia and reperfusion in postischemic contractile dysfunction, intracellular Na+ concentration ([Na+]i) was measured in isolated perfused rat hearts using 23Na nuclear magnetic resonance spectroscopy. The extension of the ischemic period from 9 minutes to 15, 21, and 27 minutes (at 37 degrees C) increased [Na+]i at the end of ischemia from 270.0+/-10.4% of preischemic level (mean+/-SE, n=5) to 348.4+/-12.0% (n=5), 491.0+/-34.0% (n=7), and 505.3+/-12.1% (n=5), respectively, whereas the recovery of developed pressure worsened with the prolongation of the ischemic period (95.1+/-4.2%, 84.3+/-1. 2%, 52.8+/-13.7%, and 16.9+/-6.4% of preischemic level). The kinetics of [Na+]i recovery during reperfusion was analyzed by the fitting of a monoexponential function. When the hearts were reperfused with low-[Ca]o (0.15 mmol/L) solution, the time constants of the recovery (tau) after 15-minute (8.07+/-0.85 minutes, n=5) and 21-minute ischemia (6.44+/-0.90, n=5) were significantly extended, with better functional recovery (98.5+/-1.4% for 15-minute [P<0.05]; 98.0+/-1.0% for 21-minute [P<0.05]) compared with standard reperfusion ([Ca]o=2.0 mmol/L, tau=3.58+/-0.28 minutes for 15-minute [P<0.0001]; tau=3.02+/-0.20 for 21-minute [P<0.0001]). A selective inhibitor of Na+/Ca2+ exchanger also decelerated the [Na+]i recovery, which suggests that the recovery reflects the Na+/Ca2+ exchange activity. In contrast, high-[Ca]o reperfusion (5 mmol/L) accelerated the [Na+]i recovery after 9-minute ischemia (tau=2.48+/-0.11 minute, n=5 [P<0.0001]) and 15-minute ischemia (tau=2.10+/-0.07, n=6 [P<0. 05]), but functional recovery deteriorated only in the hearts with 15-minute ischemia (29.8+/-9.4% [P<0.05]). [Na+]i recovery after 27-minute ischemia was incomplete and decelerated by low-[Ca]o reperfusion, with limited improvement of functional recovery (42. 5+/-7.9%, n=5 [P<0.05]). These results indicate that intracellular Na+ accumulation during ischemia is the substrate for reperfusion injury and that the [Na+]i kinetics during reperfusion, which is coupled with Ca2+ influx, also determines the degree of injury.

Effect of angina pectoris on myocardial protection in patients with reperfused anterior wall myocardial infarction: retrospective clinical evidence of "preconditioning".

OBJECTIVES We examined whether angina pectoris occurring shortly before the onset of acute myocardial infarction can actually preserve postischemic left ventricular function in humans. BACKGROUND Experimental studies indicate that brief, transient episodes of ischemia render the heart very resistant to infarction from a subsequent sustained ischemic insult, an effect termed ischemic preconditioning. However, no clinical data are available concerning the implications of angina pectoris shortly before the onset of infarction in humans. METHODS We studied 84 patients with an acute anterior myocardial infarction. All patients had total occlusion of the proximal or medial portion of the left anterior descending coronary artery and achieved reflow within 6 h of onset. Patients were classified into three groups on the basis of duration of antecedent angina pectoris: group 1 = no angina (37 patients); group 2 = new angina pectoris occurring < or = 7 days of onset of infarction (22 patients); group 3 = angina pectoris beginning > 7 days before onset of infarction (25 patients). All patients underwent left ventriculography on the day of, and 28 days after, onset of infarction to determine ejection fraction and regional wall motion in the territory of the left anterior descending coronary artery by the centerline method. RESULTS Angiographic collateral flow grade was higher in group 3 than in groups 1 and 2 ([mean +/- SD] group 1 = 0.08 +/- 0.7, group 2 = 0.7 +/- 0.7, group 3 = 1.5 +/- 0.8). Although there were no differences in baseline ejection fraction and regional wall motion among the three groups, the degree of improvement was significantly greater in groups 2 and 3 than in group 1 (late minus baseline ejection fraction: group 1 = 0 +/- 8%, group 2 = 7 +/- 10% group 3 = 6 +/- 10% [p < 0.05 group 1 vs. groups 2 and 3]; late minus baseline regional wall motion: group 1 = 0.2 +/- 0.4, group 2 = 0.6 +/- 0.5, group 3 = 0.5 +/- 0.6 SD/chord [p < 0.05, group 1 vs. group 2]). When the study was limited to those patients with no or poor collateral flow (31 in group 1, 19 in group 2, 10 in group 3), only group 2 patients had a significant improvement in wall motion. Angina pectoris within 24 h before onset of infarction was more frequent in group 2 (82%) than group 3 (28%, p < 0.05). CONCLUSIONS Episodes of angina pectoris occurring shortly before the onset of infarction may preserve myocardial contractile function in reperfused myocardial infarction despite less support from collateral flow channels, although these are suggestive results in a limited number of patients.

Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure: a prospective study.

OBJECTIVES We sought to prospectively compare the prognostic value of cardiac iodine-123 (I-123) metaiodobenzylguanidine (MIBG) imaging with that of heart rate variability (HRV) in patients with mild-to-moderate chronic heart failure (HF). BACKGROUND Cardiac I-123 MIBG imaging, which reflects cardiac adrenergic nerve activity, provides prognostic information on chronic HF patients. Reduced HRV, indicating derangement in cardiac autonomic control, was also reported to be associated with a poor prognosis in chronic HF patients. METHODS At study entry, I-123 MIBG imaging and 24-h Holter monitoring were performed in 65 chronic HF outpatients with a radionuclide left ventricular ejection fraction <40%. The cardiac MIBG heart to mediastinum ratio (H/M) and washout rate (WR) were obtained from MIBG imaging. The time and frequency domain parameters of HRV were calculated from 24-h Holter recordings. RESULTS At a mean follow-up of 34 +/- 19 months, WR (p < 0.0001), H/M on the delayed image (p = 0.01), and normalized very-low-frequency power (n-VLFP) (p = 0.047) showed a significant association with the cardiac events (sudden death in 3 and hospitalization for worsening chronic HF in 10 patients) on univariate analysis. Multivariate analysis revealed that WR was the only independent predictor of cardiac events, although the predictive accuracy for the combination of abnormal WR and n-VLFP significantly increased, compared with that for abnormal WR (82% vs. 66%, p < 0.05). CONCLUSIONS Cardiac MIBG WR has a higher prognostic value than HRV parameters in patients with chronic HF. The combination of abnormal WR and n-VLFP would be useful to identify chronic HF patients at a higher risk of cardiac events.

Mechanism of early contractile failure during hypoxia in intact ferret heart: evidence for modulation of maximal Ca2+-activated force by inorganic phosphate.

We tested the hypothesis that accumulation of H+ or inorganic phosphate (Pi) is responsible for the early contractile failure of hypoxia by measuring maximal Ca2+-activated pressure and 3IP nuclear magnetic resonance spectra in Langendorff-perfused ferret hearts at 30°C. Maximal Ca2+-activated pressure was identified by the saturation of pressure with respect to [Ca2+]0 observed during tetani as [Ca2*], was increased to 15 mM in HEPES-buffered, 100% O2-bubbled perfusate and during hypoxia induced by bubbling with room air or with 100% N2. Tetani were produced by pacing at 8–12 Hz following exposure to ryanodine (1–5 μM), an inhibitor of Ca2+ release from the sarcoplasmic reticulum, and were elicited once a minute to measure maximal Ca2+-activated pressure during acquisition of nuclear magnetic resonance spectra. An inverse correlation was observed between [Pi] and maximal Ca2+-activated pressure (r = −0.87 mean, n = 12), with an average decline of 8.6% in pressure per 1 μmol/g wet wt. increase in [Pi]. Intracellular pH (pH() showed no significant correlation with maximal Ca2+-activated pressure (r = 0.49 mean, n = 12). Two other protocols, 1) pacing at variable rates and 2) gated measurements at two different times during the tetanus, were also used to correlate [Pi], pH, and maximal Ca3+-activated pressure. These protocols confirmed the highly significant correlation between [Pi] and maximal Ca2+-activated pressure, as well as the lack of correlation with pH,. Acidosis induced by NH4CI (20 mM) or by bubbling with 95% O2/5% CO2 was associated with < 20% depression of maximal Ca2+-activated pressure in the pH, range down to 6.8, but much greater depression at lower pH,. The data are consistent with depression of maximal Ca2+-activated force during the early phase of hypoxia by Pi but not by H+.