Yoshio Yasumura

Effects of Ghrelin Administration on Left Ventricular Function, Exercise Capacity, and Muscle Wasting in Patients With Chronic Heart Failure

Background—Ghrelin is a novel growth hormone–releasing peptide that also induces vasodilation, inhibits sympathetic nerve activity, and stimulates feeding through growth hormone–independent mechanisms. We investigated the effects of ghrelin on left ventricular (LV) function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). Methods and Results—Human synthetic ghrelin (2 &mgr;g/kg twice a day) was intravenously administered to 10 patients with CHF for 3 weeks. Echocardiography, cardiopulmonary exercise testing, dual x-ray absorptiometry, and blood sampling were performed before and after ghrelin therapy. A single administration of ghrelin elicited a marked increase in serum GH (25-fold). Three-week administration of ghrelin resulted in a significant decrease in plasma norepinephrine (1132±188 to 655±134 pg/mL; P<0.001). Ghrelin increased LV ejection fraction (27±2% to 31±2%; P<0.05) in association with an increase in LV mass and a decrease in LV end-systolic volume. Treatment with ghrelin increased peak workload and peak oxygen consumption during exercise. Ghrelin improved muscle wasting, as indicated by increases in muscle strength and lean body mass. These parameters remained unchanged in 8 patients with CHF who did not receive ghrelin therapy. Conclusions—These preliminary results suggest that repeated administration of ghrelin improves LV function, exercise capacity, and muscle wasting in patients with CHF.

Morphology of vulnerable coronary plaque: insights from follow-up of patients examined by intravascular ultrasound before an acute coronary syndrome.

OBJECTIVES To determine the morphologic features of coronary plaques associated with acute coronary syndrome, we prospectively followed patients with atherosclerotic disease identified by intravascular ultrasound (IVUS). BACKGROUND Although clinical evaluation of the vulnerable atherosclerotic plaque is important, few data exist regarding the morphology of the vulnerable plaque in clinical settings. METHODS We examined 114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patients. All the sites exhibited atherosclerotic lesions by IVUS. These lesions consisted of 22 concentric and 92 eccentric plaques with a percent plaque area averaging 59 +/- 12%. RESULTS During the follow-up period of 21.8 +/- 6.4 months (range 1 to 24), 12 patients had an acute coronary event at a previously examined coronary site at an average of 4.0 +/- 3.4 months after the initial IVUS study. All the preexisting plaques related to the acute events exhibited an eccentric pattern and the mean percent plaque area was 67 +/- 9%, which was greater than plaque area in the other 90 patients without acute events (57 +/- 12%, p < 0.05). There was no statistically significant difference in lumen area between two patient groups (6.7 +/- 3.0 vs. 7.5 +/- 3.7 mm2). Among 12 coronary sites with an acute occlusion, 10 sites contained the echolucent zones, eight of these shallow and two deep, likely representing a lipid-rich core. In 90 sites without acute events, an echolucent zone in the shallow portion was seen at only four sites (p < 0.05). CONCLUSIONS Large eccentric plaque containing an echolucent zone by IVUS can be at increased risk for instability even though the lumen area is preserved at the time of initial study. Compensatory enlargement of vessel wall due to remodeling may contribute to the relatively small degree of stenosis by angiography.

Early changes in left ventricular function in chronic asymptomatic alcoholics: relation to the duration of heavy drinking ☆

OBJECTIVES This study sought to assess preclinical cardiac abnormalities in chronic alcoholic patients and possible differences among alcoholics related to the duration of heavy drinking. BACKGROUND Chronic excessive alcohol intake has been reported as a possible cause of dilated cardiomyopathy. However, before the appearance of severe cardiac dysfunction, subtle signs of cardiac abnormalities may be identified. METHODS We studied 30 healthy subjects (age 44 +/- 8 years) and 89 asymptomatic alcoholics (age 45 +/- 8 years, p = NS) divided into three groups, with short (S, 5-9 years, n = 31), intermediate (I, 10-15 years, n = 31) and long (L, 16-28 years, n = 27) duration of alcoholism. Transmitral early (E) and late (A) Doppler flow velocities, E/A ratio, deceleration time of E (DT) and isovolumic relaxation time (IVRT) were obtained. Left ventricular (LV) wall thickness and volumes were also determined by echocardiography, and LV mass and ejection fraction (EF) were calculated. RESULTS The alcoholics had prolonged IVRT (92 +/- 11 vs. 83 +/- 7 ms, p < 0.001), longer DT (180 +/- 20 vs. 170 +/- 10 ms, p < 0.01), smaller E/A (1.25 +/- 0.34 vs. 1.40 +/- 0.32, p < 0.05), larger LV volumes (73 +/- 8 vs. 65 +/- 7 ml/m2, p < 0.001 for end-diastolic volume index; 25 +/- 4 vs. 21 +/- 2 ml/m2, p < 0.001 for end-systolic volume index), higher LV mass index (92 +/- 14 vs. 78 +/- 8 g/m2, p < 0.001) and thicker posterior wall (9 +/- 1 vs. 8 +/- 1 mm, p < 0.001). Ejection fraction did not differ between the two groups (66 +/- 4 vs. 67 +/- 2%). Deceleration time of the early transmitral flow velocity was longer in groups L (187 +/- 18 ms) and I (185 +/- 16 ms) compared with group S (168 +/- 17 ms, p < 0.001 for L and I vs. S), whereas A was higher in group L compared with S (43 +/- 10 vs. 51 +/- 10 cm/s, p < 0.005). Multiple regression analysis identified duration of heavy drinking as the most important variable affecting DT and A. CONCLUSIONS Left ventricular dilation with preserved EF and impaired LV relaxation characterized LV function in chronic asymptomatic alcoholic patients. It appeared that the progression of abnormalities in LV diastolic filling related to the duration of alcoholism.

Efficiency of energy transfer from pressure-volume area to external mechanical work increases with contractile state and decreases with afterload in the left ventricle of the anesthetized closed-chest dog.

We studied the effects of ventricular end-systolic elastance (Ees) and effective arterial elastance (Ea) on the efficiency of energy transfer from pressure-volume area (PVA) to external mechanical work (EW) in the left ventricle of anesthetized closed-chest dogs. PVA represents the total mechanical energy generated by ventricular contraction, which is an intermediate form of energy between oxygen consumption, the total energy input, and EW, the effective energy output. PVA and EW were determined from ventricular pressure and volume, which were continuously measured with a volumetric conductance catheter. Measurements of Ees were obtained by transiently increasing afterload by an inflation of a Fogarty catheter in the thoracic descending aorta. Ea was determined as the ratio of end-systolic pressure to stroke volume. The EW/PVA efficiency of a steady-state contraction increased from 55% to 64%, with a 58% increase in Ees after dobutamine. Ees, which was smaller than Ea before dobutamine, became nearly equal to Ea after dobutamine, maximizing EW for a given end-diastolic volume. EW/PVA efficiency decreased with an abrupt increase in afterload before and after dobutamine. The sensitivity of the decrease in the EW/PVA efficiency to an increase in end-systolic pressure was significantly less after than before dobutamine. We could account for all these changes in EW/PVA efficiency by the relative changes in Ees and Ea in the pressure-volume diagram.

CARDIAC COOLING INCREASES EMAX WITHOUT AFFECTING RELATION BETWEEN O2 CONSUMPTION AND SYSTOLIC PRESSURE-VOLUME AREA IN DOG LEFT VENTRICLE

We studied the effects of cardiac cooling by 7 +/- 2 degrees C (SD) from 36 degrees C on both contractility index (Emax) and the relation between O2 consumption per beat (VO2) and systolic pressure-volume area (PVA) of the left ventricle in the excised cross-circulated dog heart preparation. PVA represents the total mechanical energy generated by a contraction. The VO2-PVA relation divides measured VO2 into unloaded VO2 and excess VO2. The slope of the VO2-PVA relation represents inversely the efficiency of the contractile machinery to convert chemical energy from the excess VO2 to total mechanical energy. Cooling is known to decrease myosin ATPase activity (Q10 of 2-3), which in turn is expected to increase the chemomechanical efficiency of cross bridges. Therefore, we expected an increase in the efficiency and hence a decreased slope of the VO2-PVA relation with cooling. The cooling increased Emax by 46 +/- 13% and the time to Emax by 45 +/- 27%. Pacing rate was constant or had to be slightly decreased to avoid arrhythmias with cooling. We found that neither the slope of the VO2-PVA relation nor unloaded VO2 significantly (p greater than 0.05) changed with the cooling. This result contradicts the expected increase in the efficiency with cooling. We conclude that cardiac cooling by 7 degrees C from 36 degrees C does not increase the efficiency of the contractile machinery in excised cross-circulated dog left ventricle.

Augmentation of vessel squeezing at coronary-myocardial bridge by nitroglycerin: Study by quantitative coronary angiography and intravascular ultrasound☆☆☆★★★

BACKGROUND Nitroglycerin is known to augment vessel wall squeezing at the site with coronary-myocardial bridging (CMB). This study was designed to define the mechanism of nitroglycerin-induced augmentation of CMB in clinical settings. METHODS We analyzed nitroglycerin reactivity at the site with CMB in 39 patients. Maximal and minimal diameters of CMB during a cardiac cycle were measured by quantitative angiography before and after intracoronary administration of 250 microgram nitroglycerin. In 15 patients, CMB sites were observed by intravascular ultrasound to determine the intimal thickness and the time-serial change in vessel area. RESULTS Before nitroglycerin, CMB was demonstrated with angiography in 25 patients, and the remaining 14 patients showed CMB after nitroglycerin. The maximal diameter during diastole increased from 1. 4 +/- 0.4 mm to 1.9 +/- 0.4 mm after nitroglycerin, whereas the minimal diameter during systole decreased from 1.0 +/- 0.4 mm to 0.7 +/- 0.4 mm (P <.01). Thus nitroglycerin augmented the percent vessel narrowing during systole from 24% +/- 21% to 65% +/- 16% (P <.01). Under these conditions, intravascular ultrasound showed the reduction of the cross-sectional area of the sites with CMB by -38% +/- 16% (P <.01) during systole, and this phenomenon continued to early diastole (-30% +/- 16%). The intimal thickness was 0.32 +/- 0. 10 mm, which suggests the absence of atherosclerotic disease at CMB sites. CONCLUSIONS These results indicate that nitroglycerin-induced augmentation of the percent narrowing of CMB can be derived from further systolic compression of the vessel lumen as well as diastolic expansion, probably because of the increase in vessel compliance after nitroglycerin. We suggest that the delayed dilation of coronary lumen during the early diastole may contribute to the occurrence of myocardial ischemia.

Improvement in left ventricular function in response to carvedilol is accompanied by attenuation of neurohumoral activation in patients with dilated cardiomyopathy.

BACKGROUND We sought to evaluate whether improvement in ejection fraction (EF) with carvedilol therapy is accompanied by improvement in neurohumoral factors. METHODS AND RESULTS Forty-two patients with dilated cardiomyopathy were given carvedilol for 3 to 5 months. Changes in EF, plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and norepinephrine levels were determined. Iodine-123 metaiodobenzylguanidine (MIBG) images were also obtained before and after carvedilol therapy. Myocardial uptake of MIBG was calculated as the heart to mediastinal activity ratio (H/M). Storage and release of MIBG was calculated as percent myocardial MIBG washout rate (WR). We divided patients into 2 groups: 27 responders whose EF increased by more than 5% and 15 nonresponders whose EF increased by 5% or less. EF of responders increased by 15 +/- 5% and that of nonresponders by 1 +/- 4%. Although MIBG image-derived indexes of nonresponders remained unchanged, the delayed H/M (1.91 +/- 0.34 v 2.24 +/- 0.53, P < .01) and WR (49 +/- 11 v 39 +/- 9%, P < .01) of responders improved, respectively. The plasma ANP (51 +/- 50 v 27 +/- 24 pg/mL, P < .01) and BNP (194 +/- 197 v 49 +/- 62 pg/mL, P < .01) levels of responders decreased. The degree of changes in the plasma BNP level correlated with changes in EF (r = -.698, P < .01). CONCLUSION The improvement in EF with carvedilol therapy was proved to be accompanied by an improvement in neurohumoral factors.

Adaptive Servo-Ventilation Therapy for Patients With Chronic Heart Failure in a Confirmatory, Multicenter, Randomized, Controlled Study

BACKGROUND Adaptive servo-ventilation (ASV) therapy is expected to be novel nonpharmacotherapy with hemodynamic effects on patients with chronic heart failure (CHF), but sufficient evidence has not been obtained. METHODS AND RESULTS A 24-week, open-label, randomized, controlled study was performed to confirm the cardiac function-improving effect of ASV therapy on CHF patients. At 39 institutions, 213 outpatients with CHF, whose left ventricular ejection fraction (LVEF) was <40% and who had mild to severe symptoms [New York Heart Association (NYHA) class: ≥II], were enrolled. After excluding 8 patients, 102 and 103 underwent ASV plus guideline-directed medical therapy (GDMT) [ASV group] and GDMT only [control group], respectively. The primary endpoint was LVEF, and the secondary endpoints were HF deterioration, B-type natriuretic peptide (BNP), and clinical composite response (CCR: NYHA class+HF deterioration). LVEF and BNP improved significantly at completion against the baseline values in the 2 groups. However, no significant difference was found between these groups. HF deterioration tended to be suppressed. The ASV group showed a significant improvement in CCR corroborated by significant improvements in NYHA class and ADL against the control group. CONCLUSIONS Under the present studys conditions, ASV therapy was not superior to GDMT in the cardiac function-improving effect but showed a clinical status-improving effect, thus indicating a given level of clinical benefit.

Exercise training without ventricular remodeling in patients with moderate to severe left ventricular dysfunction early after acute myocardial infarction

BACKGROUND The purpose of this study was to determine whether or not patients with moderate to severe left ventricular (LV) dysfunction benefit from exercise training starting early after acute myocardial infarction (AMI) without deteriorating LV remodeling. METHODS We investigated changes in exercise capacity and LV end-diastolic dimension (LVDd by two-dimensional echocardiography) before and after exercise training in 126 patients after AMI. Patients were divided into three groups according to LV ejection fraction (EF) at the beginning of exercise training: 74 patients with LVEF>/=45% (Group H), 35 patients with 35%</=LVEF<45% (Group M), and 17 patients with LVEF<35% (Group L). Exercise training was prescribed at a moderate intensity (50-60% of heart rate reserve or Karvonens equation). Exercise capacity was assessed by peak work rate (WR) and peak oxygen uptake (VO(2)) by upright cardiopulmonary exercise test before and after 3 months of exercise training. LVDd was measured before and at 27+/-10 months of follow-up period. RESULTS At the baseline, Group L had a significantly lower LVEF (H 55+/-7 vs. M 40+/-3 vs. L 30+/-3%, P<0.05), significantly greater LVDd (49+/-6 vs. 52+/-7 vs. 56+/-6 mm, P<0.05), and a higher incidence of anterior infarction (P<0.01) compared with Groups H and M, whereas there were no difference in age, sex, coronary risk factors, the incidence of multivessel disease, prior myocardial infarction, peak WR or peak VO(2) among the three groups. After 3 months of exercise training, exercise capacity increased significantly (all P<0.01) in all groups. The magnitudes of the increases in peak VO(2) (%Deltapeak VO(2): 18+/-20 vs. 15+/-19 vs. 18+/-17%, NS) and peak WR (%Deltapeak WR: 17+/-17 vs. 16+/-14 vs. 15+/-13%, NS) were similar among the three groups. In addition, there was no significant correlation between %Deltapeak VO(2) and baseline LVEF. No increase in LVDd was observed in any group at follow-up (H 48+/-5 to 49+/-4 mm vs. M 53+/-8 to 52+/-8 mm vs. L 57+/-5 to 57+/-7 mm, NS in each group). CONCLUSION Patients with moderate to severe LV dysfunction benefit from exercise training starting early after AMI without deteriorating LV remodeling, with a similar magnitude of improvement in exercise capacity to that in patients with mild LV dysfunction.

Changes in myocardial gene expression associated with β-blocker therapy in patients with chronic heart failure

Abstract Background The left ventricular functional recovery by β-blocker therapy is now attributed to time-dependent biologic effects on cardiomyocytes. Methods and results To elucidate the cellular mechanism of these biologic effects, we treated 9 patients with dilated cardiomyopathy for 4 months with β-blockers and examined the gene expressions linked to an improvement of left ventricular ejection fraction (EF). Gene expressions of the biopsied right ventricular endomyocardium were assessed by real-time reverse transcription-polymerase chain reaction. A decrease in β-myosin heavy chain (1.23±0.49 versus 0.86±0.45, P Conclusions The functional recovery resulting from β-blockers may be associated with the restoration of the unfavorable gene expression that controls Ca2+ handlings in the failing heart.