Shin-ichi Momomura

Reduced Myocardial Flow Reserve in Non–Insulin-Dependent Diabetes Mellitus

OBJECTIVES We analyzed myocardial flow reserve (MFR) in patients with non-insulin-dependent (type II) diabetes mellitus (NIDDM) without symptoms and signs of ischemia. BACKGROUND Diminished MFR in diabetes has been suggested. However, it remains controversial whether MFR is related to glycemic control, mode of therapy or gender in NIDDM. METHODS Myocardial blood flow (MBF) was measured at baseline and during dipyridamole loading in 25 asymptomatic, normotensive, normocholesterolemic patients with NIDDM and 12 age-matched control subjects by means of positron emission tomography and nitrogen-13 ammonia, after which MFR was calculated. RESULTS Baseline MBF in patients with NIDDM ([mean +/- SD] 74.0 +/- 24.0 ml/min per 100 g body weight) was comparable to that in control subjects (73.0 +/- 17.0 ml/min per 100 g). However, MBF during dipyridamole loading was significantly lower in patients with NIDDM (184 +/- 99.0 ml/min per 100 g, p < 0.01) than in control subjects (262 +/- 120 ml/min per 100 g), as was MFR (NIDDM: 2.77 +/- 0.85; control subjects: 3.8 +/- 1.0, p < 0.01). A significantly decreased MFR was seen in men (2.35 +/- 0.84) compared with women with NIDDM (3.18 +/- 0.79, p < 0.05); however, no significant differences were found in terms of age, hemoglobin a1c and baseline MBF. MFR was comparable between the diet (2.78 +/- 0.80) and medication therapy groups (2.76 +/- 0.77) and was inversely correlated with average hemoglobin A1c for 5 years (r = -0.55, p < 0.01) and fasting plasma glucose concentration (r = -0.57, p < 0.01) but not age or lipid fractions. CONCLUSIONS Glycemic control and gender, rather than mode of therapy, is related to MFR in NIDDM.

Reduced coronary flow reserve in hypercholesterolemic patients without overt coronary stenosis.

BACKGROUND Reduced coronary flow reserve (CFR) in hypercholesterolemic patients without evidence of ischemia has been reported. However, it remains uncertain whether this abnormality occurs without overt coronary atherosclerosis. This study aimed to clarify whether CFR is impaired even in anatomically normal coronary arteries in hypercholesterolemic patients and to compare CFR between familial hypercholesterolemic (FH) patients and secondary hypercholesterolemic (SH) patients. METHODS AND RESULTS Twenty-two patients with hypercholesterolemia (11 FH, 11 SH) and 11 control subjects were studied. Baseline myocardial blood flow (MBF) and MBF during dipyridamole loading were measured in segments perfused by angiographically normal coronary arteries with the use of positron emission tomography and 13N-ammonia, and CFR was calculated. Baseline MBF (mL/min per 100 g heart wt) in FH (81.3 +/- 31.4) and SH (70.0 +/- 20.7) patients was not different from that in control subjects (75.0 +/- 34.9). However, MBF during dipyridamole loading was significantly lower in FH patients (129 +/- 19.1) than in control subjects (322 +/- 174, P < .01) and SH patients (210 +/- 71.2, P < .01). CFR in FH patients (1.59 +/- 0.41) was also significantly lower compared with both control subjects (4.22 +/- 1.42, P < .01) and SH patients (3.00 +/- 0.96, P < .01). CFR in SH patients was also significantly lower than that in control subjects (P < .05). CFR correlated significantly with both plasma total cholesterol (r = .67, P < .01) and LDL cholesterol concentrations (r = .69, P < .01). CONCLUSIONS CFR was decreased even in anatomically normal coronary arteries in hypercholesterolemic patients. This abnormality was more prominent in FH patients.

Prognosis of Patients With Heart Failure and Obstructive Sleep Apnea Treated With Continuous Positive Airway Pressure

BACKGROUND Therapy with continuous positive airway pressure (CPAP) provides several benefits for patients with heart failure (HF) complicated by obstructive sleep apnea (OSA). However, the effect on the prognosis of such patients remains unknown. AIMS To determine whether CPAP therapy and compliance affects the prognosis of HF patients with OSA. METHODS We classified 88 patients with HF and moderate-to-severe OSA into a CPAP-treated group (n = 65) and an untreated group (n = 23), and then those treated with CPAP were further subclassified according to CPAP therapy compliance. The frequency of death and hospitalization was analyzed using multivariate analysis. RESULTS During a mean (+/- SD) period of 25.3 +/- 15.3 months, 44.3% of the patients died or were hospitalized. Multivariate analysis showed that the risk for death and hospitalization was increased in the untreated group (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.07 to 3.68; p = 0.030) and in less compliant CPAP-treated patients (HR, 4.02; 95% CI, 1.33 to 12.2; p = 0.014). CONCLUSION Therapy with CPAP significantly reduced the risk of death and hospitalization among patients with HF and OSA. However, reduced compliance with CPAP therapy was significantly associated with an increased risk of death and hospitalization.

Nitric oxide-mediated effects of interleukin-6 on [Ca2+]i and cell contraction in cultured chick ventricular myocytes.

Cytokines have significant roles in some cardiovascular disorders, but direct myocardial effects of cytokines remain to be elucidated. In the present study, we examined both the early and delayed effects of interleukin-6 (IL-6) on cultured chick embryo ventricular myocytes. Exposure of these cells to human recombinant IL-6 significantly decreased peak systolic [Ca2+]i (71.0 +/- 0.6% of the control value) and the amplitude of cell contraction (66.0 +/- 7.4% of the control value) within a few minutes. Pretreatment with NG-monomethyl-L-arginine (L-NMMA) or methylene blue completely inhibited the IL-6-induced early changes. Subsequent addition of L-arginine reversed the effects of L-NMMA. The levels of cGMP were significantly increased after 30 minutes of exposure to IL-6 (134.4 +/- 9.1% of the control value). Pretreatment with L-NMMA or EGTA significantly inhibited the IL-6-induced early elevation of cGMP. These results suggest that IL-6 acutely decreases intracellular Ca2+ transients and depresses cell contraction by nitric oxide (NO)-cGMP-mediated pathway. Therefore, IL-6 may enhance the Ca(2+)-dependent constitutive NO synthase activity in cardiac myocytes. On the other hand, 24-hour exposure to IL-6 also increased the levels of cGMP (159.0 +/- 22.8% of the control value) regardless of pretreatment with EGTA. These delayed increases in cGMP were also shown to be coupled with decreases in intracellular Ca2+ transients and the amplitude of cell contraction. Thus, IL-6 may induce Ca(2+)-independent NO synthase in cardiac myocytes. Together with the previous reports that have suggested the possible roles of IL-6 in myocardial stunning or endotoxic shock, this negative inotropic effect of IL-6 may contribute to these clinical settings.

Effect of Flow-triggered Adaptive Servo-ventilation Compared with Continuous Positive Airway Pressure in Chronic Heart Failure Patients with Coexisting Obstructive Sleep Apnea and Cheyne-Stokes Respiration

Background—In patients with chronic heart failure (CHF), the presence of sleep-disordered breathing, including either obstructive sleep apnea or Cheyne-Stokes respiration-central sleep apnea, is associated with a poor prognosis. A large-scale clinical trial showed that continuous positive airway pressure (CPAP) did not improve the prognosis of such patients with CHF, probably because of insufficient sleep-disordered breathing suppression. Recently, it was reported that adaptive servo-ventilation (ASV) can effectively treat sleep-disordered breathing. However, there are no specific data about the efficacy of flow-triggered ASV for cardiac function in patients with CHF with sleep-disordered breathing. The aim of this study was to compare the efficacy of flow-triggered ASV to CPAP in patients with CHF with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea. Methods and Results—Thirty-one patients with CHF, defined as left ventricular ejection fraction <50% and New York Heart Association class ≥II, with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea, were randomly assigned to either CPAP or flow-triggered ASV. The suppression of respiratory events, changes in cardiac function, and compliance with the devices during the 3-month study period were compared. Although both devices decreased respiratory events, ASV more effectively suppressed respiratory events (&Dgr;AHI [apnea-hypopnea index], −35.4±19.5 with ASV; −23.2±12.0 with CPAP, P<0.05). Compliance was significantly greater with ASV than with CPAP (5.2±0.9 versus 4.4±1.1 h/night, P<0.05). The improvements in quality-of-life and left ventricular ejection fraction were greater in the ASV group (&Dgr;LVEF [left ventricular ejection fraction], +9.1±4.7% versus +1.9±10.9%). Conclusions—These results suggest that patients with coexisting obstructive sleep apnea and Cheyne-Stokes respiration-central sleep apnea may receive greater benefit from treatment with ASV than with CPAP.

Comparison of Unitary Displacements and Forces Between 2 Cardiac Myosin Isoforms by the Optical Trap Technique: Molecular Basis for Cardiac Adaptation

To provide information on the mechanism of cardiac adaptation at the molecular level, we compared the unitary displacements and forces between the 2 rat cardiac myosin isoforms, V1 and V3. A fluorescently labeled actin filament, with a polystyrene bead attached, was caught by an optical trap and brought close to a glass surface sparsely coated with either of the 2 isoforms, so that the actin-myosin interaction took place in the presence of a low concentration of ATP (0.5 micromol/L). Discrete displacement events were recorded with a low trap stiffness (0.03 to 0.06 pN/nm). Frequency distribution of the amplitude of the displacements consisted of 2 gaussian curves with peaks at 9 to 10 and 18 to 20 nm for both V1 and V3, suggesting that 9 to 10 nm is the unitary displacement for both isoforms. The duration of the displacement events was longer for V3 than for V1. On the other hand, discrete force transients were recorded with a high trap stiffness (2.1 pN/nm), and their amplitude showed a broad distribution with mean values between 1 and 2 pN for V1 and V3. The durations of the force transients were also longer for V3 than for V1. These results indicate that both the unitary displacements and forces are similar in amplitude but different in duration between the 2 cardiac myosin isoforms, being consistent with the reports that the tension cost is higher in muscles consisting mainly of V1 than those consisting mainly of V3.

Increased Nitric Oxide in the Exhaled Air of Patients with Decompensated Liver Cirrhosis

Patients with liver cirrhosis often present with several systemic hemodynamic disturbances, including hypotension, low systemic vascular resistance, and a reduced sensitivity to vasoconstrictors [1]. As cirrhosis progresses, vascular resistance continues to decrease, and the low arterial pressure may lead to secondary disturbances in renal and hepatic blood flow and to ascites [1]. The precise mechanisms of these hemodynamic disorders have not yet been clearly elucidated. Excessive production of vasodilators, such as prostacyclin, bradykinin, substance P, and atrial natriuretic peptide, has been proposed, but there is no clear evidence to show that vasodilators are involved. Vallance and Moncada [2] hypothesized that nitric oxide, originally discovered as an endothelium-derived relaxing factor [3], may be a causative factor in hemodynamic disorders in patients with liver cirrhosis. High concentrations of circulating endotoxin are frequently found in patients with cirrhosis who have no clinical evidence of infection [4]. Thus, the endotoxemia of liver cirrhosis may induce nitric oxide synthase directly in blood vessels or indirectly through cytokines, leading to an increased synthesis and release of nitric oxide that may account for the hemodynamic abnormalities. Recent studies show that nitric oxide concentration in exhaled air can be measured [5-7] and that it is increased in patients with bronchial asthma [5, 6]. To test the hypothesis that an increased synthesis and release of nitric oxide accounts for hemodynamic abnormalities in patients with liver cirrhosis, we investigated whether nitric oxide output in exhaled air is increased in these patients. Methods Patients Fifty-six patients were consecutively selected from those hospitalized in our department. All had biopsy-proven chronic hepatitis or liver cirrhosis; none had primary lung disease, hypertension, or infection. They could walk in the ward unaided and did not need intensive care. Physical examination findings and blood data were analyzed to classify hepatocellular function in liver cirrhosis according to the Child criteria. The clinical background of these patients is summarized in Table 1. Healthy volunteers served as controls (15 men; 34 2 years of age; body surface area, 1.84 0.03 m2). All medications were discontinued 24 hours before each study began. No antihypertensives or vasodilators, including nitrates and angiotensin-converting enzyme inhibitors, were used in these patients. The study was approved by the hospital ethics committee, and informed consent was obtained from each study participant. Table 1. Clinical Background of Patients with Chronic Hepatitis and Liver Cirrhosis Nitric Oxide Measurement The nitric oxide concentration in exhaled air was determined at least 3 hours after meals while each participant was at rest in the sitting position, as previously described [7]. Each participant was asked to inhale synthetic air (Taiyo Sanso Co., Osaka, Japan) free of nitric oxide (< 3 parts per billion [ppb]) through a mask and a T-valve, and to exhale the air into a wide-bore Teflon tube (internal diameter, 25 mm; length, 600 mm). Exhaled air was continuously drawn from this tube with a vacuum pump and was introduced into a chemiluminescence analyzer (APNE-350E, Horiba Co., Kyoto, Japan). Measurement of nitric oxide concentration was based on the reaction of nitric oxide with ozone. The sensitivity of the analyzer to nitric oxide ranged from 2 to 1000 ppb. The system was calibrated with dilutions of certified nitric oxide gas (450 ppb in nitrogen; Taiyo Sanso Co.) using mass flowmeters (Estec Co., Kyoto, Japan). Expired volume was measured with a hot-wire flow meter connected to the T-valve on the expiratory side, and minute ventilation was calculated using a breath-by-breath respirometer (RM-280, Minato Medical Science Co., Tokyo, Japan). The nitric oxide concentration and minute ventilation were recorded with a computer-assisted data recorder (DS1100, Fukuda Denshi Co., Tokyo, Japan), and the output of nitric oxide was calculated as follows: nitric oxide output = (nitric oxideex nitric oxidein) x minute ventilation/body surface area, where nitric oxideex was the nitric oxide concentration in exhaled air, and nitric oxidein was the nitric oxide concentration in inhaled air. Nitric oxide concentration and minute ventilation were monitored simultaneously for 10 minutes, and the data obtained during the last 3 minutes was averaged. During the study period, the ambient levels of nitric oxide concentration were less than 5 ppb. Nitric oxide output was reproducible in patients with cirrhosis and in controls (coefficient of variation, 10.8% [n = 5] for patients and 9.3% [n = 5] for controls) on separate days, and there was no significant time-course change in nitric oxide output at rest. Echocardiographic Measurement To examine the relation between systemic hemodynamics and nitric oxide production, we measured cardiac output using transthoracic two-dimensional echocardiography (SSD-2200, Aloka Co., Tokyo, Japan) in 19 patients with liver cirrhosis and in 6 controls. This was done on the same day that nitric oxide concentrations were measured. A physician, who was blinded to the patient characteristics and the exhaled nitric oxide output values, obtained echocardiographic views and recorded them on videotape. Another physician, who was also blinded to these data, measured cardiac output using the echocardiographic images. Left ventricular dimension was measured in the long-axis view of the left ventricle while the patient was in the left lateral decubitus position. Left ventricular volume and cardiac index were obtained by the following formulae according to the Teichholz equation [8]: left ventricular volume = 7.0 x dimension3/(2.4 + dimension); cardiac index = (left ventricular end-diastolic volume -end-systolic volume) x heart rate/body surface area. Blood pressure was measured with a sphygmomanometer. Total peripheral resistance index was calculated as mean blood pressure 80/cardiac index. The cardiac index obtained by this method on separate days was reproducible in patients with cirrhosis and in controls (coefficient of variation, 9.1% [n = 6] in patients and 8.6% [n = 5] in controls). Statistical Analysis Values are expressed as the mean SE. Differences between patients and controls were compared using one-way analysis of variance (ANOVA) followed by the Fisher test. The correlation coefficient was calculated using the least-squares method. Statistical significance was set at P < 0.05. Results Patients with decompensated liver cirrhosis had markedly depressed liver function but normal serum creatinine levels (Table 1). There were no intergroup differences in minute ventilation per m2 body surface area (patients with chronic hepatitis, 5.1 0.3 L/min; Child A patients, 5.6 0.3 L/min; Child B patients, 5.4 0.2 L/min; Child C patients, 6.2 0.3 L/min; and controls, 5.4 0.2 L/min; P = 0.12). The level of exhaled nitric oxide output per m2 body surface area was significantly greater in patients with Child C (190 11 nL/min; P < 0.001) or Child B liver cirrhosis (166 12 nL/min; P < 0.001) than in controls (97 8 nL/min) (Figure 1). In patients with Child A liver cirrhosis (119 10 nL/min; P = 0.17) or chronic hepatitis (129 19 nL/min; P = 0.13), the level of nitric oxide output per m2 body surface area was similar to that in controls. Figure 1. Nitric oxide (NO) output in exhaled air in controls, patients with chronic hepatitis (CH), and patients with liver cirrhosis. The results of hemodynamic measurements showed that patients with Child C liver cirrhosis had a greater cardiac index per m2 body surface area (4.3 0.3 L/min compared with 2.9 0.2 L/min; P < 0.001) and a smaller total peripheral resistance per m2 body surface area (1732 125 dyne/s x cm5 compared with 2680 235 dyne/s x cm5; P = 0.004) than controls. There was a positive correlation between the level of nitric oxide output and cardiac index (r = 0.621; P < 0.001) (Figure 2). Figure 2. Relation between nitric oxide (NO) output and cardiac index in patients with liver cirrhosis and controls. Discussion We have shown that nitric oxide output is increased in the air exhaled by patients with cirrhosis, especially patients with decompensated cirrhosis. Although we did not identify the origin of the increased synthesis of nitric oxide, several potential sources can be considered. Patients with liver cirrhosis often have endotoxemia even when they have no signs of infection [4], and elevated concentrations of cytokines, such as tumor necrosis factor-, have been shown in patients with liver diseases [9, 10]. The liver may produce large amounts of nitric oxide in these patients: Hepatocytes and Kupffer cells are known to produce nitric oxide in vitro in response to lipopolysaccharide and several cytokines [11, 12]. The plasma levels of cytokines, including tumor necrosis factor, are much lower in patients with liver cirrhosis than in these in vitro studies [10-15]. However, in vitro studies have also shown that endotoxin and cytokines also induce nitric oxide synthase in other tissues, including vascular endothelium, smooth muscle, and bronchial epithelium [13-15]. Thus, it is possible that vascular and bronchial tissues in the lungs of patients with liver cirrhosis produce nitric oxide as a result of continuous stimulation by the lower concentrations of cytokines, because the plasma levels of cytokines in patients with cirrhosis are similar to those in normal persons who have become hypotensive through the administration of endotoxin [10, 16]. Because most nitric oxide is inactivated by hemoglobin or rapidly metabolized to nitrite and nitrate [3], nitric oxide in exhaled air may be the residual of excessive local production of nitric oxide by the lung rather than a product of the liver. Because plasma nitrite and nitrate levels reflect the sum of nitric oxide production in the entire body, includ

End-tidal CO2 pressure decreases during exercise in cardiac patients: association with severity of heart failure and cardiac output reserve.

OBJECTIVES We measured end-tidal CO2 pressure (PETCO2) during exercise and investigated the relationship between PETCO2 and exercise capacity, ventilatory parameters and cardiac output to determine the mechanism(s) of changes in this parameter. BACKGROUND It is unclear whether PETCO2 is abnormal at rest and during exercise in cardiac patients. METHODS Cardiac patients (n = 112) and normal individuals (n = 29) performed exercise tests with breath-by-breath gas analysis, and measurement of cardiac output and arterial blood gases. RESULTS PETCO2 was lower in patients than in normal subjects at rest and decreased as the New York Heart Association class increased, whereas the partial pressure of arterial CO2 did not differ among groups. Although PETCO2 increased during exercise in patients, it remained lower than in normal subjects. PETCO2 in relation to cardiac output was similar in patients and normal subjects. PETCO2 at the respiratory compensation point was positively correlated with the O2 uptake (r = 0.583, p < 0.0001) and the cardiac index at peak exercise (r = 0.582, p < 0.0001), and was negatively correlated with the ratio of physiological dead space to the tidal volume. The sensitivity and specificity of PETCO2 to predict an inadequate cardiac output were 76.6% and 75%, respectively, when PETCO2 at respiratory compensation point and a cardiac index at peak exercise that were less than the respective control mean-2 SD values were considered to be abnormal. CONCLUSIONS PETCO2 was below normal in cardiac patients at rest and during exercise. PETCO2 was correlated with exercise capacity and cardiac output during exercise, and the sensitivity and specificity of PETCO2 regarding decreased cardiac output were good. PETCO2 may be a new ventilatory abnormality marker that reflects impaired cardiac output response to exercise in cardiac patients diagnosed with heart failure.

Clinical implications of provocation tests for coronary artery spasm: safety, arrhythmic complications, and prognostic impact: multicentre registry study of the Japanese Coronary Spasm Association.

AIMS Provocation tests of coronary artery spasm are useful for the diagnosis of vasospastic angina (VSA). However, these tests are thought to have a potential risk of arrhythmic complications, including ventricular tachycardia (VT), ventricular fibrillation (VF), and brady-arrhythmias. We aimed to elucidate the safety and the clinical implications of the spasm provocation tests in the nationwide multicentre registry study by the Japanese Coronary Spasm Association. METHODS AND RESULTS A total of 1244 VSA patients (M/F, 938/306; median 66 years) who underwent the spasm provocation tests were enrolled from 47 institutes. The primary endpoint was defined as major adverse cardiac events (MACEs). The provocation tests were performed with either acetylcholine (ACh, 57%) or ergonovine (40%). During the provocation tests, VT/VF and brady-arrhythmias developed at a rate of 3.2 and 2.7%, respectively. Overall incidence of arrhythmic complications was 6.8%, a comparable incidence of those during spontaneous angina attack (7.0%). Multivariable logistic regression analysis demonstrated that diffuse right coronary artery spasm (P < 0.01) and the use of ACh (P < 0.05) had a significant correlation with provocation-related VT/VF. During the median follow-up of 32 months, 69 patients (5.5%) reached the primary endpoint. The multivariable Cox proportional hazard model revealed that mixed (focal plus diffuse) type multivessel spasm had an important association with MACEs (adjusted hazard ratio, 2.84; 95% confidence interval, 1.34-6.03; P < 0.01), whereas provocation-related arrhythmias did not. CONCLUSION The spasm provocation tests have an acceptable level of safety and the evaluation of spasm type may provide useful information for the risk prediction of VSA patients.

Hyperglycemia Rather Than Insulin Resistance Is Related to Reduced Coronary Flow Reserve in NIDDM

To clarify if coronary flow reserve (CFR) is related to insulin resistance or hyperglycemia in normotensive NIDDM, myocardial blood flow (MBF) at baseline and during dipyridamole loading were measured with 13N-ammonia positron-emission tomography. CFR was significantly reduced in NIDDM patients compared with agematched control subjects. CFR in patients with well-controlled NIDDM was significantly higher than in those with poorly controlled NIDDM, whereas insulin resistance was comparable between the two groups. CFR in NIDDM patients was not related to the degree of insulin resistance. CFR correlated significantly with average fasting glucose concentration and average HbA1c, but not with insulin resistance, age, lipid parameters, or blood pressure. In conclusion, control of blood glucose concentration rather than insulin resistance is most likely related to the reduced CFR in NIDDM.