Rehabilitation outcomes of stroke patients with low left ventricular ejection fraction in the subacute rehabilitation phase.

OBJECTIVE: To examine the left ventricular ejection fraction in patients with subacute stroke and compare rehabilitation outcomes between those with decreased left ventricular ejection fraction and those without. DESIGN: Retrospective chart review. SUBJECTS: A total of 482 consecutive patients with stroke admitted to a convalescent rehabilitation hospital. METHODS: Patients were assessed using transthoracic echocardiography within 7 days of admission. The patients were divided into a group with low left ventricular ejection fraction and a group with preserved left ventricular ejection fraction. Functional Independence Measure (FIM) scores at admission and discharge, FIM gain, FIM efficiency, and discharge disposition were compared between groups. RESULTS: The low left ventricular ejection fraction group had significantly lower cognitive and total FIM scores on admission than the preserved left ventricular ejection fraction group. The patients in the low left ventricular ejection fraction group tended to be transferred to acute hospitals more frequently. How-ever, the total score of discharge FIM, FIM gain, and FIM efficiency did not differ significantly between the groups when rehabilitation was continued until discharge. CONCLUSION: Stroke patients with low left ventricular ejection fraction in the subacute phase could achieve almost the same functional outcomes as those of patients with preserved left ventricular ejection fraction. Although the general medical condition should be considered, the finding of low left ventricular ejection fraction did not pose a barrier to successful rehabilitation after stroke.

Echocardiographic abnormalities in patients with stroke during the subacute rehabilitation phase.

OBJECTIVE: To evaluate cardiac function using echocardiography in patients with stroke admitted to subacute rehabilitation units. DESIGN: Retrospective, cross-sectional study. PARTICIPANTS: A total of 750 consecutive patients with stroke who were admitted to a suburban rehabilitation hospital. Mean age 67.5 years (standard deviation (SD) 12.3 years). Mean time since stroke 36.7 days (SD 13.2 days). METHODS: Patients were assessed using transthoracic echocardiography within 7 days of admission. The prevalence of echocardiographic abnormalities was analysed and compared between cerebral infarction and haemorrhage using the Mantel-Haenszel method controlled for age. RESULTS: Arrhythmias were found in 13.7% of the patients, 94.2% of whom had atrial fibrillation. Left atrial enlargement and left ventricular hypertrophy were found in 20.4% and 19.5% of all patients, respectively. Left ventricular asynergy was detected in 6.1% of all patients, but 47.8% of them had no history of myocardial infarction. Left ventricular ejection fraction was low in 12.2% of all patients. Abnormal rhythms and left atrial enlargement were significantly more frequent in patients with cerebral infarction than in those with cerebral haemorrhage (p < 0.01). CONCLUSION: The prevalence of cardiac problems is high among patients with subacute stroke regardless of a history of heart disease, and this should be taken into account when planning rehabilitation programmes.

Prognostic value of coronary flow reserve assessed by transthoracic Doppler echocardiography on long-term outcome in asymptomatic patients with type 2 diabetes without overt coronary artery disease.

BACKGROUND: Cardiovascular risk stratification of asymptomatic diabetic patients is important and remains a difficult clinical problem. Our aim was to test the hypothesis that coronary flow reserve (CFR) assessed by noninvasive transthoracic Doppler echocardiography predicts prognosis in those patients. METHODS: From February 2002 to January 2005, we evaluated 135 consecutive asymptomatic patients (74 male; mean age, 63 ± 9 years) with type 2 diabetes without a history of coronary artery disease. Adenosine triphosphate (0.14 mg/kg/min) stress Doppler echocardiography was performed to evaluate CFR of the left anterior descending artery. Patients with a CFR < 2.0 were also excluded based on the suspicion of significant coronary artery stenosis in the left anterior descending artery. RESULTS: There were 111 patients (60 male; mean age, 64 ± 9 years) enrolled. During a median follow-up of 79 months, 20 events (5 deaths, 7 acute coronary syndromes, 8 coronary revascularizations) occurred. The optimal cut-off value of CFR to predict events was 2.5 (area under the receiver-operating characteristic curve = 0.65). Multivariate analysis showed that the independent prognostic indicators were male gender (p < 0.05) and a CFR < 2.5 (p < 0.01). Kaplan-Mayer analysis revealed that the event rate was significantly higher (log-lank, p < 0.01) in patients with CFR < 2.5 than in those with CFR ≥ 2.5. CONCLUSIONS: CFR obtained by transthoracic Doppler echocardiography provides independent prognostic information in asymptomatic patients with type 2 diabetes without overt coronary artery disease. Patients with CFR < 2.5 had a worse long-term outcome.

The impact of sleep deprivation on the coronary circulation.

Epidemiologic studies have reported that sleep deprivation is associated with cardiovascular events. However, it remains unknown how sleep deprivation affects the coronary circulation. We assessed the impact of sleep deprivation on the coronary circulation using coronary flow velocity reserve (CFVR) measurements with transthoracic Doppler echocardiography. We studied 26 healthy male volunteers. Each subject's CFVR was measured in the morning after sleep deprivation (less than 4 h) or normal sleep (more than 7 h) on different days. Sleep durations were 3.7 ± 0.9 h (sleep deprivation) and 7.1 ± 0.2 h (normal sleep). CFVR after sleep deprivation was significantly lower than that after normal sleep (3.3 ± 0.6 versus 4.2 ± 0.9, p<0.001). Short sleep duration attenuated CFVR compared with normal sleep duration. This finding suggests that sleep deprivation might serve as a trigger for cardiovascular events.

Prediction of the response to beta-blocker therapy in patients with dilated cardiomyopathy: comparison of 123I-MIBG scintigraphy and low-dose dobutamine stress echocardiography.

BACKGROUND: In this study, we aimed to compare low-dose dobutamine stress echocardiography (DSE) and iodine 123-metaiodobenzylguanidine (MIBG) scintigraphy for predicting the response to beta-blocker therapy in patients with dilated cardiomyopathy (DCM). METHODS: MIBG imaging was performed in 10 patients with DCM (mean EF 28 ± 8%), who were subsequently treated with beta-blocker therapy. The heart-to-mediastinum (H/M) MIBG uptake ratio was evaluated in initial and delayed images, and the percent washout ratio of myocardial MIBG was determined. DSE was also performed in all patients to measure left ventricular ejection fraction (LVEF) at rest and during dobutamine infusion (10 µg/kg/min). LVEF at rest was also assessed by echocardiography before and after 6 months of beta-blocker therapy. RESULTS: LVEF was significantly improved after beta-blocker therapy (28 ± 8 to 41 ± 11%, p < 0.001). The relative change in LVEF after beta-blocker therapy was significantly correlated with the relative change in LVEF during DSE (r = 0.68, p < 0.03). The H/M MIBG uptake ratio in both early and delayed imaging was not significantly correlated with the relative change in LVEF in response to beta-blockade therapy. CONCLUSIONS: The relative change in LVEF during DSE, but not MIBG imaging predicted the relative change in LVEF in response to beta-blockade therapy in a limited number of DCM patients.

Effect of angiotensin-converting enzyme inhibitor on serum asymmetric dimethylarginine and coronary circulation in patients with type 2 diabetes mellitus.

Measurements of serum asymmetric dimethylarginine (ADMA), an endogenous nitric oxide synthase inhibitor, and coronary flow velocity reserve (CFVR) using transthoracic Doppler echocardiography were performed at baseline and after 4 weeks of temocapril therapy (2 mg/day) in 18 patients with type 2 diabetes. Although blood pressure, fasting blood sugar and lipid profiles remained unchanged, serum ADMA concentrations decreased significantly (0.51+/-0.08 to 0.46+/-0.07 micromol/l, p<0.01) and CFVR increased significantly (2.78+/-0.36 to 3.35+/-0.46, p<0.001) after the treatment. Moreover, a strong correlation was observed between the difference of ADMA and that of CFVR (r=-0.80, p<0.001). Temocapril reduced serum ADMA concentrations, improved CFVR beyond its blood pressure lowering effect. Our results suggest that decrease in ADMA by temocapril treatment is related to improvement of coronary circulation as determined by CFVR in patients with type 2 diabetes.

Relaxation effects of lavender aromatherapy improve coronary flow velocity reserve in healthy men evaluated by transthoracic Doppler echocardiography.

PURPOSE: It has been reported that mental stress is an independent risk factor for cardiovascular events and impairs coronary circulation. Lavender aromatherapy, one of the most popular complementary treatments, is recognized as a beneficial mental relaxation therapy. However, no study has examined the effect of this therapy on coronary circulation. We aimed to assess the effect of lavender aromatherapy on coronary circulation by measuring coronary flow velocity reserve (CFVR) with noninvasive transthoracic Doppler echocardiography (TTDE). MATERIAL AND METHODS: We enrolled 30 young healthy men (mean age 34+/-4.7 years, range 24-40 years). Coronary flow velocities in the left anterior descending coronary artery were recorded by TTDE at rest and during hyperemia induced with an intravenous infusion of adenosine triphosphate (ATP). CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR was assessed at baseline and immediately after lavender aromatherapy (four drops of essential oil diluted with 20 ml of hot water and inhaled for 30 min). Simultaneously, serum cortisol was measured as a marker of stress hormones. To exclude the relaxation effects of rest, the same measurements were repeated in the same volunteers without aromatherapy as a control study. RESULTS: CFVR measurements were obtained in all volunteers (100%). Blood pressure and heart rate responses to ATP infusion were not affected by lavender aromatherapy. Serum cortisol significantly decreased after lavender aromatherapy (8.4+/-3.6 to 6.3+/-3.3, p<0.05), but remained unchanged in controls (9.1+/-3.5 to 8.1+/-3.9, p=ns). In addition, CFVR significantly increased after lavender aromatherapy (3.8+/-0.87 to 4.7+/-0.90, p<0.001), but not in controls (3.9+/-0.8 to 3.9+/-0.8, p=ns). CONCLUSIONS: Lavender aromatherapy reduced serum cortisol and improved CFVR in healthy men. These findings suggest that lavender aromatherapy has relaxation effects and may have beneficial acute effects on coronary circulation.

Cibenzoline improves coronary flow velocity reserve in patients with hypertrophic obstructive cardiomyopathy.

The effect of cibenzoline, a class-Ia antiarrhythmic drug, on coronary flow velocity reserve (CFVR) was examined in patients with hypertrophic cardiomyopathy using transthoracic Doppler echocardiography. Coronary flow velocity reserve was assessed in 11 patients with hypertrophic obstructive cardiomyopathy (HOCM) and 12 patients with hypertrophic nonobstructive cardiomyopathy (HNCM), before and after the intravenous administration of cibenzoline (1 mg/kg). Coronary hyperemia was induced by an intravenous infusion of adenosine triphosphate and CFVR was calculated as the ratio of hyperemic to basal mean coronary diastolic flow velocity. At baseline, CFVR was significantly correlated with left ventricular outflow tract pressure gradient (LVPG) in patients with HOCM (r = 0.67, P < 0.03). In patients with HOCM, administration of cibenzoline significantly improved impaired CFVR (2.0 +/- 0.8 to 3.0 +/- 1.0, P < 0.001), and reduced LVPG (55 +/- 30 to 23 +/- 18 mmHg, P < 0.001), while CFVR remained unchanged in patients with HNCM (2.6 +/- 0.9 to 2.9 +/- 0.8, P not significant). Cibenzoline not only reduces LVPG but also improves CFVR in patients with HOCM. In addition left ventricular outflow obstruction plays an important role in impaired coronary circulation in patients with HOCM.

Effect on coronary flow velocity reserve in patients with type 2 diabetes mellitus: comparison between angiotensin-converting enzyme inhibitor and angiotensin II type 1 receptor antagonist.

BACKGROUND: The effects of angiotensin antagonists on coronary circulation in type 2 diabetes are unclear. We aimed to assess whether 4 weeks of treatment with angiotensin-converting enzyme inhibitor or angiotensin II type 1 receptor antagonist improves coronary flow velocity reserve (CFVR) in patients with type 2 diabetes. METHODS: Twenty-four asymptomatic patients with type 2 diabetes were randomly assigned to temocapril (2 mg/d) or candesartan (8 mg/d). Coronary flow velocity reserve, calculated as the ratio of adenosine-induced hyperemic to basal coronary flow velocity, was measured with transthoracic Doppler echocardiography. Coronary flow velocity reserve measurement and venous blood sampling were performed before and after 4 weeks of treatment. We also obtained CFVR and venous blood data in the 8 healthy controls. RESULTS: Coronary flow velocity reserve was significantly lower in patients than controls (temocapril group 2.74 +/- 0.28, candesartan group 2.65 +/- 0.30, controls 3.53 +/- 0.23, P < .0001 for both, respectively). Blood pressure was reduced in both diabetic groups (n = 12 each) similarly 4 weeks after treatment. There were no significant differences between the 2 groups in venous blood data before or after treatment. However, CFVR increased significantly in the temocapril group (2.74 +/- 0.28 to 3.31 +/- 0.36, P < .0001), but not in the candesartan group (2.65 +/- 0.30 to 2.71 +/- 0.43, P = ns). CONCLUSIONS: Coronary flow velocity reserve in patients with type 2 diabetes improved after treatment with temocapril but not with candesartan, suggesting that angiotensin-converting enzyme inhibitor, but not angiotensin II type 1 receptor antagonist, might have beneficial effects on coronary microangiopathy associated with type 2 diabetes.

Physiologic assessment of coronary artery stenosis without stress tests: noninvasive analysis of phasic flow characteristics by transthoracic Doppler echocardiography.

We evaluated the significance of the diastolic-to-systolic blood flow velocity ratio (DSVR) determined by transthoracic Doppler echocardiography, for a physiologic assessment of the severity of coronary stenosis without stress tests, as compared with thallium 201 single photon emission computed tomography. In 95 patients undergoing thallium 201 single photon emission computed tomography for coronary artery disease, the flow velocity in the distal left anterior descending coronary artery was obtained with transthoracic Doppler echocardiography. The mean and peak DSVR values were calculated using mean and peak coronary flow velocity. DSVR was successfully measured for 82 patients (86.3%), including 33 patients with reversible perfusion defects in the left anterior descending coronary artery territories. For predicting reversible perfusion defects in thallium 201 single photon emission computed tomography, the best cut-off points were 1.5 for mean DSVR (sensitivity 81.8%, specificity 85.7%) and 1.6 for peak DSVR (sensitivity 75.7%, specificity 83.6%). Noninvasive measurement of DSVR with transthoracic Doppler echocardiography provides physiologic estimation of the left anterior descending coronary artery stenosis severity at high success rate, without stress tests.

Effect of mental stress on coronary flow velocity reserve in healthy men.

The effect of mental stress on coronary flow velocity reserve (CFVR) was examined in healthy men using transthoracic Doppler echocardiography. In the mental stress group (n = 31), CFVR was significantly reduced at 15 (to 3.3 +/- 0.8, p <0.001) and 30 (to 3.7 +/- 0.8, p <0.01) minutes after mental stress testing, compared with before mental stress (4.3 +/- 0.9), whereas it did not change in each of 3 measurements in control subjects (n = 10). Mental stress impaired coronary circulation even after a certain interval after the stress.

Acute effect of oral vitamin C on coronary circulation in young healthy smokers.

BACKGROUND: Recent studies suggest that smokers' coronary endothelial function is impaired because of increased oxidative stress, and their coronary flow velocity reserve (CFVR) is reduced. It is uncertain whether oral antioxidant vitamin C restores impaired CFVR in smokers. Recent technological advances in transthoracic Doppler echocardiography (TTDE) have resulted in the successful measurement of coronary flow velocity and noninvasive CFVR assessment. METHODS: We studied 13 healthy young male smokers and 12 nonsmokers. Coronary flow velocities in the left anterior descending coronary artery (LAD) were recorded with TTDE at rest and during hyperemia induced with intravenous infusion of adenosine triphosphate (ATP). CFVR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFVR and plasma concentrations of vitamin C were assessed at baseline and 2 and 4 hours after oral intake (2 g). RESULTS: Heart rate and blood pressure responses to ATP infusion were not affected by oral vitamin C, but plasma concentrations of vitamin C increased to physiological levels in both groups. CFVR was significantly higher in nonsmokers than in smokers at baseline (4.3 +/- 0.4 vs 3.8 +/- 0.8, P <.05). After oral vitamin C, it was increased significantly in smokers (3.8 +/- 0.8 to 4.5 +/- 0.7, P <.005, 4.5 +/- 0.8, P <.005, respectively), but not in nonsmokers (4.3 +/- 0.4 to 4.3 +/- 0.3, 4.4 +/- 0.7). CONCLUSIONS: This study demonstrated that oral vitamin C restores coronary microcirculatory function and impaired CFVR against oxidative stress in smokers.

Mammalian 5-formyluracil-DNA glycosylase. 2. Role of SMUG1 uracil-DNA glycosylase in repair of 5-formyluracil and other oxidized and deaminated base lesions.

In the accompanying paper [Matsubara, M., et al. (2003) Biochemistry 42, 4993-5002], we have partially purified and characterized rat 5-formyluracil (fU)-DNA glycosylase (FDG). Several lines of evidence have indicated that FDG is a rat homologue of single-strand-selective monofunctional uracil-DNA glycosylase (SMUG1). We report here that rat and human SMUG1 (rSMUG1 and hSMUG1) expressed from the corresponding cDNAs indeed excise fU in single-stranded (ss) and double-stranded (ds) DNA. The enzymes also excised uracil (U) and uracil derivatives bearing an oxidized group at C5 [5-hydroxyuracil (hoU) and 5-hydroxymethyluracil (hmU)] in ssDNA and dsDNA but not analogous cytosine derivatives (5-hydroxycytosine and 5-formylcytosine) and other oxidized damage. The damage specificity and the salt concentration dependence of rSMUG1 (and hSMUG1) agreed well with those of FDG, confirming that FDG is rSMUG1. Consistent with the damage specificity above, hSMUG1 removed damaged bases from Fenton-oxidized calf thymus DNA, generating abasic sites. The amount of resulting abasic sites was about 10% of that generated by endonuclease III or 8-oxoguanine glycosylase in the same substrate. The HeLa cell extract and hSMUG1 exhibited a similar damage preference (hoU.G > hmU.A, fU.A), and the activities for fU, hmU, and hoU in the cell extract were effectively neutralized with hSMUG1 antibodies. These data indicate a dual role of hSMUG1 as a backup enzyme for UNG and a primary repair enzyme for a subset of oxidized pyrimidines such as fU, hmU, and hoU.

Induction of apoptosis and ubiquitin hydrolase gene expression by human serum factors in the early phase of acute myocardial infarction.

The physiologic events leading to apoptosis in myocardial infarction and the molecules involved in the death process have not been clarified unequivocally. We developed a method to search for serum factors that induce apoptosis of human cells, using serum obtained from patients within 1 day of the onset of acute myocardial infarction (AMI). Serum factors were found to have the ability to increase the caspase-3 activity levels in human RSa cells, which are susceptible to apoptosis inducers. The factors obtained from AMI patients by elution at about 0.5 mol/L KCl from a dye-ligand column were named AMI-SFs (serum factors from AMI). Electrophoretic analysis showed DNA fragmentation in AMI-SF-treated RSa cells, but not in RSa cells treated with fractions from AMI patients 1 week after clinical onset of illness. AMI-SF-induced DNA fragmentation was also demonstrated by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling analysis, whereas a suppression of fragmentation was seen in RSa cells treated with AMI-SFs in combination with a caspase-3 inhibitor. The increase in caspase-3 activity was not inhibited by neutralizing antibodies to tumor necrosis factor-alpha, interleukin-6, human interferon-beta, or interferon-gamma. Polymerase chain reaction-based messenger RNA differential display and Northern blotting revealed an increase in the messenger RNA expression level of human ubiquitin hydrolase in AMI-SF-treated RSa cells. Antisense oligonucleotides for ubiquitin hydrolase inhibited the increase in caspase-3 activity. These findings suggested that serum from AMI patients in the acute phase contains factors that induce apoptosis, possibly by inducing the expression of the ubiquitin hydrolase gene, at least in the human cells tested.

Novel nuclear and mitochondrial glycosylases revealed by disruption of the mouse Nth1 gene encoding an endonuclease III homolog for repair of thymine glycols.

Endonuclease III, encoded by nth in Escherichia coli, removes thymine glycols (Tg), a toxic oxidative DNA lesion. To determine the biological significance of this repair in mammals, we established a mouse model with mutated mNth1, a homolog of nth, by gene targeting. The homozygous mNth1 mutant mice showed no detectable phenotypical abnormality. Embryonic cells with or without wild-type mNth1 showed no difference in sensitivity to menadione or hydrogen peroxide. Tg produced in the mutant mouse liver DNA by X-ray irradiation disappeared with time, though more slowly than in the wild-type mouse. In extracts from mutant mouse liver, we found, instead of mNTH1 activity, at least two novel DNA glycosylase activities against Tg. One activity is significantly higher in the mutant than in wild-type mouse in mitochondria, while the other is another nuclear glycosylase for Tg. These results underscore the importance of base excision repair of Tg both in the nuclei and mitochondria in mammals.