Sedentary behaviour may cause differences in physical outcomes and activities of daily living in older cardiovascular disease patients participating in phase I cardiac rehabilitation.

This study aimed to investigate the rate of sedentary behaviour and differences in physical outcomes and activities of daily living (ADL) based on sedentary behaviour time of hospitalized older cardiovascular disease patients undergoing phase I cardiac rehabilitation. Older cardiovascular disease patients were enrolled from October 2020 to September 2023 and were divided into the high sedentary behaviour group (≥ 480 min/day) and low sedentary behaviour group (< 480 min/day). Patients' clinical characteristics, usual gait speed, and Five Times Sit to Stand Test time were compared as indices of physical outcomes. Motor, cognitive, and total Functional Independence Measure (FIM) scores were used as indices of ADL and compared between groups using analysis of covariance. Final analysis included 402 patients (mean age: 76.7 years, female: 35.3%). The high sedentary behaviour group included 48.5% of the study patients. After adjustment for baseline characteristics, gait speed (0.80 ± 0.27 vs. 0.96 ± 0.23 m/s, p < 0.001) was lower and FTSST time (11.31 ± 4.19 vs. 9.39 ± 3.11 s, p < 0.001) was higher in the high sedentary behaviour group versus low sedentary behaviour group. Motor (85.82 ± 8.82 vs. 88.09 ± 5.04 points, p < 0.001), cognitive (33.32 ± 2.93 vs. 34.04 ± 2.24 points, p < 0.001), and total FIM scores (119.13 ± 10.66 vs. 122.02 ± 6.30 points, p < 0.001) were significantly lower in the high sedentary behaviour group versus low sedentary behaviour group after adjustment. In older cardiovascular disease patients in phase I cardiac rehabilitation, sedentary behaviour time might influence physical outcomes and ADL at discharge. It is thus important to consider the amount of sedentary behaviour time spent by these patients during daily life while hospitalized.

Determinants of Anaerobic Threshold at Each Stage of Renal Dysfunction in Patients With Heart Disease.

Patients with heart disease have a low anaerobic threshold (AT), and the determinants of AT may differ, depending on the severity of renal dysfunction. This study aimed to verify the determinants of AT for each stage of renal function in patients with heart disease. We consecutively enrolled 250 patients with heart disease who underwent cardiopulmonary exercise testing in our institution. The patients were divided into 3 groups by their estimated glomerular filtration rate (eGFR): <45, 45 to 59, and ≥60 ml/min/1.73 m2. A multivariate linear regression analysis was performed to evaluate the independent determinants of AT for each group. In total, 201 patients were analyzed. AT decreased with the deterioration of renal function (eGFR <45, 10.9 ± 2.1 vs eGFR 45 to 59, 12.4 ± 2.5 vs eGFR ≥60, 14.0 ± 2.6 ml/min/kg, p <0.001). In the eGFR <45 group, left ventricular ejection fraction and hemoglobin were significantly associated with AT (ß = 0.427, p = 0.006 and ß = 0.488, p = 0.002, respectively). In the eGFR 45 to 59 and ≥60 groups, ΔPETO2 (end-tidal oxygen partial pressure from rest to AT) showed a significant association with AT (ß = 0.576, p <0.001 and ß = 0.308, p = 0.003, respectively). The determinants of AT depended on the stage of renal dysfunction in patients with heart disease. In conclusion, in the eGFR <45 group, the determinants of AT were left ventricular ejection fraction and hemoglobin, whereas in the eGFR 45 to 59 and eGFR ≥60 groups, the determinant of AT was ΔPETO2.

Relation of sedentary behaviour to physical function in phase I cardiac rehabilitation.

Increased sedentary behaviour (SB) is reportedly associated with mortality and morbidity in cardiovascular disease. However, its relation with physical function is not well understood in phase I cardiac rehabilitation (CR). This study aimed to investigate the rate of SB and the relation between SB and physical function among patients participating in phase I CR. This prospective multicentre cohort study enrolled patients participating in CR from October 2020 to July 2022. Patients with probable dementia and difficulty walking alone were excluded. We used sitting SB time as the index of SB and the Short Performance Physical Battery (SPPB) as the index of physical function at discharge. Patients were divided into the low SB group (< 480 min/day) or high SB group (≥ 480 min/day). We analysed and compared the two groups. The final analysis included 353 patients (mean age: 69.6 years, male: 75.6%), of whom 47.6% (168 of 353) were high SB patients. Total sitting SB time was higher in the high SB group versus the low SB group (733.6 ± 155.3 vs 246.4 ± 127.4 min/day, p < 0.001), and mean SPPB score was lower in the high SB group versus the low SB group (10.5 ± 2.4 vs 11.2 ± 1.6 points, p = 0.001). Multiple regression analysis identified SB as an explanatory variable for total SPPB score (p = 0.017). Patients with high SB had significantly lower SPPB scores than those with low SB. These findings underscore the importance of considering SB when improving physical function. Effective strategies to improve physical function can be developed that consider SB in phase I CR.

End-tidal oxygen partial pressure is a strong prognostic predictive factor in patients with cardiac disease.

BACKGROUND: Cardiopulmonary exercise testing (CPET) variables represent central and peripheral factors and combined factors in the pathology of patients with cardiac disease. The difference in end-tidal oxygen partial pressure from resting to anaerobic threshold (ΔPETO2 ) may represent predominantly peripheral factors. This study aimed to verify the prognostic significance of ΔPETO2 for major adverse cardiac and cerebrovascular events (MACCE) in cardiac patients, including comparison with the minute ventilation-carbon dioxide production relationship (VE/VCO2 slope), and peak oxygen uptake (VO2 ). METHODS: In total, 185 patients with cardiac disease who underwent CPET were consecutively enroled in this retrospective study. The primary endpoint was 3-year MACCE. The ability of ΔPETO2 , VE/VCO2 slope, and peak VO2 to predict MACCE was examined. RESULTS: Optimal cut-off values for predicting MACCE were 2.0 mmHg for ΔPETO2 (area under the curve [AUC]: 0.829), 29.8 for VE/VCO2 slope (AUC: 0.734), and 19.0 mL/min/kg for peak VO2 (AUC: 0.755). The AUC of ΔPETO2 was higher than those of VE/VCO2 slope and peak VO2 . The MACCE-free survival rate was significantly lower in the ΔPETO2 ≤ 2.0 group versus the ΔPETO2 > 2.0 group (44.4% vs. 91.2%, p < 0.001). ΔPETO2 ≤ 2.0 was an independent predictor of MACCE after adjustment for age and VE/VCO2 slope (hazard ratio [HR], 7.28; p < 0.001) and after adjustment for age and peak VO2 (HR, 6.52; p < 0.001). CONCLUSION: ΔPETO2 was a strong predictor of MACCE independent of and superior to VE/VCO2 slope and peak VO2 in patients with cardiac disease.

Relationship between health literacy and physical function of patients participating in phase I cardiac rehabilitation: a multicenter clinical study.

Health literacy (HL) is an important decision factor for health. Both low HL and low physical function cause adverse events in cardiovascular disease patients, but their relationship is not well documented. To clarify the relationship between HL and physical function of patients participating in cardiac rehabilitation and calculate the cutoff value of the 14-item HL scale (HLS) for low handgrip strength, this multicenter clinical study named the Kobe-Cardiac Rehabilitation project for people around the World (K-CREW) was conducted among four affiliated hospitals with patients who underwent cardiac rehabilitation. We used the 14-item HLS to assess HL, and the main outcomes were handgrip strength and Short Physical Performance Battery (SPPB) score. The study included 167 cardiac rehabilitation patients with a mean age of 70.5 ± 12.8 years, and the ratio of males was 74%. Among them, 90 patients (53.9%) had low HL and scored significantly lower in both handgrip strength and SPPB. Multiple linear regression analysis revealed that HL was a determinant factor (ß = 0.118, p = 0.04) for handgrip strength. Receiver operating characteristic analysis revealed the cutoff value of the 14-item HLS for screening for low handgrip strength was 47.0 points, and the area under the curve was 0.73. This study showed that HL was significantly associated with handgrip strength and SPPB in cardiac rehabilitation patients and suggests the possibility of early screening for low HL to improve physical function in cardiac rehabilitation patients with low HL.

Health Literacy Is Associated with Activities of Daily Living of Patients Participating in Cardiac Rehabilitation: A Multicenter Clinical Study.

The activities of daily living (ADL) in patients with cardiac disease tend to decline. A previous study revealed that ADL relates to physical and cognitive functions associated with health literacy (HL). However, the relationship between HL and ADL is not well documented. This study aimed to clarify this relationship among patients participating in cardiac rehabilitation. This multicenter study, the Kobe-Cardiac Rehabilitation project for people around the World (K-CREW), included patients who participated in cardiac rehabilitation from October 2020 to December 2021. Patients with probable dementia and difficulty walking alone were excluded. We used the 14-item Health Literacy Scale (HLS-14) to assess HL and the Functional Independence Measure (FIM) to assess ADL at discharge. Patients were divided by their HLS-14 score into the low HL group (<50 points) or the high HL group (≥50 points). We analyzed the relationship between the HLS-14 and FIM scores. We investigated 268 cardiac rehabilitation patients (median age, 71.0 years; male ratio, 76.9%). Low HL patients accounted for 51.1% of all patients and had significantly lower motor and cognitive FIM scores. Functional HL related better to the FIM scores (r = 0.28-0.36) than did other HL subclasses. Multiple regression analysis identified HLS-14 as an explanatory variable (p = 0.002) for the total FIM score. Patients with low HL had significantly lower ADL than those with high HL. These findings underscore the importance of considering HL in cardiac rehabilitation.

Older phase 2 cardiac rehabilitation patients engaged in gardening maintained physical function during the COVID-19 pandemic.

This study aimed to clarify the effects of gardening on hemodynamic response, rating of perceived exertion (RPE) during exercise, and body weight in patients in whom phase 2 cardiac rehabilitation (CR) was interrupted due to the Coronavirus disease 2019 (COVID-19) pandemic. Among 76 outpatients participating in consecutive phase 2 CR in both periods from March to April and June to July 2020, which were before and after CR interruption, respectively, at Sanda City Hospital were enrolled. The inclusion criterion was outpatients whose CR was interrupted due to COVID-19. Patients under the age of 65 were excluded. We compared the data of hemodynamic response and RPE during exercise on the last day before interruption and the first day after interruption when aerobic exercise was performed at the same exercise intensity in the gardener group and the non-gardener group. Forty-one patients were enrolled in the final analysis. After CR interruption, the gardener group did not show any significant difference in all items, whereas the non-gardener group experienced significant increase in HR (Peak) (p = 0.004) and worsening of the Borg scale scores for both dyspnea and lower extremity fatigue (p = 0.039 and p = 0.009, respectively). Older phase 2 CR patients engaged in gardening did not show any deterioration in hemodynamic response or RPE during exercise, despite CR interruption and refraining from going outside. Gardening may be recommended as one of the activities that can maintain or improve physical function in older phase 2 CR patients during the COVID-19 pandemic.

Determinants of Peak Oxygen Uptake at Each Stage of Renal Dysfunction in Patients with Heart Disease.

Background: Identifying the causes of low peak oxygen uptake (peak V̇ O 2 ) in heart disease patients with renal dysfunction is necessary for prognostic improvement strategies. The purpose of this study was to verify the determinants of peak V̇ O 2 for each stage of renal function in heart disease patients, focusing on end-tidal oxygen partial pressure ( PETO 2 ). Methods: Two hundred fifty heart disease patients who underwent cardiopulmonary exercise testing (CPET) in our institution were consecutively enrolled. Patients were divided into three groups by their estimated glomerular filtration rate (eGFR): < 45, 45-59 and ≥ 60 mL/min/1.73 m 2 . Patient characteristics and CPET parameters including Δ 2 (rest-anaerobic threshold) were compared between the groups. The relationship between Δ PETO PETO 2 and peak V̇ O 2 was also investigated for each group. Results: In total, 201 patients were analyzed. Δ PETO 2 decreased with the deterioration of renal function (eGFR < 45, 0.1 mmHg vs. eGFR 45-59, 2.4 mmHg vs. eGFR ≥ 60, 5.2 mmHg, p < 0.001). In the eGFR < 45 group, left ventricular ejection fraction (LVEF) and hemoglobin (Hb) were significantly associated with peak V̇ O 2 ß = 0.518, p < 0.001 and ß = 0.567, p < 0.001, respectively), whereas Δ PETO 2 was not. In the eGFR 45-59 group, age, Hb, and Δ PETO 2 showed a significant association with peak V̇ O 2 ( ß = -0.354, p = 0.006; ß = 0.258, p = 0.007; ß = 0.501, p < 0.001; respectively). In the univariate analysis, eGFR 45-59 group showed the highest coefficient of determination of Δ PETO 2 to peak V̇ O 2 ( R 2 = 0.247, p < 0.001). Conclusions: The determinants of peak V̇ O 2 in heart disease patients depended on the stage of renal function. The determinants of peak V̇ O 2 in patients with eGFR < 45 were LVEF and Hb, while Δ PETO 2 was the strongest predictor of peak V̇ O 2 in patients with eGFR 45-59.

Relationship of end-tidal oxygen partial pressure to the determinants of anaerobic threshold in post-myocardial infarction patients.

The anaerobic threshold (AT), obtained during cardiopulmonary exercise testing (CPET), is an important prognostic measure and can be used to develop an exercise prescription in patients after a myocardial infarction (post-MI). The purpose of this study was to examine the central and peripheral determinants of AT in post-MI patients end-tidal oxygen partial pressure (PETO2) measures. We performed cardiopulmonary exercise testing (CPET) on 148 consecutively enrolled post-MI patients to determine PETO2 measured at the AT (AT PETO2) and ΔPETO2 (difference between resting PETO2 and AT PETO2). We subsequently investigated the relationship between these measures of PETO2 and the individual AT for each patient. Multivariate linear regression analysis indicated that AT PETO2 and ΔPETO2 were independently and significantly associated with the AT (ß = -0.344, p < 0.001 and ß = 0.228, p < 0.001, respectively). Furthermore, the independent factors of AT PETO2 were left ventricular ejection fraction (p = 0.005), resting ventilatory equivalent for carbon dioxide (p = 0.002), and resting dead-space gas volume to tidal volume ratio (p < 0.001). However, the independent factors for ΔPETO2 were history of diabetes (p = 0.047), estimated glomerular filtration rate (p = 0.001), and resting systolic blood pressure (p = 0.017). These findings suggested that AT PETO2 was associated with central determinants; whereas, and ΔPETO2 was associated with peripheral determinants, The AT PETO2 and ΔPETO2 provide variable insight regarding the cause of exercise intolerance and can be used to determine appropriate therapies.

Impact of worsening renal function on peak oxygen uptake in patients with acute myocardial infarction.

AIM: Worsening renal function (WRF) induced by acute myocardial infarction (AMI) is a strong predictor of cardiovascular events and mortality. Peak oxygen uptake may contribute to prognosis in AMI patients with WRF, however, the impact of WRF on peak oxygen uptake is unclear. METHODS: Among 154 patients with AMI who underwent emergency percutaneous coronary intervention and participated in phase II cardiac rehabilitation, those who underwent cardiopulmonary exercise testing were consecutively enrolled. WRF was defined as a ≥20% decrease in estimated glomerular filtration rate (eGFR [ml/min/1.73 m2 ]) from admission to that at cardiopulmonary exercise testing. The association of WRF with peak oxygen uptake was evaluated by multivariate regression analysis. The non-WRF group was divided into two subgroups according to eGFR <60/≥60 at cardiopulmonary exercise testing, and eGFR at cardiopulmonary exercise testing and peak oxygen uptake of all three groups were compared. RESULTS: Ninety-four patients were enrolled in the final analysis. Multiple linear regression analysis showed that WRF was associated with peak oxygen uptake (p = .003). Comparing the non-WRF group with eGFR at cardiopulmonary exercise testing <60 and the WRF group, although eGFR at cardiopulmonary exercise testing was similar (p = 1.000), peak oxygen uptake in the WRF group was significantly lower (p = .026). CONCLUSION: WRF, not eGFR at cardiopulmonary exercise testing was significantly associated with peak oxygen uptake in patients with AMI. This result suggests that when considering the relationship between renal function and peak oxygen uptake, WRF must be taken into account.

Impact of the COVID-19 pandemic on phase 2 cardiac rehabilitation patients in Japan.

This study aimed to clarify the effects of the interruption of cardiac rehabilitation (CR) and refraining from going outside due to the COVID-19 pandemic on hemodynamic response and rating of perceived exertion (RPE) during exercise including differences by age in phase 2 CR outpatients. Among 76 outpatients participating in consecutive phase 2 CR in both periods from March to April and June to July 2020, which were before and after CR interruption, respectively, at Sanda City Hospital were enrolled. The inclusion criterion was outpatients whose CR was interrupted due to COVID-19. We compared the data of hemodynamic response and RPE during exercise on the last day before interruption and the first day after interruption when aerobic exercise was performed at the same exercise intensity in the < 75 years group and ≥ 75 years group. Fifty-three patients were enrolled in the final analysis. Post-CR interruption, peak heart rate increased significantly (p = 0.009) in the < 75 years group, whereas in the ≥ 75 years group, weight and body mass index decreased significantly (p = 0.009, 0.011, respectively) and Borg scale scores for both dyspnea and lower extremities fatigue worsened significantly (both, p < 0.001). CR interruption and refraining from going outside due to the COVID-19 pandemic affected the hemodynamic response, RPE during exercise and body weight in phase 2 CR outpatients. In particular, patients aged ≥ 75 years appeared to be placed at an increased risk of frailty.

Increased Heart Rate during Walk Test Predicts Chronic-Phase Worsening of Renal Function in Patients with Acute Myocardial Infarction and Normal Kidney Function.

Chronic-phase worsening renal function (WRF) in patients with acute myocardial infarction (AMI) has been associated with poor prognosis. However, there is no consensus on either the method of prevention or the cause. The aim of this study was to determine factors predictive of chronic-phase WRF from the viewpoint of circulatory dynamics response to exercise during hospitalization of AMI patients without renal dysfunction on admission. We studied 186 consecutively AMI patients who underwent the 200-m walk test. Chronic-phase WRF was defined as a 20% decrease in estimated glomerular filtration rate (eGFR) from baseline to 8-10 months after AMI onset. Heart rate (HR) and systolic blood pressure recorded during the 200-m walk test were evaluated as circulatory dynamics responses. In total, 94 patients were enrolled. Multiple linear regression analysis showed that ΔHR (peak-rest) associated significantly with ΔeGFR (ß = 0.427, p = 0.018). The receiver operating characteristic curve of ΔHR to predict chronic-phase WRF showed an area under the curve of 0.77, with a cut-off value of 22.0 bpm having a 95% sensitivity and 55% specificity. Among circulatory dynamics responses during exercise in the acute phase after AMI, ΔHR was an independent predictor of chronic-phase WRF.

Beneficial effect of anti-platelet therapies on atherosclerotic lesion formation assessed by phase-contrast X-ray CT imaging.

We have applied an imaging system of phase-contrast X-ray CT to the detection of atherosclerotic plaque components by means of the differences of tissue mass densities. In this study, we investigated the effect of the anti-platelet therapies, widely used for secondly prevention of cardiovascular events, on plaque stability and examined whether this novel technique could detect the changes of plaque components under the therapy. Apolipoprotein E-deficient mice were fed on high-cholesterol diet alone and either with 0.1% cilostazol or clopidogrel for 10 weeks. We assessed atherosclerotic lesion volumes and components at brachiocephalic artery by the phase-contrast X-ray CT imaging and histochemistry. The phase-contrast X-ray CT imaging could reveal that cilostazol and clopidogrel significantly decreased atherosclerotic lesion volumes at brachiocephalic artery (31.2% reduction in cilostazol group and 37.4% reduction in clopidogrel group), compared with control group. In addition, the mass densities calculated by this method revealed the anti-platelet treatment increased stable plaque areas including high collagen content, but decreased unstable plaque areas including lipid and macrophage content. These findings were confirmed by histological analyses. Real-time PCR analyses indicated that anti-platelets inhibited gene expressions of cytokines and adhesion molecules, such as IFNγ and ICAM-1. Anti-platelet therapies had a beneficial effect on plaque stability maybe due to anti-inflammatory actions. Phase-contrast X-ray CT imaging could quantify the plaque volume and qualify the plaque components affected by anti-platelet therapies. This novel phase-contrast X-ray CT imaging system could be a plausible method to detect the unstable plaque non-invasively in the future.

Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis.

RATIONALE: Angiogenesis contributes to physiological and pathological conditions, including atherosclerosis. The Rap1 small G protein regulates vascular integrity and angiogenesis. However, little is known about the effectors of Rap1 involved in angiogenesis. It is not known whether afadin, an adherens junction protein that connects immunoglobulin-like adhesion molecule nectins to the actin cytoskeleton and binds activated Rap1, plays a role in angiogenesis. OBJECTIVE: We investigated the role of endothelial afadin in angiogenesis and attempted to clarify the underlying molecular mechanism. METHODS AND RESULTS: Treatment of human umbilical vein endothelial cells (HUVECs) with vascular endothelial growth factor (VEGF) and sphingosine 1-phosphate (S1P) induced the activation of Rap1. Activated Rap1 regulated intracellular localization of afadin. Knockdown of Rap1 or afadin by small interfering RNA inhibited the VEGF- and S1P-induced capillary-like network formation, migration, and proliferation, and increased the serum deprivation-induced apoptosis of HUVECs. Knockdown of Rap1 or afadin decreased the accumulation of adherens and tight junction proteins to the cell-cell contact sites. Rap1 regulated the interaction between afadin and phosphatidylinositol 3-kinase (PI3K), recruitment of the afadin-PI3K complex to the leading edge, and the activation of Akt, indicating the involvement of Rap1 and afadin in the PI3K-Akt signaling pathway. Binding of afadin to Rap1 regulated the activity of Rap1 in a positive-feedback manner. In vivo, conditional deletion of afadin in mouse vascular endothelium using a Cre-loxP system impaired the VEGF- and S1P-induced angiogenesis. CONCLUSIONS: These results demonstrate a novel molecular mechanism by which Rap1 and afadin regulate the VEGF- and S1P-induced angiogenesis.

Oral anti-CD3 antibody treatment induces regulatory T cells and inhibits the development of atherosclerosis in mice.

BACKGROUND: Accumulating evidence suggests that several subsets of regulatory T cells that actively mediate immunologic tolerance play crucial roles in atherogenesis. Recently, orally administered anti-CD3 monoclonal antibody has been shown as an inducer of novel regulatory T cells expressing latency-associated peptide (LAP) on their surface, which potently prevents systemic autoimmunity. In the present study, we hypothesized that oral anti-CD3 antibody treatment may inhibit atherosclerosis in mice. METHODS AND RESULTS: Six-week-old apolipoprotein E-deficient mice on a standard diet were orally given anti-CD3 antibody or control immunoglobulin G on 5 consecutive days, and atherosclerosis was assessed at age 16 weeks. Oral administration of anti-CD3 antibody significantly reduced atherosclerotic lesion formation and accumulations of macrophages and CD4(+) T cells in the plaques compared with controls. We observed a significant increase in LAP(+) cells and CD25(+)Foxp3(+) cells in the CD4(+) T-cell population in anti-CD3-treated mice, in association with increased production of the antiinflammatory cytokine transforming growth factor-beta and suppressed T-helper type 1 and type 2 immune responses. Neutralization of transforming growth factor-beta in vivo abrogated the preventive effect of oral anti-CD3 antibody. CONCLUSIONS: Our findings indicate the atheroprotective role of oral anti-CD3 antibody treatment in mice via induction of a regulatory T-cell response. These findings suggest that oral immune modulation may represent an attractive therapeutic approach to atherosclerosis.

Plasma tetrahydrobiopterin/dihydrobiopterin ratio: a possible marker of endothelial dysfunction.

BACKGROUND: Although endothelium-dependent vasodilatation has been used as a marker of endothelial dysfunction (ED), there have been no reliable plasma markers for ED. Oxidative stress, which is a major determinant of ED, oxidizes tetrahydrobiopterin (BH4), an essential cofactor of endothelial type nitric oxide synthase (eNOS), and resulted in the relative deficiency of BH4. METHODS AND RESULTS: In 163 patients with cardiovascular disorders, the plasma levels of BH4 and 7, 8-dihydrobiopterin (BH2) by high performance liquid chromatography were measured and compared with the flow-mediated (FMD) vasodilatory response of the brachial artery, which was measured by ultrasonography. The effects of atorvastatin on plasma pteridine levels and FMD were examined in patients with multiple coronary risk factors. There was a positive relationship between FMD and plasma BH4 levels and a negative relationship between FMD and plasma BH2 levels. Subsequently, a strong positive relationship between FMD and the BH4/BH2 ratio (r=0.585, P<0.0001) was found. Although we did not find any significant relationship between pteridine levels and individual traditional risk factors, the BH4/BH2 ratio in patients with more than 2 risk factors showed significant reductions compared with that in those without risk factors. Statin treatment improved FMD in association with an increase in the plasma BH4/BH2 ratio. CONCLUSIONS: Plasma pteridine levels were associated with endothelial dysfunction in cardiovascular disorders.

Beneficial effects of exogenous tetrahydrobiopterin on left ventricular remodeling after myocardial infarction in rats: the possible role of oxidative stress caused by uncoupled endothelial nitric oxide synthase.

BACKGROUND: Reactive oxygen species (ROS) is deeply involved in the process of ventricular remodeling after myocardial infarction (MI). Under oxidative stress, endothelial nitric oxide synthase (eNOS) can be converted to a ROS generator, because a relative lack of tetrahydrobiopterin (BH4), an essential cofactor for NO synthesis, leads to eNOS uncoupling. The uncoupled eNOS generates superoxide rather than NO. The possible role of ROS generated by eNOS in ventricular remodeling after MI was investigated. METHODS AND RESULTS: Rats were treated with oral BH4 supplementation starting at 3 days before coronary artery ligation. At 4 weeks after MI, there was augmented superoxide production in association with reduced BH4/dihydrobiopterin (BH2) ratio and eNOS dimer/monomer protein ratio in the heart. Treatment with BH4 increased BH4/BH2 ratio and eNOS dimer/monomer ratio, and decreased superoxide production. In BH4-treated MI rats, left ventricular size was smaller, thickness of the non-infarcted posterior wall was thinner, and cardiac function was preserved compared with the control MI rats. CONCLUSIONS: The present study suggested that ventricular remodeling process after MI leads to BH4 oxidation and resulted in uncoupled eNOS-derived superoxide generation, which further augmented the remodeling process and deteriorated cardiac function.

Atherosclerotic plaque imaging using phase-contrast X-ray computed tomography.

Reliable, noninvasive imaging modalities to characterize plaque components are clinically desirable for detecting unstable coronary plaques, which cause acute coronary syndrome. Although recent clinical developments in computed tomography (CT) have enabled the visualization of luminal narrowing and calcified plaques in coronary arteries, the identification of noncalcified plaque components remains difficult. Phase-contrast X-ray CT imaging has great potentials to reveal the structures inside biological soft tissues, because its sensitivity to light elements is almost 1,000 times greater than that of absorption-contrast X-ray imaging. Moreover, a specific mass density of tissue can be estimated using phase-contrast X-ray CT. Ex vivo phase-contrast X-ray CT was performed using a synchrotron radiation source (SPring-8, Japan) to investigate atherosclerotic plaque components of apolipoprotein E-deficient mice. Samples were also histologically analyzed. Phase-contrast X-ray CT at a spatial resolution of 10-20 mum revealed atherosclerotic plaque components easily, and thin fibrous caps were detected. The specific mass densities of these plaque components were quantitatively estimated. The mass density of lipid area was significantly lower (1.011 +/- 0.001766 g/ml) than that of smooth muscle area or collagen area (1.057 +/- 0.001407 and 1.080 +/- 0.001794 g/ml, respectively). Moreover, the three-dimensional assessment of plaques could provide their anatomical information. Phase-contrast X-ray CT can estimate the tissue mass density of atherosclerotic plaques and detect lipid-rich areas. It can be a promising noninvasive technique for the investigation of plaque components and detection of unstable coronary plaques.

Xenogenic macrophage immunization reduces atherosclerosis in apolipoprotein E knockout mice.

Atherosclerosis is a complex chronic inflammatory disease in which macrophages play a critical role, and the intervention of the inflammatory process in atherogenesis could be a therapeutic strategy. In this study, we investigated the efficacy of xenogenic macrophage immunization on the atherosclerotic lesion formation in a model of murine atherosclerosis. Apolipoprotein E knockout (apoE-KO) mice were repeatedly immunized with formaldehyde-fixed cultured human macrophages (phorbol ester-stimulated THP-1 cells), using human serum albumin as a control protein or HepG2 cells as human control cells, once a week for four consecutive weeks. The vehicle phosphate-buffered saline was injected in the nonimmunized controls. THP-1 immunization induced antibodies that are immunoreactive with mouse macrophages. Although the plasma lipid levels were unchanged by the immunization, the atherosclerotic lesion area in the aortic root was significantly reduced by >50% in 16-wk-old THP-1-immunized apoE-KO mice compared with that in control mice. THP-1 immunization reduced in vivo macrophage infiltration, reduced in vitro macrophage adhesion, and changed cytokine production by macrophages to the antiatherogenic phenotype. Xenogenic macrophage immunization protects against the development of atherosclerosis in apoE-KO mice by modulating macrophage function in which antibodies induced by the immunization are likely to be involved. This method is a novel and potentially useful cell-mediated immune therapeutic technique against atherosclerosis.