Detection of dynamic lung hyperinflation using cardiopulmonary exercise testing and respiratory function in patients with stable cardiac disease: a multicenter, cross-sectional study.

BACKGROUND: Many patients with heart disease potentially have comorbid chronic obstructive pulmonary disease (COPD); however, there are not enough opportunities for screening, and the qualitative differentiation of shortness of breath (SOB) has not been well established. We investigated the detection rate of SOB based on a visual and qualitative dynamic lung hyperinflation (DLH) detection index during cardiopulmonary exercise testing (CPET) and assessed potential differences in respiratory function between groups. METHODS: We recruited 534 patients with heart disease or patients who underwent simultaneous CPET and spirometry (369 males, 67.0 ± 12.9 years) to scrutinize physical functions. The difference between inspiratory and expiratory tidal volume was calculated (TV E-I) from the breath-by-breath data. Patients were grouped into convex (decreased TV E-I) and non-convex (unchanged or increased TV E-I) groups based on their TV E-I values after the start of exercise. RESULTS: Among the recruited patients, 129 (24.2%) were categorized in the convex group. There was no difference in clinical characteristics between the two groups. The Borg scale scores at the end of the CPET showed no difference. VE/VCO2 slope, its Y-intercept, and minimum VE/VCO2 showed no significant difference between the groups. In the convex group, FEV1.0/FVC was significantly lower compared to that in the non-convex group (69.4 ± 13.1 vs. 75.0 ± 9.0%). Moreover, significant correlations were observed between FEV1.0/FVC and Y-intercept (r=-0.343), as well as between the difference between minimum VE/VCO2 and VE/VCO2 slope (r=-0.478). CONCLUSIONS: The convex group showed decreased respiratory function, suggesting a potential airway obstruction during exercise. A combined assessment of the TV E-I and Y-intercept of the VE/VCO2 slope or the difference between the minimum VE/VCO2 and VE/VCO2 slopes could potentially detect COPD or airway obstruction.

Partial Pressure of End-Tidal Oxygen and Blood Lactate During Cardiopulmonary Exercise Testing in Healthy Older Participants and Patients at Risk of Cardiac Disease.

Background: The partial pressure of end-tidal oxygen (PETO2) and end-tidal oxygen concentration (ETO2) are among the indices that can be measured by exhaled gas analysis. Several observational studies have shown that skeletal muscle function is impaired in patients with cardiac disease; thus, the assessment of skeletal muscle function is important. Additionally, although it has recently been suggested that the difference in PETO2 from rest to the ventilatory anaerobic threshold (VAT) reflects oxygen availability in peripheral factors, primarily skeletal muscle, the evidence for this is not well established. Therefore, we hypothesized and investigated whether increased blood lactate (BLa) levels, resulting from decreased skeletal muscle and mitochondrial oxygen availability, and PETO2 dynamics during cardiopulmonary exercise testing (CPET) would be related. Methods: All participants performed the symptomatic limited CPET, and their BLa levels were measured. The difference in PETO2 and ETO2 from rest to VAT determined by the V-slope method (ΔPETO2 and ΔETO2) was calculated and compared with the increase in BLa due to exercise testing. Results: We recruited 22 healthy older participants (nine males; 69.4 ± 6.8 years) and 11 patients with cardiovascular risk (eight males; 73.0 ± 8.8 years). ΔPETO2 and ΔETO2 did not differ between the two groups (P = 0.355 and P = 0.369, respectively), showing no correlation between increase in BLa from rest to VAT, but were significantly correlated with an increase in BLa from rest to the end of exercise (ΔPETO2, P = 0.030; ΔETO2, P = 0.029). The correlation was particularly pronounced among those at cardiovascular risk (ΔPETO2, P = 0.012; ΔETO2, P = 0.011). Conclusions: ΔPETO2 and ΔETO2 from rest to VAT during CPET may be useful as indices reflecting skeletal muscle oxygen utilization capacity.

The concept of detection of dynamic lung hyperinflation using cardiopulmonary exercise testing.

Dynamic lung hyperinflation (DLH) caused by air trapping, which increases residual air volume, is a common cause of shortness of breath on exertion in chronic obstructive pulmonary disease (COPD). DLH is commonly evaluated by measuring the decrease in maximal inspiratory volume during exercise, or using the hyperventilation method. However, only few facilities perform these methods, and testing opportunities are limited. Therefore, we investigated the possibility of visually and qualitatively detecting DLH using data from a cardiopulmonary exercise test (CPET). Four men who underwent symptom-limiting CPET were included in this study, including a male patient in his 60s with confirmed COPD, a 50s male long-term smoker, and 2 healthy men in their 20s and 70s, respectively. We calculated the difference between the inspiratory tidal volume (TV I) and expiratory tidal volume (TV E) per breath (TV E-I) from the breath-by-breath data of each CPET and plotted it against the time axis. No decrease in TV E-I was observed in either of the healthy men. However, in the patient with COPD and long-term smoker, TV E-I began to decrease immediately after the initiation of exercise. These results indicate that DLH can be visually detected using CPET data. However, this study was a validation of a limited number of cases, and a comparison with existing evaluation methods and verification of disease specificity are required.

Prolonged mean response time in older adults with cardiovascular risk compared to healthy older adults.

BACKGROUND: During incremental exercise (Inc-Ex), the mean response time (MRT) of oxygen uptake (V̇O2) represents the time delay before changes in muscle V̇O2 reflect at the mouth level. MRT calculation by linear regression or monoexponential (τ') fitting of V̇O2 data are known to be highly variable, and a combination of incremental and constant load exercise (CL-Ex) is more reproducible. METHODS: We evaluated MRT in older adults using linear regression and combination methods. We recruited 20 healthy adults (male: 9, 69.4 ± 6.8 years) and 10 cardiovascular risk subjects (male: 8, 73.0 ± 8.8 years). On day 1, they performed Inc-Ex using a 10W/min ramp protocol, for determination of the ventilatory anaerobic threshold (VAT) using the V-slope method. On day 2, they performed Inc-Ex to VAT exercise intensity and CL-Ex for 25min total. The MRT was calculated from the CL-Ex V̇O2 average and the time at equivalent V̇O2 in the Inc-Ex. We also assessed the amount of physical activity using the International Physical Activity Questionnaire short form (IPAQ-SF). RESULTS: The MRT of healthy participants and those at cardiovascular risk were 49.2 ± 36.3 vs. 83.6 ± 45.4s (p = 0.033). Total physical activity in the IPAQ-SF was inversely correlated with MRT. CONCLUSION: The MRT was significantly prolonged in cardiovascular risk participants compared to healthy participants, possibly related to the amount of daily physical activity. Individual MRT may be useful for adjustment of exercise intensity, but this should also be based on daily physical activity and individual condition during exercise.

The Ratio of Oxygen Uptake From Ventilatory Anaerobic Threshold to Respiratory Compensation Point Is Maintained During Incremental Exercise in Older Adults.

Introduction: The period from ventilatory anaerobic threshold (VAT) to respiratory compensation point (RCP) during incremental exercise (isocapnic buffering phase) has been associated with exercise tolerance and skeletal muscle composition. However, several reports compare younger and older healthy adults, and specific age-related changes are unclear. This study aimed to examine the oxygen uptake (VO2) from VAT to RCP and its change over time in younger and older healthy adults. Methods: A total of 126 consecutive participants were divided into two groups (95 younger and 31 older than 50 years of age) who underwent cardiopulmonary exercise testing, and VAT and RCP were determined. The ratio (RCP/VAT) and difference (ΔVO2 RCP-VAT) were calculated from the VO2 of VAT and RCP and compared between groups and ages. Statistical analyses included t-tests and Spearman's correlation tests, and the significance level was set at <5%. Results: RCP/VAT was not significantly different (1.40 ± 0.19 vs. 1.59 ± 0.24, p = 0.057) but weakly correlated with age (r = -0.229, p = 0.013, y = -0.0031x + 1.7588, lowering rate: 0.185%/year). Conversely, ΔVO2 RCP-VAT was significantly lower in the older group (7.7 ± 3.1 vs. 13.8 ± 4.9 ml/kg/min, p < 0.001) and correlated significantly with age (r = -0.499; p < 0.001; y = -0.1303x + 16.855; lowering rate, 0.914%/year). Conclusion: ΔVO2 RCP-VAT was considered to be a poor indicator of lactate buffering capacity in the IB phase because both VAT and RCP were greatly affected by age-related decline. Conversely, RCP/VAT was suggested to be an index not easily affected by aging.

Gas exchange threshold to guide exercise training intensity of older individuals during cardiac rehabilitation.

ABSTRACT: The gas exchange threshold (GET), which is determined during incremental exercise (Inc-Ex) testing, is often considered a safe training intensity for cardiac rehabilitation. However, there are only a limited number of reports on the actual implementation of this method. We assessed the applicability of GET-guided exercise using a constant load exercise (CL-Ex) protocol.We recruited 20 healthy older individuals (healthy, age: 69.4 ±â€Š6.8 years) and 10 patients with cardiovascular diseases or risk factors (patient, age: 73.0 ±â€Š8.8 years). On day 1, we determined the GET during symptomatic maximal Inc-Ex. On day 2, CL-Ex at work rate (watt: W) where the GET manifested during Inc-Ex (therefore, not corrected for the known oxygen response delay) was maintained for 20 minute. Arterialized blood lactate (BLa) levels were also determined.Oxygen uptake reached a steady state in all participants, with a mean respiratory exchange ratio of < 1.0. The mean BLa at the GET during Inc-Ex was 1.51 ±â€Š.29 mmol·l-1 in the healthy group and 1.78 ±â€Š.42 mmol·L-1 in the patient group, which was about .5 mmol·L-1 above the resting level. During CL-Ex, BLa increased significantly over the value at the GET (Inc-Ex). However, it reached a steady-state level of 2.65 ±â€Š1.56 (healthy) and 2.53 ±â€Š0.95 (patient) mmol·L-1. The %peak oxygen uptake, %peak heart rate, and %heart rate reserve during CL-Ex were 58.8 ±â€Š11.5, 71.8 ±â€Š10.3, and 44.9 ±â€Š17.4, respectively. All participants could complete CL-Ex with mean perceived exertion ratings (Borg/20) of 11.8 ±â€Š1.3 (healthy) and 12.2 ±â€Š1.3 (patient). These heart rate-related indices and exertion ratings were all within the recommended international guidelines for cardiac rehabilitation.CL-Ex at the GET appears to be the optimal exercise intensity for cardiac rehabilitation.

Blood pressure-lowering effect of repeated Waon therapy in non-smokers with hypertension.

ABSTRACT: Waon therapy (WT) has been used as a thermal therapy in chronic heart failure patients. However, its effect in patients with hypertension is unclear. This study aimed to reveal the hypotensive effect of WT in patients with hypertension. WT was performed on 31 patients with hypertension (63.9 ±â€Š11.9 years, male: 17) on standard hypertension treatment focusing on lifestyle modification and medication. Systolic and diastolic blood pressures were measured before and after WT using an upper arm automated sphygmomanometer. We investigated the effect of single and repeated (1 time/d, >5 times) WT sessions on blood pressure and further compared its effect between current smoking (n = 11, 55.4 ±â€Š6.4 years, 8.5 ±â€Š2.4 times) and non-smoking (n = 11, 66.9 ±â€Š8.5 years, 12.2 ±â€Š5.9 times) groups. A total of 370 sessions of WT were conducted. Systolic and diastolic blood pressures significantly decreased after a single WT session (systolic blood pressure: 118.5 ±â€Š10.1 to 115.1 ±â€Š9.0 mm Hg, P < .001; diastolic blood pressure: 70.5 ±â€Š6.4 to 65.9 ±â€Š5.3 mm Hg, P < .001). The blood pressure decrease following repeated WT was not significant when all participants were considered (systolic blood pressure: 122.3 ±â€Š15.2 to 116.9 ±â€Š19.6 mm Hg; diastolic blood pressure: 73.8 ±â€Š16.7 to 68.2 ±â€Š13.2 mm Hg); however, it was significant in the non-smoking group (systolic blood pressure: 124.2 ±â€Š11.3 to 108.8 ±â€Š13.4 mm Hg, P < .001; diastolic blood pressure: 73.6 ±â€Š4.9 to 62.1 ±â€Š7.6 mm Hg, P < .001). Repeated WT (at least 5 sessions) decreased blood pressure in patients with hypertension, especially in non-smokers. WT is a simple method to reduce blood pressure in non-smoking patients with hypertension.

New method for the mathematical derivation of the ventilatory anaerobic threshold: a retrospective study.

BACKGROUND: Ventilatory anaerobic threshold (VAT) is a useful submaximal measure of exercise tolerance; however, it must be visually determined. We developed a new mathematical method to objectively determine VAT. METHODS: We employed two retrospective population data sets (A/B). Data A (from 128 healthy subjects, patients with cardiovascular risk factors, and cardiac subjects at institution A, who underwent symptom-limited cardiopulmonary exercise testing) were used to develop the method. Data B (from 163 cardiac patients at institution B, who underwent pre-/post-rehabilitation submaximal exercise testing) were used to apply the developed method. VAT (by V-slope) was visually determined (vVAT), assuming that the pre-VAT segment is parallel to the respiratory exchange ratio (R) = 1 line. RESULTS: First, from data A, exponential fitting of ramp V-slope data yielded the equation y = ba x, where a is the slope of the exponential function: a smaller value signified a less steep curve, representing less VCO2 against VO2. Next, a tangential line parallel to R = 1 was drawn. The x-axis value of the contact point was the derived VAT, termed the expVAT (VCO2) (calculated as LN (1/[b*LN(a)]/LN(a). This point represents an instantaneous ΔVCO2/ΔVO2 of 1.0. Second, in a similar way, the relation of VO2 vs. VE (minute ventilation) was fitted exponentially. The tangent line that crosses zero was drawn and the x-axis value was termed expVAT (VE) (calculated as 1/LN(a). For data A, the correlation coefficients (r) of vVAT versus VAT (CO2), and VAT (VE) were 0.924 and 0.903, respectively (p < 0.001), with no significant difference between mean values with the limits of agreement (1.96*SD of the pair difference) being ±276 and ± 278 mL/min, respectively. expVAT (VCO2) and expVAT (VE) significantly correlated with VO2peak (r = 0.971, r = 0.935, p < 0.001). For data B, after cardiac rehabilitation, expVAT (CO2) and exp. (VE) (mL/min) increased from 641 ± 185 to 685 ± 201 and from 696 ± 182 to 727 ± 209, respectively (p < 0.001, p < 0.008), while vVAT increased from 673 ± 191 to 734 ± 226 (p < 0.001). During submaximal testing, expVAT (VCO2) underestimated VAT, whereas expVAT (VE) did not. CONCLUSIONS: Two new mathematically-derived estimates to determine VAT are promising because they yielded an objective VAT that significantly correlated with VO2peak, and detected training effect as well as visual VAT did.

Very Early Lactate Threshold in Healthy Young Men as Related to Oxygen Uptake Kinetics.

We assessed the correspondence between the V-slope ventilatory threshold (VT) and the lactate threshold (LT) by using a distinctive slow submaximal ramp protocol to ensure that sufficient data points exist around the threshold. Twenty healthy young men participated. A submaximal test based on a prior maximal test (25 watt/min, medium ramp) was performed with an individual slow-ramp protocol (6-17 watt/min, slow ramp), in which the time to reach the VT workload was estimated to be 10 minutes. The LT was determined visually by detecting a rise above the resting value, without or with log-log transformation (LT1, LT2). The point at which the blood lactate exceeded the minimal difference (LMD) of 2 resting values was also calculated. The VT appeared significantly earlier under the slow-ramp protocol compared to the medium-ramp protocol (from 19.3 ± 3.9 to 15.0 ± 4.0 mL/kg/min VO2, P < 0.001). The mean LT1 and LT2 values appeared even earlier than the VT (LT1, P = 0.004; LT2, P = 0.002) (LT1, 11.9; LT2, 13.4; LMD, 17.0; VT, 15.0 mL/kg/min VO2). As the mean % of peak VO2, each occurred at 29.9%, 33.7%, 42.5%, and 37.8%. The VT correlated significantly with LT1, LT2, and LMD (r = 0.61, 0.64, 0.80; P = 0.004, 0.002, <0.001). Mean blood lactate showed a similar trend (1.30, 1.43, 1.81, 1.68 mmol/L, respectively). Furthermore, the ΔVO2/Δ work rate slope increased (from 10.8 ± 0.9 to 11.5 ± 0.9; P = 0.01) with the slow ramp, and the lower LT was associated with the greater increase in slope (LT1, r = -0.47, P = 0.03; LT2, r = -0.59, P =  .005), that is, the lower LT was an indication that on the faster medium ramp the slope would decrease. The LMD and VT did not show this relation. Under slow-ramp exercise testing in healthy young men, the VT appeared earlier than under medium-ramp exercise testing. In addition, the LT appeared even earlier (at approximately 30% of peak VO2) than the VT, although they correlated. This very early onset of LT was, however, associated with evidence of reduced oxygen uptake kinetics.

Pravastatin attenuates left ventricular remodeling and diastolic dysfunction in angiotensin II-induced hypertensive mice.

BACKGROUND: A substantial proportion of patients with heart failure have a normal ejection fraction and diastolic dysfunction. However, there are few data available to guide the therapy of these patients. The effects of statins on cardiac remodeling are well documented in animal models and it is reported that statin therapy revealed a survival benefit in patients with diastolic heart failure (DHF). However, the exact mechanisms of statins possibly explaining the decreased cardiovascular morbidity and mortality in patients with DHF have not been elucidated. METHODS: We used 8-week-old male C57BL/6J mice, in which angiotensin II was subcutaneously infused for 4 weeks to mimic cardiac remodeling and fibrosis. They were treated with either normal saline or pravastatin in daily doses, which did not lower the serum cholesterol levels and blood pressure. RESULTS: Pravastatin improved diastolic dysfunction in angiotensin II-induced hypertensive mice, which was associated with the amelioration of left ventricular hypertrophy and remodeling. However, statin treatment showed no effect on the increased systolic blood pressure or cholesterol levels by angiotensin II infusion. The cardioprotective effects of pravastatin were closely associated with the downregulation of collagen I, transforming growth factor-beta, matrix metalloproteinases-2 and -3, atrial natriuretic factor, interleukin-6, tumor necrosis factor-alpha, ROCK1 gene expression, and the upregulation of endothelial nitric oxide synthase gene expression. CONCLUSIONS: The beneficial effects of pravastatin on DHF and structural remodeling are through cholesterol- independent mechanism of statins or "pleiotropic" effects of statins involving improving or restoring endothelial function and decreasing vascular inflammation. These findings suggest the potential involvement of ROCK1. Thus, treatment with pravastatin might be beneficial in patients with DHF.

No positive association between adrenergic receptor variants of alpha2cDel322-325, beta1Ser49, beta1Arg389 and the risk for heart failure in the Japanese population.

AIMS: We investigated the correlation of adrenergic receptor polymorphisms, alpha(2c)Del322-325, beta(1)Ser49Gly and beta(1)Arg389Gly, with the risk of heart failure in the Japanese population. METHODS: These polymorphisms were analysed by polymerase chain reaction-restriction fragment length polymorphism in patients with chronic heart failure due to idiopathic dilated cardiomyopathy (DCM) and compared with the control group. RESULTS: There were no differences or any trends in the allele and genotype frequencies of the beta(1)Ser49Gly and beta(1)Arg389Gly polymorphisms. The allele frequency of the alpha(2c)Del322-325 variant was lower in patients than in controls (0.11 vs. 0.04, P = 0.011 < 0.017, by Bonferroni correction), while the genotype frequency just failed to reach significance (P = 0.022 > 0.017, by Bonferroni correction). CONCLUSIONS: In this population, the variants beta(1)Ser49, beta(1)Arg389, and alpha(2c)Del322-325 do not appear to be risk factors for chronic heart failure due to DCM. The alpha(2c)Del322-325 variant may in fact confer some protection.

Blockade of macrophage migration inhibitory factor ameliorates experimental autoimmune myocarditis.

Macrophage migration inhibitory factor (MIF) is a cytokine that plays a critical role in the regulation of macrophage effector functions and T-cell activation. However, its role in the pathogenesis of experimental autoimmune myocarditis (EAM) has remained unresolved. In this study, we studied the role of the MIF in EAM. We investigated the expression of MIF in EAM using enzyme-linked immunosorbent assay, Northern blotting, and immunohistochemistry. Moreover, a neutralizing antibody (Ab) to MIF was injected intraperitoneally from day 0 to 20 (experiment 1), or from day 13 to 19 (experiment 2), after the immunization. Disease severity was estimated by the macroscopic and microscopic findings for the heart, heart weight to body weight ratio, and cellular and humoral immune responses on day 21. Enhanced MIF protein and mRNA expression in the heart tissue and an elevated serum MIF concentration were confirmed in EAM. In experiment 1, the anti-MIF Ab treatment markedly inhibited the onset of EAM. Moreover, a significant reduction in disease severity was also achieved even after the delayed anti-MIF Ab treatment in experiment 2. Furthermore, we demonstrated that MIF blockade decreased the expression of VCAM-1, TNF-alpha, and IL-1beta and the migration of T-cells and macrophages in the EAM heart. These results demonstrate an important role of MIF in the pathogenesis of EAM and suggest that MIF blockade may be a promising new strategy for the treatment of myocarditis.

Role of osteopontin in cardiac fibrosis and remodeling in angiotensin II-induced cardiac hypertrophy.

Osteopontin (OPN) is upregulated in several experimental models of cardiac fibrosis and remodeling. However, its direct effects remain unclear. We examined the hypothesis that OPN is important for the development of cardiac fibrosis and remodeling. Moreover, we examined whether the inhibitory effect of eplerenone (Ep), a novel aldosterone receptor antagonist, was mediated through the inhibition of OPN expression against cardiac fibrosis and remodeling. Wild-type (WT) and OPN-deficient mice were treated with angiotensin II (Ang II) for 4 weeks. WT mice receiving Ang II were divided into 2 groups: a control group and an Ep treatment group. Ang II treatment significantly elevated blood pressure and caused cardiac hypertrophy and fibrosis in WT mice. Ep treatment and OPN deficiency could reduce the Ang II-induced elevation of blood pressure and ameliorate the development of cardiac fibrosis, whereas Ep-only treatment abolished the development of cardiac hypertrophy. Most compelling, the reduction of cardiac fibrosis led to an impairment of cardiac systolic function and subsequent left ventricular dilatation in Ang II-treated OPN-deficient mice. These results suggest that OPN has a pivotal role in the development of Ang II-induced cardiac fibrosis and remodeling. Moreover, the effect of Ep on the prevention of cardiac fibrosis, but not cardiac hypertrophy, might be partially mediated through the inhibition of OPN expression.

A newly developed angiotensin II type 1 receptor antagonist, CS866, promotes regression of cardiac hypertrophy by reducing integrin beta1 expression.

Previous studies have demonstrated that integrins link the extracellular matrix to the hypertrophic response pathway of cardiac myocytes in vitro. To examine the direct relation between integrin beta1 and cardiac hypertrophy in vivo, we studied the effects of a newly developed angiotensin II type 1 (AT1) blocker, CS866 (ARB; 10 mg/kg/day), an angiotensin-converting enzyme inhibitor, temocapril (ACEI, 10 mg/kg/day), or both on modulation of integrin beta1 in the hypertrophied hearts of stroke-prone spontaneously hypertensive rats (SHRSP) 6 to 12 weeks of age. Treatments with ARB, ACEI, and combination therapy significantly reduced systolic blood pressure. However, the reduction in cardiac hypertrophy was greater in SHRSP treated with ARB or combination therapy than in those treated with ACEI. Multiplex reverse transcription-polymerase chain reaction revealed significantly higher mRNA expression of atrial natriuretic factor, AT1 receptor, and integrin beta1 in untreated SHRSP than in normotensive Wistar-Kyoto rats (WKY). The mRNA levels of ANP, AT1 receptor, and integrin B1 in SHRSP were significantly decreased by treatment with ARB, ACEI, or combination therapy. Decreased mRNA expression of ANP, AT1 receptor, and integrin beta1 in the treated SHRSP was associated with reductions in blood pressure; ARB and combination therapy produced greater decreases in expression than did ACEI. These observations suggest that CS866 has a beneficial effect on myocyte hypertrophy and that down-regulation of AT1 receptor and suppression of integrin beta1 participate in the regression of pressure-induced cardiac hypertrophy in vivo. The correlation between the expression of integrin beta1 and AT1 receptor was significant. Our results also suggest that integrin expression by myocytes might be modulated by angiotensin II via AT1 receptor.

Osteopontin deficiency attenuates atherosclerosis in female apolipoprotein E-deficient mice.

OBJECTIVE: Osteopontin (OPN), a noncollagenous adhesive protein, is implicated in atherosclerosis, in which macrophages within atherosclerotic plaques express OPN. However, it is not known whether the elevated OPN expression is a cause or result of atherosclerosis. METHODS AND RESULTS: We generated mice that lacked OPN and crossed them with apolipoprotein (apo) E-deficient mice and analyzed these mice with a mixed C57BL/6x129 background after 36 weeks on a normal chow diet. In female mice, OP+/-E-/- and OP-/-E-/- mice had significantly smaller atherosclerotic and inflammatory lesions compared with OP+/+E-/- mice, and that was reflected by smaller area of MOMA-2-positive staining. In male mice, however, there was no significant difference in the atherosclerosis lesion areas among 3 genotypes. In both OP-/-E-/- and OP+/+E-/- mice, typical atherosclerotic lesions were detected, which include necrotic core, foamy cell collections, and cholesterol clefts. However, we found that vascular mineral-deposited areas in 60-week-old male OP-/-E-/- mice were significantly increased compared with those in OP+/+E-/- male mice. CONCLUSIONS: These results suggest that OPN plays a promoting effect in atherosclerosis and inhibitory effect in vascular calcification. The suppression of OPN expression in females should be considered a therapeutic possibility in atherosclerosis.

VEGF-mediated angiogenesis is impaired by angiotensin type 1 receptor blockade in cardiomyopathic hamster hearts.

OBJECTIVE: Coronary microcirculation plays an important role in the progression of cardiac remodeling. Among angiogenic factors, it has been reported that angiotensin II may contribute to neovascularization. However, it is unknown whether inhibition of the renin-angiotensin system suppresses angiogenesis, especially within the heart. Our aim was to evaluate the effects of the angiotensin-converting enzyme inhibitor enalapril and the angiotensin II receptor type I blocker valsartan on cardiac microvasculature, function, vascular endothelial growth factor (VEGF) expression, and survival in cardiomyopathic hamsters. METHODS: Male cardiomyopathic hamsters (BIO TO2) were administered either a placebo (group C), enalapril (30 mg/kg/day) (group E), or valsartan (40 mg/kg/day) (group V), starting at the age of 6 weeks. This continued until death. Hemodynamic study, histological analysis, and northern blot analysis were performed at 39 weeks. RESULTS: Group V showed significant increases in percent fibrosis, end diastolic pressure, and LV dP/dt min, and significant decreases in percent fractional shortening, LV dP/dt max, capillary density, and the level of mRNA expression of VEGF compared with group C. Group E showed significant increases in percent fractional shortening while the capillary density and level of mRNA expression of VEGF were unchanged. The 300-day survival rate was significantly lower in group V (25.0%) but higher in group E (100%) than that of group C (66.7%). CONCLUSIONS: Therapy with valsartan may have adverse effects on survival rate concomitant with the progression of cardiac remodeling owing to impaired VEGF-mediated angiogenesis. Therapy with enalapril has a neutral effect on VEGF-mediated angiogenesis, leading to the suppression of cardiac remodeling and an increase in life expectancy.

Adenovirus-mediated gene transfer of ICOSIg fusion protein ameliorates ongoing experimental autoimmune myocarditis.

Experimental autoimmune myocarditis (EAM) has been used as a model for human myocarditis. We previously demonstrated that blockade of B7/CD28 or CD40/CD40 ligand (CD40L) had a potential preventive effect on EAM, but less therapeutic effect on ongoing EAM. Thus, we searched for the involvement of other costimulatory molecules in EAM. We demonstrated the expression of inducible costimulator (ICOS)/ICOSL molecules in the lymph nodes, spleen, and heart in the EAM rat. We constructed adenovirus vectors containing ICOSIg (Adex1CAICOSIg) to achieve effective inhibition of ICOS/ICOSL interaction, and examined the effects of Adex1CAICOSIg on EAM. Adex1CAICOSIg treatment shortly after the immunization did not inhibit the onset and severity of EAM compared to control rats. On the other hand, delayed treatment with Adex1CAICOSIg significantly inhibited ongoing EAM. The survival rate in rats treated with Adex1CAICOSIg was significantly higher than that of the control group. Furthermore, the affected area ratio of the Adex1CAICOSIg treatment group was significantly lower than that of the control group. This study indicates that ICOS/ICOSL costimulation makes an important contribution to the progression of EAM and that the blockade of this pathway by gene transfer has therapeutic potential for ongoing autoimmune myocarditis.