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.

Two phase imaging of 99mTc-SESTAMIBI and 123I-BMIPP for patients with angina pectoris.

We saw three cases of angina pectoris in which 99mTc-SESTAMIBI delayed images at rest were useful in diagnosing ischemia risk areas. These findings indicated that delayed 99mTc-SESTAMIBI images may be more sensitive to slight ischemia than 123I-BMIPP images, and suggested that imaging with 99mTc-SESTAMIBI twice at rest may be more effective. The addition of 123I-BMIPP SPECT was considered to be useful in making an evaluation of the severity of ischemia.

Detection of stunned myocardium in post-reperfusion cases of acute myocardial infarction.

OBJECTIVE: This study was designed to evaluate the correlation between improvements in serial images obtained by SPECT imaging with Tc-99m MIBI (MIBI) and I-123 BMIPP (BMIPP) and the recovery of cardiac function in acute myocardial infarction (AMI) patients after reperfusion therapy. METHODS: Twenty five patients who were admitted to the emergency room within 24 hours after the onset of the first event of AMI were enrolled in this study. The culprit coronary arteries were identified by CAG and were treated with direct percutaneous transluminal coronary angiography (PTCA), followed by stent implantation. To determine risk areas, initial image at the onset was acquired by the freeze method, in which MIBI was injected before the treatment and the image was collected after the reperfusion therapy. After the reperfusion treatment was completed, MIBI SPECT images at rest were performed on days 7 and 60. Both early and late images, including gated SPECT images were acquired after 30-60 minutes and 6 hours post injection, respectively. In addition, BMIPP SPECT images at rest were obtained 30 minutes after injection of 148 MBq BMIPP on days 7 and 60 (BMIPP image). The obtained image was divided into 48 segments and percent uptake of each segment was calculated. The number of abnormal areas (NAA) was defined as the segment with a % uptake less than 60% of normal uptake, and the change of NAA over time was evaluated. RESULTS: The NAA on the MIBI-early image significantly improved between thepre image and the day 7 image (p < 0.001), but no similar improvement was observed between day 7 and day 60. On the other hand, the NAA of the MIBI-delayed image did not significantly improve up to day 7, but a slight improvement was observed on days 7 and 60 (p < 0.05). A significant improvement in the NAA of the BMIPP image was observed between day 7 and day 60, as shown in the delayed image (p < 0.05). An excellent correlation on the NAA between the MIBI-delayed image and the BMIPP image was observed with r = 0.983 (p < 0.001) at day 7 and r = 0.984 (p < 0.001) at day 60 resulting in a consistent diagnosis. Analysis of the myocardial function by means of gated SPECT indicated that the wall motion significantly improved as the myocardial perfusion improved up to day 7 and thereafter a steady improvement was observed up to day 60. The improvement in the NAA in MIBI-delayed images in the subacute phase (day 7) and in the chronic phase (day 60) as well as BMIPP images showed excellent correlation with the improvement in RWM and RWT (MIBI-delayed image: r = 0.550 (RWM), r = 0.647 (RWT)), (BMIPP image: r = 0.536 (RWM), r = 0.565 (RWT)). CONCLUSION: We conclude that insufficient ATP production caused by mitochondrial dysfunction in stunned myocardium is closely related to MIBI delayed and BMIPP image Furthermore, MIBI delayed imaging as well as BMIPP imaging will provide a clue to the state of stunned myocardium after reperfusion therapy in patients with AMI.

Long-term combined therapy with an angiotensin type I receptor blocker and an angiotensin converting enzyme inhibitor prolongs survival in dilated cardiomyopathy.

The efficacy of ACE inhibitors (ACEIs) in the treatment of chronic heart failures is well documented. However, ACEIs may provide incomplete blockade of the renin-angiotensin system (RAS) because of the alternative pathways for angiotensin II (All) production. We hypothesized that more complete blockade of RAS by adding an AT1 receptor blocker (ARB) may have greater potential to decrease mortality associated with heart failure and improve cardiac function than monotherapy with ACEIs. The objective of this study was to evaluate the effect of combined therapy on cardiac functions and survival in cardiomyopathic hamsters. Male cardiomyopathic hamsters (BIO TO2) were administered either placebo (group C), enalapril (30 mg/kg/day) (group E), or enalapril (30 mg/kg/day) + valsartan (500 mg/ kg/day) (group EV), starting at the age of 6 weeks. Kaplan-Meier analysis was performed to assess the differences in survival. Cardiac functions were evaluated by echocardiogram and cardiac catheterization. Group EV showed significant increases in fractional shortening, LV dP/dTmax, and deceleration time, and showed significant decreases in left ventricular diastolic dimension, LV dP/dTmin, and early diastolic mitral velocity/atrial systolic velocity. Treatment with enalapril resulted in longer survival compared with placebo. Moreover, life expectancy (median probability of survival: 433 days) increased significantly in group EV compared with group E (P<0.05) as well as group C (P<0.001). It is concluded that combined therapy improved cardiac function and survival compared to placebo or enalapril monotherapy.

Altered microvasculature is involved in remodeling processes in cardiomyopathic hamsters.

UNLABELLED: The cardiomyopathic hamster (BIO TO2) is a well-established model of heart failure. Deterioration of cardiac function in BIO TO2 is attributed to a defect in delta-sarcoglycan, whereas cardiac dysfunction in delta-sarcoglycan knockout mice is caused by microvascular abnormalities. We examined the relation between cardiac function and the microvasculature, including angiogenic factors, in BIO TO2. METHODS AND RESULTS: At the age of 5 weeks, percent fractional shortening (%FS) and positive rate of change in left ventricular pressure over time (dP/dt max) were lower in BIO TO2 than in age-matched F1B controls. Capillary density, capillary/myocyte (CM) ratio, capillary domain area (CDA), and myocyte density were similar between BIO TO2 and F1B controls. At the ages of 13 and 20 weeks, BIO had significantly lower capillary and myocyte densities and a significantly higher CM ratio and CDA. Myocyte density positively correlated with %FS and dP/dt max. There were no significant differences in mRNA expression for VEGF, Flt-1, angiopoietin-1, or angiopoietin-2 between BIO TO2 and F1B control. CONCLUSION: Progressive myocyte loss is responsible for deterioration of cardiac function in BIO TO2. The impaired neovascularization may be involved in the progress of cardiac remodeling in cardiomyopathic hamsters.