Overweight causes left ventricular diastolic asynchrony and diastolic dysfunction: a study based on speckle tracking echocardiography in healthy subjects.

BACKGROUND: Left ventricular (LV) diastolic dysfunction is often observed in healthy subjects and can be a cause of heart failure with preserved ejection fraction (EF). We aimed to investigate the role of LV diastolic asynchrony as a cause of diastolic dysfunction in healthy subjects. METHODS: In 40 healthy subjects, two-dimensional speckle tracking imaging (2DSTI) was performed to measure the peak early diastolic longitudinal strain rates (Esr) of the apical, mid-ventricular, and basal segments of the septum and posterior wall. A mean value of the Esr of the 6 segments (mEsr) was calculated. The time from aortic valve closure to the Esr was measured for each segment, and the standard deviation (SDTEsr) was calculated. The peak global early diastolic strain rate (gEsr) was measured with a region of interest (ROI) on the whole LV myocardium. LV flow propagation velocity (FPV) was measured using conventional Doppler techniques. RESULTS: SDTEsr was not correlated with age, but was significantly correlated with body mass index (BMI) (r = 0.41, p < 0.01). Although no significant correlation was observed between mEsr and FPV, gEsr and SDTEsr significantly correlated with FPV (r = 0.41, p < 0.01; r = -0.54, p < 0.001). As a result of the multiple regression analysis, SDTEsr was the single determinant of FPV. CONCLUSIONS: Diastolic asynchrony, associated with overweight but not with aging, may contribute to diastolic dysfunction in healthy subjects.

Early diastolic mitral annular velocity at the interventricular septal annulus correctly reflects left ventricular longitudinal myocardial relaxation.

AIMS: Early diastolic mitral annular velocity (e') obtained by tissue Doppler imaging (TDI) is widely used to evaluate left ventricular (LV) diastolic function based on the assumption that it reflects myocardial relaxation in the long-axis direction. In this study, we aimed to determine whether or not e' truly reflects early diastolic longitudinal myocardial relaxation, and which is the most useful for evaluating LV diastolic function among e' measured at the interventricular-septal annulus (IS-e'), that measured at the lateral annulus (LW-e') or their mean value (M-e'). METHODS AND RESULTS: IS-e', LW-e', and M-e' were measured using colour TDI in 15 patients with hypertrophic cardiomyopathy, 13 patients with hypertension, and 19 control subjects. Using two-dimensional speckle-tracking imaging, early diastolic myocardial strain rates (SR(E)) were measured for the IS (IS-SR(E)), LW (LW-SR(E)), and entire LV myocardium (G-SR(E)). IS-e' was excellently correlated with IS-SR(E) (r = 0.90, P < 0.001); the correlation was better than that between LW-e' and LW-SR(E) (r = 0.75, P < 0.001). IS-e' and M-e' were well correlated with G-SR(E) (r = 0.88, P < 0.001 and r = 0.86, P< 0.001, respectively) and with LV early diastolic flow propagation velocity (FPV) (r = 0.77, P < 0.001 and r = 0.78, P < 0.001, respectively). The correlations of LW-e' to G-SR(E) (r = 0.80, P < 0.001) and FPV (r = 0.75, P < 0.001) did not reach this level. CONCLUSION: IS-e' well reflected LV longitudinal myocardial relaxation and LV diastolic function, and was found to be more useful in evaluating LV diastolic function than LW-e'.

Novel strain rate index of contractility loss caused by mechanical dyssynchrony. - A predictor of response to cardiac resynchronization therapy-.

BACKGROUND: Time-delay indexes are limited in predicting the response to cardiac resynchronization therapy (CRT), partly because they do not reflect the residual left ventricular (LV) contractility. We computed a novel index of LV contractility loss due to dyssynchrony (the strain rate (SR) dispersion index: SRDI) by using the speckle-tracking SR and compared the efficacy of the SRDI, time-delay indexes, and strain delay index (SDI), the previously reported index of wasted energy due to dyssynchrony, for predicting the acute response to CRT. METHODS AND RESULTS: Echocardiography was performed in 19 heart failure patients (LV ejection fraction (EF) 25 ± 6%) before and 2 weeks after CRT. The standard deviation of time to peak velocity, or strain, was calculated as time-delay indexes. The SRDI was calculated as the average of segmental peak systolic SR minus global peak systolic SR. Longitudinal SDI (L-SDI), longitudinal SRDI (L-SRDI), and circumferential SRDI (C-SRDI) significantly correlated with the change in global longitudinal strain (Δglobal LSt), whereas the time-delay indexes did not. Although the time-delay indexes were comparable between responders (Δglobal LSt ≥ 0.3%) and nonresponders, the L-SDI, L-SRDI, and C-SRDI were greater in responders. The area under the receiver operating characteristic curve of the L-SRDI, L-SDI, and C-SRDI for predicting responders was 0.89, 0.81, and 0.78, respectively. CONCLUSIONS: The SRDI correlated fairly well with an improvement in global LV systolic function after CRT.

Angiotensin II receptor blocker, valsartan, increases myocardial blood volume and regresses hypertrophy in hypertensive patients.

BACKGROUND: Although a reduction in myocardial blood volume (MBV), an in vivo index of the myocardial microvasculature, measured by myocardial contrast echocardiography in patients with hypertension (HT), can be demonstrated, it is still unknown whether a decreased MBV can be improved by antihypertensive treatment. METHODS AND RESULTS: Eleven HT patients (mean age 58 years, 7 men) with left ventricular hypertrophy (LVH) and 10 age- and sex-matched normal controls were studied. Harmonic power Doppler images were acquired at end-diastole of every 6(th) beat and MBV was calculated as 10(X/10)x100%, where X (dB) is myocardial contrast intensity minus the contrast intensity of the adjacent intracavity blood pool. Baseline blood pressure (BP) and left ventricular mass index (LVMI) in the HT patients were higher and MBV was lower than in the controls (2.52 +/-0.37% vs 3.31 +/-0.61%, P<0.01). MBV did not correlate with mean BP, but was inversely correlated with LVMI (r=0.61, P<0.01). After treatment with valsartan for 6 months, LVMI significantly decreased and MBV increased (2.72 +/-0.26%, P<0.05 vs baseline) in the patients with HT. There was a significant inverse correlation between the changes in MBV and those of LVMI (r=0.62, P<0.05), but not between MBV and mean BP. CONCLUSIONS: Valsartan, an angiotensin II receptor blocker, corrected the decreased MBV in association with regression of LVH in patients with HT.

Right ventricular diastolic dysfunction in patients with left ventricular hypertrophy: analysis of right ventricular myocardial relaxation using two-dimensional speckle tracking imaging.

BACKGROUND: Although several previous studies have suggested the presence of right ventricular (RV) diastolic dysfunction in patients with hypertrophic cardiomyopathy (HCM) and those with hypertensive left ventricular hypertrophy (HT-LVH), the mechanisms are still unclear. This study aimed to clarify the relationship between the RV global diastolic dysfunction in these patients and the regional myocardial diastolic function, including synchronicity of the interventricular septum and RV free wall. METHODS: In 20 age-matched patients with HT-LVH, 20 patients with HCM and 22 control subjects without pulmonary hypertension, RV isovolumic relaxation time (IRTR) was measured using continuous-wave Doppler echocardiography. The early diastolic peak strain rate (E SR) and time from QRS to E SR (T-E SR) were measured in the apical, mid-ventricular and basal segments of the interventricular septum and RV free wall using two-dimensional speckle tracking imaging (2DST). RESULTS: IRTR was more prolonged both in HT-LVH and in HCM than in the controls. The averaged septal E SR was reduced both in HT-LVH and in HCM (P < 0.0001, respectively), but the averaged RV free wall E SR was decreased only in HCM (P = 0.0007). E SR averaged for six septal and RV free wall segments was correlated with IRTR (r = -0.46, P = 0.0001). Neither intergroup difference nor correlation with IRTR was observed in a coefficient of variation of T-E SR for the six segments. CONCLUSIONS: RV global diastolic function is impaired in patients with HT-LVH and HCM due to relaxation abnormalities, not an asynchrony, of the myocardium surrounding the RV cavity. The detection of RV free wall relaxation abnormality using 2DST may be useful to differentiate HCM from HT-LVH.

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.

Prevalence and clinical importance of spontaneous echo contrast within the carotid artery in patients with ischemic cerebrovascular disease.

OBJECTIVE: Spontaneous echo contrast (SEC) is composed of numerous microechoes swirling in the cardiovascular lumen, usually appearing during blood stasis. This study aimed to clarify the clinical importance of SEC in the carotid artery (CA) in patients with ischemic cerebrovascular disease (ICVD). METHODS: In 264 CAs of 132 consecutive patients with ICVD and in 40 CAs of 20 healthy control subjects, SEC was classified as none, faint, or dense, and CA abnormalities, including plaque, plaque ulcer, mural thrombus, and internal CA stenosis, were assessed with 10-MHz sonography. RESULTS: The overall prevalence of SEC was greater in CAs of patients with ICVD (164/264 [62%]) than in CAs of control subjects (6/40 [15%]; P < .0001). Dense SEC was more specifically detected in CAs of ICVD with the prevalence of 81 (31%) of 264, which was greater than that of controls (1/40 [3%]; P = .0002). Dense SEC was more frequently detected in CAs with plaque (38/98 [39%]) than in those without (43/166 [26%]; P = .0285), in CA plaque with ulcerative lesions (7/10 [70%]) than in those without (31/88 [35%]; P = .0325), in CA plaque with a thrombus (11/12 [92%]) than in those without (27/86 [31%]; P < .0001), and in CAs with severe stenosis (11/13 [85%]) than in those with mild stenosis (25/75 [33%]; P = .0005) and in those without stenosis (45/176 [26%]; P < .0001). CONCLUSIONS: Dense SEC was frequently observed in CAs of patients with ICVD, especially in those with local atheromatous lesions, although the influence of systemic factors could not be excluded. Dense SEC within a CA may be a marker of ICVD.

Role of left ventricular regional diastolic abnormalities for global diastolic dysfunction in patients with hypertrophic cardiomyopathy.

BACKGROUND: The usefulness of Doppler strain rate imaging for assessment of left ventricular regional diastolic function has not been fully determined. OBJECTIVE: We aimed to clarify the relationships between diastolic strain rates and global diastolic function and find a useful index for regional diastolic function in patients with hypertrophic cardiomyopathy (HCM). METHODS: Strain rate curves were obtained using an apical approach at 12 different sites of the left ventricular myocardium in 25 patients with HCM and 20 control subjects, and peak early diastolic strain rate (ESR), peak late diastolic strain rate, and the time from QRS to ESR were measured. The flow propagation velocity was measured using color M-mode Doppler echocardiography as a global diastolic index. RESULTS: Each of the spatially averaged values of ESR and ESR/peak late diastolic strain rate and the coefficients of variation of time from QRS to ESR was significantly correlated with flow propagation velocity, but the best correlation was observed in ESR. Although both ESR and peak late diastolic strain rate of each myocardial segment of patients with HCM tended to decrease as the wall thickness increased, only ESR significantly decreased even in the segments without apparent hypertrophy. CONCLUSIONS: In patients with HCM, the reduction of ESR was more closely associated with global diastolic dysfunction than asynchrony, and ESR may be a useful and sensitive index for regional diastolic function.

[Dilation of the brachial artery in response to sublingual nitroglycerin can predict the antihypertensive effects of valsartan: a study using novel high-frequency high-frame-rate ultrasound imaging].

OBJECTIVES: The efficacy of antihypertensive agents can vary in patients. Four to 8 weeks may be required before antihypertensive agents become fully effective. Predicting the efficacy can help agent selection and dose setting. This study determined whether nitroglycerin-induced vasodilation of brachial arteries can predict the antihypertensive action of angiotensin II receptor antagonist. METHODS: Untreated uncomplicated patients with essential hypertension, who gave informed consent, were studied (n = 20, mean age 55 years). Before antihypertensive treatment, nitroglycerin-induced vasodilation of the brachial arteries was measured using a novel method of 15 MHz high-frequency high-frame-rate ultrasound imaging (Hitachi EUB8000). Diameter of the brachial artery at the end-systolic phase was measured before and after 0.3 mg nitroglycerin sublingual spray and percentage vasodilation (%D-N) was calculated. The reduction of mean blood pressure after nitroglycerin (%BP-N) was calculated. Valsartan monotherapy (40-80 mg/day)was administered for 3-6 months (mean 132 days). Reduction of mean blood pressure after valsartan monotherapy (%BP-V) was calculated. RESULTS: Valsartan decreased systolic blood pressure from 138 +/- 13 to 130 +/- 17 mmHg, and diastolic blood pressure from 83 +/- 11 to 78 +/- 11 mmHg (p < 0.05). %D-N was correlated closely with %BP-V (r = - 0.70, p < 0.001). %BP-N had no correlation with %BP-V (r = 0.13, p = 0.58). CONCLUSIONS: Direct vasodilatory action of nitroglycerin on vascular smooth muscle cells may predict the chronic antihypertensive effect of angiotensin II receptor antagonist.

Increased plasma concentrations of N-terminal pro-brain natriuretic peptide reflect the presence of mildly reduced left ventricular diastolic function in hypertension.

BACKGROUND: The potential use of assays of N-terminal pro-brain natriuretic peptide for detection of diastolic abnormalities associated with alterations in blood pressure has not been elucidated. This study was designed to determine whether increased plasma concentrations of N-terminal pro-brain natriuretic peptide sensitively reflect abnormal diastolic function associated with hypertension. METHODS: Concentrations of N-terminal pro-brain natriuretic peptide in plasma were assayed in 40 previously untreated hypertensive patients without overt congestive heart failure and in 20 age and sex-matched controls. Hypertensive patients were studied with the use of pulsed Doppler and color M-mode Doppler echocardiography for the evaluation of left ventricular diastolic function. RESULTS: Concentrations of N-terminal pro-brain natriuretic peptide were elevated in hypertensive patients [75.1+/-75.2 (SD) pg/ml compared with 37.9+/-38.5 in controls, P<0.05]. In hypertensive patients, concentrations of N-terminal pro-brain natriuretic peptide were negatively correlated with the ratio of color M-mode flow propagation velocity to transmitral E velocity consistent with the view that increased concentrations of N-terminal pro-brain natriuretic peptide are indicative of alterations in diastolic function. Hypertensive patients with N-terminal pro-brain natriuretic peptide values above the mean value in the control group exhibited significantly increased brachial intimal-medial thickness and reduced wall stress, consistent with the view that increased N-terminal pro-brain natriuretic peptide was associated with favorable peripheral arterial remodeling. CONCLUSIONS: Elevated concentrations of N-terminal pro-brain natriuretic peptide in plasma reflect the presence of left ventricular diastolic abnormalities and peripheral arterial remodeling in asymptomatic patients with hypertension.

A fundamental study for quantitative measurement of ultrasound contrast concentration by low mechanical index contrast ultrasonography.

PURPOSE: In high mechanical index (MI) contrast ultrasonography it has been shown that the power of contrast signal intensity (CI) has a strong linear correlation with the concentration of the ultrasound contrast agent under conditions of constant applied acoustic pressure. However, it is unclear whether the linearity is preserved in low-MI contrast ultrasonography. Thus, we investigated the relationship between ultrasound contrast concentration and CI in vitro. METHODS: Solutions of the ultrasound contrast agents Definity and Imagent were prepared at concentrations of 0.5, 2, 8, 32, and 128 µl/l. Placing a jelly block between the transducer and the solution, the solutions were transmitted using pulse subtraction imaging with an MI of 0.05, 0.1, and 0.5. CI was measured in dB in a region of interest 3 mm in height placed just below the border between the jelly and the solution. Data were plotted using double logarithm scales, where the concentration was expressed in dB as 10 × log (concentration). RESULTS: CI in dB had a strong linear correlation with concentration in dB for both agents with any MI. Best fitted slopes were close to 1, indicating that the power of CI is proportional to the concentration. CONCLUSIONS: In low-MI contrast ultrasonography, the power of CI is proportional to contrast concentration, and CI in dB is logarithmic to the concentration. Thus, the microbubble concentration can be quantitatively measured even in low-MI contrast ultrasonography.

Loss of insulin receptor substrate-1 signaling induces the cardiovascular and proteo(fibrino)lytic system derangements typical of insulin resistance.

BACKGROUND: Type 2 diabetes and insulin resistance have been associated with several cardiac features including diastolic heart failure, impaired ventricular function, perimicrovascular fibrosis and increased expression of plasminogen activator inhibitor type-1 (PAI-1) in coronary arterial walls. Insulin receptor substrate-1 (IRS-1) is one mediator of insulin signaling. This study was performed to determine whether induction of cardiac manifestations typical of insulin resistance and increased PAI-1 expression occur developmentally or post-developmentally as a result of loss of IRS-1-mediated signaling. METHODS: IRS-1 knockout mice were studied at 20 weeks of age. RESULTS: Compared with control mice, the left ventricular (LV) and cardiac mass to body weight ratios were increased. Diastolic and systolic LV diameters and decreased fractional shortening were indicative of LV dilatation and dysfunction. Coronary perimicrovascular fibrosis, an increased coronary arterial wall to lumen ratio, increased immunoreactivity of PAI-1 in the tunica media and increased PAI-1 mRNA expression were present consistent with constrained mural proteo(fibrino)lysis. These cardiac manifestations were similar to those we and others have observed previously in insulin-resistant mice without impaired IRS-1-mediated signaling. CONCLUSIONS: Loss of IRS-1 signaling is sufficient to induce cardiac manifestations typical of insulin resistance including increased coronary arterial mural PAI-1 expression. Furthermore, increased PAI-1 expression is not dependent on IRS-1 signaling.

Sensitive detection of myocardial viability in chronic coronary artery disease by ultrasonic integrated backscatter analysis.

BACKGROUND: Myocardial viability is not synonymous with contractile reserve and identifiable in a significant percentage of dysfunctional myocardial segments without contractile reserve. The usefulness of ultrasonic tissue characterization by the phase-corrected magnitude of cyclic variation of integrated backscatter (MVIB) in chronic coronary artery disease is not fully validated. Thus, whether MVIB predominantly reflects the contractile reserve or myocardial viability of chronically dysfunctional myocardium was determined. METHODS: The MVIB of severely dysfunctional interventricular septum or posterior wall was measured in 34 consecutive patients with previous myocardial infarction. Dobutamine stress echocardiography and fluorine-18 fluorodeoxyglucose positron emission tomography were used as the standards of contractile reserve and myocardial viability, respectively. RESULTS: Among 44 dysfunctional segments, only 15 were judged as having contractile reserve and 29 were judged as not by dobutamine stress echocardiography, whereas 26 segments showed myocardial viability using fluorine-18 fluorodeoxyglucose positron emission tomography and 18 did not. MVIB was greater in segments with than in those without contractile reserve (4.7 +/- 2.2 vs -1.4 +/- 4.9 dB, P < .0001), but there was considerable overlap between the groups. On the other hand, MVIB of segments with and without myocardial viability (4.1 +/- 2.6 vs -4.3 +/- 3.3 dB, P < .0001) was distinctly different and predicted myocardial viability with a sensitivity of 92% and a specificity of 94%. CONCLUSIONS: For patients with chronic coronary artery disease, MVIB better reflects myocardial viability than it does contractile reserve. Ultrasonic tissue characterization, in concordance with fluorine-18 fluorodeoxyglucose positron emission tomography, is a sensitive method for detecting myocardial viability.

[Effects of low-dose pergolide therapy on cardiac valves in patients with Parkinson's disease].

BACKGROUND: Pergolide mesilate is widely used to treat Parkinson's disease in both the USA and Japan, but the maintenance dose is distinctly different between the USA (usually more than 1.5 mg/day) and Japan (usually less than 1.5 mg/day). Although several reports from the USA have suggested that mitral, aortic, and tricuspid valvular lesions were caused by pergolide, it is unclear whether low-dose pergolide therapy causes such valvular lesions. OBJECTIVES: The effects of low-dose pergolide therapy on cardiac valves were studied in Japanese patients with Parkinson's disease. METHODS: One hundred and five consecutive patients with Parkinson's disease approved for our protocol were enrolled in this study. Forty patients were treated with low-dose pergolide (0.05-1.5 mg/day for 2-115 months), and were included in the pergolide group (mean age 71 +/- 6 years). The other 44 patients received no ergot-derived dopamine receptor agonists, and 32 patients acted as age-matched controls (mean age 71 +/- 7 years). Both groups of patients underwent echocardiographic examination to detect organic lesions in cardiac valves such as thickening of the leaflet, annular calcification, restriction of valve motion and valvular tenting, and valvular regurgitation greater than 2 + on the 4-point scale. RESULTS: No significant difference was observed in the incidence of aortic, mitral and pulmonic valve lesions between the pergolide group and the control group. Although no organic lesions were detected in the tricuspid valve, the incidence of tricuspid regurgitation was significantly higher in the pergolide group than in the control group (p < 0.05). CONCLUSIONS: Although low-dose pergolide of less than 1.5 mg/day does not cause serious damage in the left-sided valves, it may induce tricuspid regurgitation.

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.

Maladaptive arterial remodeling with systemic hypertension associated with increased concentrations in blood of plasminogen activator inhibitor type-1 (PAI-1).

Increased carotid artery intima-media thickness (IMT), but not necessarily peripheral vessel IMT, accompanies atherosclerosis. We hypothesized that IMT in a peripheral, muscular artery known to be resistant to atherosclerotic changes would increase with hypertension, thereby limiting increases in wall stress and potentially preserving endothelial cell function reflected by flow-mediated dilation (FMD). Plasminogen activator inhibitor type-1 (PAI-1) can inhibit vascular smooth muscle cell migration contributing to increased IMT. Thus, increased PAI-1 may attenuate the mural adaptive response. A high-resolution scanner designed to delineate brachial artery FMD and IMT was used in studies of previously untreated patients with essential hypertension (n = 18) and age- and gender-matched normotensive subjects (n = 15). Brachial IMT was increased with hypertension (0.36 +/- 0.07 vs 0.27 +/- 0.03 mm in controls, p <0.01), and FMD was lower (3.6 +/- 1.5% vs 7.8 +/- 3.6, p <0.01). PAI-1 antigen in blood was increased (40.5 +/- 31.8 vs 26.3 +/- 11.6 ng/ml, p <0.05). IMT and FMD correlated positively (r = 0.63, p <0.05) in hypertensive patients. FMD correlated inversely with wall stress (r = -0.57, p <0.05). IMT correlated inversely with PAI-1 (r = -0.61, p <0.05). These observations support the hypothesis that increased PAI-1 attenuated increases in neointimal vascular smooth muscle cell cellularity. Thus, increased PAI-1 may attenuate a mural, adaptive response to hypertension associated with preservation of endothelial cell function.

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.

Sensitive method of detecting myocardial ischemia during dobutamine stress echocardiography.

To test the hypothesis that dobutamine-induced myocardial ischemia causes early-systolic asynchrony predominantly in the regional left ventricular wall, color kinesis (CK) images during dobutamine stress echocardiography (DSE) were recorded in 13 patients with coronary artery disease and in 10 patients without, all of whom showed normal wall motion at rest. Based on the visual interpretation of DSE and the angiographic findings, 21 segments in the short-axis images at the papillary muscle level were defined as ischemic, and 60 segments of the patients without coronary artery disease were defined as normal. The incremental fractional segmental area change (IFAC) was calculated at 33-ms intervals from the CK images. At the peak dose, IFACs during the first 33 and 33-67 ms were significantly lower in the ischemic segments than in the normal ones, and IFACs during 133-167, 200-233 and 233-267 ms were significantly higher in the ischemic segments. The ratio (peak/low dose) of the cumulative fractional area change at 100 ms gave the best sensitivity (= specificity) for differentiating the 2 groups (86%). Dobutamine-induced ischemia is characterized by an early-systolic asynchrony rather than a change in overall wall excursion and CK can provide an objective assessment of ischemia developing during DSE.