Hiroya Kondo

Endothelial dysfunction in the early stage of atherosclerosis precedes appearance of intimal lesions assessable with intravascular ultrasound

The objective of this study was to clarify whether morphologic evaluation of the in vivo artery with intravascular ultrasound provides as sensitive a marker as endothelial dysfunction or microscopic histologic assessment. Endothelial dysfunction assessed with the changes in the vessel diameter during acetylcholine infusion has been used as a more sensitive marker of atherosclerosis than the angiographic estimates of morphologic structure of the vessel. Recent advent of intravascular ultrasound has provided such high-resolution images of the vessels that morphologic changes in the vessel structure are sensitively and accurately detected. Twenty-two rabbits were divided into three groups: six rabbits fed a cholesterol-rich diet for 2 weeks as the hypercholesterolemia group, eight rabbits fed with the diet for 8 weeks as the atherosclerosis group, and eight rabbits fed a normal diet as the normal group. After evaluating the atherosclerotic lesions by intravascular ultrasound, the cross-sectional area was measured in the baseline and during the infusion of acetylcholine (0.05, 0.5, and 5 micrograms/kg/min) and nitroglycerin (5 micrograms/kg/min). No atherosclerotic lesions were detectable with intravascular ultrasound in any rabbit despite the presence of microscopic intimal lesions in the vessels in the rabbits of the atherosclerosis group. The cross-sectional area increased during acetylcholine infusion in the rabbits of the normal and the hypercholesterolemia groups. In contrast, in the rabbits of the atherosclerosis group, the cross-sectional area did not significantly increase during acetylcholine infusion at the rate of 0.5 microgram/kg/min and even tended to decrease at the rate of 5 micrograms/kg/min (-3.8% +/- 3.7%, P < 0.05 vs the normal group). Dilating responses to nitroglycerin infusion were similar among all three groups. In conclusion, impairment of the endothelium-dependent vasodilating response assessed with intravascular ultrasound in the in vivo vessel precedes the appearance of echographic atherosclerotic findings. Thus intravascular ultrasound, if used in combination with drug intervention to assess endothelial function, would provide even more accurate assessment of the vessels than conventional intravascular ultrasound alone.

Evolving changes in Doppler Mitral flow velocity pattern in rats with hypertensive hypertrophy

OBJECTIVES The aim of our study was to explore evolving changes in a mitral flow velocity pattern (MFVP) and its hemodynamic and pathological correlates in hypertensive rats in an isolated diastolic heart failure model. BACKGROUND Development of left ventricular (LV) hypertrophy and concomitant diastolic dysfunction cause heart failure in hypertensive hearts even with normal systolic function; however, associated evolving change in MFVP is still unclear. METHODS Mitral flow velocity pattern was recorded every 2 weeks from 7 to 19 weeks in six hypertensive rats. Hemodynamic and pathological correlates of Doppler mitral flow indexes were examined as an additional part of the study using the hypertensive rats at the age of 13 weeks (compensatory stage, n = 7) and at 19 weeks (heart failure stage, n = 8). RESULTS Initial development of pressure overload LV hypertrophy resulted in a decrease in early diastolic filling wave (E), a reciprocal increase in the filling wave due to atrial contraction (A) and prolongation of deceleration time of E wave (relaxation abnormality pattern). These changes were associated with an increase in tau, an index of LV relaxation, but without a change in LV end-diastolic pressure. Transition to congestive heart failure caused an increase in E, a decrease in A and shortening of deceleration time. These changes were not associated with further increase in tau but with elevation of LV end-diastolic pressure, reflecting marked LV hypertrophy and myocardial fibrosis. CONCLUSIONS Development of pressure overload LV hypertrophy is associated with evolving changes in MFVP from normal to relaxation abnormality pattern and, in turn, to pseudonormalized to restrictive pattern. Analysis of MFVP may be useful to follow not only functional but also constitutional changes of the myocardium in hypertensive hearts.

Analysis of transmural trend of myocardial integrated ultrasound backscatter for differentiation of hypertrophic cardiomyopathy and ventricular hypertrophy due to hypertension

OBJECTIVES This study was undertaken to differentiate hypertrophic cardiomyopathy from hypertensive hypertrophy using a newly developed M-mode format integrated backscatter imaging system capable of calibrating myocardial integrated backscatter with the power of Doppler signals from the blood. BACKGROUND Myocardial integrated ultrasound backscatter changes in patients with hypertrophic cardiomyopathy; however, it is unknown whether ultrasound myocardial tissue characterization may be useful in differentiating hypertrophic cardiomyopathy from hypertensive hypertrophy. METHODS Calibrated myocardial integrated backscatter and its transmural gradient were measured in the septum and posterior wall in 31 normal subjects, 13 patients with hypertensive hypertrophy and 22 patients with hypertrophic cardiomyopathy. The gradient in integrated backscatter was determined as the ratio of calibrated integrated backscatter in the endocardial half to that in the epicardial half of the myocardium. RESULTS Cyclic variation of integrated backscatter was smaller and calibrated myocardial integrated backscatter higher in patients with hypertrophied hearts than in normal subjects, but there were no significant differences in either integrated backscatter measure between patients with hypertensive hypertrophy and those with hypertrophic cardiomyopathy. Transmural gradient in myocardial integrated backscatter was present only in patients with hypertrophic cardiomyopathy (5.0 +/- 1.8 dB [mean +/- SD] for the septum; 1.2 +/- 1.6 dB for the posterior wall). CONCLUSIONS Hypertrophic cardiomyopathy and ventricular hypertrophy due to hypertension can be differentiated on the basis of quantitative analysis of the transmural gradient in integrated backscatter.

Roles of renin–angiotensin and endothelin systems in development of diastolic heart failure in hypertensive hearts

OBJECTIVE Although interest in diastolic heart failure is growing because of its clinical frequency, little is known about this type of heart failure. Our laboratory recently developed a diastolic heart failure model using Dahl salt-sensitive rat. In this model, gene expression of angiotensin-converting enzyme and endothelin (ET) system in the left ventricle was enhanced at heart failure stage without downregulation of angiotensin type 1a receptor mRNA level. However, the roles of these humoral systems in the transition to diastolic failure remain unclear. METHODS Subdepressor doses of angiotensin II type 1 (AT1) receptor and ET type A (ETA) receptor antagonists were administered in this model just after onset of hypertension, and their effects were investigated. RESULTS Neither AT1 nor ETA receptor blockade inhibited the early (13 weeks) compensatory left ventricular (LV) hypertrophy. This form of compensatory hypertrophy is associated with subnormal LV end-systolic stress, which was normalized by AT1 receptor blockade but not by ETA receptor blockade. Progression of LV hypertrophy and fibrosis and transition to heart failure (19 weeks) in the untreated rats were prevented by both antagonists, resulting in normalization of LV end-diastolic pressure and lung weight. AT1 receptor blockade, but not ETA receptor blockade, normalized time constant of LV relaxation. Enhanced gene expression for ET system in the left ventricle observed in the untreated rats was suppressed with AT1 receptor antagonist administration. ETA receptor blockade slightly but significantly elevated the AT1a receptor mRNA level as compared with the untreated rats. CONCLUSIONS RAS and ET system contribute to the transition to diastolic heart failure through the development of excessive hypertrophy and ventricular fibrosis in hypertensive heart diseases, however, neither RAS nor ET system is mandatory for normal compensation for pressure overload. RAS apparently causes such diastolic effects at least partly through the ET system.

Calcineurin Inhibitor Attenuates Left Ventricular Hypertrophy, Leading to Prevention of Heart Failure in Hypertensive Rats

BackgroundThere is controversy regarding the contribution of calcineurin activation to the development of pressure-overload left ventricular (LV) hypertrophy and heart failure. The aim of this study was to explore whether the inhibition of calcineurin may prevent the transition to heart failure in hypertensive rats and, if so, to clarify in which developmental stage of LV hypertrophy calcineurin plays a key role. Methods and ResultsDahl salt-sensitive rats placed on an 8% NaCl diet from the age of 7 weeks (hypertensive rats) were randomized to no treatment (n=6) or treatment with the calcineurin inhibitor FK506 (1 mg · kg−1 · d−1) from 8 weeks (FKE, n=7) or from 17 weeks (FKL, n=7). Rats placed on a 0.3% NaCl diet were defined as control rats (n=6). The administration of FK506 from 8 weeks attenuated, although it did not block, LV hypertrophy observed in the untreated rats and prevented the transition to heart failure. The development of LV fibrosis, however, was not attenuated by the administration of FK506 from 8 weeks. The administration of FK506 from 17 weeks brought no benefit for cardiac remodeling or LV function and failed to prevent heart failure. ConclusionsCalcineurin inhibition, if started from the initial stage of pressure overload, attenuated the development of LV hypertrophy without any effect on LV fibrosis and prevented the transition to heart failure. The activation of calcineurin is involved in the development of LV hypertrophy but not of LV fibrosis, and this involvement may be crucial at the initial stage.

Ultrasonic myocardial tissue characterization in patients with dilated cardiomyopathy: Value in noninvasive assessment of myocardial fibrosis

Dilated cardiomyopathy (DCM) is usually diagnosed from the left ventricular functional viewpoint by the detection of dilated ventricular cavity and depressed myocardial contractility. Although histologic analysis of the myocardium no doubt provides clinically important information, it is possible only with microscopic examination of biopsy specimen of the myocardium. The objective of this particular study is to clarify the comparative values of the measures of ultrasonic tissue characterization, that is, calibrated myocardial integrated backscatter (IB) and the magnitude of cyclic variation in IB, with conventional echocardiographic parameters in assessing histologic condition of the myocardium. The magnitude of cyclic variation in IB and myocardial IB at end-diastole calibrate with the power of Doppler signals from the blood were measured in addition to conventional echocardiographic parameters in 14 patients with DCM. Calibrated myocardial IB was higher in patients with more fibrosis in the biopsy specimen of the heart tissue, whereas the magnitude of variation in IB or conventional echocardiographic parameters did not significantly correlate with a histologic estimate of myocardial fibrosis. Calibrated myocardial IB provides information about the myocardial fibrosis that cannot be assessable with conventional echocardiographic parameters. Calibrated myocardial IB and the magnitude of cyclic variation of IB are likely to reflect somewhat different acoustic properties of the myocardium.

Digital Subtraction High-Frame-Rate Echocardiography in Detecting Delayed Onset of Regional Left Ventricular Relaxation in Ischemic Heart Disease

BACKGROUND Because left ventricular (LV) diastolic function is impaired before systolic function in patients with ischemic heart disease and because ischemic heart disease is constituted of regional rather than global abnormalities of the left ventricle, measures of LV regional diastolic dysfunction, if possible, should provide the most sensitive assessment of the coronary involved region. The objectives of this study are to clarify whether high-frame-rate two-dimensional echocardiography, combined with digital subtraction image processing, may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease and to clarify whether this technique provides a measure for the noninvasive assessment of the coronary involved region. METHOD AND RESULTS In 30 normal subjects and 59 patients with ischemic heart disease, two-dimensional echocardiograms obtained at a rate of 60 frames per second were provided on line for digital subtraction analysis, with which digitized images were continuously subtracted on a frame-by-frame basis. The subtracted images were analyzed to determine the onset of the segmental outward motion of the LV wall in early diastole in each of 16 segments per subject. Regional relaxation index, defined as the interval from the second heart sound to the onset of outward wall motion, was significantly prolonged in the coronary involved segments compared with the normal segments (36.3 +/- 18.0 versus 101.2 +/- 34.0 ms, P < .01). The prolongation in the regional relaxation index was observed even in the coronary involved segments without reduction in systolic wall motion. When a cutoff level of 50.0 ms was used, coronary involved segments could be distinguished from normal or border segments with a sensitivity of 92% and a specificity of 81%. CONCLUSIONS Digital subtraction high-frame-rate echocardiography may be used to visualize regional LV relaxation abnormalities in patients with ischemic heart disease. The time interval from the second heart sound to the onset of the segmental outward motion of the LV wall (regional relaxation index) obtained with this technique provides a noninvasive and accurate measure for assessing coronary involved regions.

Doppler echocardiographic pulmonary venous flow-velocity pattern for assessment of the hemodynamic profile in acute congestive heart failure

The hemodynamic profile of congestive heart failure (CHF) is best described in terms of its two primary sets of hemodynamic parameters, that is, left atrial pressure and cardiac output, each of which has a specific and independently variable hemodynamic cause. To assess whether analysis of the mitral and/or pulmonary venous flow-velocity patterns provides valuable information in the noninvasive assessment of the hemodynamic profile of CHF, these patterns were obtained by using the transthoracic approach in 18 patients with acute CHF with simultaneous measurements of catheter-derived mean pulmonary capillary wedge pressure and thermodilution cardiac index. Measurements were repeated on two occasions in each case: at the acute stage of CHF and 1 to 5 days after treatment. Peak diastolic pulmonary venous forward flow velocity was higher, the ratio of pulmonary venous systolic to diastolic peak forward flow velocity was lower, and the ratio of mitral early diastolic to late diastolic flow velocity was greater in patients with higher mean pulmonary capillary wedge pressure (r = 0.80, n = 36, p < 0.01; r = -0.69, n = 36, p < 0.01; r = 0.71, n = 36, p < 0.01). Peak systolic pulmonary venous forward flow velocity and time-velocity integral of the systolic pulmonary venous flow wave were greater in patients with larger cardiac index (r = 0.80, n = 36, p < 0.01; r = 0.62, n = 36, p < 0.01). In conclusion, two primary sets of hemodynamic parameters, that is, left atrial pressure and cardiac output, can be estimated with Doppler pulmonary venous flow parameters in patients with acute CHF.

Noninvasive Assessment of Left Ventricular Relaxation Using Continuous-Wave Doppler Aortic Regurgitant Velocity Curve Its Comparative Value to the Mitral Regurgitation Method

BACKGROUND The most established parameters of left ventricular (LV) relaxation are peak negative value of the first derivative of LV pressure (-dP/dtmax) and the time constant of isovolumic LV pressure fall. The instantaneous pressure gradient between the aorta and the LV during diastole can be calculated from the continuous-wave Doppler aortic regurgitant velocity spectrum. Because the fluctuation of aortic pressure during LV isovolumic relaxation is negligibly minor and because LV minimal pressure is negligibly low, LV pressure during the isovolumic relaxation period may be derived from the continuous-wave Doppler aortic regurgitant velocity spectrum. This study was designed to clarify whether analysis of continuous-wave Doppler aortic regurgitation recording provides accurate measures of LV relaxation over a wide range of LV function and to determine comparative values of aortic and mitral regurgitation methods in the assessment of LV relaxation. METHODS AND RESULTS In eight mongrel dogs with acute ischemic LV dysfunction, the continuous-wave Doppler aortic regurgitant velocity spectrum was recorded simultaneously with high-fidelity LV and aortic pressures, while the continuous-wave Doppler mitral regurgitant velocity spectrum was recorded simultaneously with high-fidelity left atrial and LV pressures. The aortic regurgitant velocity spectrum was provided for the determination of Doppler-derived mean rate of LV pressure fall in 20 ms after the onset of aortic regurgitation (delta P/delta t-AR) and the time interval from the onset of aortic regurgitation to the point at (1-1/e)1/2 of the maximal aortic regurgitant velocity as an estimate of the time constant. The mitral regurgitant velocity spectrum was provided for Doppler-derived mean rate of LV pressure fall in 20 ms after the point of -dP/dtmax (delta P/delta t-MR) and the time interval from the point of -dP/dtmax to the point with mitral regurgitant velocity of (1/e)1/2 of the mitral regurgitant velocity at the point of -dP/dtmax as an estimate of the time constant. delta P/delta t-AR and delta P/delta t-MR correlated well with catheter-derived -dP/dtmax (r = .92, r = .98, P < .01, respectively). The time constant derived from aortic and mitral regurgitant velocity spectra (tau-AR and tau-MR) also correlated well with catheter-derived time constant (r = .84, r = .76, P < .01, respectively). However, a mean difference of the catheter-derived time constant minus tau-MR was larger than tau-AR (29 +/- 30 versus 4 +/- 17 ms, P < .01, presented as mean +/- 2 SD). CONCLUSIONS LV relaxation can be assessed from the continuous-wave Doppler aortic regurgitant velocity spectrum. The aortic regurgitation method provides an even more accurate estimate of the time constant compared with the mitral regurgitation method, particularly in the presence of LV dysfunction.

Validation of transthoracic myocardial ultrasonic tissue characterization: comparison of transthoracic and open-chest measurements of integrated backscatter

To investigate whether myocardial integrated backscatter (IB) can be measured through the chest wall, myocardial IB parameters were measured in five adult mongrel dogs with a newly developed IB imaging system capable of measurements of myocardial IB relative to backscatter from the blood. There was no significant difference in the calibrated myocardial IB between the closed chest and the open chest conditions either in the septum or in the posterior wall if a 2.5- or 3.5-MHz frequency transducer was used. There was no significant difference in the magnitude of cyclic variation in IB between the closed chest and the open chest conditions independent of the frequency of the transducer used. These data suggest that we can accurately measure not only the magnitude of cyclic variation in IB but also the calibrated myocardial IB through the chest wall with a 2.5- or 3.5-MHz frequency transducer. Such data may validate measurements of myocardial IB parameters through the chest wall even in humans.