José A. Vázquez de Prada

Incremental Doses of Dobutamine Induce a Biphasic Response in Dysfunctional Left Ventricular Regions Subtending Coronary Stenoses

BACKGROUND Dobutamine stress echocardiography has been proposed as a diagnostic tool to identify viable myocardium. How regional wall thickening responds to dobutamine in the ischemic or short-term hibernating myocardium has not been adequately defined. We hypothesized that regional wall thickening would improve initially and subsequently deteriorate with incremental doses of dobutamine in viable myocardial regions supplied by a stenotic coronary artery. This study was undertaken to determine whether this biphasic pattern of regional function characterizes the response of ischemic or hibernating myocardium to dobutamine and to explore the factors and mechanisms that determine this response. METHODS AND RESULTS Twenty-six pigs in four groups were studied: a control group (n = 5) to assess the response of myocardium perfused by nonstenotic coronary artery to incremental doses of dobutamine, and three experimental groups with a left anterior descending coronary artery stenosis producing acute myocardial ischemia (n = 7), short-term myocardial hibernation for 90 minutes (n = 7), and short-term hibernation for 24 hours (n = 7) to determine the functional and metabolic response to dobutamine under these conditions. Regional coronary flow was reduced to 40% to 60% of baseline, with significant reductions of regional wall thickening as measured by two-dimensional echocardiography and sonomicrometers. An incremental dobutamine infusion from 2.5 to 25 micrograms.kg-1.min-1 increased wall thickening and coronary flow without lactate production in the control group. In the other three groups, during the incremental dobutamine infusion, regional wall thickening improved initially, from 11.4 +/- 7.5% to 19.8 +/- 11.4%, P < .01, at dobutamine doses of 2.5 to 10 (4.5 +/- 2.2) micrograms.min-1.kg-1 but deteriorated subsequently to 5.0 +/- 5.8% at the maximal dose of dobutamine of 12.6 +/- 4.1 micrograms.min-1.kg-1. The initial improvement of regional wall thickening was associated with a small increase in regional coronary flow (from 0.53 +/- 0.18 to 0.68 +/- 0.25 mL.min-1.g-1 myocardium, P < .05) and with regional lactate production. High doses of dobutamine did not further increase regional coronary flow but markedly increased lactate production and induced regional myocardial acidosis (pH 7.26 +/- 0.07). The biphasic pattern of response to dobutamine was observed in each of the three experimental groups. Both peak improvement and peak deterioration occurred earlier and at lower dobutamine dose levels in the group with acute ischemia compared with the group with short-term hibernation for 24 hours (P < .05). CONCLUSIONS A biphasic response of wall thickening to incremental dobutamine with initial improvement and subsequent deterioration is characteristic of ischemic or short-term hibernating myocardium. The initial low-dose dobutamine infusion improved wall thickening in the ischemic or hibernating myocardial region to a modest level. This initial modest improvement was transient and at the expense of metabolic deterioration of myocardial ischemia, so that at higher doses during prolonged dobutamine infusion, wall thickening deteriorated, lactate accumulated, and myocardial acidosis developed.

Determinants of functional tricuspid regurgitation in incomplete tricuspid valve closure: Doppler color flow study of 109 patients

OBJECTIVES The aim of this study was to investigate the association between the pattern of incomplete tricuspid valve closure and the presence of tricuspid regurgitation and to identify factors that determine the severity of regurgitation associated with this pattern. BACKGROUND The incomplete tricuspid valve closure pattern (defined as apical displacement of the leaflets) has been described by two-dimensional echocardiography. However, whether this pattern is universally associated with tricuspid regurgitation and the determinants of severity of regurgitation in its presence have not been studied by Doppler color flow mapping. METHODS We identified 109 consecutive patients (mean age 62 +/- 17 years) with incomplete tricuspid valve closure who were studied by Doppler color flow mapping. We measured the linear apical displacement of the coaptation point from the tricuspid annulus and the area of displacement between the leaflets and annulus. Right atrial, ventricular and annular dimensions were measured and compared with those in a group of normal subjects. RESULTS Tricuspid regurgitation was present in all patients with the incomplete closure pattern; it was mild in 14%, moderate in 19% and severe in 67%. Apical displacement was significantly greater (p < 0.02) in those with severe regurgitation than in those with mild regurgitation or in normal subjects. Tricuspid annulus dilation was the only independent predictor of severity of regurgitation. The right ventricle was not significantly dilated in 32% of patients, and right ventricular systolic pressure was not correlated with the severity of regurgitation and was < 30 mm Hg in 11% of patients. CONCLUSIONS Tricuspid regurgitation was associated with incomplete tricuspid valve closure in all patients studied and was moderate to severe in 86%. Impaired coaptation is best reflected by the displacement area between the leaflets and the annulus. High pulmonary pressure and significant right ventricular dilation are not prerequisites for functional tricuspid regurgitation. Annular dilation is the most consistent and important determinant of this lesion.

Quantitative Three-Dimensional Reconstruction of Aneurysmal Left Ventricles In Vitro and In Vivo Validation

BACKGROUND Current two-dimensional (2D) echocardiographic measures of left ventricular (LV) volume are most limited by aneurysmal distortion, which restricts application of simple geometric models that assume symmetrical shape. 2D methods also fail to provide separate volumes of the aneurysm and nonaneurysmal residual LV cavity, which could help assess the stroke volume wasted by dyskinesis and the potential residual LV body to guide surgical approaches and predict their outcome. Three-dimensional (3D) echocardiographic reconstruction has potential advantages for assessing aneurysmal left ventricles because it is not dependent on geometric assumptions, does not require standardized views that may exclude portions of the aneurysm, and can potentially measure separate aneurysm and nonaneurysm cavity volumes of any shape. The purpose of this study was first, to validate the accuracy of 3D echocardiographic reconstruction for quantifying total LV and separate LV body and aneurysm volumes in vitro so as to provide direct standards for the separate volumes; and second, to determine the feasibility and accuracy of 3D echocardiographic reconstruction for quantifying the total volume and function of aneurysmal left ventricles in an animal model, providing a reference standard for instantaneous LV volume. METHODS AND RESULTS A recently developed 3D system that automatically combines 2D images and their locations was applied (1) to reconstruct 10 aneurysmal ventricular phantoms and 12 gel-filled autopsied human hearts with aneurysms, comparing cavity volumes (total and aneurysm) to those measured by fluid displacement; and (2) to reconstruct the left ventricle during 19 hemodynamic stages in four dogs with surgically created LV aneurysms, comparing total volumes with actual instantaneous values measured by an intracavitary balloon attached to an external column for validation and also calculating the stroke volume wasted by aneurysmal dyskinesis. 3D reconstruction reproduced the distorted aneurysmal LV shapes. In vitro, calculated volumes (aneurysm, nonaneurysm, and total) agreed well with actual values, with correlation coefficients of .99 and SEEs of 3.2 to 6.1 cm3 for phantoms and 3.4 to 4.2 cm3 for autopsied hearts (mean error, < 4% for both). In vivo, LV end-diastolic, end-systolic, and stroke volumes as well as ejection fraction calculated by 3D echocardiography correlated well with actual values (r = .99, .99, .95, and .99, respectively) and agreed closely with them (SEE = 4.3 cm3, 3.5 cm3, 1.7 cm3, and 2%, respectively). The stroke volumes wasted by the aneurysm were -20.1 +/- 19.3% of LV body (nonaneurysm) stroke volume. CONCLUSIONS Despite distorted ventricular shapes, a recently developed 3D echocardiographic system and surfacing algorithm can accurately reconstruct aneurysmal left ventricles and quantify total LV volume (validated in vivo and in vitro) as well as the separate volumes of the aneurysm and residual LV body (validated in vitro). This should improve our ability to evaluate such ventricles and guide surgical approaches.

New Method for Accurate Calculation of Regurgitant Flow Rate Based on Analysis of Doppler Color Flow Maps of the Proximal Flow Field Validation in a Canine Model of Mitral Regurgitation With Initial Application in Patients

OBJECTIVES The purpose of this study was to develop a rational and objective method for selecting a region in the proximal flow field where the hemispheric formula for calculating regurgitant flow rates by the flow convergence technique is most accurate. BACKGROUND A major obstacle to clinical implementation of the proximal flow convergence method is that it assumes hemispheric isovelocity contours throughout the Doppler color flow map, whereas contour shape depends critically on location in the flow field. METHODS Twenty mitral regurgitant flow rate stages were produced in six dogs by implanting grommet orifices into the anterior mitral leaflet and varying driving pressures so that actual peak flow rate could be determined from the known effective regurgitant orifice times the orifice velocity. Because plotting flow rate calculated by using a hemispheric formula versus alias velocities produces underestimation near the orifice and overestimation far from it, this plot was fitted to a polynomial function to allow identification of an inflection point within a relatively flat intermediate zone, where factors causing overestimation and underestimation are expected to be unimportant or balanced. The accuracy of flow rate calculation by the inflection point was compared with unselective and selective averaging techniques. Clinical relevance, initial feasibility and correlation with an independent measure were tested in 13 consecutive patients with mitral regurgitation who underwent cardiac catheterization. RESULTS 1) The accuracy of single-point calculations was improved by selecting points in the flat portion of the curve (y = 1.15x - 3.34, r = 0.87, SEE = 22.1 ml/s vs. y = 1.34x - 1.99, r = 0.71, SEE = 45.6 ml/s, p < 0.01). 2) Selective averaging of points in the flat portion of the curve further improved accuracy and decreased scatter compared with unselective averaging (y = 1.08x + 4.8, r = 0.96, SEE = 11.6 ml/s vs. y = 1.30x + 0.6, r = 0.90, SEE = 20.9 ml/s, p < 0.01). 3) The proposed algorithm for mathematically identifying the inflection point provided the best results (y = 0.96x + 4.5, r = 0.96, SEE = 9.9 ml/s), with a mean error of 1.6 +/- 9.7 ml/s vs. 11.4 +/- 11.7 ml/s for selective averaging (p < 0.01). In patients, the proposed algorithm identified an inflection point at which calculated regurgitant volume agreed best with invasive measurements (y = 1.1x - 0.61, r = 0.93, SEE = 17 ml). CONCLUSIONS The accuracy of the proximal flow convergence method can be significantly improved by analyzing the flow field mathematically to identify the optimal isovelocity zone before using the hemispheric formula to calculate regurgitant flow rates. Because the proposed algorithm is objective, operator independent and, thus, suitable for automatization, it could provide the clinician with a powerful quantitative tool to assess valvular regurgitation.

Everolimus-related pulmonary toxicity in heart transplant recipients.

Pulmonary toxicity (PT) is emerging as a frequent and serious complication of sirolimus, a proliferation signal inhibitor (PSI) used in solid-organ transplantation. Everolimus is a more recently developed PSI with molecular structure very similar to that of sirolimus. Surprisingly, although experience with everolimus is increasing and becoming substantial, there remains very little information about everolimus-related PT. Herein we report 2 heart transplant recipients who developed a non-infectious pulmonary syndrome after everolimus treatment was started. Transbronchial pulmonary biopsy specimens showed typical interstitial pneumonitis, and everolimus discontinuation resulted in rapid clinical and radiological improvement. Although PT seems to be more common after sirolimus exposure, everolimus is by no means spared from this potentially lethal complication and should always be suspected in the relevant clinical setting.

Three-dimensional echocardiography: In vivo validation for right ventricular free wall mass as an index of hypertrophy

OBJECTIVES This study tested the ability of three-dimensional echocardiography to reconstruct the right ventricular free wall and determine its mass in vivo using a system that automatically combines two-dimensional images with their spatial locations. BACKGROUND Right ventricular free wall thickness is limited as an index of right ventricular hypertrophy because right ventricular mass may increase by dilation without increased thickness and because trabeculations and oblique views can exaggerate thickness in individual M-mode and two-dimensional scans. Three-dimensional echocardiography may have potential advantages because it can integrate the entire free wall mass, uninfluenced by oblique views or geometric assumptions. METHODS The three-dimensional system was applied to 12 beating canine hearts to reconstruct the right ventricular free wall in intersecting views. The corresponding mass was compared with actual weights of the excised right ventricular free wall (15.5 to 78 g). For comparison, right ventricular sinus and outflow tract thickness were also measured by two-dimensional echocardiography, and the ability to predict mass from these values was determined. RESULTS The three-dimensional algorithm successfully reproduced right ventricular free wall mass, which agreed well with actual values: y = 1.04x + 0.02, r = 0.985, SEE = 2.7 g (5.7% of the mean value). The two-dimensional predictions showed increased scatter: The variance of mass estimation, based on thickness, was 9.5 to 12.5 (average 11) times higher than the three-dimensional method (p < 0.02). CONCLUSIONS Despite the irregular crescentic shape of the right ventricle, its free wall mass can be accurately measured by three-dimensional echocardiography in vivo, providing closer agreement with actual mass than predictions based on wall thickness. This method, with the increased efficiency of the three-dimensional system, can potentially improve our ability to evaluate the presence and progression of right ventricular hypertrophy.

Virtual Histology Intravascular Ultrasound Assessment of Cardiac Allograft Vasculopathy From 1 to 20 Years After Heart Transplantation

BACKGROUND Cardiac allograft vasculopathy (CAV) is the main cause of graft loss and death in heart transplant (HTx) recipients surviving >1 year. There is a dual etiology for coronary disease in HTx: classic atherosclerosis and an immunologically mediated disease. Intravascular ultrasound (IVUS) is highly sensitive for CAV detection; however, gray-scale IVUS is of limited value for identification of specific plaque components. We sought to characterize graft coronary artery disease by means of IVUS-virtual histology (IVUS-VH) at different time-points of follow-up and to correlate plaque composition with clinical factors. METHODS In our study we included 67 patients, who were 7.6 +/- 5.7 years post-HTx. IVUS gray-scale evaluation was performed on all patients. IVUS-VH analysis was done in those patients showing intimal thickening >0.5 mm at the three more significant lesions (three cross-sections for each) of the left anterior descending artery. RESULTS IVUS-VH analysis was obtained done on 58 patients (86.5%). We found a significant correlation between time of HTx and IVUS gray-scale parameters (plaque area and plaque burden), with both increasing over time. We also found a significant correlation between time and IVUS-VH-derived plaque components, necrotic core and calcium, which increased with time, and fibrous and fibrofatty components, both decreased at follow-up. IVUS-VH results were also related to donor age and cardiovascular risk factors. CONCLUSIONS We observed a time-related change in IVUS-VH-derived plaque composition. Necrotic core and calcium, typical atheromatous components, become more prevalent with time after HTx, especially when influenced by cardiovascular risk factors. The presence of a necrotic core in the early stages was linked to older donor age.

Avoidance of Calcineurin Inhibitors With Use of Proliferation Signal Inhibitors in De Novo Heart Transplantation With Renal Failure

BACKGROUND This study describes our experience with proliferation signal inhibitors in de novo heart transplant recipients with significant renal impairment. To circumvent further nephrotoxicity, calcineurin inhibitors were avoided in the peri-operative period. METHODS Immunosuppression in 20 patients was with a proliferation signal inhibitor (sirolimus, 14; everolimus, 6), an anti-mitotic drug, and corticosteroids from the time of transplantation. Induction was used in 9 patients (45%). All patients had preoperative significant renal dysfunction (mean glomerular filtration rate <30 ml/min/1.73 m(2)), and 4 patients required dialysis. RESULTS Post-operatively, the glomerular filtration rate significantly increased (>65 ml/min/1.73 m(2) at Month 1, remaining stable thereafter). No patients required dialysis after the first month of transplantation. Mean follow-up was 500 days. Rejection episodes occurred in 11 patients (55%), and 4 patients died (2 of rejection, although 1 death occurred 48 days after conversion to conventional treatment with tacrolimus). Half of the patients were eventually converted to conventional calcineurin-inhibitor therapy because of proliferation signal inhibitor adverse events. CONCLUSION Although this immunosuppressive approach was associated with a somewhat high rate of rejection and frequent side effects, it represents an attractive alternative in the complicated peri-operative setting of patients with significant renal impairment. This approach could serve as a temporary bridge to a conventional treatment.

Quantitative three-dimensional reconstruction of left ventricular volume with complete borders detected by acoustic quantification underestimates volume.

Recently a new acoustic-quantification (AQ) technique has been developed to provide on-line automated border detection with an integrated backscatter analysis. Prior studies have largely correlated AQ areas with volumes without direct comparison of volumes for agreement. By using complete AQ-detected borders as the input to a validated method for three-dimensional echocardiographic (3DE) reconstruction, we can compare an entire cavity volume measured with the aid of AQ against a directly measured volume. This would also explore the possibility of applying AQ to 3DE reconstruction to reduce tracing time and enhance routine applicability. To compare reconstructed volumes with actual values in a stable standard allowing direct volume measurement, the left ventricles of 13 excised animal hearts were studied with a 3DE system that automatically combines two-dimensional (2D) images and their locations. Intersecting 2D views were obtained with conventional scanning and AQ imaging, with gains optimized to permit 3D reconstruction by detecting the most continuous AQ borders for each view, with maximal cavity size. Reconstruction was performed with manually traced central endocardial reflections and AQ-detected borders visually reproduced the left ventricular shapes; the AQ reconstructions, however, were consistently smaller. The reconstructed left ventricular (LV) volumes correlated well with actual values by both manual and AQ techniques (r = 0.93 and 0.88, with standard errors of 2.3 cc and 2.0 cc, p = not significant [NS]). Agreement with actual values was relatively close for the manually traced borders (y = 0.93x + 0.68, mean difference = -0.8 +/-2.2 cc). AQ-derived reconstructions consistently underestimated LV volume by 39 +/- 10% (y = 0.62x-0.09, mean difference = -7.8 +/- 3.0 cc, different from manually traced and actual volumes by analysis of variance [ANOVA], F = 69, p<0.00001). The AQ-detected threshold signal was displaced into the cavity, and volume between walls and false tendons was excluded, leading to underestimation, which increased with increasing cavity volume (r = 0.76). The AQ technique can therefore be applied to 3DE reconstruction, providing volumes that correlate well with directly measured values in a stable in vitro standard, minimizing observer decisions regarding manual border placement after image acquisition. However, when the complete borders needed for 3D reconstruction are used, absolute volumes are underestimated with current algorithms that integrate backscatter and displace the detected threshold into the ventricular cavity.

An integrated approach to the quantification of aortic regurgitation by Doppler echocardiography

BACKGROUND Although different Doppler methods have been proposed for the quantification of aortic regurgitation, no study has prospectively compared these methods with each other and their correlation with angiography. The aim of this study was to prospectively analyze the usefulness of different Doppler echocardiography parameters by testing all such parameters in each patient. METHODS Fifty-one patients with aortic regurgitation underwent 2-dimensional and Doppler echocardiographic studies and catheterization. The following Doppler indexes were analyzed and compared with aortography. Color Doppler: (1) jet color height/left ventricular outflow tract height in parasternal long-axis view, and (2) jet color area/left ventricular outflow tract area in short-axis view. Continuous Doppler: (3) regurgitant flow pressure half-time, (4) regurgitant flow time velocity integral (in centimeters), and (5) regurgitant flow time velocity integral (in centimeters)/diastolic period (in milliseconds). Pulsed Doppler in thoracic and abdominal aorta: (6) time velocity integral of diastolic reverse flow (in centimeters), (7) time velocity integral of systolic anterograde flow/integral of diastolic reverse flow, (8) (time velocity integral of diastolic reverse flow/diastolic period) x 100, and (9) diastolic reverse flow duration/diastolic period (as a percentage). We compared these parameters with severity of regurgitation measured by angiography and classified as mild, moderate, or severe. RESULTS The most useful parameters were (1) jet color height/left ventricular outflow tract height (correctly classified 42 of 49 patients), (2) (time velocity integral of diastolic reverse flow/diastolic period) x 100 in the thoracic aorta (correctly classified 41 of 46 patients), and (3) (time velocity integral of diastolic reverse flow/diastolic period) x 100 in the abdominal aorta (correctly classified 42 of 49 patients). Sequential integration of these 3 parameters correctly classified 96% of patients (44 of 46 patients) and was achieved in 90% of cases. CONCLUSION An integrated combination of several Doppler parameters can quickly and accurately classify the degree of aortic regurgitation as determined by angiography.