J L Guerrero

Combined influence of ventricular loading and relaxation on the transmitral flow velocity profile in dogs measured by Doppler echocardiography.

The relation of the Doppler transmitral flow velocity profile to left ventricular loading conditions and diastolic properties remains poorly described. We studied seven adult mongrel dogs with an open-chest right heart bypass model in which left atrial pressure, representing preload, was varied by controlling blood flow into the pulmonary artery and left ventricular systolic pressure, representing afterload, was controlled independently by pumping blood into or from the femoral arteries. Heart rate was kept constant by crushing the sinus node and pacing the right atrium. Mitral inflow velocity profiles were measured by pulsed-wave Doppler echocardiography at multiple left atrial and left ventricular systolic pressures. In individual dogs, the peak E-wave velocity increased linearly with increasing left atrial V-wave pressure at constant left ventricular systolic pressure and decreased with increasing left ventricular systolic pressure at constant left atrial pressure. Stepwise multiple linear regression analysis of data pooled from all experimental stages in all dogs identified left atrial V-wave pressure, the time constant of relaxation (TL), and left ventricular systolic pressure, in order of decreasing significance, as predictors of the peak E-wave velocity (n = 82, multiple r = 0.87, p less than 0.0001). Multivariate analysis with the same three factors in individual dogs yielded higher r values (mean r = 0.89; range, 0.85-0.97), suggesting the presence of important interdog differences that were not accounted for by these three factors alone. When the values of codeterminant hemodynamic factors were kept within narrower limits, correlations between peak E-wave velocity and left atrial V-wave pressure (n = 35, multiple r = 0.83, p less than 0.0001), TL (n = 76, multiple r = -0.54, p less than 0.0001) and left ventricular systolic pressure (n = 20, multiple r = -0.59, p less than 0.005) improved substantially. In the pooled data, the relation of the peak E-wave velocity to left atrial V-wave pressure was shifted downward by an increase in TL (reduced relaxation rate), and the relation of the peak E-wave velocity to TL was shifted upward by an increase in left atrial V-wave pressure. Multivariate analysis also selected left atrial V-wave pressure and TL as the two most significant correlates of the velocity-time integral and deceleration rate of the E wave.(ABSTRACT TRUNCATED AT 400 WORDS)

Variable effects of changes in flow rate through the aortic, pulmonary and mitral valves on valve area and flow velocity: Impact on quantitative doppler flow calculations

Doppler echocardiographic methods for measuring volumetric flow through the aortic, pulmonary and mitral valves provide the cardiologist with several potentially interchangeable noninvasive methods for determining cardiac output. In addition, comparison of flow differences through individual valves offers the potential to quantitate shunt flow and regurgitant volumes. To date, however, no study has compared the relative accuracies of each of these flow measurements in a controlled experimental setting. Therefore, in this study, Doppler echocardiography was used to measure aortic, pulmonary and mitral valve flows in seven open chest dogs on right atrial bypass where forward cardiac output was precisely controlled with a roller pump. Correlations with roller pump output were better for Doppler measurements of aortic (r = 0.98, SD = 0.3) and mitral (r = 0.97, SD = 0.3) than for pulmonary (r = 0.93, SD = 0.5) valve flow. Interobserver reproducibility was also better for aortic (r = 0.94) and mitral (r = 0.97) than for pulmonary (r = 0.88) valve flow measurements. All valves showed flow-related increases in cross-sectional area, but the slope of this response was variable: 0.05, 0.16 and 0.21 for the aortic, the pulmonary and the mitral valve, respectively. Increased forward flow through the aortic valve, therefore, was manifested primarily by an increase in velocity, whereas increasing flow through the pulmonary and mitral valves produced more significant area changes with correspondingly smaller increases in the velocity component. Recalculation of Doppler-determined outputs, assuming a fixed valve area for the entire range of flows, resulted in a decreased correlation with roller pump output. Both velocity and valve area should be measured at each flow rate for greatest accuracy in volumetric flow calculations.

Noninvasive estimation of the instantaneous first derivative of left ventricular pressure using continuous-wave Doppler echocardiography.

BackgroundThe complete continuous-wave Doppler mitral regurgitant velocity curve should allow reconstruction of the ventriculoatrial (VA) pressure gradient from mitral valve closure to opening, including left ventricular (LV) isovolumic contraction, ejection, and isovolumic relaxation. Assuming that the left atrial pressure fluctuation is relatively minor in comparison with the corresponding LV pressure changes during systole, the first derivative of the Doppler-derived VA pressure gradient curve (Doppler dP/dt) might be used to estimate the LV dP/dt curve, previously measurable only at catheterization (catheter dP/dt). Methods and ResultsThis hypothesis was examined in an in vivo mitral regurgitant model during 30 hemodynamic stages in eight dogs. Contractility and relaxation were altered by inotropic stimulation and hypothermia. The Doppler mitral regurgitant velocity spectrum was recorded along with simultaneously acquired micromanometer LV and left atrial pressures. The regurgitant velocity profiles were digitized and converted to VA pressure gradient curves using the simplified Bernoulli equation. The instantaneous dP/dt of the VA pressure gradient curve was then derived. The instantaneous Doppler-derived VA pressure gradients, instantaneous Doppler dP/dt, dP/dtmax, and −dP/dtmax were compared with corresponding catheter measurements. This method of estimating dP/dtmax, from the instantaneous dP/dt curve was also compared with a previously proposed Doppler method of estimating dP/dtmax using the Doppler-derived mean rate of LV pressure rise over the time period between velocities of 1 and 3 m/sec on the ascending slope of the Doppler velocity spectrum. Both instantaneous Doppler-derived VA pressure gradients (r = 0.95, p < O.OOOl) and Doppler dP/dt (r = 0.92, p < 0.0001) correlated well with corresponding measurements by catheter during systolic contraction and isovolumic relaxation (pooled data). The Doppler dP/dtmax (1,266 ± 701 mm Hg/sec) also correlated well (r = 0.94) with the catheter dP/dtmax (1,200 ± 573 mm Hg/sec). There was no difference between the two methods for measurement of dP/dtmax (p=NS). Although Doppler −dP/dt. was slightly lower than the catheter measurement (961 ± 511 versus 1,057540 mm Hg/sec, p < 0.01), the correlation between measurements by Doppler and catheter was excellent (r = 0.93, p < 0.0001). The alternative method ofmean isovolumic pressure rise (896 ± 465 mm Hg/sec) underestimated the catheter dP/dtmax, (1,200 ± 573 mm Hg/sec) significantly (on average, 25%; p < O.001). ConclusionsThe present study demonstrated an accurate and reliable noninvasive Doppler method for estimating instantaneous LV dP/dt, dP/dtma, and −dP/dtmax. (Circulation 1991; 83:2101—2110)

Coronary thrombolysis with recombinant human tissue-type plasminogen activator.

The thrombolytic potency and myocardial infarct--sparing potential of recombinant tissue-type plasminogen activator (rt-PA) were studied in electrocardiographically monitored, open-chest, anesthetized dogs. Localized coronary thrombosis was produced in the left anterior descending artery by endothelial injury and instillation of thrombin and fresh blood. After 2 hr of stable thrombotic occlusion, rt-PA was infused intravenously. At a dose of 4.3 micrograms/kg/min, time to reperfusion was greater than 40 min (n = 3). However, at higher infusion rates a linear, dose-dependent time to coronary reperfusion was obtained (r = .88): at 10 micrograms/kg/min reperfusion occurred after 31 +/- 2 min (n = 3), at 15 micrograms/kg/min it was at 26 +/- 7 min (n = 4), and at 25 micrograms/kg/min, lysis was accomplished within 13 +/- 3 min (n = 3). Thrombolysis was not associated with alterations in either plasma hemostatic factors (fibrinogen, plasminogen, and alpha 2-antiplasmin) or in systemic blood pressures. Epicardial electrographic measurements revealed a significant reduction in ST elevation in all reperfused hearts. A randomized, blinded study was also carried out with 15 micrograms/kg/min of rt-PA saline in 18 dogs with 30 min of coronary thrombosis. Reperfusion in the treated group occurred after 28 +/- 3 min. No evidence of thrombolysis was noted in the saline-treated group within 240 min. Size of myocardial infarction was determined by triphenyl tetrazolium chloride staining and planimetry. Infarction involved 2.5 +/- 0.5% of the left ventricular wall in the group receiving rt-PA, but 16 +/- 3% of the left ventricle in the saline-treated group (p = .001). It is concluded that intravenous infusion of rt-PA results in rapid, dose-dependent coronary thrombolysis without systemic fibrinolytic activation and that early lysis of coronary thrombi is associated with substantial salvage of myocardial tissue.

Calculation of atrioventricular compliance from the mitral flow profile: analytic and in vitro study

The quantitative assessment of ventricular diastolic function is an important goal of Doppler echocardiography. Hydrodynamic analysis predicts that the net compliance (Cn) of the left atrium and ventricle can be quantitatively predicted from the deceleration rate (dv/dt) of the mitral velocity profile by the simple expression: Cn = - A/rho dv/dt, where A is effective mitral valve area and rho is blood density. This formula was validated using an in vitro model of transmitral filling where mitral valve area ranged from 0.5 to 2.5 cm2 and net compliance from 0.012 to 0.023 cm3/(dynes/cm2) (15 to 30 cm3/mm Hg). In 34 experiments in which compliance was held constant throughout the filling period, net atrioventricular compliance was accurately calculated from the E wave downslope and mitral valve area (r = 0.95, p less than 0.0001). In a second group of experiments, chamber compliance was allowed to vary as a function of chamber pressure. When net compliance decreased during diastole (as when the ventricle moved to a steeper portion of its pressure-volume curve), the transorifice velocity profile was concave downward, whereas when net compliance increased, the velocity profile was concave upward. Application of the preceding formula to these curved profiles allowed instantaneous compliance to be calculated throughout the filling period (r = 0.93, p less than 0.001). Numeric application of a mathematic model of mitral filling demonstrated the accuracy of this approach in both restrictive and nonrestrictive orifices.(ABSTRACT TRUNCATED AT 250 WORDS)

A Doppler-two-dimensional echocardiographic method for quantitation of mitral regurgitation.

A noninvasive method to accurately quantitate the severity of mitral insufficiency would be of major clinical value. In theory, in the absence of confounding variables, regurgitant mitral flow should represent the difference between forward mitral blood flow and aortic blood flow. Since Doppler-two-dimensional echocardiographic (D2DE) methods for measuring transvalvular mitral and aortic flow have been validated, it should be possible to use mitral and aortic flows derived by this method to calculate regurgitant mitral flow. To assess the validity and accuracy of this combined approach for quantitation of regurgitant flow, we developed an open-chest canine preparation in which we could simulate, vary, and accurately measure degrees of mitral regurgitation. Seven animals were anesthetized and prepared to allow controlled right heart output. Mitral regurgitation was than simulated by placing a flexible conduit incorporating a one-way valve and electromagnetic flowmeter between the left ventricular apex and left atrium. Flow through the tube (effective mitral regurgitation) was varied between 0.2 and 1.8 liters/min and forward cardiac output ranged between 0.5 and 4 liters/min. Transmitral and transaortic flows were calculated by previously reported Doppler methods. Doppler-derived estimates of forward flow through the aortic valve correlated well with the flow measured by flowmeter (r = .92), and regurgitant flow and regurgitant fraction calculated by the D2DE approach also compared well with those measured by flowmeter (r = .84 and .83, respectively). This study demonstrates that mitral regurgitant flow and regurgitant fraction calculated by the D2DE method provide an acceptable measure of both absolute regurgitant flow and the regurgitant fraction in the experimental setting.

Intracardiac ultrasound measurement of volumes and ejection fraction in normal, infarcted, and aneurysmal left ventricles using a 10-MHz ultrasound catheter.

BackgroundOur objective was to examine the accuracy of intracardiac ultrasound (ICUS) measurement of left ventricular (LV) volumes and ejection fraction (EF) using a 10-MHz ultrasound catheter. ICUS can image the LV in cross sections at all levels along the long axis with a transducer mounted on the tip of a catheter. Sequential serial LV cross-sectional images can be obtained during cardiac catheterization and used to calculate LV volumes by Simpsons rule. This technique may be an alternative to contrast LV angiography. Methods and ResultsA beating-heart in vivo model was created to measure LV volume directly and continuously with an intracavity high-compliance latex balloon connected to a calibrated extracardiac reservoir in eight dogs in 35 experimental stages. A 1OF ICUS catheter with a 10-MHz single-element transducer was introduced retrogradely via the aortic valve to the apex. Series of sequential LV cross-sectional images were recorded from the apex to the base during a calibrated pullback of the catheter. At each 5-mm interval, the LV cross section was traced at end diastole and end systole. LV volume was calculated by Simpsons rule by integrating all segmental areas multiplied by segmental height. The effect on accuracy of selecting 5-, 10-, or 15-mm heights or a single section at the midventricular level for measurement was assessed. The influence of distorted ventricular shape on the accuracy of ICUS measurements of LV volume was evaluated. This method was applied in 19 experimental stages in 10 intact dogs and pigs catheterized via the femoral artery. In the in vivo canine model, LV end-diastolic volume, end-systolic volume, and EF determined by ICUS using 5-, 10-, or 15-mm segments were not different from the actual measurements. But correlation and agreement between ICUS end-diastolic volume and direct measurements for 5- and 10-mm segments were significantly better than for 15-mm segments or a single section. Similar excellent correlations and agreement were observed for actual and ICUS-derived end-systolic volumes using 5-, 10-, or 15-mm segments. The ICUS-derived EF correlated very well with actual EF with a small measurement error of 3.91±2.59% for 5-mm or 4.13 ±2.79% for 10-mm segments but a significantly greater measurement error for 15-mm segments (5.35±3.76%) or single sections (14.8±12.2%). The presence of LV infarction or aneurysm did not significantly influence the accuracy of ICUS calculations for segmental heights 510 mm. Application in intact animals demonstrated a good correlation between stroke volume measured by ICUS and by thermodilution or flowmeter. ICUS-derived LV volumes correlated well with biplane angiographic volumes, with a tendency toward underestimation. There was no significant difference between ICUS-determined LV EF and EF determined by angiography. ConclusionsIntracardiac echocardiography accurately measures LV volumes and global systolic function in both regularly shaped and distorted left ventricles. This technique directly and continuously visualizes circumferential LV endocardium and wall thickness without contrast agents or geometric assumptions for calculation of LV volume. Thus, it should be particularly useful in patients at high risk for contrast-related complications or distorted LV shapes in which geometric assumptions may not be valid.

CD45 Expression in Mitral Valve Endothelial Cells After Myocardial Infarction.

RATIONALE Ischemic mitral regurgitation, a complication after myocardial infarction (MI), induces adaptive mitral valve (MV) responses that may be initially beneficial but eventually lead to leaflet fibrosis and MV dysfunction. We sought to examine the MV endothelial response and its potential contribution to ischemic mitral regurgitation. OBJECTIVE Endothelial, interstitial, and hematopoietic cells in MVs from post-MI sheep were quantified. MV endothelial CD45, found post MI, was analyzed in vitro. METHODS AND RESULTS Ovine MVs, harvested 6 months after inferior MI, showed CD45, a protein tyrosine phosphatase, colocalized with von Willebrand factor, an endothelial marker. Flow cytometry of MV cells revealed significant increases in CD45+ endothelial cells (VE-cadherin+/CD45+/α-smooth muscle actin [SMA]+ and VE-cadherin+/CD45+/αSMA- cells) and possible fibrocytes (VE-cadherin-/CD45+/αSMA+) in inferior MI compared with sham-operated and normal sheep. CD45+ cells correlated with MV fibrosis and mitral regurgitation severity. VE-cadherin+/CD45+/αSMA+ cells suggested that CD45 may be linked to endothelial-to-mesenchymal transition (EndMT). MV endothelial cells treated with transforming growth factor-β1 to induce EndMT expressed CD45 and fibrosis markers collagen 1 and 3 and transforming growth factor-β1 to 3, not observed in transforming growth factor-β1-treated arterial endothelial cells. A CD45 protein tyrosine phosphatase inhibitor blocked induction of EndMT and fibrosis markers and inhibited EndMT-associated migration of MV endothelial cells. CONCLUSIONS MV endothelial cells express CD45, both in vivo post MI and in vitro in response to transforming growth factor-β1. A CD45 phosphatase inhibitor blocked hallmarks of EndMT in MV endothelial cells. These results point to a novel, functional requirement for CD45 phosphatase activity in EndMT. The contribution of CD45+ endothelial cells to MV adaptation and fibrosis post MI warrants investigation.

Effect of dextran and aspirin on platelet adherence after transluminal angioplasty of normal canine coronary arteries

The effect of low-molecular-weight dextran and aspirin on platelet deposition after transluminal coronary angioplasty was studied in a normal canine model. Eighteen anesthetized, open-chest dogs were separated into 4 groups. All dogs received 3,000 units of intravenous heparin 10 to 20 minutes before the procedure. Dogs in Group 1 served as controls and were given no further treatment. Dogs in Group 2 received low-molecular-weight dextran by continuous intravenous infusion at a rate of 20 ml/hour for 1 hour before balloon inflation. Dogs in Group 3 were given 500 ml of low-molecular-weight dextran as an intravenous bolus over 1 hour, beginning 4 hours before the procedure. Dogs in Group 4 were fed 20 mg/kg of aspirin 3 hours before angioplasty. The dogs were killed 10 minutes after angioplasty and the arterial segments subjected to balloon inflation submitted for electron microscopic analysis. An additional group of 10 dogs was used to assess the bleeding times and platelet counts from control and drug-treated dogs. Drug treatment was associated with significant prolongation of the bleeding time and reduction in platelet number. Extensive endothelial desquamation in the area of balloon angioplasty was observed in all dogs. However, no appreciable qualitative difference in either the degree or extent of rapid platelet deposition to the exposed subendothelium was discernible between the control and any of the treatment groups. These results do not confirm previous observations with low-molecular-weight dextran. Further work on the initial and long-term platelet response after endothelial injury should be undertaken in a primate atherosclerotic model.

Synergistic combinations of recombinant human tissue-type plasminogen activator and human single-chain urokinase-type plasminogen activator. Effect on thrombolysis and reocclusion in a canine coronary artery thrombosis model with high-grade stenosis.

The synergistic effects of recombinant human tissue-type plasminogen activator (rt-PA) and single-chain urokinase-type plasminogen activator (scu-PA) on coronary arterial thrombolysis were investigated in open-chest dogs with thrombosis of the left anterior descending coronary artery and a superimposed high-grade stenosis. A 90% stenosis was generated by external constriction, reducing blood flow to 40 +/- 10% of baseline. Localized thrombosis was produced by endothelial cell injury and instillation of thrombin and fresh blood. Intravenous infusion for 60 minutes of either 30 micrograms/kg/min rt-PA alone or 10 micrograms/kg/min scu-PA alone consistently produced coronary artery recanalization (six of eight dogs and five of five dogs, respectively) but was almost always associated with reocclusion during or shortly after the end of the infusion (four of six dogs and five of five dogs, respectively). Infusion of either 15 micrograms/kg/min rt-PA or 5 micrograms/kg/min scu-PA for 60 minutes did not cause coronary artery recanalization (none of four dogs in each group). Combined infusion of 7.5 micrograms/kg/min rt-PA and 2.5 micrograms/kg/min scu-PA for 60 minutes (one fourth of the minimum thrombolytic dose of each agent) induced coronary artery recanalization (six of six dogs) but was also associated with early reocclusion (six of six dogs). Combined infusion of 3.75 micrograms/kg/min rt-PA and 1.25 micrograms/kg/min scu-PA for 60 minutes did not consistently cause recanalization (one of four dogs). Combined infusion of 15 micrograms/kg/min rt-PA and 5 micrograms/kg/min scu-PA for 60 minutes caused recanalization in all of six dogs but was associated with reocclusion in all six.(ABSTRACT TRUNCATED AT 250 WORDS)