Che-Ping Cheng

Determination of Left Ventricular Chamber Stiffness From the Time for Deceleration of Early Left Ventricular Filling

BACKGROUNDnA noninvasive measure of left ventricular (LV) chamber stiffness (KLV) would be clinically useful. Our theoretical analysis predicts that KLV can be calculated from the time for deceleration of LV early filling (tdec) by [formula: see text] where p = density of blood, L = effective mitral length, and A = mitral area.nnnMETHODS AND RESULTSnWe tested this hypothesis in eight conscious dogs instrumented for measurement of LV pressure (P) with use of a micromanometer and volume (V) with use of sonomicrometers. KLV was determined as the slope of the late diastolic portion of the LV P-V loop. KLV was varied from 0.99 +/- 0.35 to 2.58 +/- 0.92 mm Hg/mL with use of three graded doses of phenylephrine. We assumed that p = 1.0 and that L/A = 3.4. Thus, we predicted that KLV = (0.08/tdec)2. The LV filling pattern was determined from the derivative of LV volume (dV/dt). tdec was measured from peak early filling to the end of early filling. Predicted KLV and actual KLV were closely correlated (r = .94, SEE = 0.06 mm Hg/mL, P < .05). The regression line was close to the line of identity (slope = 0.95, intercept = 0.13 mm Hg/mL). Dobutamine did not alter the relation between tdec and KLV.tdec determined from the mitral valve flow velocity measured with Doppler echocardiography correlated well with that measured by dV/dt (r = .89, P < .01) but was 0.02 seconds longer. KLV-calculated tdec from the corrected Doppler tdec provided a good estimate of measured KLV (r = .75, SEE = 0.5 mm Hg/mL, P < .01).nnnCONCLUSIONSnLV chamber stiffness can be determined from the time for deceleration of LV early filling, which can be measured noninvasively.

Mechanism of altered patterns of left ventricular filling during the development of congestive heart failure.

BACKGROUNDnThe mechanism of the alterations in the pattern of left ventricular (LV) filling during the development of congestive heart failure (CHF) is not fully understood.nnnMETHODS AND RESULTSnWe studied six conscious dogs instrumented to measure LV and left atrial (LA) pressures and LV volume as CHF was induced by rapid pacing. Diastolic filling dynamics were serially measured over 4 weeks during normal sinus rhythm. Four days after we initiated pacing, the peak early diastolic filing rate decreased from 108 +/- 24 to 88 +/- 27 mL/s (P < .05) as the maximal early diastolic LA-LV pressure gradient decreased associated with a slowing of the rate of LV relaxation. Subsequently, the peak early filling rate progressively increased, returning to control at 1 week, and by the fourth week, it had increased to 168 +/- 39 mL/s (P < .05). These changes in early filling rates occurred as the maximal early diastolic LA-LV pressure gradient increased in association with a progressive increase in LV pressure despite further progressive slowing of the rate of LV relaxation. Throughout the development of CHF, peak early filling rate and the maximal LA-LV pressure gradient correlated (r = .99, P < .001). The early filling deceleration rate increased and deceleration time progressively decreased over the 4 weeks as LV stiffness and net LA plus LV stiffness increased (P < .05). As predicted by a theoretical analysis, the deceleration time was linearly related to the reciprocal of the square root of LV stiffness (r = .94, P < .01).nnnCONCLUSIONSnEarly in CHF, slowing of LV relaxation reduces the maximal early diastolic LA-LV pressure gradient, decreasing the peak early filling rate. As CHF progresses, this is overcome by an increase in LA pressure that augments the early diastolic LA-LV pressure gradient, increasing peak early filling rate. Increasing LV stiffness during the development of CHF progressively shortens the early filling deceleration time and augments the early filling deceleration rate. These observations suggest that the early filling deceleration time reflects LV stiffness.

Comparison of measures of left ventricular contractile performance derived from pressure-volume loops in conscious dogs.

Three measures of left ventricular (LV) performance derived from pressure (P)-volume (V) loops have been proposed: the end-systolic P-V (PES-VES) relation, the stroke work-end-diastolic V (SW-VED) relation, and maximum dP/dt-VED (dP/dtmax-VED) relation. We evaluated the variability of repeated determinations, and inotropic and load sensitivity of these relations in conscious dogs. LVV was determined from three orthogonal LV diameters measured by sonomicrometry. Three to six sets of variably loaded P-V loops were generated by transient caval occlusions before and again after increasing inotropic state by infusing dobutamine (6 +/- 1 microgram/kg/min, mean +/- SD) and after increasing PES by 49 +/- 17 mm Hg with phenylephrine following autonomic blockade. The slope (MSW) of the SW-VED relation was the least variable at constant inotropic state (coefficient of variation, 4 +/- 3%) compared with the slope (EES) of the PES-VES relation (8 +/- 3%) or the slope (dE/dtmax) of the dP/dtmax-VED relation (11 +/- 6%, p less than 0.05). The extrapolated volume-axis intercept of the SW-VED relation was much less variable than the intercepts of the PES-VES or dP/dtmax-VED relations. MSW, EES, and dE/dtmax all increased (p less than 0.05) in response to dobutamine. The extrapolated volume-axis intercepts of the PES-VES and dP/dtmax-VED relations increased with dobutamine, whereas the volume intercept of the SW-VED relation was unchanged. MSW had the smallest increase in response to dobutamine (124 +/- 22% of control) compared to EES (178 +/- 67% of control) and dE/dtmax (211 +/- 68% of control, p less than 0.05). The position of the PES-VES relation, quantified as the VES at PES = 100 (V100), showed less variability (2 +/- 1%) than the slope of the PES-VES relation (8 +/- 3%, p less than 0.05). V100 decreased from 30.8 +/- 17.4 to 26.7 +/- 13.7 ml during dobutamine (p less than 0.05). After phenylephrine, EES, MSW, and dE/dtmax decreased by less than 10% (p = NS). The PES-VES relation shifted to the left with this increased afterload and V100 decreased by 3.2 +/- 1.5 ml (p less than 0.05), whereas the position of the SW-VED and dp/dtmax-VED relations were relatively unchanged.(ABSTRACT TRUNCATED AT 400 WORDS)

Mechanism of augmented rate of left ventricular filling during exercise.

At rest, most of left ventricular (LV) filling occurs early in diastole. This LV filling occurs in response to the pressure gradient produced as LV pressure falls below left atrial (LA) pressure. Because mitral valve flow occurs in response to an LA to LV pressure gradient, augmented diastolic mitral valve flow during exercise may be due to an increased mitral valve pressure gradient resulting from a rise in LA pressure and/or a fall in LV early diastolic pressure. Accordingly, we studied 13 conscious dogs, instrumented to measure micromanometer LV and LA pressures, and determined LV volume from three ultrasonic dimensions during exercise. The animals ran on a treadmill for 8-15 minutes at 5-8 miles/hr. With reflexes intact, during exercise, the heart rate increased from 116 +/- 20 to 189 +/- 24 beats per minute (mean +/- SD, p less than 0.01), the maximum rate of change of LV volume (dV/dtmax) increased from 185 +/- 44 to 282 +/- 76 ml/sec (p less than 0.01), the ejection fraction and cardiac output increased, and the duration of diastole decreased from 296 +/- 83 to 162 +/- 71 msec (p less than 0.01). Mitral valve opening pressure, mean LA pressure (10.9 +/- 4.4 versus 10.2 +/- 3.9 mm Hg, p = NS), and LV end-diastolic pressure (12.8 +/- 4.8 versus 13.1 +/- 3.3 mm Hg, p = NS) were all relatively unchanged. The time constant of the fall of isovolumic LV pressure decreased from 28 +/- 3.3 to 21 +/- 4.4 msec (p less than 0.05). The early diastolic portion of the LV pressure-volume loop was shifted downward during exercise, with the minimum LV pressure decreasing from 3.3 +/- 2.8 to -2.8 +/- 3.4 mm Hg (p less than 0.05) and the maximum mitral valve pressure gradient increasing from 5.5 +/- 1.7 to 11.8 +/- 3.5 mm Hg (p less than 0.01). A similar downward shift of the early diastolic portion of the LV pressure-volume loop was produced by infusion of dobutamine (6 micrograms/kg/min i.v.) at rest, as well as by exercise when the heart rate was held constant by right ventricular pacing at 190-210 beats per minute. The downward shift during exercise was prevented by beta-blockade (metoprolol, 0.5 mg/kg i.v.). We conclude that during exercise, sympathetic stimulation and tachycardia produce a downward shift of the early diastolic portion of the LV pressure-volume loop.(ABSTRACT TRUNCATED AT 400 WORDS)

Diastolic mitral annular velocityduring the development of heart failure

OBJECTIVESnWe sought to investigate the mechanism of reduced diastolic mitral annular velocity with diastolic dysfunction, despite elevated left atrial (LA) pressure.nnnBACKGROUNDnThe peak rate of left ventricular (LV) early diastolic filling (E) and velocity of the mitral annulus due to long-axis lengthening (E(M)) are reduced in mild diastolic dysfunction. With more severe dysfunction, E increases in response to increased LA pressures. In contrast, E(M) decreases, despite increased LA pressure.nnnMETHODSnWe studied eight dogs instrumented to measure LA pressure, LV pressure, and internal dimensions during the progressive development of heart failure (HF) produced by rapid pacing.nnnRESULTSnEarly diastolic filling decreased after four days of pacing from 114 +/- 32 to 88 +/- 22 ml/s (p < 0.05), but with more severe HF, it progressively increased to 155 +/- 32 ml/s (p < 0.05). In contrast, E(M) progressively decreased from 44 +/- 12 mm/s during the control period to 24 +/- 8 mm/s after four weeks (p < 0.05). Although E(M) was related to the time constant of LV relaxation (tau) (R(2) = 0.85), E was not. The latter occurred coincident with termination of the early diastolic LA to LV pressure gradient during all conditions. In contrast, with increasing HF, E(M) was progressively delayed after LA to LV pressure crossover by 37 +/- 12 ms (p < 0.05). The time from E to E(M) was related to tau (R(2) = 0.97).nnnCONCLUSIONSnWith slowed relaxation during the development of HF, E(M) is reduced and delayed so that it occurs after early, rapid filling. Thus, with slowed relaxation, E(M) does not respond to the early diastolic LA to LV pressure gradient, because it occurs when LV pressure is greater than or equal to LA pressure.

Response of the left ventricular end-systolic pressure-volume relation in conscious dogs to a wide range of contractile states.

We assessed the linearity and slope of the left ventricular end-systolic pressure (PES)-volume (VES) relation over a wide range of contractile states in conscious dogs. The animals were instrumented to determine left ventricular volume from ultrasonic left ventricular internal dimensions and measure left ventricular pressure with a micromanometer. Studies were performed 1-2 weeks after instrumentation while the animals were conscious. Contractile state was increased by incremental infusion of dobutamine (0, 2, 4, 6, and 8 micrograms/kg/min i.v.) and decreased by verapamil (10 mg i.v.) given after autonomic blockade. The 44 +/- 11 mm Hg (mean +/- SD) portion of the PES-VES relation generated by bicaval occlusion demonstrated a slight but consistent nonlinearity, apparent as a concavity toward the volume axis. This nonlinearity, present at all inotropic states, did not prevent the PES-VES relation from being well approximated by a straight line (r = 0.984 +/- 0.020, SEE = 2.1 +/- 1.4 mm Hg); furthermore, the slope of the PES-VES line provided a sensitive index of contractile state, progressively increasing with incremental doses of dobutamine and decreasing in response to verapamil. The volume-axis intercept of the linear approximation of the PES-VES relation was 2.9 +/- 3.3 ml less (p less than 0.05) than the volume-axis intercept of the nonlinear quadratic fit. Thus, the linear PES-VES relation, whose slope is sensitive to a wide variety of inotropic states, is a reasonable and useful description of the left ventricle in the range of PES-VES points that can be produced by bicaval occlusion in the conscious dog. However, linear extrapolation of the relation beyond the range of data points may not be accurate.

Allopurinol Enhances the Contractile Response to Dobutamine and Exercise in Dogs With Pacing-Induced Heart Failure

Background —Superoxide (O2−) generated by enhanced xanthine oxidase (XO) activity may contribute to the increased myocardial oxidative stress in heart failure (CHF). Because blocking XO with allopurinol augments myofilament Ca2+ sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF. Methods and Results —We studied the effect of allopurinol on the contractile response to dobutamine and exercise in 7 chronically instrumented conscious dogs before and after producing CHF by rapid pacing. Left ventricular (LV) contractile performance was measured by the slopes of the LV end-systolic pressure-volume relation (EES) and stroke work–end-diastolic volume relation (MSW). Before CHF, allopurinol produced no change in LV contractile performance and did not alter the response to dobutamine or exercise. After CHF, allopurinol produced significant (P <0.05) increases in EES (5.0±0.6 versus 3.3±0.6 mm Hg/mL) and MSW. Dobutamine and allopurinol produced greater increases in EES (5.4±0.6 versus 7.4±0.6 mm Hg/mL) and MSW (60.1±7.4 versus 73.7±4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dtmax, stroke volume, and MSW were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol. Conclusions —Allopurinol has no discernable effects on LV contractile function or adrenergic responsiveness in normal, conscious animals. In pacing-induced CHF, however, allopurinol improves LV systolic function at rest and during adrenergic stimulation and exercise.

Effect of heart failure on the mechanism of exercise-induced augmentation of mitral valve flow.

The exercise response of left ventricular (LV) filling dynamics may be altered by congestive heart failure (CHF). Accordingly, we studied 18 conscious dogs, instrumented to measure micromanometer LV and left atrial (LA) pressures and determine LV volume from three dimensions. CHF was produced by 4-5 weeks of right ventricular rapid pacing. Before CHF, exercise (5.5-8.5 mph for 8-15 minutes) increased the maximum rate of LV filling (dV/dtmax) (197 +/- 37 versus 297 +/- 56 ml/sec [mean +/- SD], p < 0.05) in response to an increase in the maximum early diastolic LA to LV pressure gradient (5.8 +/- 2.0 versus 9.8 +/- 1.9 mm Hg, p < 0.05) produced by a fall in minimum LV pressure (1.0 +/- 2.9 versus -3.9 +/- 3.1 mm Hg, p < 0.01), whereas mean LA pressure was unchanged (6.4 +/- 3.1 versus 6.4 +/- 4.2 mm Hg, p = NS). The time constant of LV relaxation was shortened (28.1 +/- 3.2 versus 21.0 +/- 4.2 msec, p < 0.05). After CHF, dV/dtmax (141 +/- 51 versus 200 +/- 59 ml/sec, p < 0.05) and the maximum LA to LV pressure gradient (6.0 +/- 1.1 versus 11.1 +/- 2.7 mm Hg, p < 0.05) continued to increase with exercise (3-5.0 mph for 4-8 minutes). However, the time constant of LV relaxation was prolonged (35.6 +/- 4.8 versus 38.9 +/- 5.5 msec, p < 0.05), and minimum LV pressure (15.1 +/- 5.6 versus 17.6 +/- 5.9 mm Hg, p < 0.05) and mean LA pressure increased (22.6 +/- 7.2 versus 29.1 +/- 7.3 mm Hg, p < 0.05). These altered effects of exercise on LV diastolic filling dynamics persisted when heart rate and wall stress during exercise before and after CHF were matched by varying the level of exercise. We conclude that, during normal exercise, mitral valve flow is augmented by a fall of early diastolic LV pressure without a rise in LA pressure. After CHF, early diastolic LV pressure does not fall but increases during exercise. Thus, the increase in the early diastolic LA to LV pressure gradient and the rate of mitral valve flow results from an increase in LA pressure during exercise after CHF. This study suggests that the failure of the enhancement of LV relaxation and an increase in early diastolic LV pressure with exercise after CHF may contribute to exercise intolerance in CHF.

Altered Ventricular and Myocyte Response to Angiotensin II in Pacing-Induced Heart Failure

Alterations in the cardiac response to angiotensin II (Ang II) may contribute to the functional impairment in tachycardia-induced heart failure (congestive heart failure [CHF]). Accordingly, we studied the response to Ang II in eight conscious instrumented dogs before and after inducing CHF. Left ventricular (LV) performance was assessed by measuring LV pressure and LV volume. Isolated myocyte function was evaluated using computer-assessed videomicroscopy. In conscious animals before CHF, Ang II produced a load-dependent slowing of the time constant of LV relaxation (tau) and did not depress intact LV contractile function. After CHF, although Ang II produced a similar increase in LV systolic pressure, the increases in LV diastolic pressure and time constant tau were much greater, and contractile performance was depressed. These changes persisted when the elevation of end-systolic pressure was prevented by nitroprusside. Similar changes were also present after autonomic blockade. In isolated myocytes, before CHF, Ang II (10(-6) mol/L) produced a slight positive inotropic effect. In contrast, after CHF, Ang II produced a negative inotropic effect and slowed the rate of relengthening. The effects in the intact LV and myocytes were reversed by an Ang II AT1 receptor blocker (losartan). We conclude that pacing-induced CHF alters the LV and myocyte response to Ang II, so that Ang II produces direct depressions in intact LV contraction, relaxation, and filling and exacerbates myocyte contractile dysfunction. These effects are mediated through the activation of AT1 receptors.

Diastolic Dysfunction as a Cause of Exercise Intolerance

Tachycardia accompanying exercise shortens the duration of diastole, reducing the time available for the left ventricular (LV) filling. Thus, the LV must fill more rapidly for the stroke volume to increase (or even be maintained) during exercise. Normally, this is accomplished without requiring an excessive increase in left atrial (LA) pressure by an acceleration of LV relaxation and a fall in LV early diastolic pressure during exercise. This response is lost following the development of heart failure due to systolic dysfunction, both in experimental animals and in patients. In fact, in such situations, LV relaxation slows and LV early diastolic pressure increases due to exercise. Thus, any diastolic dysfunction present at rest in CHF during systolic dysfunction is exacerbated during exercise. Similarly, patients with primary diastolic dysfunction heart failure with preserved systolic function may not be able to augment LV filling rates without an abnormal increase in LA pressure. Thus, diastolic dysfunction may contribute to exercise intolerance, both in systolic dysfunction and primary diastolic dysfunction. Acute studies suggest that treatment with angiotensin II receptor blockers or verapamil may improve exercise tolerance in some patients with primary diastolic dysfunction.