W L Maughan

Effective arterial elastance as index of arterial vascular load in humans.

BackgroundThis study tested whether the simple ratio of ventricular end-systolic pressure to stroke volume, known as the effective arterial elastance (Ea), provides a valid measure of arterial load in humans with normal and aged hypertensive vasculatures. Methods and ResultsVentricular pressure-volume and invasive aortic pressure and flow were simultaneously determined in 10 subjects (four young normotensive and six older hypertensive). Measurements were obtained at rest, during mechanically reduced preload, and after pharmacological interventions. Two measures of arterial load were compared: One was derived from aortic input impedance and arterial compliance data using an algebraic expression based on a three-element Windkessel model of the arterial system [Ea(Z)I, and the other was more simply measured as the ratio of ventricular end-systolic pressure to stroke volume [Ea(PV)]. Although derived from completely different data sources and despite the simplifying assumptions of Ea(PV), both Ea(Z) and Ea(PV) were virtually identical over a broad range of altered conditions: Ea(PV) = 0.97 · Ea(Z) +0.17; n = 33, r2 = 0.98, SEE = 0.09, p < 0.0001. Whereas Ea(PV) also correlated with mean arterial resistance, it exceeded resistance by as much as 25% in older hypertensive subjects (because of reduced compliance and wave reflections), which better indexed the arterial load effects on the ventricle. Simple methods to estimate Ea (PV) from routine arterial pressures were tested and validated. ConclusionsEa(PV) provides a convenient, useful method to assess arterial load and its impact on the human ventricle. These results highlight effects of increased pulsatile load caused by aging or hypertension on the pressure-volume loop and indicate that this load and its effects on cardiac performance are often underestimated by mean arterial resistance but are better accounted for by Ea.

Comparative influence of load versus inotropic states on indexes of ventricular contractility: experimental and theoretical analysis based on pressure-volume relationships.

We examined the quantitative influence of carefully controlled alterations in end-diastolic volume and afterload resistance on multiple simultaneously determined ejection and isovolumetric phase indexes of left ventricular contractile function in 23 isolated supported canine ventricles. The influence of load change on each index was compared with its sensitivity to inotropic stimulation, and this sensitivity was in turn contrasted to the response of the end-systolic pressure-volume relationship (ESPVR). Experimental data demonstrated various degrees of load sensitivity among the indexes, with a generally curvilinear relationship between load and index response for both preload and afterload alterations. The curvilinear nature of these relationships meant that over a select range of loading, many indexes demonstrated relative load independence. They also often displayed greater sensitivity to inotropic change than the ESPVR, and both factors help explain their enduring clinical utility. To further explore the influence of load and contractile state on several of the indexes, we developed a theoretical analysis, using variables common to pressure-volume relationships, in which these dependencies could be derived. The theoretical models fit very well with the experimental data, and reaffirmed the frequently curvilinear nature of the relationships. We conclude that while many clinical indexes of ventricular contractile function show significant load dependence, the information they provide can be reasonably interpreted within defined ranges of load and inotropic alteration. Any advantage of the ESPVR will derive not from the magnitude of its response to inotropic change, which is smaller than most other indexes, but from its relative insensitivity to load alteration over a wider range of load.

Determination of left ventricular end-systolic pressure-volume relationships by the conductance (volume) catheter technique.

Using a multielectrode conductance catheter to estimate continuous left ventricular volume we determined the end-systolic pressure-volume relationship (ESPVR) in situ in open-chest anesthetized dogs. Dogs (n = 8) were studied in the control state and after pharmacologic sympathectomy (hexamethonium) and surgical vagotomy both before and after the administration of dobutamine. ESPVR was measured during brief (5 to 6 sec) preload reduction by balloon occlusion of the inferior vena cava (IVCBO). The relationship was highly reproducible. The slope (Ecs) and volume intercept (Vo) (mean +/- SD) in the control series were 5.8 +/- 3.6 mm Hg/ml and 6.5 +/- 12.5 ml, respectively. Upon release of the IVCBO (preload recovery), Ecs was 7.7 +/- 3.6 mm Hg/ml and Vo was 12.4 +/- 9.6 ml (p less than .01). Autonomic blockade produced a 50% reduction in Ecs and a concomitant decrease in Vo (p less than .01), and eliminated the difference between ESPVR generated by preload reduction (IVCBO) and preload recovery (IVCBO release). Subsequent dobutamine infusion increased Ecs to 6.1 +/- 3.5 mm Hg/ml and Vo to 4.1 +/- 6.9 ml, consistent with reported changes of the ESPVR with positive inotropic intervention. A small artifact of right ventricular filling was observed in the left ventricular volume catheter signal, but this did not appreciably alter the ESPVR. These results demonstrate the feasibility of the determination of ESPVR in situ by the conductance catheter and brief IVCBO and underline the importance of the use of rapid load changes to minimize reflex activation during the measurements.

The use of left ventricular end-ejection pressure and peak pressure in the estimation of the end-systolic pressure-volume relationship.

The end-systolic pressure-volume relationship (ESPVR) as derived from left ventricular pressure-volume loops has gained increasing acceptance as an index of ventricular contractile function. In animal experiments the ESPVR has been defined as a line connecting the upper left corners of several differently loaded pressure-volume (P-V) loops with a slope parameter Ees and a volume axis intercept parameter Vo. In the clinical setting, several variants of the ESPVR have been determined with use of peak left ventricular pressure, end-ejection pressure, and end-ejection volume. The maximum P-V ratio has also frequently been measured. We attempted to determine which of these alternatives resulted in good approximations of the reference ESPVR in eight isolated canine ventricles that ejected into a simulated arterial impedance system with resistance, compliance, and characteristic impedance. We determined various versions of the ESPVR from the same set of beats quickly obtained with little change in inotropic background. To vary ventricular pressure wave forms, each of the arterial impedance parameters was independently controlled at 50%, 100%, and 200% of normal. Against each of the nine combinations of the impedance parameters four P-V loops were obtained under four preloads and from each of the sets of four P-V loops, the reference ESPVR, linear regression of the peak pressure on end-ejection volume (ESPVRPP-EEV), and linear regression of end-ejection pressure on end-ejection volume (ESPVREEPV) were determined. In addition, the maximum P-V ratio (MPVR) was calculated for each P-V loop.(ABSTRACT TRUNCATED AT 250 WORDS)

Diminished contractile response to increased heart rate in intact human left ventricular hypertrophy. Systolic versus diastolic determinants.

BackgroundExperimental studies indicate that in addition to diastolic dysfunction, hypertrophied myocardium can display depressed contractile responses, particularly at rapid heart rates, compounding reserve limitations. This study tests whether such abnormalities exist in intact human subjects at physiological paced rates and, if so, whether they are linked to simultaneous rate-dependent deterioration in diastolic function. Methods and ResultsTen subjects with left ventricular hypertrophy (LVH) and 8 normal control subjects were studied. Most LVH patients presented with dyspnea and/or pulmonary edema and had concentric hypertrophy. Since rapid pacing simultaneously alters cardiac filling volumes and pressures, pressurevolume relation analysis was used to better define changes in contractile response. Patients were instrumented with a conductance catheter and micromanometer for pressure-volume data recording and a balloon occluder at the right atrial-inferior vena caval junction to vary filling and thus generate function relations. Data were obtained at baseline and at three atrial pacing rates (100, 120, 150 min-1). In addition, single-beat force-interval data were used to indirectly examine calcium cycling kinetics. LVH subjects demonstrated baseline diastolic abnormalities, including prolonged relaxation, elevated end-diastolic pressure, and reduced chamber compliance. However, systolic function was similar to that in control subjects. With rapid pacing, normal subjects displayed a positive contractile response, whereas this was markedly diminished in LVH subjects. With abrupt termination of pacing and return to slower sinus rhythm, LVH subjects displayed greater initial potentiation followed by a more rapid decline than control subjects, suggesting abnormalities of calcium handling. Despite contractile abnormalities, diastolic function did not further deteriorate with rapid pacing and thus did not appear to be tightly linked to the systolic changes ConclusionsPacing stress in intact human LVII can result in systolic impairment superimposed on preexisting but not worsened diastolic dysfunction. Abnormal calcium handling probably contributes prominently to this response.

Effect of acute volume load on refractoriness and arrhythmia development in isolated, chronically infarcted canine hearts.

In normal isolated, perfused canine ventricles, increased ventricular volume leads to shortening of refractoriness. To test the hypothesis that myocardium within an infarction zone is more susceptible to volume-induced changes in refractoriness than is normal myocardium, we measured strength-interval curves at low and high end-diastolic volumes at control and infarcted sites in 14 isolated, blood perfused, canine hearts with chronic (greater than 25 days) infarctions. In addition, the effect of volume load on inducing ventricular arrhythmias was studied at one to six sites in 11 hearts. Differences in refractoriness and inducibility at low (22 +/- 5 ml) and high (48 +/- 6 ml) end-diastolic volumes were compared. At control sites, volume load reduced the absolute refractory period from 178 +/- 16.5 to 175 +/- 16.7 msec (p less than 0.05), but no significant change in the relative refractory period occurred. At infarcted sites, the change in refractoriness with volume load was greater, and the absolute refractory period decreased from 171.5 +/- 21 to 160.6 +/- 26.3 msec (p less than 0.01), and the relative refractory period decreased from 180.1 +/- 22.1 to 169.9 +/- 26 msec (p = 0.05). This differential effect of volume load on refractoriness led to an increased dispersion of overall refractoriness at high volume. Infarcted sites showing the largest changes in refractoriness were characterized by patchy scars extending at least to the midmyocardium, whereas sites located within areas of transmural scar, endocardial scar, or rare microfoci of fibrosis showed no increased sensitivity to volume load. Of eight hearts in which no tachyarrhythmias were inducible during programmed electrical stimulation at low volume, four had tachyarrhythmias induced at high volume. Sites of stimulation associated with a conversion from noninducible to inducible tachyarrhythmias showed a larger degree of shortening of refractoriness (change in absolute refractory period: 24.7 +/- 16.5 vs. 3.9 +/- 6.5 msec, p less than 0.05). These data indicate that volume loading may have electrophysiologic significance and that it may be of greater functional importance under pathologic conditions.

Influence of coronary occlusion during PTCA on end-systolic and end-diastolic pressure-volume relations in humans.

The influence of acute coronary occlusion on systolic and diastolic left ventricular pressure-volume relations was studied in 10 patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Pressure-volume relations were obtained by conductance catheter and micromanometer techniques and with volume load altered by transient inferior vena caval occlusion. End-systolic and end-diastolic pressure-volume relations were obtained at baseline, during 60-90 seconds of ischemia, and at return to baseline after angioplasty balloon deflation. Coronary occlusion significantly altered systolic and diastolic chamber function. Systolic dysfunction was characterized by a reproducible rightward shift of the end-systolic pressure-volume relation (+25.4 +/- 18.4 ml) that was greater for proximal left anterior descending and circumflex coronary artery occlusions (+41 ml) than for distal or right coronary artery occlusions (+15.4 ml, p less than 0.05). Occlusion also lowered chamber systolic function indexes, such as the end-systolic pressure-volume relation slope (from 4.2 to 2.8 mm Hg/ml) and preload recruitable stroke work (from 97 to 78.6 mm Hg). All systolic (and diastolic) changes were resolved with successful angioplasty. Diastolic abnormalities during angioplasty were characterized by prolonged pressure relaxation and an upward shift of the resting diastolic pressure-volume data and by an apparent increase in chamber elastic stiffness. However, when end-diastolic data from multiple beats during inferior vena caval occlusion were compared, control and ischemic end-diastolic pressure-volume relations displayed little or no difference. Thus, elevations in resting diastolic pressure-volume relations and apparent increase in chamber elastic stiffness during coronary occlusion in humans appear dominated by altered right ventricular or pericardial loading. These data indicate that pressure-volume analysis is useful in assessing the functional significance of coronary lesions and reperfusion.

Alternating contractility in pulsus alternans studied in the isolated canine heart.

We examined pulsus alternans in seven isolated, perfused canine left ventricles ejecting into a simulated arterial impedance. Left ventricular pressure-volume loops were measured during pulsus alternans while filing-source pressure was lowered. In all cases two distinct linear end-systolic pressure-volume relationships (ESPVRs) were noted for the strong and weak beats. The slopes of the ESPVRs of the strong beats were significantly greater than those of the weak beats (mean difference 0.9 +/- 0.6 mm Hg/ml, p less than .01), while the intercepts were not significantly different (mean difference 0.06 +/- 0.5 ml). Diastolic pressure-volume relationships for the strong and weak beats were not significantly different, excluding incomplete relaxation as a cause of pulsus alternans. Although the weak beats had both a smaller preceding end-diastolic volume and a larger end-systolic volume, the presence of two distinct ESPVRS for the strong and weak beats shows there is alternating ventricular chamber contractility in pulsus alternans that is not solely due to the Starling mechanism. The magnitude of alternation in pump function parameters such as pressure and stroke volume during pulsus alternans reflects the complex interactions of alternating contractile state with alternations in preload and afterload.

End-systolic measures of regional ventricular performance.

Dimension change measures of regional ventricular function, such as absolute or percent wall thickening (delta T or % delta T) or segmental shortening (delta L or % delta L), are highly load dependent. In 16 anesthetized mongrel dogs we assessed use of the end-systolic pressure-thickness and end-systolic pressure-length relationships (ESPTR, ESPLR) as more load-independent measures of regional function. We found that the ESPTR and ESPLR could be measured without detectable baroreceptor-mediated reflex changes in cardiac contractile state. Systemic administration of dobutamine shifted the ESPTR to the right and the ESPLR to the left of control, mainly due to a change in the slope (Ees) of the relationships. Both delta T, % delta T and delta L, % delta L failed to detect the positive inotropic effect of dobutamine because of an associated reduction in preload. With systemic administration of propranolol, ESPTR, ESPLR, delta T, % delta T, and delta L, % delta L detected the negative inotropic effect. Thus systemic propranolol shifted the ESPTR to the left and the ESPLR to the right of control, mainly due to a change in Ees. Regional administration of dobutamine shifted the ESPTR and the ESPLR in the direction of positive contractility in the region receiving the drug, whereas simple dimension change measures of regional function failed to detect the inotropic effect because preload fell and the timing of regional end-systole was altered. With regional propranolol both the ESPTR, ESPLR and simple dimension change measures detected the negative inotropic effect. Thus the ESPTR, ESPLR is a reliable measure of regional ventricular function and may be better than simple dimension change measures of regional function, particularly when loading conditions or the timing of regional systole is altered by an intervention.

Effect of heart rate on the canine end-systolic pressure-volume relationship.

Although the rate dependence of isolated muscle contractility is well known, the ventricular end-systolic pressure-volume relationship (ESPVR) has been reported to be insensitive to heart rate. To resolve this contradiction, we used an isolated, ejecting canine heart preparation perfused at a constant coronary arterial pressure. Heart rate was changed from 60 to 200 beats/min in steps of 20 beats/min. At least 10 pressure-volume loops under different filling pressures were obtained at each heart rate in each of six hearts. Over a heart rate range from 60 to 120 beats/min, the slope of the ESPVR (Ees) increased significantly from 3.5 +/- 0.4 (SE) to 5.3 +/- 0.6 mm Hg/ml. In the range between 120 and 180 beats/min there was little change in Ees (5.3 +/- 0.6 to 5.4 +/- 0.6 mm Hg/ml), but at 200 beats/min Ees increased slightly to 5.7 +/- 0.5 mm Hg/ml. The volume axis intercept (V0) of the ESPVR changed little over the range of heart rate from 60 to 160 beats/min (10.2 +/- 2 ml to 9.4 +/- 1.3 ml) but increased to 15.2 +/- 1.2 ml at a rate of 200 beats/min. The change in ESPVR with increase in heart rate from 60 to 120 beats/min (i.e., increase in Ees without change in V0) is the same as those seen with a positive inotropic intervention with calcium or cathecholamines, whereas the V0 changes over the range from 160 to 200 beats/min is similar to those seen with regional ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)