Single-beat estimation of right ventricular end-systolic pressure-volume relationship

Assessment of right ventricular (RV) contractility from end-systolic pressure-volume relationships (ESPVR) is difficult due to problems in measuring RV instantaneous volume and to effects of changes in RV preload or afterload. We therefore investigated in anesthetized dogs whether RV ESPVR and contractility can be determined without measuring RV volume and without changing RV preload or afterload. The maximal RV pressure of isovolumic beats (P(max)) was predicted from isovolumic portions of RV pressure during ejecting beats and compared with P(max) measured during the first beat after pulmonary artery clamping. In RV pressure-volume loops obtained from RV pressure and integrated pulmonary arterial flow, end-systolic elastance (E(es)) was assessed as the slope of P(max)-derived ESPVR, pulmonary artery effective elastance (E(a)) as the slope of end-diastolic to end-systolic relation, and coupling efficiency as the E(es)-to-E(a) ratio (E(es)/E(a)). Predicted P(max) correlated with observed P(max) (r = 0.98 +/- 0.02). Dobutamine increased E(es) from 1.07 to 2.00 mmHg/ml and E(es)/E(a) from 1.64 to 2.49, and propranolol decreased E(es)/E(a) from 1.64 to 0.91 (all P < 0.05). After adrenergic blockade, preload reduction did not affect E(es), whereas hypoxia and arterial constriction markedly increased E(a) and somewhat increased E(es) due to the Anrep effect. Low preload did not affect E(es)/E(a) and high afterload decreased E(es)/E(a). In conclusion, in the right ventricle 1) P(max) can be calculated from normal beats, 2) P(max) can be used to determine ESPVR without change in load, and 3) P(max)-derived ESPVR can be used to assess ventricular contractility and ventricular-arterial coupling efficiency.     

Altered LV inotropic reserve and mechanoenergetics early in the development of heart failure

To test the hypothesis that alterations in left ventricular (LV) mechanoenergetics and the LV inotropic response to afterload manifest early in the evolution of heart failure, we examined six anesthetized dogs instrumented with LV micromanometers, piezoelectric crystals, and coronary sinus catheters before and after 24 h of rapid ventricular pacing (RVP). After autonomic blockade, the end-systolic pressure-volume relation (ESPVR), myocardial O(2) consumption (MVO(2)), and LV pressure-volume area (PVA) were defined at several different afterloads produced by graded infusions of phenylephrine. Short-term RVP resulted in reduced preload with proportionate reductions in stroke work and the maximum first derivative of LV pressure but with no significant reduction in baseline LV contractile state. In response to increased afterload, the baseline ESPVR shifted to the left with maintained end-systolic elastance (E(es)). In contrast, after short-term RVP, in response to comparable increases in afterload, the ESPVR displayed reduced E(es) (P < 0.05) and significantly less leftward shift compared with control (P < 0.05). Compared with the control MVO(2)-PVA relation, short-term RVP significantly increased the MVO(2) intercept (P < 0.05) with no change in slope. These results indicate that short-term RVP produces attenuation of afterload-induced enhancement of LV performance and increases energy consumption for nonmechanical processes with maintenance of contractile efficiency, suggesting that early in the development of tachycardia heart failure, there is blunting of length-dependent activation and increased O(2) requirements for excitation-contraction coupling, basal metabolism, or both. Rather than being adaptive mechanisms, these abnormalities may be primary defects involved in the progression of the heart failure phenotype.     

Dynamic effects of positive-pressure ventilation on canine left ventricular pressure-volume relations.

Positive-pressure ventilation (PPV) may affect left ventricular (LV) performance by altering both LV diastolic compliance and pericardial pressure (Ppc). We measured the effect of PPV on LV intraluminal pressure, Ppc, LV volume, and LV cross-sectional area in 17 acute anesthetized dogs. To account for changes in lung volume independent of changes in Ppc and differences in contractility, measures were made during both open- and closed-chest conditions, during closed chest with and without chest wall binding, and after propranolol-induced acute ventricular failure (AVF). Apneic end-systolic pressure-volume relations (ESPVR) were generated by inferior vena caval occlusions. With the open chest, PPV had no effects. With the chest closed, PPV inspiration decreased LV end-diastolic volume (EDV) along its diastolic compliance curve and decreased end-systolic volume (ESV) such that the end-systolic pressure-volume domain was shifted to a point left of the LV ESPVR, even when referenced to Ppc. The decrease in EDV was greater in control than in AVF conditions, whereas the shift of the ESV to the left of the ESPVR was greater with AVF than in control conditions. We conclude that the hemodynamic effects of PPV inspiration are due primarily to changes in intrathoracic pressure and that the inspiration-induced decreases of LV EDV reflect direct effects of intrathoracic pressure on LV filling. The decreases in LV ESV exceed the amount explained solely by a reduction in LV ejection pressure.     

Evaluation of BM-573, a novel TXA2 synthase inhibitor and receptor antagonist, in a porcine model of myocardial ischemia-reperfusion

AIMS: To investigate whether BM-573 (N-tert-butyl-N'-[2-(4'-methylphenylamino)-5-nitro-benzenesulfonyl]urea), an original combined thromboxane A2 synthase inhibitor and receptor antagonist, prevents reperfusion injury in acutely ischemic pigs. METHODS: Twelve animals were randomly divided in two groups: a control group (n = 6) intravenously infused with vehicle, and a BM-573-treated group (n = 6) infused with BM-573 (10 mg kg(-1) h(-1)). In both groups, the left anterior descending (LAD) coronary artery was occluded for 60 min and reperfused for 240 min. Either vehicle or BM-573 was infused 30 min before LAD occlusion and throughout the experiment. Platelet aggregation induced by arachidonic acid ex vivo measured was prevented by BM-573. RESULTS: In both groups, LAD occlusion decreased cardiac output, ejection fraction, slope of stroke work--end-diastolic volume relationship, and induced end-systolic pressure-volume relationship (ESPVR) rightward shift, while left ventricular afterload increased. Ventriculo-arterial coupling and mechanical efficiency decreased. In both groups, reperfusion further decreased cardiac output and ejection fraction, while ESPVR displayed a further rightward shift. Ventriculo-arterial coupling and mechanical efficiency remained impaired. Area at risk, evidenced with Evans blue, was 33.2+/-3.4% of the LV mass (LVM) in both groups, and mean infarct size, revealed by triphenyltetrazolium chloride (TTC), was 27.3+/-2.6% of the LVM in the BM-573-treated group (NS). Histological examination and immunohistochemical identification of desmin revealed necrosis in the anteroseptal region similar in both groups, while myocardial ATP dosages and electron microscopy also showed that BM-573 had no cardioprotective effect. CONCLUSIONS: These data suggest that BM-573 failed to prevent reperfusion injury in acutely ischemic pigs.     

Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs

Respiratory distress syndrome (RDS) causes pulmonary hypertension. It is often suggested that this increased afterload for the right ventricle (RV) might lead to cardiac dysfunction. To examine this, we studied biventricular function in an experimental model. RDS was induced by lung lavages in seven newborn lambs. Five additional lambs served as controls. Cardiac function was quantified by indexes derived from end-systolic pressure-volume relations obtained by pressure-conductance catheters. After lung lavages, a twofold increase of mean pulmonary arterial pressure (from 15 to 34 mmHg) was obtained and lasted for the full 4-h study period. Stroke volume was maintained (5.2 +/- 0.6 ml at baseline and 6.1 +/- 1.4 ml at 4 h of RDS), while RV end-diastolic volume showed only a slight increase (from 6.5 +/- 2.3 ml at baseline to 7.7 +/- 1.3 ml at 4 h RDS). RV systolic function improved significantly, as indicated by a leftward shift and increased slope of the end-systolic pressure-volume relation. Left ventricular systolic function showed no changes. In control animals, pulmonary arterial pressure did not increase and right and left ventricular systolic function remained unaffected. In the face of increased RV afterload, the newborn heart is able to maintain cardiac output, primarily by improving systolic RV function through homeometric autoregulation.     

Effects of changes in left ventricular contractility on indexes of contractility in mice

Measurement of left ventricular (LV) function is often overlooked in murine studies, which have been used to analyze the effects of genetic manipulation on cardiac phenotype. The goal of this study was to address the effects of changes in LV contractility on indexes of contractility in mice. LV function was assessed in vivo in closed-chest mice by echocardiography and by LV catheterization using a conductance pressure-volume (P-V) catheter with three different interventions that alter contractility by 1) atrial pacing to increase inotropy by augmentation of the force-frequency relation (modest increment of inotropy), 2) dobutamine to maximize inotropy, and 3) esmolol infusion to decrease contractility. Load-independent parameters derived from P-V relations, such as slope of end-systolic P-V relations (ESPVR) and slope of the first maximal pressure derivative over time (dP/dt(max))-end-diastolic volume relation (dP/dt-EDV), and standard echocardiographic parameters were measured. The dP/dt-EDV changed the most among parameters after atrial pacing and dobutamine infusion (percent change, 162.8 +/- 95.9% and 271.0 +/- 44.0%, respectively). ESPVR was the most affected by a decrease in LV contractility during esmolol infusion (percent change, -49.8 +/- 8.3%). However, fractional shortening failed to detect changes in contractility during atrial pacing and esmolol infusion and its percent change was <20%. This study demonstrated that contractile parameters derived from P-V relations change the most during a change in LV contractility and should therefore best detect a small change in contractility in mice. Heart rate has a modest but significant effect on P-V relationship-derived indexes and must be considered in the evaluation of murine cardiac physiology.     

Nonlinear isochrones in murine left ventricular pressure-volume loops: how well does the time-varying elastance concept hold?

The linear time-varying elastance theory is frequently used to describe the change in ventricular stiffness during the cardiac cycle. The concept assumes that all isochrones (i.e., curves that connect pressure-volume data occurring at the same time) are linear and have a common volume intercept. Of specific interest is the steepest isochrone, the end-systolic pressure-volume relationship (ESPVR), of which the slope serves as an index for cardiac contractile function. Pressure-volume measurements, achieved with a combined pressure-conductance catheter in the left ventricle of 13 open-chest anesthetized mice, showed a marked curvilinearity of the isochrones. We therefore analyzed the shape of the isochrones by using six regression algorithms (two linear, two quadratic, and two logarithmic, each with a fixed or time-varying intercept) and discussed the consequences for the elastance concept. Our main observations were 1) the volume intercept varies considerably with time; 2) isochrones are equally well described by using quadratic or logarithmic regression; 3) linear regression with a fixed intercept shows poor correlation (R(2) < 0.75) during isovolumic relaxation and early filling; and 4) logarithmic regression is superior in estimating the fixed volume intercept of the ESPVR. In conclusion, the linear time-varying elastance fails to provide a sufficiently robust model to account for changes in pressure and volume during the cardiac cycle in the mouse ventricle. A new framework accounting for the nonlinear shape of the isochrones needs to be developed.     

Improved contractile performance of right ventricle in response to increased RV afterload in newborn lamb

Pulmonary hypertension results in an increased afterload for the right ventricle (RV). To determine the effects of this increased afterload on RV contractile performance, we examined RV performance before and during 4 h of partial balloon occlusion of the pulmonary artery and again after releasing the occlusion in nine newborn lambs. RV contractile performance was quantified by indexes derived from systolic RV pressure-volume relations obtained by a combined pressure-conductance catheter during inflow reduction. An almost twofold increase of end-systolic RV pressure (from 22 to 38 mmHg) was maintained during 4 h. Cardiac output (CO) (0.74 +/- 0.08 l/min) and stroke volume (4.3 +/- 0.4 ml) were maintained, whereas end-diastolic volume (7.9 +/- 1.3 ml) did not change significantly during this period. RV systolic function improved substantially; the end-systolic pressure-volume relation shifted leftward indicated by a significantly decreased volume intercept (up to 70%), together with a slightly increased slope. In this newborn lamb model, maintenance of CO during increased RV afterload is not obtained by an increased end-diastolic volume (Frank-Starling mechanism). Instead, the RV maintains its output by improving contractile performance through homeometric autoregulation.     

Impact of Acute Changes of Left Ventricular Contractility on the Transvalvular Impedance: Validation Study by Pressure-Volume Loop Analysis in Healthy Pigs

Background

The real-time and continuous assessment of left ventricular (LV) myocardial contractility through an implanted device is a clinically relevant goal. Transvalvular impedance (TVI) is an impedentiometric signal detected in the right cardiac chambers that changes during stroke volume fluctuations in patients. However, the relationship between TVI signals and LV contractility has not been proven. We investigated whether TVI signals predict changes of LV inotropic state during clinically relevant loading and inotropic conditions in swine normal heart.

Methods

The assessment of RVTVI signals was performed in anesthetized adult healthy anesthetized pigs (n = 6) instrumented for measurement of aortic and LV pressure, dP/dt_max and LV volumes. Myocardial contractility was assessed with the slope (Ees) of the LV end systolic pressure-volume relationship. Effective arterial elastance (Ea) and stroke work (SW) were determined from the LV pressure-volume loops. Pigs were studied at rest (baseline), after transient mechanical preload reduction and afterload increase, after 10-min of low dose dobutamine infusion (LDDS, 10 ug/kg/min, i.v), and esmolol administration (ESMO, bolus of 500 µg and continuous infusion of 100 µg·kg−1·min−1).

Results

We detected a significant relationship between ESTVI and dP/dtmax during LDDS and ESMO administration. In addition, the fluctuations of ESTVI were significantly related to changes of the Ees during afterload increase, LDDS and ESMO infusion.

Conclusions

ESTVI signal detected in right cardiac chamber is significantly affected by acute changes in cardiac mechanical activity and is able to predict acute changes of LV inotropic state in normal heart.     

Load as an acute determinant of end-diastolic pressure-volume relation

Afterload-induced changes in myocardial relaxation are a mechanism for diastolic dysfunction when afterload is elevated beyond certain limits. The present study investigated the effects of acute afterload and preload changes on the position of the end-diastolic (ED) pressure-volume (P-V) relation. Beat-to-beat afterload elevations were induced in seven open-chest rabbits by gradually occluding the ascending aorta to increase peak left ventricular pressure (LVP) from baseline to isovolumetric level. Afterload elevations were performed at three ED LVP: 2.0 +/- 0.2 (low), 5.7 +/- 0.2 (mid), and 9.6 +/- 0.6 (high) mmHg. Preload was altered with caval occlusions and/or intravenous dextran. Afterload elevations induced an upward shift of the diastolic P-V relation, which became more important as afterload and/or preload increased. For instance, maximal afterload elevations shifted this relation upward 2.2 +/- 0. 5, 5.1 +/- 0.8, and 12.1 +/- 1.7 mmHg at low, mid, and high preload, respectively. These effects were partially due to changes in relaxation rate and time available to relax. In conclusion, load is an acute determinant of the ED P-V relation, which, therefore, does not provide a load-independent assessment of diastolic function.     

Less afterload sensitivity in short-term hibernating than in acutely ischemic and stunned myocardium

Short-term hibernating myocardium is characterized by reduced contractile function during persistent moderate ischemia, the recovery of metabolic parameters, and the absence of necrosis. To study the afterload dependence of regional wall excursion in short-term hibernating myocardium, in 11 enflurane-anesthetized swine the left anterior descending coronary artery was cannulated and hypoperfused for 90 min to reduce anterior systolic wall thickening (WT, sonomicrometry) by 60%. Under control conditions, at 5 and 90 min ischemia the descending thoracic aorta was acutely constricted to increase left ventricular (LV) pressure by 30 mmHg. Under control conditions, increased LV pressure resulted in decreased WT [i.e., a negative slope of the relationship between WT and LV end-systolic pressure: -11.2 +/- 4.2 (SD) microm/mmHg]. This slope was further significantly decreased at 5 min ischemia (-26.5 +/- 8.8 microm/mmHg) but returned toward control values in short-term hibernating myocardium at 90 min ischemia (-17.2 +/- 6.6 microm/mmHg). At 30 min reperfusion, the slope was once more significantly decreased (-27.8 +/- 8.1 microm/mmHg). In conclusion, WT in short-term hibernating myocardium is less afterload dependent than in acutely ischemic and reperfused myocardium.     

Respiratory phasic effects of inspiratory loading on left ventricular hemodynamics in vagotomized dogs.

Exaggerated inspiratory swings in intrathoracic pressure have been postulated to increase left ventricular (LV) afterload. These predictions are based on measurements of LV afterload by use of esophageal or lateral pleural pressure. Using direct measurements of pericardial pressure, we reexamined respiratory changes in LV afterload. In 11 anesthetized vagotomized dogs, we measured arterial pressure, LV end-systolic (ES) and end-diastolic transmural (TM) pressures, stroke volume (SV), diastolic left anterior descending blood flow (CBF-D), and coronary resistance. Dogs were studied before and while breathing against an inspiratory threshold load of -20 to -25 cmH2O compared with end expiration. Relative to end expiration, SV and LVES TM pressures decreased during inspiration and increased during early expiration, effects exaggerated during inspiratory loading. In all cases, LV afterload (LVES TM pressure) changed in parallel with SV. LV end-diastolic TM pressure did not change. CBF-D paralleled arterial pressure, and there were no changes in coronary resistance. In two dogs, regional LVES segment length paralleled calculated changes in LVES TM pressure. We conclude that 1) LV afterload decreases during early inspiration and increases during early expiration, changes secondary to those in SV; 2) changes in CBF-D are secondary to changes in perfusion pressure during the respiratory cycle; and 3) the use of esophageal or lateral pleural pressure to estimate LV surface pressure overestimates changes in LV TM pressures during respiration.     

Effect of chest strapping on regional lung function.

We studied lung mechanics and regional lung function in five young men during restrictive chest strapping. The effects on lung mechanics were similar to those noted by others in that lung elastic recoil increased as did maximum expiratory flow at low lung volumes. Chest strapping reduced the maximum expiratory flow observed at a given elastic recoil pressure. Breathing helium increased maximum expiratory flow less when subjects were strapped than when they were not. These findings indicated that strapping decreased the caliber of airways upstream from the equal pressure point. Regional lung volumes from apex to base were measured with xenon 133 while subjects were seated. The distribution of regional volumes was measured at RV, and at volumes equal to strapped FRC and strapped TLC; no change due to chest strapping was observed. Similarly, the regional distribution of 133Xe boluses inhaled at RV and strapped TLC was unaffected by chest strapping. Closing capacity decreased with chest strapping. We concluded that airway closure decreased during chest strapping and that airway closure was not the cause of the observed increase in elastic recoil of the lung. The combination of decreased slope of the static pressure-volume curve and unchanged regional volumes suggested that strapping increased the apex-to-base pleural pressure gradient.     

Changes in lung mechanics during asthma induced by exercise.

Pulmonary and airway mechanics were assessed in seven asthmatic patients in remission, when asthma was induced by exercise and again after spontaneous recovery or bronchodilator treatment. After exercise there was a sustained fall in forced expiratory volume in 1 s (FEV 1.0) in all patients, varying from 30 to 80 percent of the initial value. Total lung capacity (TLC) increased significantly in four of the seven patients. In one of the four patients the increase in TLC was associated with an increase in static transpulmonary pressure at full inflation but in the remaining three patients it was associated with a parallel shift of the pressure-volume curve of the lung without change in its slope. In all patients residual volume increased, regardless of change in TLC; both pressure-volume and maximum expiratory flow-volume curves suggested that widespread airway closure (or virtual closure) occurred at positive transpulmonary pressures when asthma was induced. Loss of lung recoli pressure sometimes contributed to the reduction in maximum expiratory flow but diffuse airway narrowing was probably the dominant abnormality. When air-flow obstruction became more severe the ratio of expiratory to inspiratory time was increased and although expiratory flow limitation was present excessive expiratory pressures were not generated.     

Right ventricular adaptation to pulmonary hypertension: an interspecies comparison

Right ventricular (RV) adaptation is an important prognostic factor in acute and chronic pulmonary hypertension. Pulmonary vascular basal tone and hypoxic reactivity are known to vary widely between species. We investigated how RV adaptation to acute pulmonary hypertension is preserved in species with low, intermediate, and high pulmonary vascular resistance and reactivity. Acute pulmonary hypertension was induced by hypoxia, distal embolism, and proximal constriction in anesthetized dogs (n = 10), goats (n = 8), and pigs (n = 8). Pulmonary vessels were assessed by flow-pressure curves and by impedance to quantify distal resistance, proximal elastance, and wave reflections. RV function was assessed by pressure-volume curves to quantify afterload, contractility, and ventricular-arterial coupling efficiency. First, hypoxia was associated with a progressive increase of resistance, elastance, and wave reflection from dogs to goats and from goats to pigs. RV contractility increased proportionally to RV afterload, and optimal coupling was preserved in all species. Second, embolism increased resistance and wave reflection but not elastance. The increase in RV contractility matched the increase in RV afterload and optimal coupling was preserved. Finally, proximal pulmonary artery constriction increased resistance, increased and accelerated wave reflection, and markedly increased elastance. RV contractility increased markedly and coupling showed a nonsignificant trend to decrease. We conclude that optimal or near-optimal ventricular-arterial coupling is maintained in acute pulmonary hypertension, whether in absence or presence of chronic species-induced pulmonary hypertension.     

Left ventricular mechanoenergetics after hyperpolarized cardioplegic arrest by nicorandil and after depolarized cardioplegic arrest by KCl

We hypothesized that there are no differences in left ventricular (LV) mechanoenergetics between after hyperpolarized cardioplegic arrest by nicorandil (nicorandil arrest) and after depolarized one by high potassium chloride (KCl arrest). The aim of the present study was to test this hypothesis using LV curved end-systolic pressure-volume relation (ESPVR) and linear pressure-volume area (PVA)-myocardial oxygen consumption per beat (VO2) relation. All hearts underwent 30 min global ischemia (30 degrees C) after infusion of 5 ml of cardioplegia. Cardioplegia consisted of either 30 mmol/l KCl (7 hearts) or nicorandil (100 micromol/l) in Tyrode solution (6 hearts). After a 30-min blood reperfusion, ESPVR and VO2-PVA relation were assessed again. Mean end-systolic pressure (ESP(mLVV)) and mean PVA at midrange LV volume (PVA(mLVV)) significantly (P < 0.05) decreased to 79.1 +/- 13.4% and 85.4 +/- 17.1% of control after KCl arrest and to 85.3 +/- 14.8% and 86.4 +/- 16.9% of control after nicorandil arrest. There were no significant differences in both decreases of mean ESP(mLVV) and PVA(mLVV) between each arrest. The slopes of VO2-PVA relations were also unchanged after each arrest. There was a significant (P < 0.005) difference in the decreases of mean VO2 intercepts of VO2-PVA relations between post-KCl arrest (73.9 +/- 8.2% of control) and post-nicorandil arrest (99.2 +/- 10.1% of control), however. Proteolysis of alpha-fodrin due to Ca2+ overload was significantly marked after KCl arrest. The present results indicate that the total calcium handling in excitation-contraction coupling is transiently impaired after KCl arrest, whereas it is unchanged after nicorandil arrest. This suggests the possibility that nicorandil is a better cardioplegia than KCl.     

Applications and limitations of end-systolic measures of ventricular performance

The usefulness of end-systolic measures of left ventricular performance as a load-independent method of assessing of ventricular contractility has been studied in intact, conscious dogs. The end-systolic pressure-chamber diameter (P-D) relation was shown to be linear, unaltered by preload changes, and shifted in a parallel fashion by inotropic stimulation, whereas the end-systolic pressure-volume relation appeared to increase in slope with increased contractility. A simplified measure of end-systolic relations that does not require measurement of chamber volume or diameter, the end-systolic pressure-wall thickness ( WTh ) relation, was also linear and shifted with acute changes in inotropic state. During regional ischemia, the regional end-systolic WTh relation also may provide a relatively load-independent means of detecting regional depression of myocardial contractility. With chronic pressure overload hypertrophy in dogs, the end-systolic P-D relation was markedly shifted upward and to the left, which indicates hyperfunction of the left ventricle; however, end-systolic wall stress-diameter relations were identical before and after the development of hypertrophy, which suggests that myocardial contractility was unaltered. These findings and clinical studies of mitral regurgitation imply that for assessing resting left ventricular contractility in certain chronic conditions, the use of wall stress rather than pressure may be appropriate in the end-systolic framework. Further experimental studies are needed in the intact circulation to better characterize end-systolic relations before their full potential in the clinical setting can be realized.     

Right ventricular diastolic function in canine models of pressure overload,volume overload,and ischemia

By limiting filling, abnormalities of right ventricular (RV) diastolic function may impair systolic function and affect adaptation to disease. To quantify diastolic RV pressure-volume relations and myocardial compliance (MC), a new sigmoidal model was developed. RV micromanometric and sonomicrometric data in alert dogs at control (n = 16) and under surgically induced subacute (2-5 wk) RV pressure overload (n = 6), volume overload (n = 7), and ischemia (n = 6) were analyzed. The conventional exponential model detected no changes from control in the passive filling pressure-volume (P(pf)-V) relations. The new sigmoidal model revealed significant quantifiable changes in P(pf)-V relations. Maximum RV MC (MC(max)), attained during early filling, is reduced from control in pressure overload (P = 0.0016), whereas filling pressure at maximum MC (P(MCmax)) is increased (P = 0.0001). End-diastolic RV MC increases significantly in volume overload (P = 0.0131), whereas end-diastolic pressure is unchanged. In ischemia, MC(max) is decreased (P = 0.0102), with no change in P(MCmax). We conclude that the sigmoidal model quantifies important changes in RV diastolic function in alert dog models of pressure overload, volume overload, and ischemia.     

Mode shift of an inhaled aerosol bolus is correlated with flow sequencing in the human lung.

We studied the effects on aerosol bolus inhalations of small changes in convective inhomogeneity induced by posture change from upright to supine in nine normal subjects. Vital capacity single-breath nitrogen washout tests were used to determine ventilatory inhomogeneity change between postures. Relative to upright, supine phase III slope was increased 33 +/- 11% (mean +/- SE, P < 0.05) and phase IV height increased 25 +/- 11% (P < 0.05), consistent with an increase in convective inhomogeneity likely due to increases in flow sequencing. Subjects also performed 0.5-microm-particle bolus inhalations to penetration volumes (V(p)) between 150 and 1,200 ml during a standardized inhalation from residual volume to 1 liter above upright functional residual capacity. Mode shift (MS) in supine posture was more mouthward than upright at all V(p), changing by 11.6 ml at V(p) = 150 ml (P < 0.05) and 38.4 ml at V(p) = 1,200 ml (P < 0.05). MS and phase III slope changes correlated positively at deeper V(p). Deposition did not change at any V(p), suggesting that deposition did not cause the MS change. We propose that the MS change results from increased sequencing in supine vs. upright posture.     

Influence of substrate supply on cardiac efficiency, as measured by pressure-volume analysis in ex vivo mouse hearts

In the present study, we tested the reliability of measurements of pressure-volume area (PVA) and oxygen consumption (MVo(2)) in ex vivo mouse hearts, combining the use of a miniaturized conductance catheter and a fiber-optic oxygen sensor. Second, we tested whether we could reproduce the influence of increased myocardial fatty acid (FA) metabolism on cardiac efficiency in the isolated working mouse heart model, which has already been documented in large animal models. The hearts were perfused with crystalloid buffer containing 11 mM glucose and two different concentrations of FA bound to 3% BSA. The initial concentration was 0.3 +/- 0.1 mM, which was subsequently raised to 0.9 +/- 0.1 mM. End-systolic and end-diastolic pressure-volume relationships were assessed by temporarily occluding the preload line. Different steady-state PVA-MVo(2) relationships were obtained by changing the loading conditions (pre- and afterload) of the heart. There were no apparent changes in baseline cardiac performance or contractile efficiency (slope of the PVA-MVo(2) regression line) in response to the elevation of the perfusate FA concentration. However, all hearts (n = 8) showed an increase in the y-intercept of the PVA-MVo(2) regression line after elevation of the palmitate concentration, indicating an FA-induced increase in the unloaded MVo(2). Therefore, in the present model, unloaded MVo(2) is not independent of metabolic substrate. This is, to our knowledge, the first report of a PVA-MVo(2) relationship in ex vivo perfused murine hearts, using a pressure-volume catheter. The methodology can be an important tool for phenotypic assessment of the relationship among metabolism, contractile performance, and cardiac efficiency in various mouse models.