End-diastolic Volume Relationship Research Articles

Effects of oxymatrine and matrine on left ventricular contractility using pressure-volume relationship analysis in anesthetized rats

The purpose of this study was to investigate the effects of oxymatrine and matrine on integrated cardiac function in rats using pressure-volume loop analysis. A pressure-volume loop catheter was advanced into the left ventricle in anesthetized rats. Steady-state hemodynamic and load-independent parameters were recorded before and after oxymatrine or matrine injection. Oxymatrine (200 mg/kg) and matrine (50, 100 mg/kg) significantly increased the preload recruitable stroke work, slope of maximal systolic pressure increase (dP/dtmax) – end-diastolic volume relationship, end-systolic elastance and volume axis intercept (V0), which are load-independent parameters. Furthermore, the observed increased cardiac efficiency, along with the decreased ventricular arterial coupling, pressure volume area and potential energy, reflect improved mechanoenergetics in oxymatrine (200 mg/kg) and matrine (25, 50 or 100 mg/kg) treated rats respectively. In addition, matrine (25, 50 mg/kg) decreased end-systolic volume and end-diastolic volume, and increased ejection fraction; matrine at 100 mg/kg further decreased end-systolic volume, end-diastolic volume, stroke volume and stroke work, shortened the time constant of left ventricular pressure decay, and increased dP/dtmax, and heart rate. These results suggest that both oxymatrine and matrine enhance left ventricular contractility and improve cardiac mechanical function. As the dose of matrine was much lower than that of oxymatrine, the effect of matrine on myocardial contractility was stronger than that of oxymatrine.

P625Impact of hemodialysis on a novel and noninvasive index for quantification of stroke work obtained by left ventricular pressure-volume loop area using speckle tracking echocardiography

Abstract Background Left ventricular (LV) pressure-strain and pressure-volume (P-V) loop area reflect global myocardial work (MW) and stroke work (SW), but clinical use of these indexes is limited by the need of invasive pressure measurement. A noninvasive method to obtain LV pressure-strain loop area was recently introduced to examine MW by speckle tracking echocardiography (STE). Purpose We sought to evaluate the impact of preload change on MW and SW obtained using this novel method and to examine the utility to assess LV contractile performance by the SW and end-diastolic volume (EDV) relation (SW-VED) in patient with hemodialysis (HD). Methods LV pressure in a cardiac cycle was estimated using systolic blood pressure (SBP), LV minimum diastolic pressure (mDP) and end-diastolic pressure (EDP) in 20 HD patients (age 67±9)and 25 controls (age 67±9) by utilizing the profile of an empiric, normalized reference curve adjusted according to the duration of LV isovolumic and ejection phases as defined by timing of aortic and mitral valve events by echocardiography. Pulmonary capillary wedge pressure (ePCWP) is estimated as 10.8 – 12.4 × Log (left atrial active emptying function/minimum volume): KT index as previously reported. LVEDP were estimated as 12.3 – 10.1 × KT index. We examined the relation between LV pressure decline (Tau) and mDP by catheterization in 126 patients. Tau is estimated as isovolumic relaxation time/(ln 0.9 × systolic BP − ln ePCWP) as previously reported. SW was obtained by P-V loop area using the combination of pressure (SBP, mDP and EDP) and LV volume by 3D-STE. Echo parameters and BP were measured before and after HD and before and after leg up in controls. Results The mDP obtained by catheterization had a good correlation with Tau (Tau = 33.7 + 2.06 × mDP, r=0.70, p<0.01). LVEF by 3D-STE was increased in controls after leg up (59±5 to 62±4%) associated with increased LVEDV (85±25 to 91±26ml), whereas there was no difference in LVEF before and after HD (61±9 vs 61±10%) instead of decreased EDV after HD (101±23 to 92±24ml). SBP and PCWP in HD was decreased after HD (SBP: 149±25 to 140±15, PCWP: 9.8±4.3 to 8.5±3.6mmHg). MW and SW were increased after leg up in controls (1706±443 to 1972±461mmHg% and 4072±1938 to 5044±1958mmHgml) and those were decreased after HD (1964±441 to 1794±756mmHg% and 5475±1335 to 4722±1949mmHgml). LV SW-VEDin HD without LV dilation (EDVI<70ml/m2, n=12) was decreased compared to controls (143±115 vs 241±152) and that in HD with LV dilation was further decreased compared to HD without dilation. Conclusion LVSW noninvasively obtained by P-V loop area was increased in controls associated with increased preload and decreased in HD with decreased preload and SW-VED was deceased in HD. This novel and noninvasive method may be of potential utility to assess LV contractility and have a clinical interest and value to assess LV function.

P4384Noninvasive and novel method to evaluate left ventricular contractility using pressure-volume loop area obtained by 3-dimensional speckle tracking echocardiography

Abstract Introduction Left ventricular (LV) pressure-volume (P-V) loop area reflects stroke work (SW), but clinical use of this index is limited by the need of invasive pressure measurement. A noninvasive method to obtain LV pressure-strain loop was recently introduced to assess myocardial work (MW). The minimum LV diastolic pressure (mLVP) was reported to have a strong correlation with Tau and we reported that Tau was noninvasively evaluated by speckle tracking echocardiography (STE). Purpose We sought to evaluate the impact of preload change by leg lifts on LV SW noninvasively obtained by the novel method and to examine the utility to assess LV contractility by SW and end-diastolic (ED) volume relation (SW-VED). Methods Thirty six controls (age 71±10) and 30 patients with heart failure with reduced ejection fraction (EF) <50% (HF) (age 73±6) were enrolled. LV pressure in a cardiac cycle was estimated using systolic blood pressure (SBP), minimum diastolic pressure (mDP) and ED pressure (EDP) by utilizing the profile of an empiric, normalized reference curve. The mDP and EDP were estimated as (Tau − 33.7)/2.06 and as 12.3 − 10.1 x Log (left atrial active emptying function/minimum volume) as we reported. LVSW was obtained by P-V loop by the combination of these pressures and LV volume using 3-D STE. Results LVEF and longitudinal strain in HF before leg up by 3D-STE were lower compared to normal (LVEF; normal: 58±5 vs HF: 39±10*% and strain; −12±3 vs −8±3%*, *p<0.05 vs normal). LVEF was increased after leg up by 7±6% in normal and by 8±8% in HF associated with increased LVED volume (normal: 84±24 to 90±24 and HF: 124±36* to 136±42*ml). LV MW and SW in HF before leg up were lower compared to normal (MW: 1790±412 vs 1002±432*mmHg% and SW: 3946±1682 vs 3352±1026mmHgml). LV SW increased after leg up by 26±19% in normal and by 25±20% in HF. LV SW-VED in normal was greater than HF (241±151 vs 90±54*). Conclusion LV SW noninvasively obtained by P-V loop area was increased after leg up in both normal and HF but SW-VED in HF was smaller than normal, indicating reduced contractility in HF. This noninvasive method may be a new echocardiographic approach for quantification of LV SW and contractility.

Cardiac contractility, motor function, and cross-bridge kinetics in N47K-RLC mutant mice.

We have investigated the physiology and mechanical profiles of skinned papillary muscle fibers from transgenic mice expressing the N47K mutation in the myosin regulatory light chain (RLC), shown to cause hypertrophic cardiomyopathy in humans. The results were compared with wild-type (WT) mice, both expressing the human ventricular RLC. Rate constants of a cross-bridge (XB) cycle were deduced from tension transients induced by sinusoidal length changes during maximal Ca2+ activation, and were studied as a function of MgATP, MgADP, and Pi concentrations. N47K mutant showed slower XB cycles but higher actin-activated ATPase activity compared with WT. Consequently, N47K exhibited larger tension than WT. K0 (ADP association constant) and K4 (equilibrium constant of force generation) were larger in N47K, and K1 (ATP association constant) was slightly larger in N47K vs. WT, demonstrating stronger nucleotide binding and force generation abilities of the mutant, but no changes in rigor acto-myosin binding were observed. Tension per XB was similar among groups, but N47K exhibited more XB distribution in the attached state. Larger values of tension and higher ATPase in N47K suggested that more cross-bridges participated in tension production in the mutant myocardium compared with WT. In vivo analysis of heart function, performed in ~ 12.5-month-old mice by echocardiography and invasive hemodynamics, demonstrated a significant decrease in dP/dtmax -end-diastolic volume relationship, indicating a depression of ventricular contractility in N47K mice. Our findings suggest that the N47K mutation exerts its action through direct alterations of myosin motor function that ultimately result in pathological hypertrophic remodeling in N47K hearts.

The Structure-Function Analysis of Myosin Pseudo-Phosphorylation in Mouse Model of FHC

Familial hypertrophic cardiomyopathy (FHC) is a disease of the heart caused by autosomal dominant mutations in genes coding for all major sarcomeric proteins, including the myosin regulatory light chain (RLC). In this report, we have explored the rescue strategies to ameliorate the malignant cardiomyopathy phenotype induced by an aspartic acid to valine substitution (D166V) in the RLC. Previous studies on porcine reconstituted preparations showed that the phosphorylation mimic (S15D) in the background of the D166V mutation (S15D-D166V) restored the calcium sensitivity of force and improved Vmax of myosin ATPase that were largely compromised by the D166V mutation. Transgenic carrying the S15D-D166V mutation have been generated and subjected to structural and functional measurements. Small angle X-ray studies on freshly skinned papillary muscle fibers revealed that a D166V-induced reorganization in cross-bridge mass distribution was partially reversed in Rescue Mice (abnormally increased I1,1/I1,0 ratio observed in Tg-D166V fibers returned to the value near Tg-WT). Noteworthy, pseudo-phosphorylation of D166V significantly restored fiber elasticity allowing for changes in the cross-bride mass distribution on stretch. In vivo cardiac morphology and function were assessed by non-invasive echocardiography followed by invasive left ventricular pressure-volume measurements (P-V loops). Echocardiography assessment confirmed hypertrophy in Tg-D166V mice showing an increased posterior wall thickness in systole. Invasive hemodynamics showed diastolic and systolic dysfunction in Tg-D166V mice. The end-systolic P-V relationship, a measure of heart contractility, which was largely reduced in Tg-D166V mice was completely ameliorated in Rescue Mice. In addition, the maximum dP/dt - End-Diastolic Volume relation, which was compromised in Tg-D166V was fully reversed in Rescue Mice. In conclusion, our results suggest that pseudo-phosphorylation of myosin RLC can mitigate both the structural and functional abnormalities of the FHC heart. Supported by NIH-HL108343 and HL071778 (DSC).

Measuring right ventricular function in the normal and hypertensive mouse hearts using admittance-derived pressure-volume loops

Mice are a widely used animal model for investigating cardiovascular disease. Novel technologies have been used to quantify left ventricular function in this species, but techniques appropriate for determining right ventricular (RV) function are less well demonstrated. Detecting RV dysfunction is critical to assessing the progression of pulmonary vascular diseases such as pulmonary hypertension. We used an admittance catheter to measure pressure-volume loops in anesthetized, open-chested mice before and during vena cava occlusion. Mice exposed to chronic hypoxia for 10 days, which causes hypoxia-induced pulmonary hypertension (HPH), were compared with control (CTL) mice. HPH resulted in a 27.9% increase in RV mass (P < 0.005), a 67.5% increase in RV systolic pressure (P < 0.005), and a 61.2% decrease in cardiac output (P < 0.05). Preload recruitable stroke work (PRSW) and slope of the maximum derivative of pressure (dP/dt(max))-end-diastolic volume (EDV) relationship increased with HPH (P < 0.05). Although HPH increased effective arterial elastance (E(a)) over fivefold (from 2.7 ± 1.2 to 16.4 ± 2.5 mmHg/μl), only a mild increase in the ventricular end-systolic elastance (E(es)) was observed. As a result, a dramatic decrease in the efficiency of ventricular-vascular coupling occurred (E(es)/E(a) decreased from 0.71 ± 0.27 to 0.35 ± 0.17; P < 0.005). Changes in cardiac reserve were evaluated by dobutamine infusion. In CTL mice, dobutamine significantly enhanced E(es) and dP/dt(max)-EDV but also increased E(a), causing a decrease in E(es)/E(a). In HPH mice, slight but nonsignificant decreases in E(es), PRSW, dP/dt(max)-EDV, and E(a) were observed. Thus 10 days of HPH resulted in RV hypertrophy, ventricular-vascular decoupling, and a mild decrease in RV contractile reserve. This study demonstrates the feasibility of obtaining RV pressure-volume measurements in mice. These measurements provide insight into ventricular-vascular interactions healthy and diseased states.

HMGB1 mediated LPS‐induced myocardial dysfunction in mice

The mechanism involved in the endotoxin‐induced myocardial dysfunction is not fully understood. The purpose of the present study was to demonstrate that myocardial dysfunction in endotoxinemia is mediated via an increase in myocyte production of high mobility group box 1 protein (HMGB1). In vivo, mouse model of endotoxinemia in mice was induced by i.p. injection of LPS (10 mg/kg) and myocardial function was evaluated 24 hrs later. LPS induced a decrease in myocardial contractility (end‐systolic and end‐diastolic volume relation). The decrease in myocardial contractility was diminished when the mice were received either a HMGB1 antagonist (A‐box) or an inhibitor of HMGB1 (glycyrrhizic acid). Expression of myocardial HMGB1 was increased in the heart of mice treated with LPS (immunoflorescence staining). Further, recombinant HMGB1 (10–20 μg/mouse, i.p.) resulted in a dose dependent decrease in myocardial contractility. To confirm that the source of HMGB1 was the cardiac myocytes in the hearts, isolated cardiac myocytes were exposed to LPS (10 μg/ml). Treatment of cardiac myocytes with LPS increased in intracellular levels of HMGB1 and release HMGB1 by myocytes to the supernatant (Western). Taken together, our study suggests LPS‐induced myocardial dysfunction is a result of increase in myocyte HMGB1. (CIHR MOP 81303).

Applying logic to pulmonary artery catheter use

Mansour and colleagues recommend not routinely using the pulmonary artery catheter to guide hemodynamic management in the intensive care unit, because the perceived benefits are largely intangible [1]. Pulmonary artery catheter monitoring of the right ventricular ejection fraction (RVef) and of the right ventricular end-diastolic volume (EDV), however, reflects powerful yet underutilized relationships that assess right ventricular performance. Since the cardiac output equals the product of the RVef, the EDV and the heart rate, one can assess the RVef to EDV relations as direct measures of right ventricular performance. A series of RVef, EDV and heart rate combinations can give the same cardiac output (Figure ​(Figure1);1); monitoring or targeting cardiac output alone ignores this reality. For example, in hypovolemia the EDV is low and the RVef is increased, whereas in right ventricular failure the opposite is true. Furthermore, resuscitation from hypovolemia will increase the EDV and decrease the RVef [2], while reversal of cor pulmonale will decrease the EDV and increase the RVef. Figure 1 Right ventricular ejection fraction, right ventricular end-diastolic volume and heart rate relationship with cardiac output. CO, cardiac output; EDV, right ventricular end-diastolic volume; HR, heart rate; RVef, right ventricular ejection fraction. No monitoring device other than the pulmonary artery catheter can continually assess these variables. These concepts are often used in the cardiac surgery suite, but are rarely codified for diagnosis and management. Monitoring devices can improve outcome only if they are coupled to treatments that improve outcome. Applying the above logic to previously proposed treatment protocols, such as using the mixed venous oxygen saturation [3], may therefore be the first step toward defining pulmonary artery catheter utility [4].

Left ventricular pressure-volume relationship in conscious mice

With the availability of transgenic models, the mouse has become an increasingly important subject for genetic-hemodynamic studies. Recently, we developed a technique to measure left ventricular (LV) pressure in conscious mice with an implanted LV polyethylene tube. We extended our new method by evaluating the LV pressure-volume relationship and examined the feasibility of this method in this study. We studied 17 male mice (age, 11-20 wk) with a conductance catheter inserted into the LV through the polyethylene tube. Load-independent parameters of contractility derived from pressure-volume relationship [slope of the end-systolic pressure-volume relationship (E(es)), slope of the maximum first derivative of LV pressure (dP/dt(max))-end-diastolic volume (EDV) relation, and preload-recruitable stroke work (PRSW)] were evaluated by inferior vena caval occlusion with an implanted snare. LV function assessed by this technique on two different days showed that the parameters were very similar, indicating reproducibility. Both linear and nonlinear regression analyses were performed for E(es). Contractility was enhanced by isoproterenol (E(es), 13.1 +/- 6.6 to 20.8 +/- 8.7 mmHg/microl; dP/dt(max)-EDV, 496 +/- 139 to 825 +/- 178 mmHg.s(-1).microl(-1); and PRSW, 110 +/- 23 to 127 +/- 21 mmHg), depressed by atenolol (E(es), 14.5 +/- 6.1 to 4.6 +/- 2.0 mmHg/microl; dP/dt(max)-EDV, 543 +/- 188 to 185 +/- 94 mmHg.s(-1).microl(-1); and PRSW, 117 +/- 20 to 70 +/- 15 mmHg) and isoflurane (E(es), 12.3 +/- 6.0 to 5.7 +/- 2.1 mmHg/microl; dP/dt(max)-EDV, 528 +/- 172 to 164 +/- 68 mmHg/s.microl; and PRSW, 124 +/- 19 to 48 +/- 10 mmHg), significantly. In conclusion, this is the first description of the LV pressure-volume relationship in conscious mice. These findings suggest that this method is feasible to detect changes of contractility in the conscious state, allowing serial assessment of pressure-volume-derived cardiac function indexes over time without anesthesia or repeated surgery.

Evaluation of BM-573, a novel TXA 2 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 A 2 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.

Left ventricular pressure–volume relationships during normal growth and development in the adult rat – studies in 8‐ and 50‐week‐old male Wistar rats

Left ventricular (LV) pressure-volume relations provide relatively load-independent indexes of systolic and diastolic LV function, but few data are available on pressure-volume relations during growth and development in the normal adult heart. Furthermore, to quantify intrinsic ventricular function the indexes should be normalized for heart weight. However, in many studies the indexes are reported in absolute terms, or body weight-correction is used as a surrogate for heart weight-correction. We determined pressure-volume relations in young (8-week-old, n = 13) and middle-aged (50-week-old, n = 19) male Wistar rats in relation to their heart and body weights. The animals were anaesthetized and a 2F pressure-conductance catheter was introduced into the LV to measure pressure-volume relations. Heart and body weights were significantly higher in the 50-week-old rats, whereas the heart-to-body weight ratio was significantly lower (2.74 +/- 0.32 vs. 4.41 +/- 0.37 mg g(-1), P < 0.001). Intrinsic systolic function, quantified by the slopes of the end-systolic pressure-volume relation (E(ES)), the dP/dt(MAX) vs. end-diastolic volume relation (S-dP), and the preload recruitable stroke work relation (PRSW), normalized for heart weight, was slightly decreased in the 50-week-old rats (S-dP: -6%, P < 0.004; PRSW: -3%, P < 0.06). Heart weight-corrected diastolic indexes were not significant different. The absolute indexes qualitatively showed the same results, but body-weight corrected pressure-volume indexes showed improved systolic function and significantly depressed diastolic function. Intrinsic systolic function slightly decreases from the juvenile to the middle-aged period in normal male Wistar rats. Furthermore, correction of pressure-volume indexes for body weight is not an adequate surrogate for heart weight-correction in these animals.

Preload-Adjusted 2 Wave-Intensity Peaks Reflect Simultaneous Assessment of Left Ventricular Contractility and Relaxation

The magnitudes of the first (WI1) and the second wave-intensity peak (WI2) during the ejection period can be used as indices of left ventricular (LV) contractility and relaxation, respectively. However, use of WI to characterize LV dp/dt and the end-diastolic volume (V ed) relationship may be more problematic, as WI may be affected by changes in preload. The LV pressure-volume data sets, consisting of 23 recordings obtained by the conductance method from 12 heart disease patients, were studied. End-systolic elastance (E es) and volume-axis-intercept (V0) were calculated with varying preload. Time constant of LV relaxation (tau), V ed, and WI were calculated from steady-state averaged data. The E es showed a weak correlation with WI1 (r = 0.46, p < 0.05) but a better correlation with preload-adjusted WI1 [WI1/V ed; r=0.86, WI1/V(ed)2; r = 0.92, WI1/(V ed - V0)2; r = 0.89, all p < 0.01]. Similarly, tau did not correlate with WI2 but did correlate with preload-adjusted WI2 [WI2/V ed; r = -0.73, WI2/V(ed) 2; r = -0.63, WI2/(V ed - V0)2; r = -0.78, all p < 0.01]. These data demonstrate the importance of preload-adjustment when using the WI index for simultaneous assessment of LV contractility and relaxation.

Preload-adjusted right ventricular maximal power: concept and validation.

Right ventricular (RV) maximal power (PWR(mx)) is dependent on preload. The objective of this study was to test our hypothesis that the PWR(mx) versus end-diastolic volume (EDV) relationship, analogous to the load-independent stroke work (SW) versus EDV relationship (preload-recruitable SW, PRSW), is linear, with the PWR x-axis intercept (V(0PWR)) corresponding to the PRSW intercept (V(0SW)). If our hypothesis is correct, the preload sensitivity of PWR(mx) could be eliminated by adjusting for EDV and V(0PWR). Ten dogs were instrumented with a pulmonary flow probe, micromanometers, and RV conductance catheter. Data were obtained during bicaval occlusions under various conditions and fitted to PWR(mx) = a.(EDV - V(0PWR))(beta), where a is the slope of the relationship. The PWR(mx) versus EDV relationship did not deviate from linearity (beta = 1.09, P = not significant vs. 1), and V(0PWR) correlated with V(0SW) (r = 0.93, P <0.0001). V(0PRW) was related to steady-state EDV and left ventricular end-diastolic pressure, allowing for estimation of V(0PWR) (V(0Est)) and single-beat PWR(mx) preload adjustment. Dividing PWR(mx) by the difference of EDV and V(0PWR) (PAMP(V0PWR)) eliminated preload dependency down to 50% of the baseline EDV. PWR(mx) adjustment using V(0Est) (PAMP(V0Est)) showed similar preload independency. Enhancing contractility increased PAMP(V0PWR) and PAMP(V0Est) from 176 +/- 52 to 394 +/- 205 W/ml x 10(4) and 145 +/- 51 to 404 +/- 261 W/ml x 10(4), respectively, accompanied by an increase of PRSW from 13.0 +/- 4.5 to 29.7 +/- 16.4 mmHg (all P <0.01). PAMP(V0PWR) and PAMP(V0Est) correlated with PRSW (r = 0.85; r = 0.77; both P <0.001). Numerical modeling confirmed the accuracy of our experimental data. Thus preload adjustment of PWR(mx) should consider a linear PWR(mx) versus EDV relationship with distinct V(0PWR). PAMP(V0PWR) is a preload-independent estimate of RV contractility that may eventually be determined noninvasively.

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.

The effects of acute normovolemic hemodilution on left ventricular systolic and diastolic function in the absence or presence of beta-adrenergic blockade in dogs.

Acute normovolemic hemodilution (ANH) increases cardiac output because of a reduction in blood viscosity and enhancement of left ventricular (LV) contractility. The status of LV function, especially LV diastolic function during ANH, remains controversial. We therefore examined LV systolic and diastolic function during ANH. Sixteen dogs were anesthetized with isoflurane in the absence (Group 1) and presence (Group 2) of beta-adrenergic blockade (propranolol 1 mg/kg). LV contractility was quantified by the slope (M(w)) of the stroke work and end-diastolic volume relation. Diastolic function was evaluated with the time constant of LV relaxation (T), chamber stiffness constant (K(c)), peak LV diastolic filling rate during early filling (peak E) and atrial contraction (peak A), and ratio of peak E to peak A (E/A). Normovolemic exchange of blood (50 mL/kg) for 6% hydroxyethyl starch (ANH50) significantly increased M(w) in Group 1 but not in Group 2. In both groups, ANH50 significantly decreased T. ANH50 significantly increased peak E in both groups and peak A in Group 1, and it did not change the E/A ratio or K(c) in either group. ANH causes positive inotropic effects and enhances diastolic function without beta-blockade. Even after beta-adrenergic blockade, ANH improves diastolic function through the reduction of LV ejection impedance. Acute normovolemic hemodilution enhances LV (left ventricular) diastolic function by alterations in the LV loading condition produced by hemodilution, which mainly contributes to a compensatory increase in cardiac output.

An Analytical Expression for the Regulation of Ventricular Volume in the Normal and Diseased Heart

There is increasing interest in the literature indicating that the volumetric regulation of the left ventricle (LV) and the right ventricle (RV) may be conveniently represented in a graph relating end-systolic volume (ESV) to end-diastolic volume (EDV). This view contrasts with the classical description by Starling's law, which for decades has dominated the analysis of volumetric input–output relationships of the heart. In the present study we critically survey the existing evidence for a graphical representation emphasizing the role of ESV rather than stroke volume (SV) as the dependent variable in the description of cardiac function. Mostly a linear relationship between ESV and EDV has been documented. This concept is now applied both in the study of a particular heart under consideration and in a population-based approach. We analyzed volumetric data obtained from human patients, instrumented conscious dogs, and healthy horses, and found linear relationships for volume and diameters. A distinct parallel leftward shift of the regression curve is found to be commensurate with diminished parasympathetic activity, whereas a clockwise rotation of the curve is associated with decreased sympathetic activity. The ensuing changing patterns of the ESV vs. EDV relationship have implications for ejection fraction, for which we derived an analytical formula to account for such dependence. Thus, the analytical expression of ESV vs. EDV provides a functional representation of factors regulating LV and RV volume. The new approach applies to both health and disease states, and is shown to be invariant for afterload variation, in contrast to the Starling curve. Moreover, it appears typically sensitive to various types of interventions, including those affecting chronotropic and inotropic state.

Targeted alpha(1A)-adrenergic receptor overexpression induces enhanced cardiac contractility but not hypertrophy.

Activation of the alpha(1A)-adrenergic receptor (alpha(1A)-AR)/Gq pathway has been implicated as a critical trigger for the development of cardiac hypertrophy. However, direct evidence from in vivo studies is still lacking. To address this issue, transgenic mice with cardiac-targeted overexpression of the alpha(1A)-AR (4- to 170-fold) were generated, using the rodent alpha-myosin heavy chain promoter. Heterozygous animals displayed marked enhancement of cardiac contractility, evident from increases in dP/dt(max) (80%, P<0.0001), dP/dt(max)/LVP(inst) (76%, P<0.001), dP/dt(max):dP/dt(min) (104%, P<0.0001), and fractional shortening (33%, P<0.05). Moreover, changes in the dP/dt(max)-end-diastolic volume relationship provided load-independent evidence of a primary increase in contractility. Blood pressure and heart rate were largely unchanged, and there was a small increase in (-)norepinephrine-stimulated, but not basal, phospholipase C activity. Increased contractility was directly related to the level of receptor overexpression and could be completely reversed by acute alpha(1A)- but not beta-AR blockade. Despite the robust changes in contractility, transgenic animals displayed no morphological, histological, or echocardiographic evidence of left ventricular hypertrophy. In addition, apart from an increase in atrial natriuretic factor mRNA, expression of other hypertrophy-associated genes was unchanged. To our knowledge, these data provide the first in vivo evidence for an inotropic action of the alpha(1A)-AR.

Allopurinol enhances the contractile response to dobutamine and exercise in dogs with pacing-induced heart failure.

Superoxide (O(2)(-)) 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 Ca(2+) sensitivity in reperfusion injury and CHF, we hypothesized that it may improve adrenergic inotropic responsiveness in CHF. 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 (E(ES)) and stroke work-end-diastolic volume relation (M(SW)). 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 E(ES) (5.0+/-0.6 versus 3.3+/-0.6 mm Hg/mL) and M(SW). Dobutamine and allopurinol produced greater increases in E(ES) (5.4+/-0.6 versus 7.4+/-0.6 mm Hg/mL) and M(SW) (60.1+/-7.4 versus 73.7+/-4.4 mm Hg) than did dobutamine alone. After allopurinol, dP/dt(max), stroke volume, and M(SW) were higher during CHF exercise. LV diastolic pressures were lower during CHF exercise after allopurinol. 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.

Early effects of right ventricular volume overload on ventricular performance and β-adrenergic signaling

Objective: Right ventricular dysfunction is a poorly understood but persistent clinical problem. This study was undertaken to evaluate ventricular performance and β-adrenergic receptor signaling in a tricuspid regurgitation model of right ventricular overload. Methods: Seventeen dogs were chronically instrumented with epicardial dimension transducers. By means of the shell-subtraction model, right ventricular pressure-volume relationships were evaluated in normal and right ventricular overload states. Right ventricular chamber performance was quantified by the stroke work at an end-diastolic volume relationship. Results: Right ventricular volume overload caused a 28% ± 11% and 31% ± 9% decline in chamber performance acutely and at 1 week, respectively, whereas end-diastolic volume increased from 45 ± 21 to 60 ± 30 mL (P =.019). β-Adrenergic receptor signaling in myocardial samples was assessed, examining adenylyl cyclase and G-protein–coupled receptor kinase activity. Stimulated adenylyl cyclase activity significantly decreased, and G-protein–coupled receptor kinase activity significantly increased in both left and right ventricular samples caused by increased levels of β-adrenergic receptor kinase 1. No change in β-adrenergic receptor density was seen at 1 week. Conclusions: Early right ventricular overload is associated with impaired right ventricular chamber contractility, dilation, and, importantly, a biventricular alteration of β-adrenergic receptor signaling. (J Thorac Cardiovasc Surg 2000;119:342-9)

Inhibition of nitric oxide synthesis improves left ventricular contractility in neonatal pigs late after cardiopulmonary bypass

BACKGROUNDFollowing neonatal open heart surgery a nadir occurs in left ventricular function six to 12 hours after cardiopulmonary bypass. Although initiated by intraoperative events, little is known about the mechanisms...