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.     

Global cardiac function: mechano-energetico-informatics

This review on the global cardiac function covers cardiac mechanics, energetics, and informatics that I have developed with my collaborators over the last 30 years in Japan and USA. We first established E(max) (end-systolic maximum elastance or pressure/volume ratio) as a new index of ventricular contractility using canine hearts. We then expanded the E(max) concept to PVA (systolic pressure-volume area consisting of external mechanical work and mechanical potential energy) as an innovative measure of total mechanical energy of ventricular contraction and discovered it to be a reliable determinant of ventricular energetics or O(2) consumption (V(O(2))). We have discovered that E(max) shifts the V(O(2))-PVA relation and the E(max) dependency (O(2) cost of E(max)) varies among different pathophysiological hearts. We also searched for the basis of E(max) in crossbridge behavior information contained in an X-ray diffraction of papillary muscle. Recently, we established a new integrative analysis to estimate total Ca(2+) recruited for excitation-contraction coupling in a beating heart using the E(max)-PVA-V(O(2)) information. These global, mechano-energetico-informatic approaches seem to facilitate better understanding of cardiac function, as required in the present post-genomic era when more physiomic knowledge is required not only in cardiac function but also in all other physiologic functions.     

Negative inotropism of hyperthermia increases oxygen cost of contractility in canine hearts

Heart temperature affects left ventricular (LV) function and myocardial metabolism. However, how and whether increasing heart temperature affects LV mechanoenergetics remain unclear. We designed the present study to investigate effects of increased temperature by 5 degrees C from 36 degrees C on LV contractility and energetics. We analyzed the LV contractility index (E(max)) and the relation between the myocardial oxygen consumption (MVO(2)) and the pressure-volume area (PVA; a measure of LV total mechanical energy) in isovolumically contracting isolated canine hearts during normothermia (NT) and hyperthermia (HT). HT reduced E(max) by 38% (P < 0.01) and shortened time to E(max) by 20% (P < 0.05). HT, however, altered neither the slope nor the unloaded MVO(2) of the MVO(2)-PVA relation. HT increased the oxygen cost of contractility (the incremental ratio of unloaded MVO(2) to E(max)) by 49%. When Ca(2+) infusion restored the reduced LV contractility during HT to the NT baseline level, the unloaded MVO(2) in HT exceeded the NT value by 36%. We conclude that HT-induced negative inotropism accompanies an increase in the oxygen cost of contractility.     

Relation of effective arterial elastance to arterial system properties

Effective arterial elastance (E(a)), defined as the ratio of left ventricular (LV) end-systolic pressure and stroke volume, lumps the steady and pulsatile components of the arterial load in a concise way. Combined with E(max), the slope of the LV end-systolic pressure-volume relation, E(a)/E(max) has been used to assess heart-arterial coupling. A mathematical heart-arterial interaction model was used to study the effects of changes in peripheral resistance (R; 0.6-1.8 mmHg x ml(-1) x s) and total arterial compliance (C; 0.5-2.0 ml/mmHg) covering the human pathophysiological range. E(a), E(a)/E(max,) LV stroke work, and hydraulic power were calculated for all conditions. Multiple-linear regression analysis revealed a linear relation between E(a), R/T (where T is cycle length), and 1/C: E(a) = -0.13 + 1.02R/T + 0.31/C, indicating that R/T contributes about three times more to E(a) than arterial stiffness (1/C). It is demonstrated that different pathophysiological combinations of R and C may lead to the same E(a) and E(a)/E(max) but can result in differences of 10% in stroke work and 50% in maximal power.     

Levosimendan restores the positive force-frequency relation in heart failure

Frequency potentiation of contractile function is a major mechanism of the increase in myocardial performance during exercise. In heart failure (HF), this positive force-frequency relation is impaired, and the abnormal left ventricular (LV)-arterial coupling is exacerbated by tachycardia. A myofilament Ca(2+) sensitizer, levosimendan, has been shown to improve exercise tolerance in HF. This may be due to its beneficial actions on the force-frequency relation and LV-arterial coupling (end-systolic elastance/arterial elastance, E(ES)/E(A)). We assessed the effects of therapeutic doses of levosimendan on the force-frequency relation and E(ES)/E(A) in nine conscious dogs after pacing-induced HF using pressure-volume analysis. Before HF, pacing tachycardia increased E(ES), shortened τ, and did not impair E(ES)/E(A) and mechanical efficiency (stroke work/pressure-volume area, SW/PVA). In contrast, after HF, pacing at 140, 160, 180, and 200 beat/min (bpm) produced smaller a increase of E(ES) or less shortening of τ, whereas E(ES)/E(A) (from 0.56 at baseline to 0.42 at 200 bpm) and SW/PVA (from 0.52 at baseline to 0.43 at 200 bpm) progressively decreased. With levosimendan, basal E(ES) increased 27% (6.2 mmHg/ml), τ decreased 11% (40.8 ms), E(ES)/E(A) increased 34% (0.75), and SW/PVA improved by 15% (0.60). During tachycardia, E(ES) further increased by 23%, 37%, 68%, and 89%; τ decreased by 9%, 12%, 15%, and 17%; and E(ES)/E(A) was augmented by 11%, 16%, 31%, and 33%, incrementally, with pacing rate. SW/PVA was improved (0.61 to 0.64). In conclusion, in HF, treatment with levosimendan restores the normal positive LV systolic and diastolic force-frequency relation and prevents tachycardia-induced adverse effect on LV-arterial coupling and mechanical efficiency.     

Frequency-dependent left ventricular performance in women and men

We aimed to determine whether sex differences in humans extend to the dynamic response of the left ventricular (LV) chamber to changes in heart rate (HR). Several observations suggest sex influences LV structure and function in health; moreover, this physiology is also affected in a sex-specific manner by aging. Eight postmenopausal women and eight similarly aged men underwent a cardiac catheterization-based study for force-interval relationships of the LV. HR was controlled by right atrial (RA) pacing, and LV +dP/dt(max) and volume were assessed by micromanometer-tipped catheter and Doppler echocardiography, respectively. Analysis of approximated LV pressure-volume relationships was performed using a time-varying model of elastance. External stroke work was also calculated. The relationship between HR and LV +dP/dt(max) was expressed as LV +dP/dt(max) = b + mHR. The slope (m) of the relationship was steeper in women compared with men (11.8 ± 4.0 vs. 6.1 ± 4.1 mmHg·s(-1)·beats(-1)·min(-1), P = 0.01). The greater increase in contractility in women was reproducibly observed after normalizing LV +dP/dt(max) to LV end-diastolic volume (LVVed) or by measuring end-systolic elastance. LVVed and stroke volume decreased more in women. Thus, despite greater increases in contractility, HR was associated with a lesser rise in cardiac output and a steeper fall in external stroke work in women. Compared with men, women exhibit greater inotropic responses to incremental RA pacing, which occurs at the same time as a steeper decline in external stroke work. In older adults, we observed sexual dimorphism in determinants of LV mechanical performance.     

Energetics of ventricular contraction as traced in the pressure-volume diagram

The pressure-volume (P-V) relationship of the canine left ventricle can reasonably be simulated by a time-varying elastance model. In this model the total mechanical energy generated by a contraction can be determined theoretically from the change in the elastance. Applying this theory to the actual left ventricle, we have found that the area in the P-V diagram circumscribed by the end-systolic P-V relation line, the end-diastolic P-V relation curve, and the systolic segment of the P-V trajectory is equivalent to the total mechanical energy generated by ventricular contraction. We call this area the systolic P-V area (PVA). We have studied experimentally the correlation between the PVA and myocardial oxygen consumption (VO2) in the canine left ventricle. VO2 was linearly correlated with PVA regardless of the contraction mode and loading conditions in a given left ventricle. The VO2-PVA relation parallel shifted upward with positive inotropic agents. This shift comprised a significant increase in VO2 component for the unloaded contraction. We therefore consider that further analyses of the VO2-PVA relationship will greatly promote our understanding of cardiac energetics.     

Conductance catheter-based assessment of arterial input impedance, arterial function, and ventricular-vascular interaction in mice

Global assessment of both cardiac and arterial function is important for a meaningful interpretation of pathophysiological changes in animal models of cardiovascular disease. We simultaneously acquired left ventricular (LV) and aortic pressure and LV volume (V(LV)) in 17 open-chest anesthetized mice (26.7 +/- 3.2g) during steady-state (BL) and caval vein occlusion (VCO) using a 1.4-Fr dual-pressure conductance catheter and in a subgroup of eight animals during aortic occlusion (AOO). Aortic flow was obtained from numerical differentiation of V(LV). AOO increased input impedance (Z(in)) for the first two harmonics, increased characteristic impedance (0.025 +/- 0.007 to 0.040 +/- 0.011 mmHg x microl(-1) x s, P < 0.05), and shifted the minimum in Z(in) from the third to the sixth harmonic. For all conditions, the Z(in) could be well represented by a four-element windkessel model. The augmentation index increased from 116.7 +/- 7.8% to 145.9 +/- 19.5% (P < 0.01) as well as estimated pulse-wave velocity (3.50 +/- 0.94 to 5.95 +/- 1.62 m/s, P < 0.05) and arterial elastance (E(a), 4.46 +/- 1.62 to 6.02 +/- 1.43 mmHg/microl, P < 0.01). AOO altered the maximal slope (E(max), 3.23 +/- 1.02 to 5.53 +/- 1.53 mmHg/microl, P < 0.05) and intercept (-19.9 +/- 8.6 to 1.62 +/- 13.51 microl, P < 0.01) of the end-systolic pressure-volume relation but not E(a)/E(max) (1.44 +/- 0.43 to 1.21 +/- 0.37, not significant). We conclude that simultaneous acquisition of Z(in) and arterial function parameters in the mouse, based solely on conductance catheter measurements, is feasible. We obtained an anticipated response of Z(in) and arterial function parameters following VCO and AOO, demonstrating the sensitivity of the measuring technique to induced physiological alterations in murine hemodynamics.     

Validation of a novel noninvasive cardiac index of left ventricular contractility in patients

Although there are several excellent indexes of myocardial contractility, they require accurate measurement of pressure via left ventricular (LV) catheterization. Here we validate a novel noninvasive contractility index that is dependent only on lumen and wall volume of the LV chamber in patients with normal and compromised LV ejection fraction (LVEF). By analysis of the myocardial chamber as a thick-walled sphere, LV contractility index can be expressed as maximum rate of change of pressure-normalized stress (d sigma*/dt(max), where sigma* = sigma/P and sigma and P are circumferential stress and pressure, respectively). To validate this parameter, d sigma*/dt(max) was determined from contrast cine-ventriculography-assessed LV cavity and myocardial volumes and compared with LVEF, dP/dt(max), maximum active elastance (E(a,max)), and single-beat end-systolic elastance [E(es(SB))] in 30 patients undergoing clinically indicated LV catheterization. Patients with different tertiles of LVEF exhibit statistically significant differences in d sigma*/dt(max). There was a significant correlation between d sigma*/dt(max) and dP/dt(max) (d sigma*/dt(max) = 0.0075 dP/dt(max) - 4.70, r=0.88, P<0.01), E(a,max) (d sigma*/dt(max) = 1.20E(a,max) + 1.40, r=0.89, P<0.01), and E(es(SB)) [d sigma*/dt(max)=1.60 E(es(SB)) + 1.20, r=0.88, P<0.01]. In 30 additional individuals, we determined sensitivity of the parameter to changes in preload (intravenous saline infusion, n = 10 subjects), afterload (sublingual glyceryl trinitrate, n = 10 subjects), and increased contractility (intravenous dobutamine, n=10 patients). We confirmed that the index is not dependent on load but is sensitive to changes in contractility. In conclusion, d sigma*/dt(max) is equivalent to dP/dt(max), E(a,max), and E(es(SB)) as an index of myocardial contractility and appears to be load independent. In contrast to other measures of contractility, d sigma*/dt(max) can be assessed with noninvasive cardiac imaging and, thereby, should have more routine clinical applicability.     

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.     

First-order approximation for the pressure-flow relationship of spontaneously contracting lymphangions

To return lymph to the great veins of the neck, it must be actively pumped against a pressure gradient. Mean lymph flow in a portion of a lymphatic network has been characterized by an empirical relationship (P(in) - P(out) = -P(p) + R(L)Q(L)), where P(in) - P(out) is the axial pressure gradient and Q(L) is mean lymph flow. R(L) and P(p) are empirical parameters characterizing the effective lymphatic resistance and pump pressure, respectively. The relation of these global empirical parameters to the properties of lymphangions, the segments of a lymphatic vessel bounded by valves, has been problematic. Lymphangions have a structure like blood vessels but cyclically contract like cardiac ventricles; they are characterized by a contraction frequency (f) and the slopes of the end-diastolic pressure-volume relationship [minimum value of resulting elastance (E(min))] and end-systolic pressure-volume relationship [maximum value of resulting elastance (E(max))]. Poiseuille's law provides a first-order approximation relating the pressure-flow relationship to the fundamental properties of a blood vessel. No analogous formula exists for a pumping lymphangion. We therefore derived an algebraic formula predicting lymphangion flow from fundamental physical principles and known lymphangion properties. Quantitative analysis revealed that lymph inertia and resistance to lymph flow are negligible and that lymphangions act like a series of interconnected ventricles. For a single lymphangion, P(p) = P(in) (E(max) - E(min))/E(min) and R(L) = E(max)/f. The formula was tested against a validated, realistic mathematical model of a lymphangion and found to be accurate. Predicted flows were within the range of flows measured in vitro. The present work therefore provides a general solution that makes it possible to relate fundamental lymphangion properties to lymphatic system function.     

Heart failure attenuates muscle metaboreflex control of ventricular contractility during dynamic exercise

Underperfusion of active skeletal muscle elicits a reflex pressor response termed the muscle metaboreflex (MMR). In normal dogs during mild exercise, MMR activation causes large increases in cardiac output (CO) and mean arterial pressure (MAP); however, in heart failure (HF) although MAP increases, the rise in CO is virtually abolished, which may be due to an impaired ability to increase left ventricular contractility (LVC). The objective of the present study was to determine whether the increases in LVC seen with MMR activation during dynamic exercise in normal animals are abolished in HF. Conscious dogs were chronically instrumented to measure CO, MAP, and left ventricular (LV) pressure and volume. LVC was calculated from pressure-volume loop analysis [LV maximal elastance (E(max)) and preload-recruitable stroke work (PRSW)] at rest and during mild and moderate exercise under free-flow conditions and with MMR activation (via partial occlusion of hindlimb blood flow) before and after rapid ventricular pacing-induced HF. In control experiments, MMR activation at both workloads [mild exercise (3.2 km/h) and moderate exercise (6.4 km/h at 10% grade)] significantly increased CO, E(max), and PRSW. In contrast, after HF was induced, CO, E(max), and PRSW were significantly lower at rest. Although CO increased significantly from rest to exercise, E(max) and PRSW did not change. In addition, MMR activation caused no significant change in CO, E(max), or PRSW at either workload. We conclude that MMR causes large increases in LVC in normal animals but that this ability is abolished in HF.     

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.     

Pressure-volume-based single-beat estimations cannot predict left ventricular contractility in vivo

The end-systolic pressure-volume relationship is regarded as a useful index for assessing the contractile state of the heart. However, the need for preload alterations has been a serious limitation to its clinical applications, and there have been numerous attempts to develop a method for calculating contractility based on one single pressure-volume loop. We have evaluated four of these methods. Pressure-volume data were obtained by combined pressure and conductance catheters in 37 pigs. All four methods were applied to 88 steady-state pressure-volume files, including eight files sampled during dopamine infusions. Estimates of single-beat contractility (elastance) were compared with preload-varied multiple-beat elastance [E(es(MB))]. All methods had a low average bias (-0.3 to 0.5 mmHg/ml) but limits of agreement (+/-2 SD) were unacceptably high (+/-2.6 to +/-3.8 mmHg/ml). In the dopamine group, E(es(MB)) showed an increase of 1.7 +/- 0.8 mmHg/ml (mean +/- SD) compared with baseline (P < 0.001). None of the single-beat methods predicted this increase in contractility. It is therefore doubtful whether any of the methods allow for single-beat assessment of contractility.     

Acute effects of methoxamine on left ventricular-arterial coupling in streptozotocin-diabetic rats: a pressure-volume analysis

We determined the acute effects of methoxamine, a specific alpha1-selective adrenoceptor agonist, on the left ventricular-arterial coupling in streptozotocin (STZ)-diabetic rats, using the end-systolic pressure-stroke volume relationships. Rats given STZ 65 mg x kg(-1) iv (n = 8) were compared with untreated age-matched controls (n = 8). A high-fidelity pressure sensor and an electromagnetic flow probe measured left ventricular (LV) pressure and ascending aortic flow, respectively. Both LV end-systolic elastance E(LV,ES) and effective arterial elastance Ea were estimated from the pressure-ejected volume loop. The optimal afterload Q(load) determined by the ratio of Ea to E(LV,ES) was used to measure the optimality of energy transmission from the left ventricle to the arterial system. In comparison with controls, diabetic rats had decreased LV end-systolic elastance E(LV,ES), at 513 +/- 30 vs. 613 +/- 29 mmHg x mL(-1), decreased effective arterial elastance Ea, at 296 +/- 20 vs. 572 +/- 48 mmHg x mL(-1), and decreased optimal afterload Q(load), at 0.938 +/- 0.007 vs. 0.985 +/- 0.009. Methoxamine administration to STZ-diabetic rats significantly increased LV end-systolic elastance E(LV,ES), from 513 +/- 30 to 602 +/- 38 mmHg x mL(-1), and effective arterial elastance Ea, from 296 +/- 20 to 371 +/- 28 mmHg x mL(-1), but did not change optimal afterload Q(load). We conclude that diabetes worsens not only the contractile function of the left ventricle, but also the matching condition for the left ventricular-arterial coupling. In STZ-diabetic rats, administration of methoxamine improves the contractile status of the ventricle and arteries, but not the optimality of energy transmission from the left ventricle to the arterial system.     

Reversible effects of isoproterenol-induced hypertrophy on in situ left ventricular function in rat hearts

The aim of the present study was to evaluate specifically left ventricular (LV) function in rat hearts as they transition from the normal to hypertrophic state and back to normal. Either isoproterenol (1.2 and 2.4 mg.kg(-1).day(-1) for 3 days; Iso group) or vehicle (saline 24 microl.day(-1) for 3 days; Sa group) was infused by subcutaneous implantation of an osmotic minipump. After verifying the development of cardiac hypertrophy, we recorded continuous LV pressure-volume (P-V) loops of in situ ejecting hypertrophied rat hearts. The curved LV end-systolic P-V relation (ESPVR) and systolic P-V area (PVA) were obtained from a series of LV P-V loops in the Sa and Iso groups 1 h or 2 days after the removal of the osmotic minipump. PVA at midrange LV volume (PVA(mLVV)) was taken as a good index for LV work capability (13, 15, 20, 21). However, in rat hearts during remodeling, whether PVA(mLVV) is a good index for LV work capability has not been determined yet. In the present study, in contrast to unchanged end-systolic pressure at midrange LV volume, PVA(mLVV) was significantly decreased by isoproterenol treatment relative to saline; however, these measurements were the same 2 days after pump removal. Simultaneous treatment with a beta(1)-blocker, metoprolol (24 mg.kg(-1).day(-1)), blocked the formation of cardiac hypertrophy and thus PVA(mLVV) did not decrease. The reversible changes in PVA(mLVV) reflect precisely the changes in LV work capability in isoproterenol-induced hypertrophied rat hearts mediated by beta(1)-receptors. These results indicate that the present approach may be an appropriate strategy for evaluating the effects of antihypertrophic and antifibrotic modalities.     

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.     

Acute elevation of triglycerides increases left ventricular contractility and alters ventricular-vascular interaction

Acute elevation of circulating lipids, such as the postprandial state, contributes to increased cardiovascular risk. However, the effect of acutely elevated triglycerides on arterial and left ventricular function is not completely understood. We aimed to assess whether an acute increase in triglycerides affects ventricular-vascular interaction. Fifteen healthy men (age, 49 ± 8 yr) underwent blinded, randomized infusion of saline and intravenous fat emulsion to acutely raise plasma triglycerides. All subjects underwent both randomization trials, in random order on two separate days. Ventricular-vascular interaction measures were recorded by tonometry (central blood pressure) and echocardiography (left ventricular volumes, strain, and strain rate) at baseline and after 1 h infusion. Net ventricular-vascular interaction was defined by the effective arterial elastance (E(A))-to-left ventricular end-systolic elastance (E(LV)) ratio (E(A)/E(LV)). When compared with saline, the infusion of intravenous fat emulsion increased triglycerides and free fatty acids (ΔP < 0.001 for both) and improved left ventricular contractility (ΔE(LV), end-systolic volume and strain rate; P < 0.05 for all). However, arterial function was unchanged (ΔE(A), brachial and central blood pressure; P > 0.05 for all). Overall, E(A)/E(LV) was decreased by an infusion of intravenous fat emulsion (P = 0.004) but not saline (P > 0.05, P = 0.001 for Δ between trials). We conclude that intravenous fat emulsion and acute elevation of blood lipids (including triglycerides and free fatty acids) alter ventricular-vascular interaction by increasing left ventricular contractility without affecting arterial load. These findings may have implications for cardiovascular responses to parenteral nutrition.     

Effects of sodium nitroprusside in aortic stenosis associated with severe heart failure: pressure-volume loop analysis using a numerical model

In the recently published clinical study [Use of Nitroprusside in Left Ventricular Dysfunction and Obstructive Aortic Valve Disease (UNLOAD)], sodium nitroprusside (SNP) improved cardiac function in patients with severe aortic stenosis (AS) and left ventricular (LV) systolic dysfunction. We explored the possible mechanisms of these findings using a series of numerical simulations. A closed-loop lumped parameters model that consists of 24 differential equations relating pressure and flow throughout the circulation was used to analyze the effects of varying hemodynamic conditions in AS. Hemodynamic data from UNLOAD study subjects were used to construct the initial simulation. Systemic vascular resistance (SVR), heart rate, and aortic valve area were directly entered into the model while end-systolic and end-diastolic pressure-volume (P-V) relationships were adjusted using previously published data to match modeled and observed end-systolic and end-diastolic pressures and volumes. Initial simulation of SNP treatment by a reduction of SVR was not adequate. To obtain realistic model hemodynamics that reliably reproduce SNP treatment effects, we performed a series of simulations while simultaneously changing end-systolic elastance (E(es)), end-systolic volume at zero pressure (V(0)), and diastolic P-V shift. Our data indicate that either an E(es) increase or V(0) decrease is necessary to obtain realistic model hemodynamics. In five patients, we corroborated our findings by using the model to duplicate individual P-V loops obtained before and during SNP treatment. In conclusion, using a numerical model, we identified ventricular function parameters that are responsible for improved hemodynamics during SNP infusion in AS with LV dysfunction.