End-systolic Pressure-volume Ratio Research Articles

Abstract 14613: Preclinical Animal Model of Doxorubicin-induced Left Ventricular Dysfunction: Echocardiography and Pressure-volume Analysis

Introduction: There is a need to implement a preclinical model in addition to the well established ischemic or volume-overload models that would mimic the clinical course of patients with chemotherapy-induced heart failure. Doxorubicin is an anthracycline chemotherapeutic that is widely used in oncology, although its cardiotoxicity. Hypothesis: Doxorubicin-induced left ventricular dysfunction in rats fulfills echocardiography and hemodynamic characteristics of chemotherapy-induced heart failure. Methods: We randomly assigned Ren-2 transgenic hypertensive (TGR, n = 17) and normotensive rats (HanSD, n = 22), at the age of 8 weeks to doxorubicin (2.5 mg/kg in 0.5 ml of normal saline) or placebo in 6 intraperitoneal doses within two weeks (cumulative doxorubicin dose 15 mg/kg). Two weeks later, we performed echocardiography study, pressure-volume analysis (PV), and we weighed the organs. Results: In doxorubicin groups, there was a decrease in the left ventricle weight (1,22 vs. 0,85 g in TGR), while an increase in wall stress (22036 vs. 29754 μL*mmHg/g in TGR). Echocardiography suggested heart remodeling with a decrease in relative wall thickness - RWT (1.02 vs. 0.65 mm in TGR), and together with PV analysis showed a decrease in systolic parameters - left ventricle ejection fraction - LVEF (71.41 vs. 59.96 % in TGR), end-systolic pressure-volume ratio - ESPVR (0.82 vs. 0.45 mmHg/uL in TGR) and preload recruitable stroke work - PRSW (75.71 vs. 60.98 mmHg in TGR). Ventricular-arterial coupling (VAC = Ea/Ees, a measure of cardiac efficiency) was worsened in the doxorubicin groups (1.69 vs. 2.52 in TGR). For all the above p < 0.05, in HanSD, the results were similar (all p < 0.05). Conclusions: Our results suggest that systolic dysfunction and decrease of cardiac efficiency in this model could be caused by heart atrophy, and such an animal model could potentially be an easily reproducible model of chemotherapy-induced heart failure in preclinical cardio-oncology studies.

Exercise cardiac magnetic resonance to differentiate athlete's heart from structural heart disease.

The distinction between left ventricular (LV) dilation with mildly reduced LV ejection fraction (EF) in response to regular endurance exercise training and an early cardiomyopathy is a frequently encountered and difficult clinical conundrum. We hypothesized that exercise rather than resting measures would provide better discrimination between physiological and pathological LV remodelling and that preserved exercise capacity does not exclude significant LV damage. We prospectively included 19 subjects with LVEF between 40 and 52%, comprising 10 ostensibly healthy endurance athletes (EA-healthy) and nine patients with dilated cardiomyopathy (DCM). In addition, we recruited five EAs with a region of subepicardial LV. Receiver operating characteristic fibrosis (EA-fibrosis). Cardiac magnetic resonance (CMR) imaging was performed at rest and during supine bicycle exercise. Invasive afterload measures were obtained to enable calculations of biventricular function relative to load (an estimate of contractility). In DCM and EA-fibrosis subjects there was diminished augmentation of LVEF (5 ± 6% vs. 4 ± 3% vs. 14 ± 3%; P = 0.001) and contractility [LV end-systolic pressure-volume ratio, LVESPVR; 1.4 (1.3-1.6) vs. 1.5 (1.3-1.6) vs. 1.8 (1.7-2.7); P < 0.001] during exercise relative to EA-healthy. Receiver-operator characteristic curves demonstrated that a cut-off value of 11.2% for ΔLVEF differentiated DCM and EA-fibrosis patients from EA-healthy [area under the curve (AUC) = 0.92, P < 0.001], whereas resting LVEF and VO2max were not predictive. The AUC value for LVESPVR ratio was similar to that of ΔLVEF. Functional cardiac evaluation during exercise is a promising tool in differentiating healthy athletes with borderline LVEF from those with an underlying cardiomyopathy. Excellent exercise capacity does not exclude significant LV damage.

Celsior preserves cardiac mechano-energetics better than University of Wisconsin solution by preventing oxidative stress.

Identity of the optimal heart preservation solution remains unknown. Because oxidative stress contributes to contractile failure in the ischaemic/reperfused myocardium and the main characteristic of Celsior is its antioxidant effect, it is important to elucidate the relationship between the inhibitory effect on oxidative stress and cardiac mechano-energetics. We therefore evaluated the efficacy of Celsior from both aspects by comparison with the University of Wisconsin solution (UWS). We used 18 excised cross-circulated canine hearts. Excised hearts were preserved with UWS (n = 6) or Celsior (n = 6) for 3 h at 4 °C; the remaining six served as controls. Hearts were then cross-circulated and rewarmed. The end-systolic pressure-volume ratio (LV Emax) and the ventricular pressure-volume area, which is a measure of total mechanical energy, were assessed after reperfusion. Biopsies were taken from the endocardium after excising the heart, before reperfusion, after reperfusion and 4 h after reperfusion to assess the inhibitory effect of each agent on oxidative stress. Endo-myocardial biopsy samples were studied immunohistochemically for expression of 4-hydroxy-2-nonenal (HNE)-modified protein, which is a major lipid peroxidation product. Emax in the UWS group was significantly smaller than in the control group, whereas the Emax in the Celsior group was preserved. Oxygen cost of Emax in the UWS group was significantly higher than in the Celsior group. Myocardial HNE-modified protein levels increased gradually, both under preservation and after reperfusion in the UWS group. Myocardial HNE-modified protein levels in the Celsior group were lower, mainly before and 4 h after reperfusion compared with the UWS group. Celsior may maintain cardiac contractility and conserve oxygen cost by inhibiting oxidative stress.

Abstract 18506: Right Ventricular and Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction: An Exercise Cardiac Magnetic Resonance Study

Introduction: Right ventricular dysfunction (RVD) is a marker of adverse outcome in HFpEF patients. While RVD in HFpEF has been demonstrated using dobutamine stress and invasive hemodynamic studies, detailed assessment of RV and pulmonary vascular (PV) function using simultaneous exercise cardiac MRI and invasive hemodynamic measurements has never been performed. Methods In a prospective study, we performed CPET to determine maximal power output (Pmax) in patients with HFpEF (n=11, age 73±9 years) and in healthy controls (n=8, age 53±7 years). We also investigated asymptomatic subjects with echocardiographic evidence of LV concentric remodeling (LVCR) and impaired relaxation (n=4, age 63±7 years). All participants then performed a three-stage supine bicycle exercise test during real-time CMR imaging (at 25%, 50% and 66% of Pmax) with continuous recording of pulmonary arterial pressures using fluid-filled catheters. We determined the ratio of mPAP relative to cardiac output (mPAP/CO slope) as a measure of PV reserve and the change in RV end-systolic pressure volume ratio (dRVESPR) as a measure for RV contractile reserve. Results At rest, there was no difference in LV or RV ejection fraction (EF) between HFpEF patients and controls (p=NS). However, during exercise, HFpEF patients showed a decline in RVEF (-3.9±1.7%), contrasting with a marked increase in RVEF in the control group (+12.49±2.33%, p&lt;0.001 for interaction workload*group, figure 1A). HFpEF patients had a greater mPAP/CO slope (p&lt;0.001, figure 1B) and a significantly lower dRVESPVR (p&lt;0.001) than controls. Interestingly, asymptomatic subjects with LVCR showed an intermediate response to exercise (figure 1A-B). Conclusion In patients with HFpEF, RV functional reserve and pulmonary pressure-flow relationships are markedly impaired. These data suggest an important role for cardiac exercise MRI in phenotyping heart failure patients and guiding RV or pulmonary vasculature targeted therapy.

Accuracy of Echocardiography to Evaluate Pulmonary Vascular and RV Function During Exercise

ObjectivesThe authors have compared exercise echocardiography and exercise cardiac magnetic resonance imaging with simultaneous invasive pressure registration (ExCMRip) for the assessment of pulmonary vascular and right ventricular (RV) function. BackgroundExercise echocardiography may enable early diagnosis of pulmonary vascular disease, but its accuracy is untested. MethodsExercise imaging was performed in 61 subjects (19 athletes, 9 healthy nonathletes, 8 healthy BMPR2 [bone morphogenetic protein receptor type II] mutation carriers, 5 patients with new or worsening dyspnea after acute pulmonary embolism, and 20 patients with chronic thromboembolic pulmonary hypertension). Echocardiographic variables included mean pulmonary artery pressure (mPAP) and systolic pulmonary artery pressure (sPAP), cardiac output (CO), RV fractional area change, tricuspid annular systolic excursion, and RV end-systolic pressure-area ratio as a surrogate measure of RV contractile reserve. ExCMRip provided measurements of CO, RV ejection fraction, mPAP, sPAP, and RV end-systolic pressure-volume ratio at rest and during exercise. Abnormal pulmonary vascular reserve was defined as mPAP/CO slope >3 mm Hg/l/min by ExCMRip. ResultsEchocardiographic determination of mPAP/CO was possible in 53 of 61 subjects (87%). mPAP/CO by echocardiography was higher than that obtained by ExCMRip (+0.9 mm Hg/l/min; 95% limits of agreement, −3.6 to 5.4), but enabled accurate identification of patients with abnormal pulmonary vascular reserve (area under the receiver-operating characteristic curve, 0.88 [95% confidence interval (CI): 0.77 to 1.00; p < 0.0001]). Simplified relationships between sPAP and exercise intensity had similar accuracy in identifying subjects with pulmonary vascular disease (area under the receiver-operating characteristic curve, 0.95 [95% CI: 0.88 to 1.01]; p < 0.0001). RV fractional area change by echocardiography correlated strongly with RV ejection fraction by ExCMRip, whereas a moderate correlation was found between tricuspid annular systolic excursion and RV ejection fraction. A moderate correlation was found between ratios of peak exercise to resting RV end-systolic pressure-area ratio and RV end-systolic pressure-volume ratio (r = 0.64; p < 0.0001). ConclusionsEchocardiographic estimates of RV and pulmonary vascular function are feasible during exercise and identify pathology with reasonable accuracy. They represent valid screening tools for the identification of pulmonary vascular disease in routine clinical practice.

Abstract 16599: Impaired Right Ventricular Contractile Reserve During Exercise in Endurance Athletes With Right Ventricular Arrhythmias

Introduction: Ventricular arrhythmias in endurance athletes (EAs) frequently originate from a mildly dysfunctional right ventricle (RV). We evaluated whether RV dysfunction in EAs with ventricular arrhythmias of RV origin (EA-VAs) becomes more apparent during exercise than at rest. Methods: Ten healthy EAs, 7 healthy non-athletes (NAs) and 17 EA-VAs (8 with ICD) first underwent cardiopulmonary exercise testing to determine maximal power (Pmax). Then, exercise echocardiography was performed at 25%, 50% and 66% of Pmax to measure the RV end-systolic pressure-area ratio (ESPAR), a surrogate of RV contractility, which was calculated as systolic pulmonary artery pressure/RV end-systolic area. Finally, all subjects without ICD underwent cardiac MRI during supine bicycle exercise at similar workloads with simultaneous invasive pulmonary artery pressure measurement to determine the RV end-systolic pressure-volume ratio (SP/ESV). Results: At rest, RV ESPAR was similar in EA-VAs relative to NAs (P=0.1), although slightly lower than in NAs (P=0.02). During exercise, EA-VAs had an impaired increase in RV ESPAR compared to both EAs and NAs (interaction P&lt;0.0001; Figure 1A). Also the slopes of RV ESPAR to absolute workload (in Watts) were lower in EA-VAs than in EAs and NAs (P&lt;0.0001) and correlated highly with the slopes of RV SP/ESV to workload obtained by MRI and invasive pressure measures (R=0.75; P&lt;0.0001). Figure 1B shows that resting and peak exercise RV ESPAR cutoffs of 1.4 and 3.9 mmHg/cm 2 had a sensitivity of 77% and 79% and specificity of 80% and 100%, respectively, to identify EA-VAs. Conclusion: EA-VAs have impaired RV contractility which is evident during exercise but hardly at rest. This strengthens the association between RV arrhythmias and functional impairment. Our data suggest that exercise echocardiography is sufficiently accurate to determine RV contractile reserve in a non-invasive manner and may assist in risk stratification of RV remodeling in EAs.

Myocardial contractility in the stress echo lab: from pathophysiological toy to clinical tool

Up-regulation of Ca2+ entry through Ca2+ channels by high rates of beating is involved in the frequency-dependent regulation of contractility: this process is crucial in adaptation to exercise and stress and is universally known as force-frequency relation (FFR). Disturbances in calcium handling play a central role in the disturbed contractile function in myocardial failure. Measurements of twitch tension in isolated left-ventricular strips from explanted cardiomyopathic hearts compared with non-failing hearts show flat or biphasic FFR, while it is up-sloping in normal hearts. Starting in 2003 we introduced the FFR measurement in the stress echo lab using the end-systolic pressure (ESP)/End-systolic volume index (ESVi) ratio (the Suga index) at increasing heart rates. We studied a total of 2,031 patients reported in peer-reviewed journals: 483 during exercise, 34 with pacing, 850 with dobutamine and 664 during dipyridamole stress echo. We demonstrated the feasibility of FFR in the stress echo lab, the clinical usefulness of FFR for diagnosing latent contractile dysfunction in apparently normal hearts, and residual contractile reserve in dilated idiopathic and ischemic cardiomyopathy. In 400 patients with left ventricular dysfunction (ejection fraction 30 ± 9%) with negative stress echocardiography results, event-free survival was higher (p < 0.001) in patients with ΔESPVR (the difference between peak and rest end-systolic pressure-volume ratio, ESPVR) ≥ 0.4 mmHg/mL/m2. The prognostic stratification of patients was better with FFR, beyond the standard LV ejection fraction evaluation, also in the particular settings of severe mitral regurgitation or diabetics without stress-induced ischemia. In the particular setting of selection of heart transplant donors, the stress echo FFR was able to correctly select 34 marginal donor hearts efficiently transplanted in emergency recipients. Starting in 2007, we introduced an operator-independent cutaneous sensor to monitor the FFR: the force is quantified as the sensed pre-ejection myocardial vibration amplitude. We demonstrated that the sensor-derived force changes at increasing heart rates are highly related with both max dP/dt in animal models, and with the stress echo FFR in 220 humans, opening a new window for pervasive cardiac heart failure monitoring in telemedicine systems.

Reduced End-Systolic Pressure-Volume Ratio Response to Exercise

Background— Limitations in the predictive value of negative exercise echocardiography in type 2 diabetes mellitus has been linked to a reduced end-systolic pressure-volume response (ESPVR). We sought whether abnormal ESPVR reflected subclinical diabetic heart disease by examining the association between the ESPVR and markers of myocardial dysfunction and to establish if the change (Δ) or peak systolic blood pressure/end-systolic left ventricular volume ratio (SP/ESV) is a better marker of contractile reserve in type 2 diabetes mellitus. Methods and Results— Resting and exercise echocardiography was performed in 167 apparently healthy patients with type 2 diabetes mellitus (97 men; age, 55±10 years) without ischemia, other cardiac disease, or noncardiac complications of diabetes. Standard echocardiographic and color tissue Doppler measures (early diastolic tissue velocity, strain, and strain rate) were acquired at baseline and peak stress in apical long-axis views. Calibrated integrated backscatter was calculated from a resting parasternal long-axis view. ΔSP/ESV was calculated as [(peak stress SP/ESV)−(rest SP/ESV)]. The 83 subjects who demonstrated a ΔSP/ESV ≤12 mm Hg/mL/m 2 after exercise were older and had lower peak heart rate, resting diastolic and stress systolic tissue velocity, stress ejection fraction, and exercise capacity than the remainder. There was no significant association between ΔSP/ESV and metabolic derangement or echocardiographic measures of deformation or backscatter. Change in Sm and stress ejection fraction were independent correlates of ΔSP/ESV. Conclusions— ΔSP/ESV ratio is associated with established features of subclinical diabetic heart disease as well as determinants of contractile reserve (peak hemodynamic response and stress systolic function). Peak ESPVR is poorly associated with markers of myocardial dysfunction.

Mechanisms Underlying Improvements in Ejection Fraction With Carvedilol in Heart Failure

Reductions in heart rate (HR) with beta-blocker therapy have been associated with improvements in ejection fraction (EF). However, the relative contributions of HR reduction, positive inotropism, afterload reduction, and reverse remodeling to improvements in EF are unknown. Twenty-nine patients (63+/-12 years old) with New York Heart Association class II-III heart failure underwent serial measurements of left ventricular volumes using 3-dimensional echocardiography and blood pressures by sphygmomanometry at baseline, 2 weeks, 2, 6, and 12 months after initiation of carvedilol. From these parameters, left ventricular contractility (indexed by the end-systolic pressure-volume ratio), total peripheral resistance, and effective arterial elastance (E(a)) were derived. Overall, EF increased by 7-percentage points after 6 months of therapy (from 25+/-9 to 32+/-9, P<0.0001). This change was due to an increase in stroke volume (P<0.001) with no significant change in end-diastolic volume (P=0.15). The EF change correlated with increased contractility, decreased HR and decreased total peripheral resistance (P<0.003 in each case). In those patients whose EF increased at least 5 points, approximately 60% of the increase was due to HR reduction, approximately 30% was due to increased contractility, and <20% was due to the decrease in total peripheral resistance. Decreased HR, improved chamber contractility and afterload reduction each contributed significantly to improved EF with carvedilol.

Endotoxin Removal with a Polymyxin B-Immobilized Hemoperfusion Cartridge Improves Cardiopulmonary Function After Cardiopulmonary Bypass

Cardiac surgery using cardiopulmonary bypass (CPB) is performed widely, given the progress in cardioprotective methods. However, endotoxemia caused by CPB leads to systemic inflammatory response syndrome and deterioration of organ function. We evaluated the effectiveness of endotoxin removal with a polymyxin B-immobilized hemoperfusion cartridge (PMX) in CPB. Pigs weighing about 25 kg were divided into control (n = 5) and PMX (n = 5) groups. Normothermic CPB was performed in the control group, while endotoxin was removed with PMX under normothermic CPB in the PMX group. Endotoxin removal was performed from the start to end of CPB. The end-systolic pressure-volume ratio (E(max)), left ventricular pressure (LVP), maximum and minimum rates of increase in LVP (+/-LVdp/dt), and cardiac output (CO) were measured 2 h after CPB, and the recovery rates of the parameters were compared between the two groups. A histopathological study was also conducted. The recovery rates of E(max), CO, and LVP were significantly better (P < 0.05) in the PMX group than in the control group. The PaO(2) 2 h after CPB was significantly higher (P < 0.05) in the PMX group than in the control group. The interleukin (IL)-8 level 2 h after CPB was significantly lower (P < 0.05) in the PMX group. Histopathologically, the heart and pulmonary tissues were better preserved in the PMX group. The PMX treatment reduced the inflammatory reaction caused by CPB, and cardiac and pulmonary functions after normothermic CPB were well preserved.

Efficacy of MCI-186, a free-radical scavenger and antioxidant, for resuscitation of nonbeating donor hearts

Oxygen-derived free radicals are responsible in part for reperfusion injury in globally ischemic myocardium. In this study, the efficacy for resuscitation of nonbeating donor hearts of MCI-186, a free-radical scavenger and antioxidant, was investigated in a pig transplantation model. Cardiac arrest was induced by asphyxiation. After 30 minutes of global ischemia, the hearts were excised and immediately reperfused from the aortic root with normoxemic blood cardioplegia (PO2 100 mm Hg) for 20 minutes, followed by perfusion with hyperoxemic blood (PO2 300 mm Hg). MCI-186 (3 mg/kg) was administered into the aortic root for the first 30 minutes of reperfusion in the treated group (n = 6), and untreated hearts were used as a control group (n = 6). Transplantation was performed with the heart beating. Posttransplantation recovery of cardiac output, end-systolic pressure-volume ratio, and first derivative of pressure of the left ventricle in the treated group were significantly better than those in the control group. The coronary sinus-aortic root difference in malondialdehyde levels remained low throughout reperfusion in the treated group but abruptly increased after initiation of oxygenated blood perfusion in the control group. The MCI-186-treated hearts showed low degree of edema and well-preserved ultrastructure with normal-appearing organelles, whereas the untreated hearts had marked swelling of mitochondria and scant glycogen granules. MCI-186 exerts a cardioprotective action at least partly by inhibition of lipid peroxidation. Antioxidant therapy at the initial reperfusion is essential to successful resuscitation of nonbeating hearts by continuous myocardial perfusion.

Efficacy of an endothelin-A receptor antagonist in heart transplantation from asphyxiated canine non-heart-beating donors

Hypoxic perfusion before arrest, an indeterminate period of warm ischemia, and subsequent reperfusion are major causes of cardiac allograft dysfunction in non-heart-beating donors (NHBDs). The present study was undertaken to elucidate the cardioprotective effects of ET(A) receptor antagonist FR139317 for hearts obtained from asphyxiated NHBDs in a canine transplantation model. Hypoxic cardiac arrest was induced in 17 donor dogs. FR139317 (10 mg/kg) was given to 7 of the dogs over a period of 10 min before disconnecting the ventilator. The hearts were preserved with FR 139317-supplemented cardioplegic solution (FR group). The remaining 10 did not receive FR 139317 at any time during the experiment (control group). Orthotopic transplantation was performed after a mean myocardial ischemic time of 4h. During the agonal period, the highest systolic pulmonary artery pressure in the FR group was lower than that in the control group (47 +/- 14 vs. 58 +/- 27 mmHg). All animals in the FR group were weaned from cardiopulmonary bypass, whereas only five of the controls were weaned, two of which were identified to have dominant right ventricular failure. After transplantation, recovery rates of the left ventricular end-systolic pressure-volume ratio (E(max)) and the maximum first derivative of pressure measured over time (max dP/dt) were not significantly different between the groups, but recovery rates of the cardiac index, left ventricular minimum dP/dt and exponential time constant of LV relaxation (tau) in the FR group were higher than those in the control group. The ET(A) receptor antagonist FR 139317 reduced pressure overload on the right ventricle by decreasing the peak pulmonary artery pressure before donor arrest. Cardioprotective effects of this agent for heart transplantation from NHBDs are manifested by preserved diastolic properties of the left ventricle.

Resuscitation of Non-Beating Donor Hearts Using Continuous Myocardial Perfusion: The Importance of Controlled Initial Reperfusion

Warm ischemia is a major cause of cardiac allograft failure in transplants from non-heart-beating donors. To minimize myocardial ischemia, we used a continuous myocardial perfusion technique for resuscitation of donor hearts. The purpose of the present study was to investigate an optimal duration of controlled initial reperfusion. Cardiac arrest was induced by asphyxia in 18 donor pigs. The hearts were harvested 30 minutes after global warm ischemia. Continuous myocardial reperfusion was immediately commenced from the aortic root with blood cardioplegic solution (20 degrees C, 40 mm Hg) and then with oxygenated blood (20 degrees to 37 degrees C, 40 to 60 mm Hg). Animals were divided into three groups according to the duration of the initial reperfusion: group I = 5 minutes, group II = 20 minutes, and group III = 60 minutes. Orthotopic transplantation was performed while keeping the heart beating by continuous myocardial perfusion. Cardiac function was evaluated before anoxia and after transplantation. Lactate extractions were determined during reperfusion. Myocardial edema was assessed by heart weight and posterior wall thickness of the left ventricle. Recovery rates of cardiac function in group II hearts after transplantation were better than in groups I and III (cardiac output, 61% +/- 9% versus 41% +/- 5% versus 44% +/- 4%, respectively; p < 0.05; left ventricular end-systolic pressure-volume ratio, 64% +/- 8% versus 36% +/- 9% versus 42% +/- 6%, respectively; p < 0.05). Lactate extractions in groups II and III returned to 0 within 20 minutes of reperfusion. Myocardial edema after transplantation in group II hearts was less than in groups I and III. The best recovery was observed in the non-beating donor hearts resuscitated by continuous myocardial perfusion when the initial controlled reperfusion with lukewarm blood cardioplegic solution at 40 mm Hg lasted for 20 minutes.

Celsior Preserved Cardiac Mechanoenergetics Better Than Popular Solutions in Canine Hearts

Better protective effects of Celsior on cardiac function than the other conventional solutions have been reported in acute experiments and in clinical trials for at-risk patients. However, no study has yet precisely elucidated how these preservation solutions affect cardiac mechanoenergetics. Therefore, we evaluated the effects of St. Thomas' Hospital solution No. 2, University of Wisconsin solution, and Celsior on left ventricular contractility (Emax: end-systolic pressure-volume ratio) and oxygen consumption. We used 32 canine excised cross-circulated hearts. Twenty-three hearts served as donor hearts after hypothermic ischemia with one of the three solutions, and the remaining 9 served as controls. After arrest with each solution, the hearts were preserved for 4 hours at 4 degrees C. Then, we measured left ventricular pressure, volume, and oxygen consumption to obtain Emax and the relation between ventricular pressure-volume area (a measure of total mechanical energy) and oxygen consumption. We also evaluated the oxygen cost of Emax by changing Emax with calcium administration. Celsior did not significantly affect E(max) (6.3 +/- 2.4 in control versus 5.3 +/- 1.3 mm Hg.mL(-1).100 g with Celsior) nor the oxygen cost of Emax (1.2 +/- 0.6 versus 1.6 +/- 0.5 mL O2.mL.mm Hg(-1).beat(-1).100 g(-2), respectively). In contrast, St. Thomas' Hospital and University of Wisconsin solutions significantly decreased Emax (4.5 +/- 1.1 and 3.5 +/- 0.9 mm Hg.mL(-1).100 g, respectively) and increased the oxygen cost of Emax (2.5 +/- 0.8 and 2.4 +/- 0.9 mL O2.mL.mm Hg(-1).beat(-1).100 g(-2), respectively) compared with control and Celsior-preserved hearts. The slope and intercept of the oxygen consumption versus pressure-volume area relation showed no significant difference among the four groups. Celsior showed better protective effects on cardiac mechanoenergetics than St. Thomas' Hospital and University of Wisconsin solutions in the acute phase of heart transplantation.

Left Ventricular Function at Peak All-Out Anaerobic Exercise in Older Men

Background: All-out anaerobic exercise may be dangerous for the older population, due to hypoxia and inappropriate blood pressure response. Objectives: This study compared and evaluated left ventricular function at peak all-out anaerobic effort in 12 well-trained older (58 ± 1 years) and 12 young men (22 ± 1 years). Methods: Subjects were studied by echocardiography at peak all-out anaerobic exercise, on a cycle ergometer. Results: Seven older subjects experienced ECG abnormalities. Significant (p < 0.05) differences between the older group and the young group, respectively, were noted for: cardiac output (9.8 ± 0.9 and 15.8 ± 0.9 l·min^–1), left ventricular end-systolic pressure-volume ratio (4.7 ± 0.8 and 4.4 ± 4.9), left ventricular end-diastolic volume (104.8 ± 6.9 and 125.7 ± 6.2 ml), ejection fraction (67.1 ± 6.0 and 59.8 ± 5.5%), left ventricular end-systolic pressure volume ratio (4.4 ± 0.4 and 4.8 ± 0.3 ratio), and total peripheral resistance (966.0 ± 84.0 and 660 ± 82.8 dyn·s^–1·cm^–5). Conclusions: Data suggest that during all-out anaerobic exercise, forces opposing ejection were not reduced enough to avoid left ventricular dysfunction and ECG abnormalities in the older subjects. This is attributed to functional changes with age in the myocardium and associated blood vessels, leading to impairment of left ventricular function and blunted inotropic and chronotropic responses to catecholamine. Therefore, an all-out anaerobic-type effort should not be given to an older subject due to the great hazardous potential.

The calcium sensitizer levosimendan improves the function of stunned myocardium after percutaneous transluminal coronary angioplasty in acute myocardial ischemia

ObjectivesWe assessed the effects of levosimendan on left ventricular (LV) function in patients with acute myocardial ischemia and after coronary angioplasty. BackgroundThe calcium sensitizer levosimendan improves the function of myocardium in experimental stunning. MethodsTwenty-four patients with an acute coronary syndrome underwent angioplasty followed by double-blinded, randomized treatment with 24 μg/kg of levosimendan (n = 16) or placebo (n = 8). Left ventricular pressures and volumes were recorded by cineventriculography and micromanometer-tipped catheters 10 min after angioplasty before drug administration (baseline) and 20 min after drug administration. Left ventricular function was assessed by the pressure–volume loop, and regional function analysis by the Slager method. ResultsThe number of hypokinetic segments decreased with levosimendan, from 8.9 ± 0.9 to 6.5 ± 1.1 (mean ± SEM), as compared with an increase from 7.8 ± 1.0 to 8.5 ± 1.1 with placebo (p = 0.016). A leftward and/or upward shift of the systolic part of the pressure–volume loop, indicating improved systolic function, was observed in eight of 16 of the levosimendan-treated and one of eight of the placebo patients (p = 0.178). In addition, the single-beat elastance was increased by levosimendan (p = 0.045). The pressure–volume area (p = 0.001), end-systolic pressure (p = 0.002), and volume index (p < 0.001) were decreased by levosimendan, but there was no change in the end-systolic pressure–volume ratio. End-diastolic pressure remained unchanged, whereas the end-diastolic volume index was decreased by levosimendan (p = 0.002). The time constant of isovolumic LV pressure fall decreased with levosimendan (p = 0.001). ConclusionsLevosimendan improved the function of stunned myocardium without obvious impairment of diastolic function.

A new technique for assessing myocardial improvement using pressure-volume loops during mechanical circulatory assistance

Background: Successful mechanical circulatory support (MCS) for end-stage heart failure may lead to LVAD removal without transplantation if cardiac function can be accurately assessed. End-systolic pressure-volume ratio (ESPVR), a load-independent index of myocardial contractility, may be used to predict myocardial improvement. Preload manipulation, required to calculate ESPVR, can be achieved by changing LVAD unloading rate (rpm or beat rate, for continuous flow or pulsatile pumps, respectively).

Temperature-dependent postextrasystolic potentiation and Ca(2+) recirculation fraction in canine hearts.

We have found that cardiac temperature proportionally changes O(2) cost of contractility, defined as O(2) consumption for myocardial total Ca(2+) handling normalized to contractility in terms of the end-systolic pressure-volume ratio (maximal elastance, E(max)), in the canine left ventricle (temperature sensitivity, Q(10) = 2). We have separately found that a decrease in the recirculation fraction (RF) of Ca(2+) within myocardial cells underlies an increased O(2) cost of E(max) in stunned hearts. We therefore hypothesized that a similar change in RF would underlie the Q(10) of O(2) cost of E(max). We tested this hypothesis by analyzing RF calculated from an exponential decay component of the transiently alternating postextrasystolic potentiation in the canine left ventricle. RF decreased from 0.7 to 0.5 as cardiac temperature increased from 33 to 38 degrees C with Q(10) of 0.5, reciprocal to that of O(2) cost of E(max). We conclude that Q(10) of ATP-consuming reactions involved in Ca(2+) handling and E(max) response to it could reasonably account for the reciprocal Q(10) of RF and O(2) cost of E(max).

Left Ventricular-Arterial System Coupling at Peak Exercise in Dilated Nonischemic Cardiomyopathy

We assessed the ventricular-arterial coupling at peak exercise in 20 patients with dilated cardiomyopathy (ejection fraction, 27+/-12%) and 7 normal subjects by radionuclide ventriculography during exercise, coupled with respiratory gas analysis. The end-systolic pressure-volume ratio, taken as an index of contractility, and the effective arterial elastance were calculated at rest and at peak exercise. The end-systolic pressure/volume ratio increased from 3.7+/-2.7 to 6.9+/-4.0 mm Hg/mL at peak exercise in the normal subjects, but did not change significantly (from 0.9+/-0.5 to 1.0+/-0.6 mm Hg/mL) in the patients. Arterial elastance did not change significantly in the patients (+17+/-32%, not significant [NS] vs rest) or in the normal subjects (+22+/-28%, NS vs rest). The change in ejection fraction during exercise correlated both with the end-systolic pressure/volume ratio and with effective arterial elastance changes (r=0.60 and 0.68, respectively). We conclude that ventricular arterial coupling is further altered at peak exercise in these patients because of the lack of increase in contractility and not of altered effective arterial elastance response.

Effects of MCI-154, a calcium sensitizer, on left ventricular systolic and diastolic function in pacing-induced heart failure in the dog.

MCI-154 is a positive inotropic agent that increases the myofilament response to Ca2+. Whether MCI-154 has beneficial effects on left ventricular dysfunction in chronic heart failure is not known. We examined the effects of MCI-154 on left ventricular systolic and diastolic function in pacing-induced heart failure in dogs. We studied eight anesthetized dogs before and 2 to 4 weeks after rapid right ventricular pacing. Left cineventriculograms with simultaneous left ventricular pressures (tip manometer) were obtained before and during intravenous administration of MCI-154 (I.O. microgram.kg-1.min-1 for 15 minutes) in the control and heart-failure states. Left ventricular volume dynamics was derived from frame-by-frame (20-ms) analyses of left ventricular angiograms. In heart failure, left ventricular contractility as assessed by shifts of the end-systolic pressure-volume ratio, evaluated by inferior vena cava occlusion, was improved by MCI-154 (+ 1.94 mm Hg/mL, P < .05) to an extent similar to that in the control state (+2.47 mm Hg/mL, P < .05). MCI-154 also accelerated left ventricular relaxation, assessed by the time constant of isovolumic pressure decay (T1/2), in both states. The absolute decrease in T1/2 with MCI-154 in heart failure was significantly greater than in the control state (-8.2 versus -3.1 ms, P < .05). In heart failure, MCI-154 shifted the left ventricular diastolic pressure-volume relation clearly downward, suggesting increased diastolic distensibility. MCI-154 improved not only left ventricular systolic function but also diastolic relaxation and distensibility in a chronic heart failure model.