Ventricular Pressure-volume Relationship Research Articles

Time course of reverse remodeling of the left ventricle during support with a left ventricular assist device.

Support with a left ventricular assist device leads to normalization of left ventricular chamber geometry, regression of myocyte hypertrophy, alterations in left ventricular collagen content, and normalized expression of genes involved with excitation-contraction coupling in patients with heart failure. The objective of this study was to investigate the time course of these processes. Passive left ventricular pressure-volume relationships were obtained from explanted hearts of 19 patients with heart failure undergoing transplantation without left ventricular assist device support, 25 patients with heart failure supported before transplantation (duration of support ranging between 8 and 155 days), and 5 normal human hearts not suitable for transplantation. Left ventricular size was indexed by the volume at which left ventricular pressure reached 30 mm Hg. Left ventricular tissue samples were probed for sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression and processed for analysis of myocyte diameter and relative myocardial collagen content. The volume at which left ventricular pressure reached 30 mm Hg was not significantly different between hearts without and with assist device support for less than 40 days. However, the volume at which left ventricular pressure reached 30 mm Hg in patients with assist devices supported for more than 40 days was significantly smaller than that of the hearts without assist devices but was larger than that of normal hearts. A similar pattern was observed for myocyte diameter. Sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression increased to normal levels by about 20 days of support with an assist device. Relative collagen content was significantly increased in hearts supported for more than 40 days. Maximum structural reverse remodeling by left ventricular assist devices is complete by about 40 days. Molecular reverse remodeling of sarcoplasmic endoreticular calcium adenosine triphosphatase 2a expression is quicker, being complete by about 20 days.

Left ventricular outflow tract mean systolic acceleration as a surrogate of the slope of the left ventricular end-systolic pressure-volume relationship Fabrice Bauer, Michael Jones, Takahiro Shiota, Michael Firstenberg, Jian Xin Qin, Hiroyuki Tsujino, Yong Jin Kim, Marta Sitges, Lisa Cardon, Arthur D. Zetts, James D. Thomas. The Cleveland Clinic Foundation, Cleveland, OH, The National Institutes of Health, Bethesda, MD

Left ventricular outflow tract mean systolic acceleration as a surrogate of the slope of the left ventricular end-systolic pressure-volume relationship Fabrice Bauer, Michael Jones, Takahiro Shiota, Michael Firstenberg, Jian Xin Qin, Hiroyuki Tsujino, Yong Jin Kim, Marta Sitges, Lisa Cardon, Arthur D. Zetts, James D. Thomas. The Cleveland Clinic Foundation, Cleveland, OH, The National Institutes of Health, Bethesda, MD

Perioperative hemodynamics in patients undergoing partial left ventriculectomy.

Effects of partial left ventriculectomy (PLV) were studied by analyzing perioperative hemodynamics with measurements of left ventricular (LV) pressure-volume (PV) relationships and thermodilution catheter measurements in the pulmonary artery. Between July and October 1996, 43 consecutive patients underwent PLV with and without mitral valvuloplasty with a thermodilution catheter and PV loop analysis immediately before and after surgery. Patients were 52+/-13 years and 67+/-13 kg, with reduced functional capacity (New York Heart Association 3.3+/-0.3) due to cardiomyopathy (24), ischemic disease (13), valvular disease (3), and Chagas' disease (3). PLV required cardiopulmonary bypass for 44+/-24 minutes, with the heart arrested in 10 patients for 26+/-22 minutes for coronary artery bypass grafting (8), aortic valve replacement (2), and autotransplantation (2). Two patients failed to come off bypass, six died in the hospital and 35 (35 [81.4%] of 43) were discharged. Changes in PV loops included decreased end-diastolic and end-systolic volume, resulting in no change in stroke volume. Pulmonary artery wedge pressure decreased despite elevated end-diastolic pressure. Ejection fraction, end-systolic elastance (E-max), afterload recruitable stroke work, and volume intercepts all improved and resulted in similar stroke work with less energy expenditure (less PV area), thus improving myocardial energetic efficiency. Results suggest that PLV improves systolic function but decreases diastolic compliance, which results in reduced net ventricular function immediately after surgery. Thus, immediate hemodynamic improvements appeared to derive from reduced severity in mitral regurgitation and perioperative load manipulation. Improved myocardial energetics may ameliorate LV function and improve the course of underlying myocardial disease.

The role of nitric oxide in the failing heart.

Nitric oxide (NO) has effects on contractility, energetics and gene expression of failing myocardium. Initial studies on isolated cardiomyocytes showed NO to reduce systolic shortening but intracoronary infusions of NO-donors or of NO synthase (NOS) inhibitors failed to elicit changes in baseline LV contractility indices such as LVdP/dt(max). Intracoronary infusions of NO-donors or of substance P, which releases NO from the coronary endothelium, however demonstrated NO to induce a downward displacement of the left ventricular (LV) diastolic pressure-volume relation, consistent with increased LV diastolic distensibility. In end-stage failing myocardium, the increased oxygen consumption is related to reduced NO production and in isolated cardiomyocytes, NO blunts the norepinephrine-induced expression of the fetal gene programme thereby preserving myocardial calcium homeostasis.In dilated cardiomyopathy, changed endomyocardial NOS gene expression has been reported. Because of lower endomyocardial NOS gene expression in patients with higher functional class and lower LV stroke work, increased endomyocardial NOS gene expression seems to be beneficial rather than detrimental for the failing heart. A beneficial effect of increased NOS gene expression could result from NO's ability to increase LV diastolic distensibility, to augment LV preload reserve, to reduce myocardial oxygen consumption and to prevent downregulation of calcium ATPase. Upregulated endomyocardial NOS gene expression has also been reported in athlete's heart and could therefore play a role in physiological LV remodeling. Reduced endomyocardial NO content because of decreased NO or increased superoxide production could lower LV diastolic distensibility and contribute to diastolic heart failure. In many conditions such as aging, hypertension, diabetes or posttransplantation, the increased incidence of diastolic heart failure is indeed paralleled by reduced endothelium-dependent vasodilation.

Pressure–volume relationships in pediatric systolic and diastolic heart failure

The left ventricular pressure–volume relationship has been used to examine ventricular systolic and diastolic function as well as to evaluate myocardial energetics and ventricular–vascular coupling. Preload, afterload and contractility can be separately examined using indices derived from simultaneous pressure and volume measurement. Due to the development of new instrumentation and diagnostic tools, these techniques now can be more readily applied to the evaluation of patients in heart failure. Indices of function can be examined on-line during diagnostic cardiac catheterization. Pharmacologic interventions can be evaluated using these methods, allowing for assessment of therapeutic interventions. Medical therapy can be optimized during these studies, allowing more effective and individualized treatment.

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)

Computerized left ventricular pressure-volume relationships (pV-loops) using disposable angiographic tip transducer pigtail catheters.

Left ventricular pressure-volume relationships expressed as pV loops could yield important hemodynamic information in the cardiac catheterization laboratory. Many clinical situations might benefit from a quantitative assessment of left ventricular function. Potential applications of pV loops include the assessment of vasoactive and inotropic drugs, balloon valvuloplasty, coronary angioplasty, and surgical treatment of valvular heart disease. For many years the clinical use of pV loops has been hindered by logistical difficulties. The ability to merge on-line concurrent digital imaging data for computation of left ventricular volume and digital left ventricular pressure wave forms obtained from high fidelity tip-transducer angiocatheters has allowed us to develop a technique which can generate pV loops during cardiac catheterization procedures. The method offers an automated measurement of left ventricular volume independent of edge detection or an interactive technique for tracing endocardial borders by a trained operator. Illustrative case studies are included to demonstrate the potential of the method during ventricular angiographic procedures. Implementation and computational time requirements of the method are discussed. The concept and the value of pV loop generation to study left ventricular performance has been known for many years. Combining digital imaging and digital physiologic data obtained with disposable tip-transducer angiocatheters with modern networking technology, the technique can more easily be applied to catheterization procedures and could enhance invasive hemodynamic assessment of left ventricular function.

The effects of a new ultra-short-acting beta-adrenergic blocker, ONO-1101, on cardiac function during and after cardiopulmonary bypass.

The administration of an ultra-short-acting beta-adrenergic antagonist, esmolol, has been introduced as a novel method for beating-heart surgery. In the present study, a new ultra-short-acting beta-blocker, ONO-1101, was administered during cardiopulmonary bypass (CPB) to investigate its effects on cardiac function and hemodynamics. Nine adult mongrel dogs underwent 60 min of CPB during which they were given either ONO-1101 (ONO group; n = 4) or saline (control group; n = 5). In the ONO group, the hearts became flaccid enough for surgery to be performed without cardiac standstill within 10 min after the commencement of ONO-1101 with significant decreases in the heart rate, the preload recruitable stroke work (PRSW), and the slope of the end-systolic left ventricular pressure-volume relationship (Emax). The mean arterial pressure and systemic vascular resistance also decreased, but were maintained above 50 mmHg during CPB without catecholamine. These indices increased to the control group level 20 min after the discontinuation of ONO-1101. The serum concentration of ONO-1101 decreased from the maximum level of 121 +/- 15 microg/ml soon after infusion to 11 +/- 5 microg/ml within 30 min after discontinuation. These data suggest that ONO-1101 may be useful to enable beating-heart surgery to be performed without aortic cross-clamp as an ultra-short-acting beta-adrenergic blocker.

Diastolic compliance is reduced in obese rabbits.

Obesity often leads to symptoms of cardiopulmonary congestion associated with normal systolic but abnormal diastolic function. This study analyzed alterations in passive diastolic compliance in obesity using the rabbit model. New Zealand White rabbits were fed a normal (n=8) or 10% added fat diet (n=8). After 12 weeks, rabbits fed the high fat diet developed obesity (5.34+/-0.11 versus 3.68+/-0. 04 kg, P</=0.05) and left ventricular hypertrophy (1.37+/-0.07 versus 0.98+/-0.03 g dry weight, P</=0.05). Compliance was assessed with the isolated heart preparation by analyzing the passive end-diastolic left ventricular pressure-volume relationship. The pressure-volume relation was fit to an exponential function by regression analysis; results showed that the modulus of stiffness was greater in obese than in lean rabbits (1.21+/-0.16 versus 0. 83+/-0.05, P</=0.05), indicating that diastolic compliance was reduced. Computer simulation analyses suggested that an isolated reduction in diastolic compliance may contribute to elevated cardiac filling pressures and exercise intolerance. These data suggest that diastolic compliance is reduced early in the development of obesity and may be an important component in the reduction of cardiac reserve in obesity.

External cardiac pressures and the left ventricular pressure-volume relationship

Wide variations in external cardiac pressures are known to occur in clinical situations and can have significant effects on cardiac performance [1,2]. We designed an experimental situation where external cardiac pressure conditions were controlled and adjusted to physiological extremes to mimic clinically relevant situations, while cardiac performance was assessed using left ventricular pressure-volume relationships (LVPVR) which are relatively preload and afterload independent.

Coupled systolic-ventricular and vascular stiffening with age: Implications for pressure regulation and cardiac reserve in the elderly

Objectives. We tested the hypothesis that age-related arterial stiffening is matched by ventricular systolic stiffening, and that both enhance systolic pressure sensitivity to altered cardiac preload.Background. Arterial rigidity with age likely enhances blood pressure sensitivity to ventricular filling volume shifts. Tandem increases in ventricular systolic stiffness may also occur and could potentially enhance this sensitivity.Methods. Invasive left ventricular pressure-volume relations were measured by conductance catheter in 57 adults aged 19 to 93 years. Patients had normal heart function and no cardiac hypertrophy and were referred for catheterization to evaluate chest pain. Twenty-eight subjects had normal coronary angiography and hemodynamics, and the remaining had either systolic hypertension or coronary artery disease without infarction. Data recorded at rest and during transient preload reduction by inferior vena caval obstruction yielded systolic and diastolic left ventricular chamber and effective arterial stiffness and pulse pressure.Results. Left ventricular volumes, ejection fraction and heart rate were unaltered by age, whereas vascular load and stiffening increased (p < 0.008). Arterial stiffening (Ea) was matched by increased ventricular systolic stiffness (Ees): Ees=0.91·Ea+0.53, (r = 0.50, p < 0.0001), maintaining arterial-heart interaction (Ea/Eesratio) age-independent. Ventricular systolic and diastolic stiffnesses correlated (r = 0.51, p < 0.0001) and increased with age (p < 0.03). Both ventricular and vascular stiffening significantly increased systolic pressure sensitivity to cardiac preload (p < 0.006).Conclusions. Arterial stiffening with age is matched by ventricular systolic stiffening even without hypertrophy. The two effects contribute to elevating systolic pressure sensitivity to altered chamber filling. In addition to recognized baroreflex and autonomic dysfunction with age, combined stiffening could further enhance pressure lability with diuretics and postural shifts in the elderly.

Optimal preload adjustment of maximal ventricular power index varies with cardiac chamber size

Background Maximal left ventricular power (PWRmax) can index contractile function and reserve; however, its marked preload dependence mandates load adjustment to yield a more cardiac-specific measurement. Prior studies have used varying methods, but supporting data have generally been lacking. We hypothesized that the optimal approach for preload adjustment varies with ventricular volume (particularly end-systolic volume) and is significantly different for dilated hearts with reduced left ventricular function compared with small to normal-sized hearts with normal systolic function.Methods Left ventricular pressure-volume relations were measured by the conductance catheter method in 36 patients, with preload altered by inferior vena cava obstruction. Patients with normal ventricles (n = 16), hypertrophy or mitral stenosis (n = 12), and dilated cardiomyopathy (n = 8) were divided into three groups based on resting end-diastolic volume: group 1, 66.3 ± 12; group 2, 118.1 ± 20; and group 3, 218.2 ± 48 ml. PWRmax was the maximal product of simultaneous left ventricular pressure and rate of volume change. PWRmax end-diastolic volume (EDV) data were fit to a power function, PWRmax = αEDVβ (where α is a scaling factor and β is the power coefficient), and the preload sensitivity of β and PWRmax/EDVβ ratios (β = 1, 2, or best fit) were compared.Results β Varied directly with chamber size: β = 0.004 · (EDV + 0.56), r = 0.65, p < 0.0001. However, it was equally well approximated by 1.0 in groups 1 and 2 (ESV <75 ml, EF >40%), whereas β = 2 was more appropriate in group 3.Conclusion PWRmax/EDV provides adequate preload independence in all but dilated hearts with reduced LV function, whereas PWRmax/EDV2 is required in the latter. These data should help clinical application of a noninvasive PWRmax index for assessing chamber contractility and contractile reserve in human beings. (Am Heart J 1998;136:281-88.)

In vivo murine left ventricular pressure-volume relations by miniaturized conductance micromanometry.

The mouse is the species of choice for creating genetically engineered models of human disease. To study detailed systolic and diastolic left ventricular (LV) chamber mechanics in mice in vivo, we developed a miniaturized conductance-manometer system. alpha-Chloralose-urethan-anesthetized animals were instrumented with a two-electrode pressure-volume catheter advanced via the LV apex to the aortic root. Custom electronics provided time-varying conductances related to cavity volume. Baseline hemodynamics were similar to values in conscious animals: 634 +/- 14 beats/min, 112 +/- 4 mmHg, 5.3 +/- 0.8 mmHg, and 11,777 +/- 732 mmHg/s for heart rate, end-systolic and end-diastolic pressures, and maximum first derivative of ventricular pressure with respect to time (dP/dtmax), respectively. Catheter stroke volume during preload reduction by inferior vena caval occlusion correlated with that by ultrasound aortic flow probe (r2 = 0.98). This maneuver yielded end-systolic elastances of 79 +/- 21 mmHg/microliter, preload-recruitable stroke work of 82 +/- 5.6 mmHg, and slope of dP/dtmax-end-diastolic volume relation of 699 +/- 100 mmHg.s-1.microliter-1, and these relations varied predictably with acute inotropic interventions. The control normalized time-varying elastance curve was similar to human data, further supporting comparable chamber mechanics between species. This novel approach should greatly help assess cardiovascular function in the blood-perfused murine heart.

Retrograde Coronary Perfusion: Effects on Iatrogenic Edema and Diastolic Properties

Background. The relative merits of antegrade infusion and retrograde infusion of cardioplegic solution in terms of heart weight, myocardial water content, and ventricular diastolic properties are undefined. Accordingly, we compared antegrade and retrograde flow of hemodiluted blood in isolated, hypothermic porcine hearts. Methods. After cardiectomy, 1 L of cold heparinized blood diluted with lactated Ringer’s solution to concentrations ranging from 100% lactated Ringer’s to 50% lactated Ringer’s and 50% blood was perfused in an antegrade (n = 6) or retrograde (n = 6) fashion at mean pressures of 62 ± 2 mm Hg (± standard error of the mean) and 49 ± 2 mm Hg, respectively. Heart weight, myocardial water content, and left ventricular pressure–volume relationships were obtained before and after perfusion. Results. In the comparison of measurements before and after perfusion, changes in heart weight (36 ± 4 g versus 5 ± 2 g; p < 0.05), myocardial water content (6.9% ± 1.0% versus 2.5% ± 0.4%; p < 0.01), and ventricular filling measured by normalized left ventricular volume at 10, 15, and 20 mm Hg were greater in the antegrade group. Conclusions. In the isolated porcine heart, retrograde flow is distinguished from antegrade flow by less change in heart weight and myocardial water content and no diastolic dysfunction.

Effects of hyperoxic ventilation on hemodilution-induced changes in anesthetized dogs.

In subjects who have undergone acute preoperative normovolemic hemodilution (ANH), intraoperative hemorrhage is generally treated by immediate return of autologous blood collected during ANH. Simply increasing blood oxygen content by hyperoxic ventilation (HV, inspiratory fraction [FIO2] 1.0) might compensate for the acute anemia, allow further ANH, and delay onset of autologous blood return. This study 1) evaluated the effects of HV (FIO2 1.0) upon ANH to a hemoglobin (Hb) concentration of 7 g per dL in anesthetized dogs ventilated with room air and 2) compared the effects of subsequent profound ANH (Hb, 3 g/dL) with and without an intravenous perfluorocarbon emulsion (perflubron 60% wt/vol) versus those of autologous red cell transfusion. The results of the entire study are presented in two parts. Organ tissue oxygenation was assessed in skeletal muscle and liver, and systemic oxygenation status was evaluated. Myocardial contractility was deduced from left ventricular pressure-volume relationship. Seven of 22 dogs underwent further hemodilution while breathing 100-percent O2, for a determination of the Hb concentration at which HV-induced effects were abolished. HV completely reversed the ANH-induced increase in cardiac index (4.6 +/- 0.7 vs. 3.8 +/- 0.9 L/min/m2 before and during HV; p < 0.05) and partially reversed the decrease in systemic vascular resistance (1784 +/- 329 vs. 2087 +/- 524 dyn x cm-5 x sec x m-2; p < 0.05). Despite unchanged global O2 delivery, organ tissue oxygenation improved during HV (mixed venous partial pressure of O2: 40 +/- 3 vs. 59 +/- 7 torr; coronary venous pressure of O2: 30 +/- 4 vs. 43 +/- 6 torr; p < 0.05; liver surface: 31 +/- 11 vs. 39 +/- 13 torr; skeletal muscle surface: 30 +/- 14 vs. 41 +/- 22 torr; p < 0.05). This improvement was due to an increased contribution of physically dissolved O2 in plasma to O2 delivery (3.2 +/- 0.2% before HV vs. 14.6 +/- 1% during HV; p < 0.05) and O2 consumption (whole body: 6 +/- 1% vs. 47 +/- 8%, p < 0.05; myocardium: 4.3 +/- 0.9% vs. 31 +/- 6%, p < 0.05). The beneficial effects of HV were lost after an additional volume-compensated exchange of 19 percent of blood volume (Hb, 5.6 g/dL). In anesthetized dogs ventilated with room air and hemodiluted to a Hb of 7 g per dL, simple oxygen therapy by HV (FIO2 1.0) rapidly improves tissue oxygenation and permits extended hemodilution to Hb of 5.8 g per dL until the HV-induced effects are lost.

Endothelin receptor blockade improves left ventricular pressure-volume relationships without altering the hypertrophic response during congestive heart failure in rats

Endothelin receptor blockade improves left ventricular pressure-volume relationships without altering the hypertrophic response during congestive heart failure in rats

Left ventricular pressure-volume relationships before and after cardiomyoplasty in patients with heart failure.

The aim of this study was to elucidate whether beneficial effects of cardiomyoplasty (CMP) in patients with dilated cardiomyopathy are the result of a decrease in existing ventricular dilatation or a prevention of further dilatation. Combined micromanometer-conductance catheters were used to evaluate left ventricular pressure-volume relationships in six patients with dilated cardiomyopathy before and at 6 and 12 months after CMP. Acute changes in preload and afterload were induced by a standardized leg-tilting intervention and a bolus infusion of nitroglycerin. After CMP, end-diastolic volume (EDV) decreased from 138+/-10 to 103+/-18 mL/m2 (P<.01) at 6 months and to 83+/-17 mL/m2 (P<.01) at 12 months. End-diastolic pressure (EDP) decreased from 20.2+/-6.4 to 13.9+/-7.7 mm Hg (P<.01) at 6 months after CMP. Peak ejection rate and ejection fraction increased at 6 months after CMP from 594+/-214 to 799+/-214 mL/s (P<.05) and from 26.6+/-4.7% to 40.1+/-8.3% (P<.05), respectively. Peak dP/dt decreased at 12 months after CMP from -842+/-142 to -712+/-168 mm Hg/s (P<.05). Leg-tilting before CMP increased EDP from 20.2+/-6.4 to 25.6+/-5.2 mm Hg (P<.01), end-systolic pressure (ESP) from 118+/-17 to 122+/-17 mm Hg (P<.05), and tau from 50.8+/-2.8 to 53.8+/-2.3 ms (P<.05). Six months after CMP, leg-tilting also increased EDV from 103+/-18 to 110+/-22 mL/m2 (P<.05) and ESV from 62+/-14 to 66+/-14 mL/m2 (P<.05). Before CMP, nitroglycerin decreased EDP from 20.2+/-6.4 to 10.4+/-3.8 mm Hg (P<.01), ESP from 118+/-17 to 96+/-11 mm Hg (P<.05), ESV from 100+/-11 to 89+/-7 mL/m2 (P<.05), and tau from 50.8+/-2.8 to 44.5+/-3.7 ms (P<.05). Six months after CMP, nitroglycerin decreased EDP, ESP, and tau to similar values. Our findings show that up to 1 year after CMP, marked decreases in left ventricular volume are present. Our measurements suggest that CMP actively reduced the dilated ventricle but did not prevent a higher EDV on an increased venous return. The latissimus dorsi muscle wrap contraction results in better synchronization of contraction and more rapid emptying of the left ventricle.

A Stable Ovine Congestive Heart Failure Model A Suitable Substrate for Left Ventricular Assist Device Assessment

Similarities in coronary circulation and heart size of sheep to that of humans are specific advantages of a sheep model of congestive heart failure (CHF). CHF was created in 11 sheep (51 +/- 4 kg) by selective sequential intracoronary injection of 90 microns microspheres under 1.5% isoflurane anesthesia. Hemodynamic characteristics were assessed at baseline, 4 weeks after establishment of CHF (ejection fraction [EF] < 35%, n = 11), and 26 weeks (n = 7) later. Baseline echocardiographic EF was 59 +/- 5% and fell to 26 +/- 5% after 5 +/- 2 embolizations. The left ventricular (LV) pressure-volume relationship showed stable decreases in LV end-systolic elastance (Ees) and preload recruitable stroke work. Intravenous infusion of dobutamine increased Ees from 2.8 +/- 1.7 to 4.3 +/- 2.2 and 4.5 +/- 1.4 mmHg/ml at heart rates of 140 and 160/min, respectively, at baseline. Increases of Ees (from 1.3 +/- 0.5 to 2.3 +/- 0.7 and 1.9 +/- 0.5 mmHg/ml at heart rates of 140 and 160/min, respectively) with dobutamine under CHF conditions did not exceed Ees values at baseline without dobutamine. This response to dobutamine infusion did not change 26 weeks after establishment of CHF. This stable ovine CHF model is proposed for studies on the long-term effects of cardiac assist devices.

Oxygen-Saving Effect of a New Cardiotonic Agent, MCI-154, in Diseased Human Hearts

Objectives. The aim of this study was to examine the left ventricular mechanoenergetic effects of a novel Ca2+sensitizing agent, MCI-154, on diseased human hearts compared with dobutamine.Background. Unlike conventional cardiotonic agents, a Ca2+sensitizer that could produce a positive inotropic action by altering the responsiveness of myofilament to Ca2+could generate force with smaller amounts of Ca2+; thus, it may potentially save energy expenditure.Methods. The left ventricular pressure-volume relation and myocardial oxygen consumption per beat (Vo2) were measured by a conductance (volume) catheter and a Webster catheter. Left ventricular contractility (Emax), systolic pressure-volume area (PVA [index of left ventricular total mechanical energy]) and Vo2were assessed before and after infusion of MCI-154 or dobutamine. The PVA-independent Vo2(Vo2mainly for excitation-contraction coupling) was assessed as the Vo2at zero PVA.Results. Both agents increased Emax comparably (dobutamine: from 3.55 ± 1.10 [mean ± SD] to 5.04 ± 1.16 mm Hg/ml per m2, p < 0.0001; MCI-154: from 3.36 ± 1.26 to 5.37 ± 2.14 mm Hg/ml per m2, p < 0.0001); dobutamine increased total Vo2(from 0.22 ± 0.08 to 0.27 ± 0.09 ml O2, p < 0.05) and PVA-independent Vo2(from 0.019 ± 0.019 to 0.091 ± 0.051 ml O2, p < 0.005); but MCI-154 did not change these variables significantly. Consequently, the oxygen cost of contractility (ΔPVA-independent Vo2/ΔEmax) was less with MCI-154 than with dobutamine (0.14 ± 0.18 vs. 1.10 ± 0.80 J/mm Hg per ml per m2, p < 0.05).Conclusions. These results suggest that the cardiotonic action mediated by MCI-154 could provide an energetic advantage over the conventional cardiotonic action with currently used inotropic agents.(J Am Coll Cardiol 1997;29:613–22)

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.