Preload Recruitable Stroke Work Slope Research Articles

Exploring the mechanisms responsible for afterload mismatch in severe aortic stenosis

Abstract Introduction Afterload mismatch (AM) is defined as a reduced ejection fraction (EF) in the setting of severe aortic stenosis (AS) (aortic valve area (AVA) of < 1cm2), but with transaortic pressure gradients in the severe range. The pathomechanism underlying the impaired EF remains unclear, especially with regards to the impact of ventricular hypertrophy and fibrosis, the role of afterload, and the integrity of the intrinsic contractile myocardial strength in AM. This knowledge gap unmasks a lack of understanding into the natural disease progression in AS. Purpose To characterise the morphological and functional contractile mechanics that distinguishes patients with reduced EF from patients with preserved EF in the setting of AS with high transvalvular gradients. Methods A prospective comparative analysis was performed on 21 sequential cases of patients with severe AS, 9 with AM (AVA < 1.0cm2; MG > 40mmHg; EF < 50%) and 12 with normal flow high gradient (NFHG) AS (AVA < 1.0cm2; MG > 40mmHg; EF > 50%). Patients with concomitant valve lesions or previously diagnosed myocardial infarction, were excluded. Myocardial morphology, function and tissue characteristics were evaluated using a) transthoracic echocardiography, b) cardiac magnetic resonance imaging, and c) an invasive hemodynamic study with pressure-volume loop derived data. Results Intrinsic load independent contractile muscle function parameters were similar between AM and NFHG AS (p-value non-significant for cardiac index, dP/dT(max), preload recruitable stroke work slope, end systolic pressure volume relationship slope and Starling contractile index slope). Afterload indices as assessed by peak systolic wall stress and valvuloarterial impedance were significantly higher in AM cases compared to NFHG AS (32.5 vs 19.9 N/cm2; p < 0.01 and 4.8 vs 3.4mmHg/ml; P = 0.05). This was driven by disproportionally higher degrees of valvular stenosis in the AM group (valve area 0.46 vs 0.78cm2; p < 0.01). The AM group expressed a more advanced disease phenotype with more symptoms (NYHA 3.3 vs 2.3; p=0.02), more pulmonary hypertension (50 vs 30mmHg; p=0.04), and more extensive myocardial fibrosis (24% vs 13% of left ventricular mass; p=0.03) (see Figure 1). Neither more severe LVH nor higher degrees of fibrosis in the AM group, was associated with a demonstrable impairment in the intrinsic contractile muscle function. Conclusion Our data suggest that the central problem in AM is related to an excessively increased afterload, primarily driven by more severe valvular stenosis, with preserved intrinsic left ventricular contractile function. AM is characterised by more severe myocardial fibrosis, as a marker of a more advanced disease phenotype, but this did not translate into worse intrinsic contractile muscle function. The known time dependence of progressive valvular stenosis and myocardial fibrosis would suggest that AM is an intermediate phase between NFHG AS and so-called low flow low gradient severe AS.A more advanced phenotype

Exploring the mechanisms responsible for reduced systolic function in high-gradient aortic stenosis

ObjectiveTo characterise the mechanics responsible for the reduced ejection fraction (rEF) in high-gradient severe aortic stenosis (AS).Methods21 patients with high-gradient severe AS (aortic valve area (AVA) <1.0 cm2 and mean...

Left atrial conduit flow rate at baseline and during exercise: an index of impaired relaxation in patients with heart failure and preserved ejection fraction

Abstract Introduction In healthy subjects, adrenergic stimulation augments left ventricular (LV) long-axis shortening/lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). Purpose We hypothesized that exercise in HFpEF would similarly impair passive LV filling in early-mid diastole, during conduit flow from pulmonary veins. Methods Twenty HFpEF patients (67.8±9.8 years; 11 women), diagnosed according to 2007 ESC recommendations, underwent ramped semi-supine bicycle exercise to submaximal target heart rate (∼100) or symptoms. Seventeen asymptomatic subjects (64.3±8.9 years; 7 women) served as controls. Simultaneous LA and LV volumes were measured from pyramidal 3D echocardiographic full-volume datasets acquired from apical window at baseline and during stress, together with brachial arterial pressure. LA conduit function was computed, from minimum LV volume to ECG P wave, as [LV volume (time) – LV minimum volume] – [LA maximum volume – LA volume (time)] and expressed as average flow rate. The slope of the single-beat preload recruitable stroke work (PRSW) quantified LV inotropic state. Results There were divergent responses in conduit flow rate, which increased by 40% during exercise in control subjects (+17.8±37.3 ml/s) but decreased by 18% in patients with HFpEF (−9.6±42.3 ml/s) (p=0.046); increments during stress correlated with PRSW slope changes (p=0.003). Conclusion In HFpEF conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with LV inotropic state changes, thereby contributing to impaired stroke volume reserve. Conduit flow can be measured as a marker of LV relaxation. Funding Acknowledgement Type of funding sources: None.

Left atrial conduit flow rate at baseline and during exercise: an index of impaired relaxation in HFpEF patients.

AimsIn healthy subjects, adrenergic stimulation augments left ventricular (LV) long‐axis shortening and lengthening, and increases left atrial (LA) to LV intracavitary pressure gradients in early diastole. Lower increments are observed in patients with heart failure with preserved ejection fraction (HFpEF). We hypothesized that exercise in HFpEF would further impair passive LV filling in early‐mid diastole, during conduit flow from pulmonary veins.Methods and resultsTwenty HFpEF patients (67.8 ± 9.8 years; 11 women), diagnosed using 2007 ESC recommendations, underwent ramped semi‐supine bicycle exercise to submaximal target heart rate (∼100 bpm) or symptoms. Seventeen asymptomatic subjects (64.3 ± 8.9 years; 7 women) were controls. Simultaneous LA and LV volumes were measured from pyramidal 3D‐echocardiographic full‐volume datasets acquired from an apical window at baseline and during stress, together with brachial arterial pressure. LA conduit flow was computed from the increase in LV volume from its minimum at end‐systole to the last frame before atrial contraction (onset of the P wave), minus the reduction in LA volume during the same time interval; the difference was integrated and expressed as average flow rate, according to a published formula. The slope of single‐beat preload recruitable stroke work (PRSW) quantified LV inotropic state. 3D LV torsion (rotation of the apex minus rotation of the base divided by LV length) was also measurable, both at rest and during stress, in 10 HFpEF patients and 4 controls. There were divergent responses in conduit flow rate, which increased by 40% during exercise in controls (+17.8 ± 37.3 mL/s) but decreased by 18% in patients with HFpEF (−9.6 ± 42.3 mL/s) (P = 0.046), along with congruent changes (+1.77 ± 1.13°/cm vs. −1.94 ± 2.73°/cm) in apical torsion (P = 0.032). Increments of conduit flow rate and apical torsion during stress correlated with changes in PRSW slope (P = 0.003 and P = 0.006, respectively).ConclusionsIn HFpEF, conduit flow rate decreases when diastolic dysfunction develops during exercise, in parallel with changes in LV inotropic state and torsion, contributing to impaired stroke volume reserve. Conduit flow is measurable using 3D‐echocardiographic full‐volume atrio‐ventricular datasets, and as a marker of LV relaxation can contribute to the diagnosis of HFpEF.

Study of the time-relationship of the mechano-electrical interaction in an animal model of tetralogy of Fallot: implications for the risk assessment of ventricular arrhythmias.

The long-term outcome of tetralogy of Fallot (TOF) is determined by progressive right ventricular (RV) dysfunction through pulmonary regurgitation (PR) and the risk of malignant arrhythmia. Although mechano-electrical coupling in TOF is well-known, its time effect on the inducibility of arrhythmia remains ill-defined. The goal of this study was to investigate the mechano-electrical properties at different times in animals with chronic PR. PR was induced by a transannular patch with limited RV scarring in infant pigs. Haemodynamic assessment included biventricular pressure-volume loops after 3 (n = 8) and 6 months (n = 7) compared to controls (n = 5). The electrophysiological study included endocardial monophasic action potential registration, intraventricular conduction velocity and induction of ventricular arrhythmia by burst pacing. Progressive RV dilation was achieved at 6 months (RV end-diastolic volume 143 ± 13 ml/m2-RV end-systolic volume 96 ± 7 ml/m2; P < 0.001), in association with depressed RV contractility (preload recruitable stroke work-slope: 19 ± 1 and 11 ± 3 Mw.ml-1.s-1 for control and 6 m; P < 0.001) and left ventricular contractility (preload recruitable stroke work-slope: 60 ± 13 and 40 ± 11 Mw.ml-1.s-1 for control and 6 m; P = 0.005). Concomitant to QRS prolongation, monophasic action potential90-duration and dispersion at the RV and left ventricle were increased at 6 months. Intraventricular conduction was delayed only in the RV at 6 months (1.8 ± 0.2 and 2.4 ± 0.6 m/s for group 6M and the control group; P = 0.035). Sustained ventricular arrhythmias were not inducible. In animals yielding the sequelae of a contemporary operation for TOF, mechano-electrical alterations are progressive and affect predominantly the RV after midterm exposure of PR. Because ventricular arrhythmias were not inducible despite significant RV dilation, the data suggest that the haemodynamic RV deterioration effectively precedes the risk of inducing sustained arrhythmia after TOF repair and opens a window for renewed stratification of contemporary risk factors of ventricular arrhythmias in patients operated on with currently used pulmonary valve- and RV-related techniques.

Role of myocardial hypertrophy on acute and chronic right ventricular performance in relation to chronic volume overload in a porcine model: Relevance for the surgical management of tetralogy of Fallot

The age for correction of tetralogy of Fallot has progressively declined to the postnatal period, often despite an increased rate of transannular patch repair. However, the long-term effect of premature exposure to chronic pulmonary insufficiency on the right ventricle remains unknown. On the basis of the relationship between the duration of pressure overload and age, the role of previous pressure load-related hypertrophy on right ventricular (RV) performance after chronic volume overload was investigated in a porcine model. RV hypertrophy (RVH), induced by pulmonary artery banding, was studied in pigs with (RVH plus pulmonary insufficiency [PI]) and without (RVH) subsequent PI. The effect of volume overload was compared between these 2 groups and pigs without RVH but with PI and controls (sham). Both acute and chronic effects on RV function were studied using conductance technology and validated using echocardiography. After chronic volume overload, the end-systolic and end-diastolic volumes were smaller in the RVH+PI group than in the PI group, including a lower pulmonary regurgitation fraction (25% ± 5% vs 35% ± 5%; P = .002). RVH resulted in better preserved systolic function, confirmed by an increased preload recruitable stroke work slope (14.7 ± 1.8 vs 9.3 ± 1.3 Mw.s/mL; P = .025) and higher RV ejection fraction (51% ± 3% vs 45% ± 4%; P = .05). Myocardial stiffness was impaired in the RVH+PI group versus the PI group (β, 0.19 ± 0.03 vs 0.12 ± 0.02 mL(-1); P = .001), presenting restrictive physiology only in the condition associating RVH and PI. The results of the present study have demonstrated that RVH attenuates the RV remodeling process related to chronic PI. It enables better preservation of contractility but at the cost of sustained diastolic impairment. These findings might help to determine the timing and strategy for repair of tetralogy of Fallot when RV outflow tract morphology indicates a definite need for transannular reconstruction.

Test of the Usefulness of a Paradigm to Identify Potential Cardiovascular Liabilities of Four Test Articles With Varying Pharmacological Properties in Anesthetized Guinea Pigs

The evaluation of proarrhythmic and hemodynamic liabilities for new compounds remains a major concern of preclinical safety assessment paradigms. Contrastingly, albeit functional liabilities can also translate to clinical morbidity and mortality, lesser preclinical efforts are focused on the evaluation of drug-induced changes in inotrope and lusitrope, particularly in the setting of concomitant hemodynamic/arrhythmic liabilities. This study aimed to establish the feasibility of an anesthetized guinea pig preparation to assess functional liabilities in the setting of simultaneous drug-induced electrocardiographic/hemodynamic changes, by evaluating the effects of various compounds with known cardiovascular properties on direct and indirect indices of left ventricular function. In short, twenty nine male guinea pigs were instrumented to measure electrocardiograms, systemic arterial pressure, and left ventricular pressure-volume relationships. After baseline measurement, all animals were given intravenous infusions of vehicle and two escalating concentrations of either chromanol 293B (n = 8), milrinone (n = 6), metoprolol (n = 7), or nicorandil (n = 8) for 10 minutes each. In all cases, these compounds produced the expected changes. The slope of preload-recruitable stroke work (PRSW), a pressure-volume derived load independent index, was the most sensitive marker of drug-induced changes in inotropy. Among the indirect functional indices studied, only the "contractility index" (dP/dtmax normalized by the pressure at its occurrence) and the static myocardial compliance (ratio of end diastolic volume and pressure) appeared to be adequate predictors of drug-induced changes in inotropy/lusitropy. Overall, the data confirms that both electrophysiological and mechanical liabilities can be accurately assessed in an anesthetized guinea pig preparation.

D011 Mesenchymal stem cells engineered to overexpress stem cell factor improve cardiac function but have malignant potential

Myocardial infarction (MI) in mice with mutations in the stem cell factor (SCF) receptor causes rapid heart failure. Implantation of mesenchymal stem cells (MSC) slows progression to heart failure after MI. We hypothesized that MSC engineered to over-express SCF would restore cardiac function better than unmodified MSC. MSC from C57Bl/6 mice bone marrow were transfected with SCF cDNA cloned into pcDNA-3, and a stable transfectant was selected in G418 medium. C57Bl/6 mice (N) underwent coronary ligation and received medium (M), or 3×105 MSC (C) or MSC transfected with SCF (CS) into the anterior left ventricle. Cardiac function was assessed by pressure-volume (PV) loops on day 28 (n=10 per group). Hearts were perfusion-fixed in situ and cut into transverse sections for computerized planimetry (n = 5 per group). When measured in vivo, myocardial SCF increased 2.9-fold in M, 5.5-fold in C, and 17.3-fold in SC groups compared to the N group (P<0.05). All analysis showed significant improvement of post MI ventricular size and function in cell groups compared to M group. PV loop analysis showed a 1.9-fold increase (P < 0.001) in the slope of preload-recruitable stroke work in CS group compared with C group. The improvement in end-systolic elastance was similar to the improvement in preload-recruitable stroke work. In addition, the left ventricular volume was 0.6-fold smaller (P<.01) in the CS group compared with the C group. However 4 out of 20 survivors in CS group developed fibrosarcomas infiltrating into the cell transplanted area within 3 months of cell implantation. Use of genetically modified MSC over-expressing SCF better prevented ventricular dilation and restored cardiac function following MI. Unfortunately, this approach was associated with tumorogenesis and our data strongly suggests that malignant transformation was caused by the specific combination of techniques that we used to generate our cell line.

Non-Elastic Deformation of Myocardium in Low-Flow Ischemia and Reperfusion: Ultrastructure–Function Relations

This study tested the hypothesis that regional low-flow ischemia and reperfusion alter myocardial material properties by causing non-elastic deformation. Twenty-two anesthetized, open-chest pigs were studied. Pigs underwent 90 min of regional low-flow ischemia (anterior LV subendocardial blood flow 29±7% of baseline) followed by 90 min reperfusion. LV pressure and regional subendocardial segment length were recorded to derive end-diastolic pressurevssegment length (EDPvsEDL) and preload-recruitable stroke work (PRSW) relations.In vivo, non-elastic myocardial deformation was inferred from increases in minimally loaded myocardial dimensions: the EDL at zero EDP (L0) and the EDL at which no regional external work was performed (Lw, the PRSW intercept). In 15 pigs, ultrastructural confirmation of non-elastic deformation was obtained from sarcomere dimensions measured by transmission electron microscopy afterin situperfusion fixation under non-ischemic conditions, after 90 min ischemia, or after 90 min ischemia plus 90 min reperfusion. Ischemia increased L0and Lwto 1.17±0.05 and 1.13±0.04 times baseline, respectively. After reperfusion, L0and Lwremained increased to 1.09±0.03 and 1.15±0.02 times baseline (allP<0.05). After reperfusion, PRSW slope was not different from baseline, but regional external work remained depressed (0.38±0.03 times baseline) due to the persistent increase in Lw. Neither L0nor Lwchanged in the posterior (non-ischemic) region. In hearts fixed after ischemia or after ischemia plus reperfusion, sarcomere length was significantly greater and transverse distance between thick myofilaments was significantly smaller in the anterior (ischemic) subendocardium than in the posterior (non-ischemic) subendocardium (P<0.01). We conclude that regional low-flow ischemia and reperfusion cause non-elastic deformation of myocardium, manifestin vivoby increased minimally loaded myocardial dimensions (L0and Lw) and ultrastructurally by increased sarcomere length and decreased transverse interfilament distance. Non-elastic deformation of myocardium may contribute to contractile dysfunction in low-flow ischemia and reperfusion.

Cardiovascular effects of xenon in isoflurane-anesthetized dogs with dilated cardiomyopathy.

Clinical interest in xenon has been rekindled recently by new recycling systems that have decreased its relative cost. The cardiovascular effects of xenon were examined in isoflurane-anesthetized dogs before and after the development of rapid left ventricular (LV) pacing-induced cardiomyopathy. Dogs (n = 10) were chronically instrumented to measure aortic and LV pressure, LV subendocardial segment length, and aortic blood flow. Hemodynamics were recorded, and indices of LV systolic and diastolic function and afterload were determined in the conscious state and during 1.5 minimum alveolar concentration isoflurane anesthesia alone and combined with 0.25, 0.42, and 0.55 minimum alveolar concentration xenon in dogs with and without cardiomyopathy. Administration of xenon to healthy dogs anesthetized with isoflurane decreased heart rate and increased the time constant (tau) of isovolumic relaxation but did not alter arterial and LV pressures, preload recruitable stroke work slope, and indices of LV afterload. Chronic rapid LV pacing increased the baseline heart rate and LV end-diastolic pressure, decreased arterial and LV systolic pressures, and produced LV systolic and diastolic dysfunction. Administration of xenon to isoflurane-anesthetized, cardiomyopathic dogs did not alter heart rate, arterial and LV pressures, myocardial contractility, and indices of early LV filling and regional chamber stiffness. More pronounced increases in tau were accompanied by increases in total arterial resistance during administration of xenon to isoflurane-anesthetized cardiomyopathic compared with healthy dogs. The results indicate that xenon produces minimal cardiovascular actions in the presence of isoflurane in dogs with and without experimental dilated cardiomyopathy.

XENON ATTENUATES ISOFLURANE-INDUCED MYOCARDIAL DEPRESSION AT CONSTANT MAC IN DOGS

S68 Introduction: Interest in xenon (XE) as an inhalational anesthetic has been rekindled recently as availability of scavenging systems may allow its cost-effective use. We tested the hypothesis that XE alters the effects of isoflurane (ISO) on systemic hemodynamics and myocardial contractility in vivo. Methods: After Animal Care Committee approval, dogs (n=6) were chronically instrumented for measurement of aortic and LV pressure, +dP/dt, cardiac output (CO), and subendocardial segment length. Myocardial contractility was evaluated using preload recruitable stroke work slope (MW). Dogs were assigned to receive XE (30,50, and 65%; end-tidal concentrations) during 1.4 MAC ISO anesthesia or in combination with ISO to maintain a constant 1.4 MAC on separate days. MAC values were 1.28 and 71% for ISO and XE, respectively. Hemodynamics were recorded in the conscious state (C), after 30 min equilibration during ISO alone, and after 15 min equilibration at each dose of XE. Comparison between interventions was performed with ANOVA followed by Student's t-test with Duncan's correction for multiplicity (*P<0.05 versus ISO alone). Results: ISO increased heart rate and decreased mean arterial and LV systolic pressures, +dP/dt, CO, systemic vascular resistance (SVR) and MW (Figure 1). Administration of XE to dogs anesthetized with 1.4 MAC ISO produced no hemodynamic effects. Administration of increasing concentrations of XE during reductions in ISO (constant MAC) increased mean arterial and LV systolic pressures, CO, +dP/dt, and MW. No changes in heart rate or SVR were observed when XE was gradually substituted for ISO.Figure 1Conclusion: The results indicate that XE is devoid of hemodynamic effects and does not alter myocardial contractility during ISO anesthesia. XE attenuated ISO-induced depression of myocardial contractility when substituted for this volatile agent to maintain constant MAC.

Positive inotropic and lusitropic effects of triiodothyronine in conscious dogs with pacing-induced cardiomyopathy.

The effects of triiodothyronine (T3) on systemic hemodynamics, myocardial contractility (preload recruitable stroke work slope; Mw), and left ventricular (LV) isovolumic relaxation (time constant; tau) were examined before and after the development of pacing-induced cardiomyopathy in conscious dogs. Dogs (n = 8) were chronically instrumented for measurement of aortic and LV pressure, dP/dtmax, subendocardial segment length, and cardiac output. Dogs received escalating doses (0.2, 2.0, and 20.0 mg/kg, intravenous) of T3 over 5 min at 1-h intervals, and peak hemodynamic effects were recorded 10 min after each dose and 24 h after the final dose. Dogs were then continuously paced at 220-240 beats/min for 21 +/- 2 days. Pacing was temporarily discontinued after the development of severe LV dysfunction, and administration of T3 was repeated. T3 produced immediate and sustained (24 h) increases (P < 0.05) in Mw and dP/dtmax in dogs before the initiation of pacing, consistent with a positive inotropic effect. No changes in tau occurred. Rapid ventricular pacing over 3 weeks increased baseline heart rate (sinus rhythm) and LV end-diastolic pressure, decreased mean arterial and LV systolic pressures, and caused LV systolic (decreases in Mw and dP/dtmax) and diastolic (increases in tau) dysfunction. T3 caused immediate and sustained increases in Mw (63 +/- 7 during control to 82 +/- 7 mmHg after the 2 mg/kg dose) and decreases in tau (65 +/- 8 during control to 57 +/- 6 ms after the 20 mg/kg dose), indicating that this hormone enhanced myocardial contractility and shortened LV relaxation, respectively, in the presence of chronic LV dysfunction. In contrast to the findings in dogs with normal LV function, T3 did not affect heart rate and calculated indices of myocardial oxygen consumption and reduced LV end-diastolic pressure (27 +/- 3 during control to 20 +/- 2 mmHg after the 2 mg/kg dose) in cardiomyopathic dogs. The findings indicate that T3 produces favorable alterations in hemodynamics and modest positive inotropic and lusitropic effects in conscious dogs with LV dysfunction produced by rapid LV pacing.

Effects of levosimendan on left ventricular function: Correlation with plasma concentrations in conscious dogs

Objectives : To test the hypothesis that the hemodynamic and left ventricular functional actions of levosimendan (Orion Pharmaceutical, Espoo, Finland), a new myofilament calcium sensitizer with phosphodiesterase-inhibiting properties, in conscious dogs are correlated with plasma concentrations of the drug measured with reverse-phase, high-performance liquid chromatography. Design : Prospective investiation. Setting : Research Laboratory. Participants : Fifteen chronically instrumented dogs. Interventions : On different experimental days, dogs were assigned to receive intravenous levosimendan (12 or 24 μg/kg loading dose and 0.2 or 0.4 μg/kg/min infusion, respectively). Measurements and Main Results : Systemic and coronary hemodynamics, left ventricular function, and plasma concentrations were determined at scheduled intervals during and after levosimendan infusions. Levosimendan increased heart rate and cardiac output and decreased left ventricular end-diastolic pressure and systemic vascular resistance. Levosimendan caused dose-related enhancement of left ventricular systolic (increases in regional preload recruitable stroke work slope and +dP dt max ) and diastolic functions (decreases in the time constant of isovolumic relaxation and regional chamber stiffness). The elimination half-life of levosimendan was 0.76 ± 0.04 hours. Conclusions : The hemodynamic actions and left ventricular functional effects of levosimendan correlated closely with plasma concentrations and returned to baseline values within 3 hours after discontinuation of the drug.

Increases in inotropic state without change in heart rate: Combined use of dobutamine and zatebradine in conscious dogs

The cardiovascular and left ventricular functional effects of dobutamine (5, 10 and 20 μg kg −1 min −1) were examined in conscious, chronically instrumented dogs in the presence and absence of control of heart rate with the specific bradycardic agent, zatebradine. Dobutamine increased heart rate, cardiac output, stroke volume, diastolic coronary blood flow velocity and pressure-work index (calculated myocardial oxygen consumption) and decreased systemic vascular resistance and diastolic coronary vascular resistance. Mean arterial pressure and left ventricular systolic and end-diastolic pressures were unchanged. Dobutamine-induced increases in heart rate and pressure-work index were attenuated by zatebradine. Dobutamine alone increased preload recruitable stroke work slope (63 ± 6 to 116 ± 11 mmHg) and + dP dt . These positive inotropic effects were unaffected by zatebradine. Dobutamine decreased the time constant of isovolumic relaxation (30 ± 3 to 25 ± 2 ms). Dobutamine-induced decreases in the time constant of isovolumic relaxation were not altered by zatebradine, indicating that changes in the time constant occurred independent of heart rate. Dobutamine also increased the maximal segment lengthening velocity to a similar degree in zatebradine-treated versus untreated dogs. Control of dobutamine-induced tachycardia by zatebradine decreases myocardial oxygen consumption but does not alter the positive inotropic and lusitropic effects of dobutamine.

Low-dose inotropic stimulation during left ventricular ischaemia does not worsen post-ischaemic dysfunction.

Inotropic agents are used clinically to improve ventricular function during ischaemia. The goal of this study was to determine whether inotropic stimulation during moderate left ventricular (LV) ischaemia exacerbated post-ischaemic LV dysfunction. In 18 open-chest, anesthetized pigs, LV pressure versus subendocardial segment length loops were used to generate regional preload-recruitable stroke work (PRSW) and LV end-diastolic pressure (EDP) versus end-diastolic segment length (EDL) relations. Ischaemia was produced by constant, partial constriction of the mid anterior descending coronary artery for 90 min. Nine pigs received dobutamine (4 micrograms.kg-1.min-1, i.v.) during the final 60 min of ischaemia (Group 2), while 9 other pigs did not (Group 1). During unstimulated ischaemia, anterior subendocardial blood flow (Group 1, 0.27 +/- .05; Group 2, 0.30 +/- .07 ml.g-1.min.-1, mean +/- s.e.m.) and steady-state PRSW (Group 1, 30 +/- 4%; Group 2, 27 +/- 5% of baseline) were similar in both groups. Dobutamine stimulation during ischaemia increased heart rate, mean arterial pressure, subendocardial blood flow, oxygen consumption and steady-state PRSW of the ischaemia zone, but not lactate release. After 60 min reperfusion, steady-state ischaemic zone PRSW remained markedly and nearly equally reduced in both groups (Group 1, 28 +/- 4%; Group 2, 23 +/- 5% of baseline). Reduced PRSW after reperfusion was due primarily to persistent rightward shift of the PRSW intercept with only a modest contribution from reduced PRSW slope. Low-dose inotropic stimulation during moderate regional LV ischaemia increases aerobic, but not anaerobic energy metabolism, and does not worsen post-ischaemic dysfunction.

Perfluorocarbon supplementation and postischemic cardiac function

During induced ischemia for cardiac surgery inefficient anaerobic energy mechanisms predominate. Sustaining aerobic metabolism with perfluorocarbon-supplemented blood cardioplegia theoretically could lead to improved postischemic recovery. Therefore we studied functional recovery after myocardial ischemia, comparing perflubron (C8F17Br) supplemented blood cardioplegia to standard blood cardioplegia. Nineteen dogs underwent 15 minutes of 37 degrees C global ischemia on cardiopulmonary bypass, followed by 90 minutes of cardioplegic arrest by use of blood cardioplegia with or without perflubron and then 30 minutes of 37 degrees C reperfusion. During ischemia myocardial oxygen tension, temperature, and pH were measured. Postischemic left ventricular recovery was assessed by means of preload recruitable stroke work, exponential end-diastolic stress-strain regression, and preservation of adenosine triphosphate and energy charge. The addition of perflubron, a new shorter half-life, lecithin-emulsified perfluorocarbon, provided superior myocardial protection when compared with standard blood cardioplegia. This benefit was evidenced by significantly increased recovery of preload recruitable stroke work slope (71% +/- 8% versus 42% +/- 9%), decreased myocardial edema, and enhanced end ischemic myocardial oxygen and pH levels. The reliable oxygen delivery system and endothelial-preserving properties of the perfluorocarbons may prove to be an invaluable asset in addition to standard blood cardioplegia in the preservation of postischemic ventricular function. These data support the further investigation of perfluorocarbon-enriched blood cardioplegia.

Effect of alkali therapy with NaHCO3 or THAM on cardiac contractility.

We examined the impact of alkali therapy on myocardial contractility in a model of myocardial ischemia in dogs using direct measurements of myocardial contractile function. Myocardial ischemia in the left anterior descending (LAD) artery territory was induced using a perfusion circuit from the internal carotid artery to the LAD artery. Myocardial contractile function was assessed using sonomicrometry for measurement of percent systolic shortening (%SS), preload recruitable stroke work (PRSW) slope, and end-systolic pressure-length relationship (ESPLR) area. Because the blood flow in LAD artery was diminished by approximately 70%, there was a significant decrease in O2 delivery and uptake by the ischemic myocardium. Ischemia led to a significant fall in LAD regional contractile function with %SS decreasing from 15 +/- 2 to 7 +/- 2%, PRSW slope from 82 +/- 10 to 37 +/- 5 mmHg, and ESPLR area from 121 +/- 2 to 48 +/- 14 mmHg.mm (P < 0.05). In six dogs, the intracoronary administration of NaHCO(3) resulted in a significant increase in pH in LAD arterial and venous blood. There was, however, no significant increase in %SS (6 +/- 2), PRSW slope (43 +/- 10 mmHg), or ESPLR area (60 +/- 13 mmHg.mm). Since administration of NaHCO(3) resulted in a significant increase in PCO2 in LAD arterial and venous blood, similar experiments were carried out in five dogs, but with the intracoronary infusion of the amine buffer THAM [tris(hydroxymethyl)aminomethane (Tris) buffer; 2-amino-2-hydroxyl-1,3-propandiol] instead of NaHCO3. Although administration of THAM resulted in a significant increase in pH and a significant decrease in PCO2, in both LAD arterial and venous blood, there was no significant improvement in any of the parameters used to assess myocardial contractile function. In conclusion, administration of alkali (NaHCO3 or THAM) does not enhance the contractile function of the ischemic myocardium.

Assessment of right ventricular function in swine using sonomicrometry and conductance

Assessment of right ventricular (RV) pressure-volume relations has been hampered by difficulty measuring instantaneous, absolute RV volume. Accordingly, several methods were tested for their ability to reflect relative RV volume and to determine changes in RV contractile state. Swine (46 to 54 kg; n = 7) were anesthetized and instrumented to measure instantaneous RV pressure, septal-to-RV free wall diameter (SFWD), RV free wall segment length (FWSL), RV volume via conductance (CV), and pulmonary artery flow, the integral of which was used as the standard for stroke volume. Flow-derived stroke volume was correlated with the systolic change in CV, FWSL, and SFWD in the steady state after incremental volume loading and on a beat-to-beat basis during transient inferior vena caval occlusion. Contractility was altered by calcium and pentobarbital and assessed by preload recruitable stroke work (PRSW). Mean (+/- standard error of the mean) correlations (r) versus stroke volume during steady state conditions were 0.85 +/- 0.04 for FWSL, 0.83 +/- 0.04 for CV, and -0.04 +/- 0.24 for SFWD. Mean r values versus stroke volume during caval occlusions were 0.83 +/- 0.03 for FWSL, 0.85 +/- 0.04 for CV, and -0.03 +/- 0.31 for SFWD. Calcium increased mean PRSW slope compared with control using CV (20.3 +/- 2.6 versus 16.1 +/- 1.9 mm Hg; p < 0.05), and pentobarbital decreased mean PRSW slope compared with control using both CV and FWSL (11.3 +/- 1.0 versus 16.1 +/- 1.9 mm Hg, p < 0.05; and 11.9 +/- 2.1 versus 26.1 +/- 4.0 mm Hg, p < 0.05, respectively). There were no changes in PRSW slope with either calcium or pentobarbital using SFWD. The PRSW function was linear with both FWSL and CV but not with SFWD. In the normal heart, both FWSL and CV, but not SFWD, accurately reflect relative instantaneous RV volume and are thus useful for determining RV contractility by pressure-volume (pressure-dimension) indices.

Comparison of the cardiovascular effects of two novel superoxide dismutase mimetics, SC-55858 and SC-54417, in conscious dogs

The hemodynamic actions and left ventricular mechanical effects of two new superoxide dismutase mimetics, SC-55858 [Manganese (II) dichloro (2 R,3 R,8 R,9 R-bis-cyclohexano-1,4,7,10,13-pentaazacyclopentadecane)] ( n = 10) and SC-55417 [Manganese (II) dichloro (trans-2,3-cyclohexano-1,4,7,10,13-pentaazacyclopentadecane)] ( n = 8), were studied in chronically instrumented dogs in the conscious state and after 30 min equilibration at 0.033, 0.067, 0.233, and 0.667 μM · kg −1 · min −1 SC-55858 or SC-54417 (total doses of 1, 2, 7, and 20 μM · kg −1). SC-55858 and SC-54417 increased heart rate and decreased mean arterial pressure and left ventricular systolic and end-diastolic pressures. SC-55858 decreased preload recruitable stroke work slope and + dP dt max and increased the time constant of isovolumic relaxation, consistent with a direct negative inotropic and lusitropic effect. In contrast, SC-54417 did not depress left ventricular systolic and diastolic function. Decreases in mean arterial pressure caused by SC-55858 may be secondary to negative inotropic effects and reduction in cardiac preload. In contrast, SC-54417 does not depress myocardial contractility but also reduces arterial pressure via venodilation.

Functional recovery after ischemia: Warm versus cold cardioplegia

Warm continuous retrograde cardioplegia has been introduced for myocardial protection during cardiac operations, particularly in the setting of acute myocardial ischemia because of its theoretical advantage of producing arrest without ischemia. To investigate the ability of warm continuous retrograde cardioplegia to provide myocardial protection after acute global ischemia, versus the more commonly used cold intermittent antegrade cardioplegia, 12 dogs were subjected to 15 minutes of normothermic global myocardial ischemia on cardiopulmonary bypass followed by 75 minutes of protected cardioplegic arrest using either warm continuous retrograde cardioplegia or cold intermittent antegrade cardioplegia. Standard blood cardioplegia at clinically used volumes and flow rates was used. Warm continuous retrograde cardioplegia animals received 30 mL/kg antegrade to induce arrest followed by 1.5 to 1.8 mL.kg-1.min-1 retrograde at 37 degrees C, whereas cold intermittent antegrade cardioplegia animals received 30 mL/kg antegrade to induce arrest followed by 15 mL/kg antegrade every 15 minutes at 10 degrees C. Load-insensitive left ventricular systolic function, diastolic function, high energy nucleotides, and edema formation were assessed before and after ischemia. Results showed that myocardial preservation using clinically reported flow rates and volumes of warm continuous retrograde cardioplegia was significantly inferior to that provided by clinically used cold intermittent antegrade cardioplegia, as demonstrated by decreased preload recruitable stroke work slope (28 +/- 11 versus 71 +/- 6), increased alpha constant of the end diastolic stress-strain relationship (14.2 +/- 3.0 versus 3.6 +/- 1.0), decreased total nondiffusable nucleotides (40.7 +/- 2.3 versus 57.4 +/- 2.3 microM/g wet weight) and increased water content (82.2% +/- 0.4% versus 80.4% +/- 0.4%).(ABSTRACT TRUNCATED AT 250 WORDS)