Myocardial Energy Consumption Research Articles

Left ventricle unloading during veno-arterial extracorporeal membrane oxygenation: review with updated evidence.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is widely used to treat medically refractory cardiogenic shock and cardiac arrest, and its usage has increased exponentially over time. Although VA-ECMO has many advantages over other mechanical circulatory supports, it has the unavoidable disadvantage of increasing retrograde arterial flow in the afterload, which causes left ventricular (LV) overload and can lead to undesirable consequences during VA-ECMO treatment. Weak or no antegrade flow without sufficient opening of the aortic valve increases the LV end-diastolic pressure, and that can cause refractory pulmonary edema, blood stagnation, thrombosis, and refractory ventricular arrhythmia. This hemodynamic change is also related to an increase in myocardial energy consumption and poor recovery, making LV unloading an essential management issue during VA-ECMO treatment. The principal factors in effective LV unloading are its timing, indications, and modalities. In this article, we review why LV unloading is required, when it is indicated, and how it can be achieved.

P1513 Myocardial work analysis is a potential novel tool to diagnose subclinical cardiac dysfunction in cirrhotic cardiomyopathy

Abstract Funding Acknowledgements This work was supported by a grant of Ministery of Research and Innovation, CNCS-UEFISCDI, project number PN-III-P1-1-TE-2016-0669, within PNCDI III Background Cirrhotic cardiomyopathy (CCM) is defined as systolic and/or diastolic cardiac dysfunction, associated with high preload and low afterload. Thus, assessment of cardiac dysfunction in these circumstances is still debatable. Left ventricular (LV) deformation is still load-dependent, and does not reflect directly myocardial energy consumption. Since myocardial work (MW)incorporates both deformation and afterload, it might be a better alternative for the assessment of LV function in CCM. Methods 80 subjects were assessed by 2D conventional and speckle tracking echocardiography (STE): 40 patients with liver cirrhosis (LC) (58 ± 8 years, 23 males), free of any cardiovascular disease or diabetes, and 40 age and gender matched normal, control subjects. Left ventricular ejection fraction (LVEF) and systolic/diastolic blood pressure (SBP/DBP) were measured. A new approach was used to evaluate myocardial work by 2DSTE: global constructive work (GCW), as the "positive" work of the heart; global wasted work (GWW), as the "negative" work of the heart; global work efficiency (GWE), as the GCW/(GCW + GWW) in %; and global work index (GWI), as the GCW added to GWW. E/E’ ratio, left atrial volume index (LAVi), and systolic pulmonary arterial pressure (sPAP) were also assessed. Results Patients with LC had significantly lower SBP/DBP than controls, with similar LVEF (Table). GCW and GWI were decreased in patients with LC, probably due to decrease in afterload, which shifts LV work to a lower level of energy. GWE and GWW were similar to controls. By segmental analysis (18 segments model), apical and mid antero-lateral segments were the first affected in terms of myocardial work, with higher WW, low WE, but without a compensatory increase in CW in other segments, suggesting a regional myocardial dysfunction. All patients with LC presented significantly elevated E/E’ ratio, LAVi, and sPAP, compared to controls (Table). Conclusion Myocardial global constructive work and global work index decrease in LC patients, compared to normal individuals, probably due to augmented peripheral vasodilatation. Apical and mid antero-lateral segments are the first affected. Assessment of global and regional MW might be a potential new tool to assess CCM, and to understand the relationship between LV remodeling and increased filling pressure under different loading conditions. Comparative myocardial work indices group SBP (mmHg) DBP LVEF (%) E/E’ LAVI sPAP GWI GWE (% ) GCW (mmHg % ) GWW (mmHg %) LC (40) 111 ±14 69 ± 12 59 ± 7 8.5 ± 2.5 45.9 ± 14.5 26 ± 9 1927 ± 379 95 ± 2 2068 ± 386 90.1 ± 49 Controls (40) 126 ± 14 76 ± 8 61 ± 7 7.5 ± 2.2 31.8 ± 6.8 21 ± 8 2123 ± 353 95± 2 2302 ± 335 94.4 ± 49 P value 0.001 0.004 0.3 0.05 0.001 0.009 0.01 0.9 0.005 0.7 Abstract P1513 Figure. Myocardial Work Cirrhotic Cardiomyopathy

P2606Analysis of myocardial work: a potential new tool for a better assessment of left ventricular function

Abstract Background Left ventricular (LV) deformation is dependent on mechanical load and does not reflect directly the myocardial energy consumption. Thus, measurement of global and regional myocardial work might be alternative and complementary methods for the assessment of myocardial function. However, there is no data regarding myocardial work changes during the heart failure continuum, from normal to diastolic dysfunction (DD), and to heart failure with preserved ejection fraction (HFpEF). Methods We assessed 80 subjects by 2D conventional and speckle tracking echocardiography (2DSTE): 25 patients with DD, 30 with HFpEF, and 25 normal, control subjects. We measured NTproBNP, LV ejection fraction (EF), and E/E' ratio. We used a new approach to calculate myocardial work, during mechanical systole and isovolumetric relaxation, by 2DSTE: global constructive work (GCW), as the “positive” work of the heart; global wasted work (GWW), as the “negative” work of the heart; global work efficiency (GWE), as the GCW/(GCW + GWW) in %; and global work index (GWI), as the GCW added to GWW. Similarly, a regional, segmental analysis was performed (18 segments model) (Figure 1). Results GCW increases in patients with DD, probably as a compensatory mechanism to preserve LV function against an increased after load, and decreases back to the normal values in HFpEF, while GWE significantly decreases from normal subjects to patients with DD, and then further in patients with HFpEF (table). Meanwhile, GWW increases from normal subjects to patients with DD, and then further in patients with HFpEF. As expected, GWI does not change significantly. By segmental analysis, first segment affected in terms of myocardial work is basal antero-septal segment, with low WE and higher WW (figure), probably due to the flat shape (based on the Laplace law), with a compensatory increased CW in the apical segments. NTproBNP level and E/E' ratio correlated only with GWW (r=0.4, p=0.013). Comparative global myocardial work Group LVEF (%) E/E' NTproBNP (pg/ml) GWI (mmHg%) GWE (%) GCW (mmHg%) GWW (mmHg%) Controls 58±6 7.3±2.4 – 2102±303 95.5±1.8 2295±279 87.9±39.6 DD 57±8 7.7±2.4 36±25 2296±431 94.8±2.3 2550±463 108±50 HFpEF 63±7 10.3±3.1 349±418 2074±485 93.5±2.5 2300±535 125±51 P (Anova) 0.004 <0.001 <0.001 0.12 0.008 0.05 0.019 Figure 1. Myocardial Work Conclusion Myocardial work efficiency decreases and wasted work increases in parallel with the severity of LV dysfunction. The first myocardial segment affected is basal antero-septal. Therefore, new parameters of myocardial work, derived from 2DSTE, might provide a better assessment of LV function in patients with DD or HFpEF. Acknowledgement/Funding This work was supported by a grant of Ministery of Research and Innovation, CNCS-UEFISCDI, project number PN-III-P1-1-TE-2016-0669, within PNCDI III

Coronary slow flow phenomenon: Not only low in flow rate but also in myocardial energy expenditure

Background and aimCoronary slow flow phenomenon (CSFP) is a miscellaneous clinical entity leading to angina-like symptoms, and electrocardiographic and scintigraphic evidence of ischemia. The impact of this syndrome on myocardial performance has not been comprehensively evaluated. In this study, we sought to evaluate the myocardial energy expenditure (MEE) in patients with CSFP and its relationship with exercise capacity. Methods and resultsA total of 64 patients (64.1% male, mean age 53.2 ± 10.3 years) with CSFP and 64 patients (60.9% male, mean age 52.2 ± 10.9 years) with normal coronary artery as control group were included. MEE was calculated by a validated formula that uses transthoracic echocardiography (TTE) parameters, including left ventricular circumferential end-systolic stress, stroke volume, and ejection timeCSFP patients had significantly lower MEE (0.79 cal/systole ± 0.15 vs. 0.91 cal/systole ± 0.09, p < 0.001). In correlation analysis, MEE had a significant negative correlation with mean corrected TIMI frame count (mTFC) (β = −0.523; p < 0.001) and positive correlations with metabolic equivalents (METs) (β = 0.560; p < 0.001), rate pressure product (β = 0.649; p < 0.001), and exercise duration (β = 0.408; p < 0.001). At multivariate analysis, MEE was demonstrated as an independent predictor of CSFP (OR 1.863, CI 95% 1.485–2.338 p < 0.001). ConclusionMyocardial energy consumption, as a calculation obtained from TTE parameters, was reduced in patients with CSFP, and it had a significant relationship with exercise capacity. Considering its significant correlation with exercise capacity, myocardial energy consumption seemed to use evaluation of myocardial performance and functional status in another cardiovascular disease.

Assessment of regional myocardial work in rats.

Left ventricular (LV) motion and deformation is dependent on mechanical load and do therefore not reflect myocardial energy consumption directly. Regional myocardial work, however, constitutes a more complete assessment of myocardial function. Strain was measured using high-resolution phase-contrast MRI in 9 adult male rats with myocardial infarction (MI) and in 5 sham-operated control animals. Timing of LV valvular events and LV dimensions were evaluated by cine MRI. A separate cohort of 14 animals (MI/sham=9/5) underwent measurement of LV pressure concurrent with identification of valvular events by Doppler-echocardiography for the purpose of generating a standard LV pressure curve, normalized to valvular events. The infarctions were localized to the anterolateral LV wall. Combining strain with timing of valvular events and a measurement of peak arterial pressure, regional myocardial work could be calculated by applying the standard LV pressure curves. Cardiac output and stroke work was preserved in the MI hearts, suggesting a compensatory redistribution of myocardial work from the infarcted region to the viable tissue. In the septum, regional work was indeed increased in MI rats compared with sham (median work per unit long-axis length in a mid-ventricular slice: 241.2 [224.1-271.2] versus 137.2 [127.0-143.8] mJ/m; P<0.001). Myocardial work in infarcted regions was zero. Additionally, eccentric work was increased in the MI hearts. Phase-contrast MRI, in combination with measurement of peak arterial pressure and MRI-derived timing of valvular events, represent a noninvasive approach for estimation of regional myocardial work in rodents.

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

Cardiac ATP-sensitive potassium (K(ATP)) channels are key sensors and effectors of the metabolic status of cardiomyocytes. Alteration in their expression impacts their effectiveness in maintaining cellular energy homeostasis and resistance to injury. We sought to determine how activation of calcium/calmodulin-dependent protein kinase II (CaMKII), a central regulator of calcium signaling, translates into reduced membrane expression and current capacity of cardiac K(ATP) channels. We used real-time monitoring of K(ATP) channel current density, immunohistochemistry, and biotinylation studies in isolated hearts and cardiomyocytes from wild-type and transgenic mice as well as HEK cells expressing wild-type and mutant K(ATP) channel subunits to track the dynamics of K(ATP) channel surface expression. Results showed that activation of CaMKII triggered dynamin-dependent internalization of K(ATP) channels. This process required phosphorylation of threonine at 180 and 224 and an intact (330)YSKF(333) endocytosis motif of the K(ATP) channel Kir6.2 pore-forming subunit. A molecular model of the μ2 subunit of the endocytosis adaptor protein, AP2, complexed with Kir6.2 predicted that μ2 docks by interaction with (330)YSKF(333) and Thr-180 on one and Thr-224 on the adjacent Kir6.2 subunit. Phosphorylation of Thr-180 and Thr-224 would favor interactions with the corresponding arginine- and lysine-rich loops on μ2. We concluded that calcium-dependent activation of CaMKII results in phosphorylation of Kir6.2, which promotes endocytosis of cardiac K(ATP) channel subunits. This mechanism couples the surface expression of cardiac K(ATP) channels with calcium signaling and reveals new targets to improve cardiac energy efficiency and stress resistance.

Circulation: Clinical Summaries

<i>Circulation:</i> Clinical Summaries

Long-term biventricular support with rotary blood pumps: prospects and pitfalls

Congestive heart failure affects 23 million people worldwide, including 7.5 million in North America (670 000 new cases per year) and 7 million in Europe [1]. Since 10% of those over 65 suffer from systolic left ventricular dysfunction, the number of patients with heart failure will double over the next 25 years. At any time, 10% of the heart failure cohort are categorized Stage D with advanced structural heart disease and symptoms at rest, despite detailed medical and cardiac resynchronization therapy. Twenty percent of these are younger than 65 years of age (around 140 000 in both the USA and Europe). The prognosis of Stage D heart failure is grim. In the REMATCH study, only 8% of the medically treated patients were alive at 2 years and continued to suffer in the interim [2]. A recurrent sentiment expressed by the Stage D patients is that they would sacrifice some duration of survival for a period of symptomatic relief [3]. Cardiac transplantation provides this for a highly selected tiny minority [4]. In contrast, cardiac resynchronization therapy is disappointing. A meta-analysis of 14 trials that randomized resynchronization against medical treatment showed only 59% of the NYHA IV device patients to have borderline symptomatic improvement to NYHA III with no survival benefit [5]. Boyle et al. [6] compared functional outcomes for NYHA IV patients after resynchronization or implantation of a left ventricular assist device (LVAD). At 6 months, resynchronized patients achieved only an additional 6 m in the 6 min walk test (insufficient to affect their daily living) and remained NYHA III or IV. In contrast, LVAD patients improved by 341 m, achieving NYHA I or II status. The study could not be randomized because 90% of the LVAD candidates were bed-bound on intravenous inotropes and could not walk beforehand. Long-term mechanical circulatory support is an increasingly realistic ‘off the shelf’ alternative to cardiac transplantation and an effective solution for those rendered ineligible through common heart failure comorbidities [7–9]. The treatment aims are uncontroversial. The first is to provide symptomatic relief and the second to achieve at least 5-year survival with a good quality of life. The third aim is cost containment by reducing the number of hospital admissions to palliate intolerable levels of breathlessness and fatigue. Hospital events account for $20.9 billion of an overall $35 billion heart failure budget in the USA. The rationale for a blood pump deployment is clear. The failing heart beats more than 120 000 times per day pumping around 7000 l of blood against an increasing afterload. As the heart dilates, the ventricular wall tension, myocardial energy and oxygen consumption increase, while sub-endocardial blood flow decreases. The LVAD unloads the failing ventricle resulting in beneficial structural and functional changes in the diseased myocardium [10–12]. Systemic blood flow returns to physiological levels to preserve the coronary and vital organ perfusion [13]. When native heart contractility and segmental wall motion improve, there is less propensity for intraventricular thrombus formation and thromboembolism. In September 2011, the Society of Thoracic Surgeons and the Food and Drugs Administration (USA) assembled a ‘Think Tank’ to focus on the need for long-term mechanical circulatory support in the USA. The group acknowledged the increasing safety profile and reliability of contemporary implantable rotary blood pumps together with the potential for stem cells to broaden the horizons of heart failure management. A need for 40 000 long-term LVADs per year was predicted, which would account for 50% of the heart failure annual budget. Between 15 and 30% of patients require biventricular support and there is no satisfactory long-term mechanical solution for these patients. The pulsatile total artificial hearts have numerous restrictions which confine their use as a bridge to transplantation [14]. INTERMACS data indicate that all total artificial heart patients are transplanted or dead within 6 months [15].

Reduction in number of sarcolemmal K ATP channels slows cardiac action potential duration shortening under hypoxia

The cardiovascular system operates under demands ranging from conditions of rest to extreme stress. One mechanism of cardiac stress tolerance is action potential duration shortening driven by ATP-sensitive potassium (K ATP) channels. K ATP channel expression has a significant physiologic impact on action potential duration shortening and myocardial energy consumption in response to physiologic heart rate acceleration. However, the effect of reduced channel expression on action potential duration shortening in response to severe metabolic stress is yet to be established. Here, transgenic mice with myocardium-specific expression of a dominant negative K ATP channel subunit were compared with littermate controls. Evaluation of K ATP channel whole cell current and channel number/patch was assessed by patch clamp in isolated ventricular cardiomyocytes. Monophasic action potentials were monitored in retrogradely perfused, isolated hearts during the transition to hypoxic perfusate. An 80–85% reduction in cardiac K ATP channel current density results in a similar magnitude, but significantly slower rate, of shortening of the ventricular action potential duration in response to severe hypoxia, despite no significant difference in coronary flow. Therefore, the number of functional cardiac sarcolemmal K ATP channels is a critical determinant of the rate of adaptation of myocardial membrane excitability, with implications for optimization of cardiac energy consumption and consequent cardioprotection under conditions of severe metabolic stress.

Levosimendan in trauma patients with acute cardiac failure

Acute heart failure (AHF) is common among trauma patients with pre-existing coronary artery disease (CAD) and myocardial perfusion defect. The therapy is aimed at increased contractility while decreasing afterload and includes β1-adrenergic agents and phosphodiesterase III inhibitors, which act by increasing the intracellular calcium (Ca) concentration, thus markedly increasing myocardial energy consumption and risk of arrhythmias. The new Ca sensitizer levosimendan enhances cardiac performance without increasing myocardial energy demand and oxygen consumption. We report new use of levosimendan in polytrauma victims with AHF.

Oxidative Stress Causes Heart Failure with Impaired Mitochondrial Respiration

Elderly people insidiously manifest the symptoms of heart failure, such as dyspnea and/or physical disabilities in an age-dependent manner. Although previous studies suggested that oxidative stress plays a pathological role in the development of heart failure, no direct evidence has been documented so far. In order to investigate the pathological significance of oxidative stress in the heart, we generated heart/muscle-specific manganese superoxide dismutase-deficient mice. The mutant mice developed progressive congestive heart failure with specific molecular defects in mitochondrial respiration. In this paper, we showed for the first time that the oxidative stress caused specific morphological changes of mitochondria, excess formation of superoxide (O(2)(*)(-)), reduction of ATP, and transcriptional alterations of genes associated with heart failure in respect to cardiac contractility. Accordingly, administration of a superoxide dismutase mimetic significantly ameliorated the symptoms. These results implied that O(2)(*)(-) generated in mitochondria played a pivotal role in the development and progression of heart failure. We here present a bona fide model for human cardiac failure with oxidative stress valuable for therapeutic interventions.

Dependence of the functional capacity of the cardiorespiratory system on the body mass in patients with coronary heart disease

The influence of excessive body mass on the development of cardiorespiratory deficiency was studied in patients with coronary heart disease (CHD). Basic parameters of hemodynamics and gas exchange were measured during a graded exercise test. In the CHD patients with excessive body mass, mean blood pressure, cardiac output, left ventricular power output, and left ventricular posterior wall thickness were significantly increased even at rest. During exercise, these patients displayed an increase in myocardial energy consumption and peripheral vascular resistance. It was concluded that an excess in body mass is critical when the increase in the body mass index (Quetelet’s index) exceeds the norm by 20%.

New inotropic concepts: rationale for and differences between calcium sensitizers and phosphodiesterase inhibitors.

Positive inotropic compounds may be harmful in the long-term treatment of chronic congestive heart failure because they may induce a calcium overload, unwanted changes in cross-bridge kinetics and an acceleration in heart rate. As a result of all three alterations, energy consumption would be increased. Different pharmacological modes of action may have different effects on the molecular mechanisms underlying the positive inotropic effect, and hence on myocardial energy consumption. Therefore, we studied the effects of a variety of cardiotonic agents on the heat released from small guinea pig papillary muscles contracting isometrically at an experimental temperature of 21 degrees C and a stimulation frequency of 12 per minute using rapid antimony-bismuth thermopiles. We were able to define the economy of muscle contraction, which was lowest with phosphodiesterase inhibitors and highest with calcium sensitizers. Compared with an increase in extracellular calcium concentration, beta 1-adrenoceptor stimulators and phosphodiesterase inhibitors profoundly decrease the economy of myocardial contraction, and calcium-sensitizers (pimobendan and EMD-53998) slightly increase myocardial economy, whereas ouabain and the calcium channel agonist BAY K 8644 have no effect on this parameter. In addition, we provide evidence that acceleration of heart rate may be harmful not only from an energetic point of view: an increase in heart rate may also decrease the contractility of the failing human myocardium (inverse force-frequency relationship). Taking these observations into consideration, an "optimal' positive inotropic compound should have no, or even negative, chronotropic effects, should not be mediated by increases in calcium transients, and should decelerate, rather than accelerate, cross-bridge kinetics.

The effects of intra-aortic balloon pumping combined with coronary sinus interventions on failing hearts: A model study

Cardiac energy balance is an important factor in evaluating cardiac function. In this work, the effects of different assist modalities and their combinations on cardiac energy balance and global cardiac function have been investigated. The simulation results indicate that coronary sinus interventions (CSIs) can provide myocardium with more energy than IAPB when coronary arterial stenosis is serious. However, IABP can decrease myocardial energy consumption and enhance cardiac output, which cannot be done by CSIs, under the condition of impaired myocardial contractility. Therefore, we conclude that the combination of IABP and CSIs is the best way of assisting failing circulation.

Preload does not influence nonmechanical O2 consumption in isolated rabbit heart

Myocardial energy consumption for nonmechanical activity (excitation-contraction coupling) has been shown to be length dependent in isolated muscle studies but no more than minimally affected by preload in the whole heart. However, unloaded O2 consumption (VO2, which is used to estimate nonmechanical VO2 in whole heart) may not be accurate for quantifying nonmechanical energy consumption, because it contains VO2 for residual cross-bridge cycling. To more accurately determine the influence of left ventricular (LV) diastolic volume on nonmechanical VO2 in whole heart, we employed a new method for quantifying nonmechanical VO2, using the drug 2,3-butanedione monoxime (BDM). We measured VO2 and force-time integral during infusion of BDM (< or = 5 mM) at high (VH) and low LV volumes (VL) in 16 excised isovolumically contracting red blood cell-perfused rabbit ventricles. LV end-diastolic pressure was 9.7 +/- 4.6 and 3.8 +/- 2.8 (SD) mmHg at VH and VL, respectively. Nonmechanical VO2, estimated as the VO2-axis intercept of the linear VO2-force-time integral relation obtained during BDM infusion, did not differ significantly between VH and VL (0.0137 +/- 0.0083 and 0.0132 +/- 0.0090 ml O2.beat-1 x 100 gLV-1, P = 0.702). A multiple linear regression analysis for the pooled data confirmed this finding (P = 0.361). We conclude that, in the rabbit heart, LV diastolic volume does not importantly affect nonmechanical energy consumption over a physiological range of LV end-diastolic pressure. This indicates that length-dependent activation does not have an energetic cost in whole rabbit heart and suggests that its predominant mechanism is increased Ca2+ affinity for the contractile proteins.

Calcium in the in situ mitochondria of rested and stimulated myocardium

Calcium is believed to provide feedback between myocardial energy consumption and production. Calcium content was proved to increase in mitochondria (MT) isolated from (1) stimulated hearts, and (2) hearts of increased contractility. In this work we compared Ca 2+ content in the intact MT of skinned strips excised at 0°C from previously stimulated or rested guinea-pig ventricles equilibrated with 43Ca and in single rested or stimulated myocytes. In both preparations Ca 2+ was released from MT by means of CCCP (carbonyl cyanide m-chlorophenyl-hydrazone; 100 μ m). CCCP released 1.58 ± 0.55 nmol Ca 2+/mg of MT protein from the strips of rested hearts and 3.86 ± 1.12 nmol Ca 2+/mg of MT protein from the stimulated muscles. Stimulated myocytes responded to the close micro-injection of CCCP with transient contracture which was not inhibited by caffeine (10 m m) or ryanodine (0.1 μ m, 45 min), although the time-course of the contracture was changed. Contracture could not be initiated in rested cells. It is suggested that in rested myocytes MT contain much less Ca 2+ than in stimulated ones.

Myocardial energetics in patients with dilated cardiomyopathy. Influence of nitroprusside and enoximone.

Cardiotonic agents influence myocardial energy consumption by vasodilation, which may reduce energy demand, and by inotropism, which may increase it. To distinguish between the two effects, myocardial oxygen consumption must be analyzed in relation to its hemodynamic determinants. The coupling of myocardial oxygen consumption with its determinants was investigated in 22 patients with idiopathic dilated cardiomyopathy (NYHA Class II and III). Predicted myocardial oxygen consumption by the pressure-work index, the Bretschneider index, and the pressure-volume area correlated moderately with measured myocardial oxygen consumption (r = 0.57, p less than 0.001; r = 0.52, p less than 0.005; and r = 0.63, p less than 0.001). Multiple regression analysis, including left ventricular peak systolic wall stress, systolic stress-time integral, pressure-volume work, maximum rate of left ventricular pressure rise, and mean velocity of circumferential fiber shortening indicated that systolic stress-time integral is the major determinant of myocardial oxygen consumption (r = 0.75, p less than 0.001) in these patients. Enoximone, a phosphodiesterase inhibitor, has an inotropic and a vasodilating effect. To investigate the inotropic portion of the energy cost of this phosphodiesterase inhibitor, the influence of enoximone on myocardial oxygen consumption and systolic stress-time integral was compared with the effects of nitroprusside, which is a vasodilator only. Nitroprusside (10 patients) and enoximone (12 patients) reduced left ventricular systolic stress-time integral from 109 +/- 22 to 71 +/- 21 (p less than 0.005) and from 104 +/- 23 to 42 +/- 10 (p less than 0.001) 10(3) dynes.sec/cm2, respectively. Myocardial oxygen consumption decreased from 159 +/- 44 to 112 +/- 23 (p less than 0.005) and from 134 +/- 28 to 109 +/- 21 (p less than 0.001) microliters/beat/100 g, respectively. In both groups, there was a significant correlation between the decrease in myocardial oxygen consumption and the decrease in systolic stress-time integral. The slopes of the respective linear regression lines were significantly different (1.27 for nitroprusside and 0.51 nl.cm2/100 g.dynes.sec for enoximone, p less than 0.05), indicating a smaller decrease of myocardial oxygen consumption for a given decrease of stress-time integral with enoximone. Applying the pressure-work index or the pressure-volume area instead of systolic stress-time integral yielded comparable results. Thus, vasodilation reduces myocardial oxygen consumption in proportion to the reduction of stress-time integral. With enoximone, the energy-saving effect of vasodilation is counteracted in part by the increased energy d

Effects of β-Blockers on the Fall of pH in the Early Phase of Ischemia in the Isolated Perfused Rat Heart

To elucidate the role played by catecholamines in the early phase of ischemic derangement of the myocardial energy metabolism, effects of beta-blockers (propranolol, pindolol, and celiprolol) and isoproterenol, and of pretreatment with reserpine and 6-hydroxydopamine (6-OHDA), were studied using the isolated perfused rat heart. beta-Blockers and isoproterenol were infused for 12 min prior to induction of global ischemia. The myocardial energy consumption rate was assessed by calculating the product of left ventricular pressure and heart rate (LVP x HR). The myocardial cell creatine phosphate (CP), ATP and pH were determined with 31P nuclear magnetic resonance (31P-NMR). Global ischemia induced by cross-clamping of the aortic inflow line for 15 min resulted in falls in CP, ATP, and pH. Propranolol (6 x 10(-8) and 1.8 x 10(-7) mol/min) and pindolol (6 x 10(-7) mol/min) produced a decrease in LVP x HR and suppressed the pH fall during ischemia. Celiprolol was without significant effects on these two parameters. Isoproterenol (6 x 10(-12) mol/min) produced an increase in LVP x HR and tended to accelerate the pH fall. Catecholamine depletion with reserpine or 6-OHDA produced no beneficial effects on the pH fall. It was concluded that the beneficial effects of beta-blockers on the pH fall during early ischemia were not due to the specific beta-blocking action but to the nonspecific cardiodepressant effects of these compounds.

Myocardial energy production and consumption remain balanced during positive inotropic stimulation when coronary flow is restricted to basal rates in rabbit heart.

The effect on myocardial energy balance of increasing oxygen demand without altering basal myocardial perfusion rate was assessed in isolated, isovolumic, retrograde blood perfused rabbit hearts. Myocardial energy requirements were increased with paired stimulation. The capacity of rapid paired stimulation to increase mechanical energy consumption was demonstrated in the presence of increased perfusion with the rate X pressure product and oxygen consumption increasing 86 and 148%, respectively, compared with control values. In contrast, rapid paired stimulation under constant, basal flow conditions did not alter the rate X pressure product, while oxygen extraction and consumption increased only 40% relative to control. Myocardial ATP, creatine-phosphate, and lactate content were identical under control and constant flow-paired stimulation conditions. The results of this study indicate that no detectable energy imbalance was produced by rapid paired stimulation with flow held constant at basal rates. These results suggest that the myocardium does not increase mechanical energy expenditure in response to inotropic or rate stimulation in the presence of restricted flow reserve and are inconsistent with the concept of "demand-induced" or "relative" myocardial ischemia.

Heat production and oxygen consumption of the isolated rabbit heart: their relation to mechanical function.

A method is described for simultaneous determination of the heat production and the oxygen consumption of the isolated, isovolumetrically beating rabbit heart. The perfusion of the heart was performed via the aorta at a constant flow rate with carbogen saturated Tyrode's solution at a temperature of 37.0 degrees C. Heart function was varied by stepwise augmentation of the left intraventricular volume (LVV) by means of a balloon catheter. The following mechanical parameter of heart function were determined: enddiastolic pressure (EDP), peak pressure (PP), developed pressure (DP), max. contraction and relaxation velocity (dP/dt-A and dP/dt-B), enddiastolic tension (Tens-EDP), peak tension (Tens-PP), developed tension (Tens-DP), and circumferential tension (Tens-Cir). DP, dP/dt-A and dP/dt-R showed a maximum response to changes of the LVV at 2.0 ml LVV and 19.3 mm Hg EDP. Heat production (H) and oxygen consumption (Q) were correlated closely to mechanical function and to each other (r = 0.89, n = 8). The ratio H/Q was 4.9 cal/ml O2 and remained constant during the experiment. The myocardial energy consumption was significantly correlated toall contraction parameters with the best fit to DP and Tens-Cir (r = 0.934 and 0.933 resp.). On the basis of the calculated mean regression lines, the function-independent and the function-dependent energy consumption were calculated.