A systematic review and meta-analysis of beta-blockers and renin-angiotensin system inhibitors for preventing left ventricular dysfunction due to anthracyclines or trastuzumab in patients with breast cancer.

AIMS: Trastuzumab and anthracyclines, often used in the treatment of breast cancer, may impair myocardial function, and reduce left ventricular ejection fraction (LVEF), potentially causing heart failure. Randomized controlled trials (RCTs) have evaluated the effects of beta-blockers (BBs), angiotensin receptor blockers (ARBs), and angiotensin-converting enzyme inhibitors (ACEI) on trastuzumab- and anthracycline-associated cardiotoxicity. We report a meta-analysis of these RCTs in patients with breast cancer. METHODS AND RESULTS: The primary analysis was on the effect of BBs and ACEI/ARBs on LVEF in patients treated with either trastuzumab or anthracyclines. A secondary analysis was done investigating the effect of BBs or ACEI/ARBs on LVEF in trastuzumab and anthracycline treatments. Only RCTs were included using the search term 'ARBs, ACEIs, BBs, anthracyclines, trastuzumab, and breast cancer' in PubMed, Embase, and CENTRAL up to 31 March 2021. A meta-analysis was conducted to estimate the mean difference (MD) in LVEF between intervention and placebo groups at follow-up. A total of nine RCTs (n = 1362) were included in the analysis. All patients were women. BBs and ACEI/ARBs were shown to attenuate the decline in LVEF during trastuzumab and anthracycline treatments [MD: 2.4; 95% confidence interval (CI): 0.3-4.2 and MD: 1.5; 95% CI: -0.6 to 3.7]. Compared with placebo, LVEF was significantly higher in patients assigned to BB or ACEI/ARB on trastuzumab (MD: 2.3; 95% CI: 0.0-4.6) but not on anthracyclines (MD: 1.9; 95% CI: -0.5 to 4.2). CONCLUSION: Both BB and ACEI/ARB therapies were associated with the preservation of LVEF during trastuzumab and anthracycline-containing regimens as compared with placebo, suggesting both to be beneficial.

Alterations of myocardial dynamic stiffness implicating abnormal crossbridge function in human mitral regurgitation heart failure.

Mitral regurgitation (MR) causes ventricular dilation, a blunted myocardial force-frequency relation, and increased crossbridge force-time integral (FTI). The mechanism of FTI increase was investigated using sinusoidal length perturbation analysis to compare crossbridge function in skinned left ventricular (LV) epicardial muscle strips from 5 MR and 5 nonfailing (NF) control hearts. Myocardial dynamic stiffness was modeled as 3 parallel viscoelastic processes. Two processes characterize intermediate crossbridge cycle transitions, B (work producing) and C (work absorbing) with Q(10)s of 4 to 5. No significant differences in moduli or kinetic constants of these processes were observed between MR and NF. The third process, A, characterizes a nonenzymatic (Q(10)=0.9) work-absorbing viscoelasticity, whose modulus increases sigmoidally with [Ca(2+)]. Effects of temperature, crossbridge inhibition, or variation in [MgATP] support associating the calcium-dependent portion of A with the structural "backbone" of the myosin crossbridge. Extension of the conventional sinusoidal length perturbation analysis allowed using the A modulus to index the lifetime of the prerigor, AMADP crossbridge. This index was 75% greater in MR than in NF (P=0.02), suggesting a mechanism for the previously observed increase in crossbridge FTI. Notably, the A-process modulus was inversely correlated (r(2)=0.84, P=0.03) with in vivo LV ejection fraction in MR patients. The longer prerigor dwell time in MR may be clinically relevant not only for its potential role as a compensatory mechanism (increased economy of tension maintenance and increased resistance to ventricular dilation) but also for a potentially deleterious effect (reduced elastance and ejection fraction).

Activation of PKC decreases myocardial O2 consumption and increases contractile efficiency in rats.

The effect of protein kinase C (PKC) activation on cardiac mechanoenergetics is not fully understood. To address this issue, we determined the effects of the PKC activator phorbol 12-myristate 13-acetate (PMA) on isolated rat hearts. Hearts were exposed to PMA with or without pretreatment with the PKC inhibitor chelerythrine. Contractile efficiency was assessed as the reciprocal of the slope of the linear myocardial O2 consumption (VO2) pressure-volume area (PVA) relation. PMA decreased contractility (Emax; -30 +/- 8%; P < 0.05) and increased coronary perfusion pressure (+58 +/- 11%; P < 0.01) without altering left ventricular end-diastolic pressure. Concomitantly, PMA decreased PVA-independent VO2 [nonmechanical energy expenditure for excitation-contraction (E-C) coupling and basal metabolism] by 28 +/- 8% (P < 0.05) and markedly increased contractile efficiency (+41 +/- 8%; P < 0.05) in a manner independent of the coronary vascular resistance. Basal metabolism was not affected by PMA. Chelerythrine abolished the PMA-induced vasoconstriction, negative inotropy, decreased PVA-independent VO2, and increased contractile efficiency. We conclude that PKC-mediated phosphorylation of regulatory proteins reduces VO2 via effects on both the contractile machinery and the E-C coupling.

Myocardial cross-bridge kinetics in transition to failure in Dahl salt-sensitive rats.

The role of altered cross-bridge kinetics during the transition from cardiac hypertrophy to failure is poorly defined. We examined this in Dahl salt-sensitive (DS) rats, which develop hypertrophy and failure when fed a high-salt diet (HS). DS rats fed a low-salt diet were controls. Serial echocardiography disclosed compensated hypertrophy at 6 wk of HS, followed by progressive dilatation and impaired function. Mechanical properties of skinned left ventricular papillary muscle strips were analyzed at 6 wk of HS and then during failure (12 wk HS) by applying small amplitude (0.125%) length perturbations over a range of calcium concentrations. No differences in isometric tension-calcium relations or cross-bridge cycling kinetics or mechanical function were found at 6 wk. In contrast, 12 wk HS strips exhibited increased calcium sensitivity of isometric tension, decreased frequency of minimal dynamic stiffness, and a decreased range of frequencies over which cross bridges produce work and power. Thus the transition from hypertrophy to heart failure in DS rats is characterized by major changes in cross-bridge cycling kinetics and mechanical performance.

Diastolic dysfunction: pathophysiology, clinical features, and assessment with radionuclide methods.

Basic to our understanding of heart failure is the distinction between systolic and diastolic ventricular dysfunction. Diastolic dysfunction implies that the ventricle cannot accept blood at normally low pressures. The ventricular filling pattern and the relation between ventricular diastolic pressure and volume reflect a dynamic interaction between time course of relaxation, conversion of elastic forces into elastic recoil, and the passive properties of the ventricle. In the early part of diastolic filling, the pressure-volume relationship is influenced primarily by relaxation; in the latter part of diastole, passive filling properties are important. Mitral inflow patterns reflect these time-varying filling dynamics and are commonly assessed with echocardiography. Disorders of diastolic filling are observed in patients with heart failure with normal ejection fraction, myocardial ischemia, and even dilated cardiomyopathy. Patients with concentric ventricular hypertrophy, normal ejection fraction, and heart failure are the prototype of patients with diastolic dysfunction. In this article we review the physiology and pathophysiology of diastole and the main clinical disorders associated with diastolic dysfunction, and we outline in brief the application of radionuclide techniques in the assessment of diastolic dysfunction.

Diastolic heart failure. Constrictive, restrictive, and pericardial.

Clinical heart failure with normal systolic function is suggestive of diastolic dysfunction. This can result from myocardial or pericardial disorders. Myocardial disorders are a broad range of pathologies leading to restrictive physiology. Amyloidosis is a prototype of restrictive cardiomyopathy leading to diastolic dysfunction. Pericardial disorders leading to diastolic heart failure are usually in the form of constrictive physiology. Differentiation between restrictive and constrictive pathologies is often difficult and require careful attention to hemodynamic and Doppler echocardiographic features.

Alterations in the determinants of diastolic suction during pacing tachycardia.

In cardiomyocytes, generation of restoring forces (RFs) responsible for elastic recoil involves deformation of the sarcomeric protein titin in conjunction with shortening below slack length. At the left ventricular (LV) level, recoil and filling by suction require contraction to an end-systolic volume (ESV) below equilibrium volume (Veq) as well as large-scale deformations, for example, torsion or twist. Little is known about RFs and suction in the failing ventricle. We undertook a comparison of determinants of suction in open-chest dogs previously subjected to 2 weeks of pacing tachycardia (PT) and controls. To assess the ability of the LV to contract below Veq, we used a servomotor to clamp left atrial pressure and produce nonfilling diastoles, allowing measurement of fully relaxed pressure at varying volumes. We quantified twist with sonomicrometry. We also assessed transmural ratios of N2B to N2BA titin isoforms and total titin to myosin heavy chain (MHC) protein. In PT, the LV did not contract below Veq, even with marked reduction of volume (end-diastolic pressure [EDP], 1 to 2 mm Hg), whereas in controls ESV was less than Veq when EDP was less than approximately 5 mm Hg. In PT, both systolic twist and diastolic untwisting rate were reduced, and there was exaggerated transmural variation in titin isoform and titin-to-MHC ratios, consistent with the more extensible N2BA being present in larger amounts in the subendocardium. Thus, in PT, determinants of suction at the level of the LV are markedly impaired. The altered transmural titin isoform gradient is consistent with a decrease in RFs and may contribute to these findings.

Ingenuous interpretation of elevated blood levels of macromolecular markers of myocardial injury: a recipe for confusion.

Several assumptions about elevations of macromolecular markers of myocardial injury in blood require critical consideration. The dichotomy of modest, persistent elevations of troponins I and T as prognostic factors in patients with unstable angina and absent elevations of isoenzymes of creatine kinase is presently unexplained. Factors influencing the appearance of macromolecular markers of myocardial injury in blood are considered, including the need to estimate baseline values, to consider elevations as deviations from baseline rather than simply points within a distribution of baseline values in normal subjects, to recognize operative biochemical and physiologic determinants of marker release from injured myocytes and washout and to take into account the influence of apoptosis. Elucidation and consideration of mechanisms underlying the appearance of specific macromolecular markers in blood appear likely to improve diagnosis and explain the prognostic power of the troponins in patients with unstable angina. Detection of proteolytic breakdown products of troponins in blood is likely to explain the modest, persistent elevations seen in some patients with unstable angina and their prognostic implications.

Altered crossbridge kinetics in the alphaMHC403/+ mouse model of familial hypertrophic cardiomyopathy.

A mutation in the cardiac beta-myosin heavy chain, Arg403Gln (R403Q), causes a severe form of familial hypertrophic cardiomyopathy (FHC) in humans. We used small-amplitude (0.25%) length-perturbation analysis to examine the mechanical properties of skinned left ventricular papillary muscle strips from mouse hearts bearing the R403Q mutation in the alpha-myosin heavy chain (alphaMHC403/+). Myofibrillar disarray with variable penetrance occurred in the left ventricular free wall of the alphaMHC403/+ hearts. In resting strips (pCa 8), dynamic stiffness was approximately 40% greater than in wild-type strips, consistent with elevated diastolic stiffness reported for murine hearts with FHC. At pCa 6 (submaximal activation), strip isometric tension was approximately 3 times higher than for wild-type strips, whereas at pCa 5 (maximal activation), tension was marginally lower. At submaximal calcium activation the characteristic frequencies of the work-producing (b) and work-absorbing (c) steps of the crossbridge were less in alphaMHC403/+ strips than in wild-type strips (b=11+/-1 versus 15+/-1 Hz; c= 58+/-3 versus 66+/-3 Hz; 27 degrees C). At maximal calcium activation, strip oscillatory power was reduced (0. 53+/-0.25 versus 1.03+/-0.18 mW/mm3; 27 degrees C), which is partly attributable to the reduced frequency b, at which crossbridge work is maximum. The results are consistent with the hypothesis that the R403Q mutation reduces the strong binding affinity of myosin for actin. Myosin heads may accumulate in a preforce state that promotes cooperative activation of the thin filament at submaximal calcium but blunts maximal tension and oscillatory power output at maximal calcium. The calcium-dependent effect of the mutation (whether facilitating or debilitating), together with a variable degree of fibrosis and myofibrillar disorder, may contribute to the diversity of clinical symptoms observed in murine FHC.

Left ventricular restoring forces: modulation by heart rate and contractility.

We used a servomotor system in open-chest dogs to rapidly clamp left atrial pressure below left ventricular (LV) diastolic pressure in order to produce nonfilling diastoles during which the LV fully relaxed at its end-systolic volume (ESV). Restoring forces (RFs) generated during contraction which result in LV filling by suction were considered to be present when the fully relaxed pressure (FRP) was negative. We characterized RFs in terms of the fully relaxed pressure-volume relation (FRPV relation, FRP plotted vs ESV), which has negative and positive portions and an equilibrium volume (FRP = 0 mmHg). A negative FRP is ordinarily present over the lower half of the physiologic filling range. Increased contractility (systemic dobutamine) shifts the FRPV relation downward, indicating greater RFs at any ESV. Intracoronary dobutamine administered via the left anterior descending coronary artery has the same effect. Acute increases in heart rate from about 100 to 150 beats/min did not alter the FRPV relation. In contrast, chronic tachycardia heart failure resulted in marked depression of the ability to generate RFs, even at very low volumes. Thus, RFs normally contribute to LV filling. They are augmented by acute increases in global and anterior wall contractility but not heart rate, within the range specified above. Chronic tachycardia heart failure markedly attenuated RFs. The latter may constitute a previously unappreciated mechanism of diastolic dysfunction in heart failure.

Mechanoenergetic alterations during the transition from cardiac hypertrophy to failure in Dahl salt-sensitive rats.

BACKGROUND: The time course and mechanisms of altered mechanoenergetics and depressed cross-bridge cycling in hypertrophied and failing myocardium are uncertain. METHODS AND RESULTS: We studied mechanoenergetics in Dahl salt-sensitive (DS) rats fed high-salt diet (HS) for 6 (HS-6) and 12 (HS-12) weeks to produce compensated hypertrophy and failure. The slope of the end-systolic pressure-volume relation (E'max) was similar in HS-6 and low-salt controls (LS-6), but reduced in HS-12 compared with controls (LS-12). Efficiency [1/slope of oxygen consumption (&f1;O2)-pressure-volume area (PVA) relation] was similar in HS-6 and LS-6 but higher in HS-12 versus LS-12 (59+/-16% versus 44+/-7%, P<0.05). Economy [1/slope of the force-time integral (FTI)-&f1;O2 relation] was similar in HS-6 and LS-6 but higher in HS-12 versus LS-12 (218+/-123 versus 74+/-39x10(3) g. s. mL O2-1. g; P<0.05). Compared with controls, myofibrillar ATPase activity was reduced by 24% in HS-6 and 44% in HS-12. V3 Isomyosin was increased in HS-6 (40+/-12% versus 9+/-8%; P<0.05) and further increased in HS-12 (76+/-10% versus 22+/-18%; P<0.05). Hypothyroid LS-12 rats had 100% V3 isomyosin, yet efficiency, economy, and ATPase values were intermediate between LS-12 and HS-12. HS-12 rats demonstrated increased troponin T3 isoform (17+/-2 versus 23+/-2%, P<0.05). There were no changes in troponin I or tropomyosin isoforms. However, the proportion of phosphorylated troponin T was reduced in HS-12 versus LS-12 hearts (P<.001). CONCLUSIONS: In DS rats, the transition to failure is associated with depressed E'max and increased efficiency and economy. These findings are linked to myofibrillar ATPase activity and suggest that mechanisms other than isomyosin switching are important determinants of ventricular energetics. A troponin T isoform switch is one potential mechanism.

Effects of dobutamine on left ventricular restoring forces.

Restoring forces, which are generated when the left ventricle contracts below its equilibrium volume (Veq), are responsible for diastolic suction. Their magnitude is inversely related to end-systolic volume (ESV). In previous studies in which the mitral valve was replaced with a prosthesis, increased contractility was shown to augment restoring forces independently of ESV. In the present study, we quantified restoring forces in the presence of an intact mitral valve in open-chest dogs (n = 6) as the fully relaxed pressure (FRP) after completion of left ventricular pressure (LVP) fall during nonfilling diastoles produced by a servomotor system that clamped left atrial pressure below LVP. A negative FRP indicated a restoring force was present. We related FRP to ESV during control, intravenous, and left anterior descending coronary artery (intracoronary) administration of dobutamine. With intravenous dobutamine, we observed an approximately parallel downward and rightward shift of the FRP-ESV relation, indicating increased restoring forces at any ESV less than Veq. The downward shift averaged -2.6 +/- 1.6 (SD) mmHg at the control Veq. A similar shift occurred with intracoronary dobutamine. In additional experiments (n = 2), we found that over a common range of ESV dobutamine slightly increased wall thickness (<10%) during nonfilling diastoles, consistent with an increase in coronary blood volume. We conclude that dobutamine increases restoring forces independently of changes in ESV in conjunction with an increase in Veq. This effect may partly be related to increased coronary blood volume.

Effect of enalapril therapy on left ventricular mass and volumes in asymptomatic chronic, severe mitral regurgitation secondary to mitral valve prolapse.

Quantitative 2-dimensional and Doppler echocardiography was used to assess the longitudinal effects of angiotensin-converting enzyme inhibition in asymptomatic patients with chronic, severe mitral regurgitation due to mitral valve prolapse. Over a 6-month period, angiotensin-converting enzyme inhibition therapy resulted in significant reductions in left ventricular volumes and mass in association with a minor reduction in regurgitant fraction.

Left ventricular systolic torsion and early diastolic filling by echocardiography in normal humans.

This study describes a novel 2-dimensional echocardiographic technique to measure left ventricular (LV) systolic twist in humans and relates this measure to early ventricular filling. LV twist is the counterclockwise rotation of the left ventricle during systole when viewed from the apex. The effect of ventricular twist has been postulated to store potential energy, which ultimately aids in diastolic recoil, leading to ventricular suction. The generated negative early diastolic pressures may augment early ventricular filling. We measured ventricular twist in 40 patients with normal transthoracic echocardiograms. End-systolic twist was determined by measuring rotation of the anterolateral papillary muscle about the center of the ventricle. LV filling was assessed by analysis of transmitral Doppler flow velocities. The mean value obtained was 9 +/- 7 degrees of rotation. Twist measurements were highly reproducible with an intraobserver correlation coefficient of r = 0.881, p <0.001. The magnitude of ventricular twist was strongly correlated positively with acceleration of the mitral E-wave (r = 0.75; p <0.0001) and negatively with the mitral E-wave acceleration time (r = -0.83; p <0.0001).

Mechanoenergetic studies in isolated mouse hearts.

We tested the feasibility of an isolated, balloon-in-ventricle, isovolumically contracting, crystalloid-perfused mouse heart preparation (n = 10) for studies of cardiac mechanoenergetics using the end-systolic pressure-volume relation (ESPVR) and myocardial oxygen consumption (VO2)-pressure-volume area (PVA) framework employed in larger species. The intraventricular balloon method was shown to be accurate for measurement of left ventricular volume, especially at relatively higher volumes. The ESPVR demonstrated contractility-dependent curvilinearity. Average slope of the ESPVR was 1,299 +/- 369 (SD) mmHg.g.ml-1, with a volume intercept of 0.018 +/- 0.006 ml. The VO2-PVA relation was well fitted by a straight line, with average slope and VO2 intercept of 3.57 +/- 1.31 x 10(-5) ml O2.mmHg-1.ml-1 and 0.92 +/- 0.21 x 10(-3) ml O2.beat-1.g-1, respectively. Decreasing perfusate Ca2+ concentration resulted in a decrease in the slope of the ESPVR, a decrease in the VO2 intercept of the VO2-PVA relation, but no significant change in its slope. Hearts from hypothyroid (n = 8) mice demonstrated similar mechanoenergetic changes. We conclude that delineation of the ESPVR and the VO2-PVA relation is feasible in the mouse heart. Our method should allow an assessment of cardiac mechanoenergetics as sophisticated as that previously possible only in larger hearts.

Decrease in forces responsible for diastolic suction during acute coronary occlusion.

BACKGROUND: The production of left ventricular (LV) restoring forces generated during contraction, which are responsible for diastolic suction, is dependent on end-systolic volume (ESV) and systolic transmural and 3D deformation. We tested the hypothesis that acute coronary occlusion would result in loss of forces that cause suction. METHODS AND RESULTS: Ten open-chest dogs were subjected to a 10-minute acute coronary occlusion (proximal left anterior descending coronary artery). A servomotor connected to the left atrium (LA) was used to rapidly clamp LA pressure during systole below the level of the succeeding LV diastolic pressure, resulting in nonfilling diastoles during which the LV fully relaxed at its ESV. LA clamps at multiple ESVs (conductance catheter) allowed delineation of positive and negative portions of the fully relaxed LV pressure-volume relation (FRPVR). A negative fully relaxed pressure (FRP) indicates the presence of restoring forces. After 10 minutes of acute coronary occlusion, there was an upward shift of the FRPVR. Thus, for example, at matched ESVs before and during coronary occlusion, FRP was -1.1+/-1.1 (+/-SD) mm Hg before versus 0.2+/-1.2 mm Hg after 10 minutes of coronary occlusion (P<.05). CONCLUSIONS: Acute coronary occlusion results in a rapid decrease in forces responsible for suction. This phenomenon is independent of the level of ESV and may contribute to ischemic diastolic dysfunction.

Altered expression of troponin T isoforms in mild left ventricular hypertrophy in the rabbit.

Alterations in troponin T (TnT) isoforms have been reported in severe human and experimental heart failure (HF), and may play a role in the depressed myofibrillar ATPase activity observed in this condition. It is unclear whether these alterations reflect very severe hemodynamic derangement or are a component of mild hypertrophic stress. Therefore, we studied the expression of TnT isoforms (SDS-PAGE, Western blots), myosin isoforms, myofibrillar ATPase activity, and left ventricular (LV) mechanoenergetics (rbc perfused, isovolumically contracting isolated heart) in a rabbit model of mild hypertrophy (LVH) due to gradual hypertension caused by 12 weeks of cellophane wrap of the kidneys (n=12). LV/body weight ratio increased by 28% in LVH compared to shams (P<0.001); no animals had evidence of HF. In LVH, the percentage of TnT2 was modestly but significantly increased compared to shams [6.2+/-1.9 (+/-S.D. ) v 3.7+/-1.0%, P<0.05], mainly as a consequence of a parallel decrease in TnT4 (P=0.07). Sham hearts ranged from 75-100% V3 isomyosin, whereas all LVH hearts had 100% of the V3 form. There were no significant differences in myofibrillar ATPase activity or mechanical variables, including contraction and relaxation rates. The slope of the VO2-pressure-volume-area relation (a measure of the energy conversion efficiency of the contractile machinery) was also unchanged. We conclude that in the rabbit, shifts in TnT isoforms toward a more "fetal" pattern occur during mild LVH and, therefore, are likely to be a general feature of the response to hemodynamic stress, rather than a phenomenon confined to end-stage disease. These modest shifts are not associated with major alterations in LV myofibrillar ATPase activity or mechanoenergetics.

Estimation of nonmechanical VO2 in isolated rabbit heart: comparison of mechanical unloading and BDM method.

To understand the mechaneoenergetics of heart muscle, it is important to be able to accurately partition energy consumption into its two major components, that used for nonmechanical activity [mainly excitation-contraction (E-C) coupling and basal metabolism] and that used for mechanical activity (cross-bridge cycling). In most experiments in the beating heart, this has been accomplished by assuming that the unloaded oxygen consumption (VO2) represents nonmechanical VO2 and subtracting it from total VO2 to yield mechanical VO2. However, unloaded VO2 is "contaminated" by an uncertain amount of energy consumption for cross-bridge cycling under unloaded conditions. We recently, reported an alternative method to estimate nonmechanical VO2 using the negative inotropic drug 2,3-butanedione monoxime (BDM), which, in theory, should not include cross-bridge cycling-related energy consumption. In the present study, we compared changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 as E-C coupling was varied by changing the perfusate Ca2+ concentration ([Ca2+]) in the isolated rabbit heart. An isolated, red blood cell-perfused, isovolumically contracting balloon in left ventricle preparation was employed. In one group (n = 8), contractility (maximal elastance), unloaded VO2, and the BDM estimate of nonmechanical VO2 were assessed at a perfusate [Ca2+] of 2.5 mM and then at 5.0 mM. In a second group (n = 6), perfusate was 1.0 and 2.5 mM. The change in contractility in each group as [Ca2+] was increased was comparable. Unloaded VO2 was systematically greater than the BDM estimate of nonmechanical VO2 under all conditions. However, the absolute change in both estimates was similar in both groups. In conclusion, over the range of perfusate [Ca2+] employed in this study, changes in unloaded VO2 and the BDM estimate of nonmechanical VO2 are similar. These results support the use of unloaded VO2, which is easier to measure and has less estimation error in individual cases than the BDM-derived value for nonmechanical VO2, as an accurate index of change in E-C coupling energy consumption.

Rapid shortening during relaxation increases activation and improves systolic performance.

BACKGROUND: Previous studies in cardiac muscle and isolated heart preparations generally have attributed positive effects of ejection to greater length-dependent activation. However, there have been some reports of an ejection-related increase in contractile function that is independent of end-diastolic volume (EDV) history. The present study was designed to more fully characterize the mechanoenergetic results of the latter effect in the intact ventricle. METHODS AND RESULTS: A servomotor was used to initiate left ventricular volume reduction (VR) at end systole, with EDV kept constant. Seven isolated, red blood cell-perfused rabbit hearts were studied at constant EDV during isovolumic contraction, slow VR (5.0 +/- 0.9 EDV/s), and rapid VR (26.8 +/- 5.1 EDV/s). Compared with isovolumic beats, VR caused an enhancement in contractility. This effect was greater for rapid VR and required > 50 beats to attain steady state. Rapid VR increased developed pressure by 15% (92.2 +/- 23.7 [mean +/- SD] versus 105.9 +/- 27.6 mm Hg), maximum dP/dt by 17% (1223 +/- 401 versus 1435 +/- 505 mm Hg.s-1), and Emax (slope of the end-systolic pressure-volume relation) by 13% (69.4 +/- 19.9 versus 78.6 +/- 23.0 mm Hg/mL) (all P < .01). Left ventricular oxygen consumption (VO2) was unchanged with slow VR and decreased by 8% with rapid VR (0.0744 +/- 0.0194 versus 0.0683 +/- 0.0141 mL O2.beat-1.100 g-1; P < .05). In separate hearts (n = 8), costs (basal metabolism and excitation-contraction coupling) were estimated by use of 2,3-butanedione monoxime. Compared with control, rapid VR was associated with a 26% increase in nonmechanical VO2 (0.0248 +/- 0.0021 versus 0.0312 +/- 0.0022 mL O2.beat-1.100 g-1; P < .01), consistent with an increase in calcium cycled per beat. CONCLUSIONS: Ejection after end systole has a positive effect on ventricular performance that cannot be ascribed to length-dependent activation and is likely related to an increase in calcium available for activation. Similarly, an increase in nonmechanical VO2 associated with ejection suggests a positive interaction between myofilament shortening and activator calcium cycling.