scholarly journals A Novel Small Molecule Troponin Activator Increases Cardiac Contractile Function Without Negative Impact on Energetics

2021 ◽  
Author(s):  
Huamei He ◽  
Tomas Baka ◽  
James Balschi ◽  
Alykhan S. Motani ◽  
Kathy K. Nguyen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Negative Impact ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Rate Pressure Product ◽  
Intact Mouse ◽  
Term Survival ◽  
Rat Hearts

Background: Current heart failure (HF) therapies unload the failing heart without targeting the underlying problem of reduced cardiac contractility. Traditional inotropes (i.e. calcitropes) stimulate contractility via energetically costly augmentation of calcium cycling and worsen patient survival. A new class of agents - myotropes - activate the sarcomere directly, independent of calcium. We hypothesize that a novel myotrope TA1 increases contractility without the deleterious myocardial energetic impact of a calcitrope dobutamine. Methods: We determined the effect of TA1 in bovine cardiac myofibrils and human cardiac microtissues, ex vivo in mouse cardiac fibers and in vivo in anesthetized normal rats. Effects of increasing concentrations of TA1 or dobutamine on contractile function, phosphocreatine (PCr) and ATP concentrations and ATP production were assessed by 31 P NMR spectroscopy on isolated perfused rat hearts. Results: TA1 increased the rate of myosin ATPase activity in isolated bovine myofibrils and calcium sensitivity in intact mouse papillary fibers. Contractility increased dose dependently in human cardiac microtissues and in vivo in rats as assessed by echocardiography. In isolated rat hearts, TA1 and dobutamine similarly increased rate pressure product (RPP). Dobutamine increased both developed pressure (DevP) and heart rate (HR) accompanied by decreased PCr to ATP ratio and decreased free energy of ATP hydrolysis (ΔG~ ATP ) and elevated left ventricular end-diastolic pressure (LVEDP). In contrast, the TA1 increased DevP without any effect on HR, LVEDP, PCr/ATP ratio or ΔG~ ATP . Conclusions: Novel myotrope, TA1, increased myocardial contractility by sensitizing the sarcomere to calcium without impairing diastolic function or depleting the cardiac energy reserve. Since energetic depletion negatively correlates with long term survival, myotropes may represent a superior alternative to traditional inotropes in heart failure management.

scholarly journals Alterations in Glucose Metabolism During the Transition to Heart Failure: The Contribution of UCP-2

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 552 ◽  
Author(s):  
Hanna Sarah Kutsche ◽  
Rolf Schreckenberg ◽  
Martin Weber ◽  
Christine Hirschhäuser ◽  
Susanne Rohrbach ◽  
...  
Keyword(s):  
Heart Failure ◽  
Glucose Metabolism ◽  
Glucose Uptake ◽  
Glucose Transporter ◽  
Contractile Function ◽  
Uncoupling Protein ◽  
Left Ventricular ◽  
Mitochondrial Uncoupling ◽  
Glut 4

The cardiac expression of the mitochondrial uncoupling protein (UCP)-2 is increased in patients with heart failure. However, the underlying causes as well as the possible consequences of these alterations during the transition from hypertrophy to heart failure are still unclear. To investigate the role of UCP-2 mechanistically, expression of UCP-2 was silenced by small interfering RNA in adult rat ventricular cardiomyocytes. We demonstrate that a downregulation of UCP-2 by siRNA in cardiomyocytes preserves contractile function in the presence of angiotensin II. Furthermore, silencing of UCP-2 was associated with an upregulation of glucose transporter type (Glut)-4, increased glucose uptake, and reduced intracellular lactate levels, indicating improvement of the oxidative glucose metabolism. To study this adaptation in vivo, spontaneously hypertensive rats served as a model for cardiac hypertrophy due to pressure overload. During compensatory hypertrophy, we found low UCP-2 levels with an upregulation of Glut-4, while the decompensatory state with impaired function was associated with an increase of UCP-2 and reduced Glut-4 expression. By blocking the aldosterone receptor with spironolactone, both cardiac function as well as UCP-2 and Glut-4 expression levels of the compensated phase could be preserved. Furthermore, we were able to confirm this by left ventricular (LV) biopsies of patients with end-stage heart failure. The results of this study show that UCP-2 seems to impact the cardiac glucose metabolism during the transition from hypertrophy to failure by affecting glucose uptake through Glut-4. We suggest that the failing heart could benefit from low UCP-2 levels by improving the efficiency of glucose oxidation. For this reason, UCP-2 inhibition might be a promising therapeutic strategy to prevent the development of heart failure.

scholarly journals Changes in myofilament proteins, but not Ca2+ regulation, are associated with a high-fat diet-induced improvement in contractile function in heart failure

2011 ◽  
Vol 301 (4) ◽  
pp. H1438-H1446 ◽  
Author(s):  
Y. Cheng ◽  
W. Li ◽  
T. A. McElfresh ◽  
X. Chen ◽  
J. M. Berthiaume ◽  
...  
Keyword(s):  
Heart Failure ◽  
Protein Expression ◽  
Contractile Function ◽  
Left Ventricular ◽  
Contractile Properties ◽  
Coronary Artery Ligation ◽  
Artery Ligation ◽  
Cell Shortening ◽  
Regulatory Properties

Pathological conditions such as diabetes, insulin resistance, and obesity are characterized by elevated plasma and myocardial lipid levels and have been reported to exacerbate the progression of heart failure (HF). Alterations in cardiomyocyte Ca2+ regulatory properties and myofilament proteins have also been implicated in contractile dysfunction in HF. However, our prior studies reported that high saturated fat (SAT) feeding improves in vivo myocardial contractile function, thereby exerting a cardioprotective effect in HF. Therefore, we hypothesized that SAT feeding improves contractile function by altering Ca2+ regulatory properties and myofilament protein expression in HF. Male Wistar rats underwent coronary artery ligation (HF) or sham surgery (SH) and were fed normal chow (SHNC and HFNC groups) or a SAT diet (SHSAT and HFSAT groups) for 8 wk. Contractile properties were measured in vivo [echocardiography and left ventricular (LV) cannulation] and in isolated LV cardiomyocytes. In vivo measures of contractility (peak LV +dP/d t and −dP/d t) were depressed in the HFNC versus SHNC group but improved in the HFSAT group. Isolated cardiomyocytes from both HF groups were hypertrophied and had decreased percent cell shortening and a prolonged time to half-decay of the Ca2+ transient versus the SH group; however, SAT feeding reduced in vivo myocyte hypertrophy in the HFSAT group only. The peak velocity of cell shortening was reduced in the HFNC group but not the HFSAT group and was positively correlated with in vivo contractile function (peak LV +dP/d t). The HFNC group demonstrated a myosin heavy chain (MHC) isoform switch from fast MHC-α to slow MHC-β, which was prevented in the HFSAT group. Alterations in Ca2+ transients, L-type Ca2+ currents, and protein expression of sarco(endo)plasmic reticulum Ca2+-ATPase and phosphorylated phospholamban could not account for the changes in the in vivo contractile properties. In conclusion, the cardioprotective effects associated with SAT feeding in HF may occur at the level of the isolated cardiomyocyte, specifically involving changes in myofilament function but not sarcoplasmic reticulum Ca2+ regulatory properties.

Redistribution and abnormal activity of phospholipase A2 isoenzymes in postinfarct congestive heart failure

2001 ◽  
Vol 280 (3) ◽  
pp. C573-C580 ◽  
Author(s):  
Jane McHowat ◽  
Paramjit S. Tappia ◽  
Song-Yan Liu ◽  
Raetreal McCrory ◽  
Vincenzo Panagia
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Phospholipase D ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Immunoblot Analysis ◽  
Left Ventricular ◽  
Hemodynamic Assessment ◽  
Intracellular Ca ◽  
Contractile Performance

Cardiac sarcolemmal (SL) cis-unsaturated fatty acid sensitive phospholipase D ( cis-UFA PLD) is modulated by SL Ca2+-independent phospholipase A2(iPLA2) activity via intramembrane release of cis-UFA. As PLD-derived phosphatidic acid influences intracellular Ca2+ concentration and contractile performance of the cardiomyocyte, changes in iPLA2 activity may contribute to abnormal function of the failing heart. We examined PLA2 immunoprotein expression and activity in the SL and cytosol from noninfarcted left ventricular (LV) tissue of rats in an overt stage of congestive heart failure (CHF). Hemodynamic assessment of CHF animals showed an increase of the LV end-diastolic pressure with loss of contractile function. In normal hearts, immunoblot analysis revealed the presence of cytosolic PLA2 (cPLA2) and secretory PLA2 (sPLA2) in the cytosol, with cPLA2 and iPLA2 in the SL. Intracellular PLA2 activity was predominantly Ca2+independent, with minimal sPLA2 activity. CHF increased cPLA2 immunoprotein and PLA2 activity in the cytosol and decreased SL iPLA2 and cPLA2immunoprotein and SL PLA2 activity. sPLA2activity and abundance decreased in the cytosol and increased in SL in CHF. The results show that intrinsic to the pathophysiology of post-myocardial infarction CHF are abnormalities of SL PLA2isoenzymes, suggesting that PLA2-mediated bioprocesses are altered in CHF.

KATP channel knockout worsens myocardial calcium stress load in vivo and impairs recovery in stunned heart

2007 ◽  
Vol 292 (4) ◽  
pp. H1706-H1713 ◽  
Author(s):  
Richard J. Gumina ◽  
D. Fearghas O'Cochlain ◽  
Christopher E. Kurtz ◽  
Peter Bast ◽  
Darko Pucar ◽  
...  
Keyword(s):  
Diastolic Pressure ◽  
Gene Knockout ◽  
Heart Function ◽  
Dobutamine Stress ◽  
Left Ventricular ◽  
Calcium Handling ◽  
Rate Pressure Product ◽  
Metabolic Demand ◽  
Male And Female

Gene knockout of the KCNJ11-encoded Kir6.2 ATP-sensitive K+ (KATP) channel implicates this stress-response element in the safeguard of cardiac homeostasis under imposed demand. KATP channels are abundant in ventricular sarcolemma, where subunit expression appears to vary between the sexes. A limitation, however, in establishing the full significance of KATP channels in the intact organism has been the inability to monitor in vivo the contribution of the channel to intracellular calcium handling and the superimposed effect of sex that ultimately defines heart function. Here, in vivo manganese-enhanced cardiac magnetic resonance imaging revealed, under dobutamine stress, a significantly greater accumulation of calcium in both male and female KATP channel knockout (Kir6.2-KO) mice compared with sex- and age-matched wild-type (WT) counterparts, with greatest calcium load in Kir6.2-KO females. This translated, poststress, into a sustained contracture manifested by reduced end-diastolic volumes in KATP channel-deficient mice. In response to ischemia-induced stunning, male and female Kir6.2-KO hearts demonstrated accelerated time to contracture and increased peak contracture compared with WT. The outcome on reperfusion, in both male and female Kir6.2-KO hearts, was a transient reduction in systolic performance, measured as rate-pressure product compared with WT, with protracted increase in left ventricular end-diastolic pressure, exaggerated in female knockout hearts, despite comparable leakage of creatine kinase across groups. Kir6.2-KO hearts were rescued from diastolic dysfunction by agents that target alternative pathways of calcium handling. Thus KATP channel deficit confers a greater susceptibility to calcium overload in vivo, accentuated in female hearts, impairing contractile recovery under various conditions of high metabolic demand.

scholarly journals Slowing of cardiomyocyte Ca2+ release and contraction during heart failure progression in postinfarction mice

2009 ◽  
Vol 296 (4) ◽  
pp. H1069-H1079 ◽  
Author(s):  
Halvor K. Mørk ◽  
Ivar Sjaastad ◽  
Ole M. Sejersted ◽  
William E. Louch
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Contractile Function ◽  
Cardiac Contractility ◽  
Posterior Wall ◽  
Left Ventricular ◽  
Shortening Velocity ◽  
Transient Time

Deterioration of cardiac contractility during congestive heart failure (CHF) is believed to involve decreased function of individual cardiomyocytes and may include reductions in contraction magnitude and/or kinetics. We examined the progression of in vivo and in vitro alterations in contractile function in CHF mice and investigated underlying alterations in Ca2+ homeostasis. Following induction of myocardial infarction (MI), mice with CHF were examined at early (1 wk post-MI) and chronic (10 wk post-MI) stages of disease development. Sham-operated mice served as controls. Global and local left ventricle function were assessed by echocardiography in sedated animals (∼2% isoflurane). Excitation-contraction coupling was examined in cardiomyocytes isolated from the viable septum. CHF progression between 1 and 10 wk post-MI resulted in increased mortality, development of hypertrophy, and deterioration of global left ventricular function. Local function in the noninfarcted myocardium also declined, as posterior wall shortening velocity was reduced in chronic CHF (1.2 ± 0.1 vs. 1.9 ± 0.2 cm/s in sham). Parallel alterations occurred in isolated cardiomyocytes since contraction and Ca2+ transient time to peak values were prolonged in chronic CHF (115 ± 6 and 158 ± 11% sham values, respectively). Surprisingly, contraction and Ca2+ transient magnitudes in CHF were larger than sham values at both time points, resulting from increased sarcoplasmic reticulum Ca2+ content and greater Ca2+ influx via L-type channels. We conclude that, in mice with CHF following myocardial infarction, declining myocardial function involves slowing of cardiomyocyte contraction without reduction in contraction magnitude. Corresponding alterations in Ca2+ transients suggest that slowing of Ca2+ release is a critical mediator of CHF progression.

Regulatory effects of phospholamban on cardiac function in intact mice

1997 ◽  
Vol 273 (6) ◽  
pp. H2826-H2831 ◽  
Author(s):  
John N. Lorenz ◽  
Evangelia G. Kranias
Keyword(s):  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Physiological Role ◽  
Cardiovascular Effects ◽  
Left Ventricular ◽  
In Vivo Evaluation ◽  
Intact Mouse ◽  
Cardiac Sarcoplasmic Reticulum ◽  
Inotropic Effects

Phospholamban (PLB) regulates Ca2+- adenosinetriphosphatase activity in cardiac sarcoplasmic reticulum and participates in the regulation of myocardial performance. Animal models with altered levels of PLB permit in vivo evaluation of the physiological role of PLB. This study examined left ventricular (LV) performance in intact PLB heterozygous and homozygous mice under basal and stimulated conditions. A Millar Mikro-Tip transducer was inserted into the right carotid artery and advanced into the LV for direct measurement of ventricular pressure and the first derivative of intraventricular pressure (dP/d t). Baseline blood pressures were increased in PLB heterozygotes and even more so in PLB homozygotes compared with wild types (WT), and there were no differences in heart rate or LV end-diastolic pressure. The increase in pressure was primarily caused by an increase in systolic pressure. Baseline values for positive and negative dP/d t were linearly correlated with PLB levels. In PLB heterozygotes, contractile response to isoproterenol (Iso) was blunted compared with WT, but maximum rates of contraction were similar between the two groups. Contractile performance in PLB homozygous mice, which under baseline conditions was similar to maximum levels seen in WT, showed a blunted response to Iso, and maximum rates of contraction were significantly greater than in either of the other groups, indicating an essential but perhaps not exclusive role for PLB in mediating the inotropic effects of β-adrenergic agonists. The effects of Iso on negative dP/d t were also blunted in both PLB heterozygous and PLB homozygous animals. Our results demonstrate that myocardial function is highly dependent on PLB level and suggest that the cardiovascular effects of PLB perturbations are largely uncompensated for in the intact mouse.

Abstract 13438: The Role and Mechanism of Chronic Beta3-Adrenergic Receptor Blockade on the Progression of Heart Failure in a Rat Model

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Xiaoqiang Sun ◽  
Che Cheng ◽  
Jing Cao ◽  
Zhi Zhang ◽  
Tiankai Li ◽  
...  
Keyword(s):  
Heart Failure ◽  
Diastolic Pressure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Plasma Norepinephrine ◽  
Functional Responses ◽  
Generating Capacity ◽  
Precise Role ◽  
Mini Pump

Background: The negative inotrope and up-regulation of β 3 -adrenergic receptors (AR) in human and animal failing hearts suggest a direct and contributing role of cardiac β 3 -AR activation on the progression of congestive heart failure (CHF). However, its precise role is still being debated. We hypothesize that up-regulation of cardiac β 3 -AR is detrimental and chronic β 3 -AR blockade may prevent CHF-caused intrinsic defects of left ventricular (LV) myocyte force-generating capacity and relaxation and improve β-AR regulation, thereby limiting the progression of CHF. Methods: We compared the alterations of LV and myocyte functional responses and [Ca 2+ ] i transient ([Ca 2+ ] iT ) in SD rats divided into 3 groups (8/group): 1) CHF 3 months after isoproterenol (ISO) (170 mg/kg, sq, for 2 days); 2) ISO/β 3 -ANT , 2 months after receiving ISO, a selective β 3 -AR antagonist (ANT), L-748,337, was initiated (10 -7 M/kg/day, sq. by mini-pump) and was given for 1 month; and 3) Sham controls . Results: Compared with controls, the animals that received ISO treatment had CHF onset at 1 month and progressed to severe HF at 3 months after ISO. Plasma norepinephrine (NE) (1295 vs 259 pg/ml) increased 5-fold; whereas, stroke volume (SV) (39 vs 91 μl) and ejection fraction (EF) (39 vs 62%) significantly decreased, and LV end-diastolic pressure (P ED ) (13.9 vs 6.0 mmHg) was doubled. These changes were paralleled with about 50% reductions in cell contraction (dL/dt max , 93 vs 186 μm/s) and relaxation (dR/dt max , 96 vs 159 μm/s) associated with a significant decrease in the peak systolic [Ca 2+ ] iT , (0.17 vs 0.26). In addition, superfusion of ISO (10 -8 M) caused much less increases in dL/dt max (39 vs 68%), dR/dt max (23 vs 54%), and [Ca 2+ ] IT (14 vs 28%). Treatment with β 3 -ANT increased SV (89 μl) and EF (60%), decreased P ED more than 90% from ISO-treated values, and corrected the elevation of plasma NE (301 pg/ml), dL/dt max (184 μm/s), dR/dt max (152 μm/s), and [Ca 2+ ] iT (0.24). ISO-induced increase in dL/dt max and [Ca 2+ ] iT also returned close to control levels. Conclusion: Chronic β 3 -ANT treatment after CHF significantly improves LV and myocyte contractile function and [Ca 2+ ] i regulation and limits the development of CHF. Thus, β 3 -AR blocker may provide a new therapeutic strategy for the treatment of CHF.

Lethal ischemia due to intracoronary endothelin in pigs

1989 ◽  
Vol 257 (1) ◽  
pp. H339-H343 ◽  
Author(s):  
D. Ezra ◽  
R. E. Goldstein ◽  
J. F. Czaja ◽  
G. Z. Feuerstein
Keyword(s):  
Diastolic Pressure ◽  
Contractile Function ◽  
Left Ventricular ◽  
Systemic Hemodynamic ◽  
Progressive Decline ◽  
Cardiac Tissues ◽  
Persistent Hypotension ◽  
Net Release

Endothelin is a recently discovered endothelium-derived peptide with potent coronary constrictor properties in vitro. To evaluate endothelin's cardiac actions in vivo, we measured coronary flow and regional myocardial shortening when intracoronary porcine endothelin was given to anesthetized open-chested pigs. Bolus adminstration into the left anterior descending (LAD) coronary artery of six pigs caused dose-related rapidly reversing depression of LAD flow and local shortening. Marked reductions in flow [-71 +/- 8 (SE) %] and shortening (-83 +/- 2%) after 30 pmol/kg demonstrated endothelin's potency in cardiac tissues. Systemic hemodynamic values were unaltered except for transient rises in left ventricular end-diastolic pressure. Endothelin-induced decrement in LAD flow was accompanied by electrocardiographic signs of myocardial ischemia and net release of local myocardial lactate. Intracoronary infusion of endothelin, 15 pmol.kg-1.min-1, caused progressive decline in LAD flow and local shortening followed by severe persistent hypotension and terminal ventricular fibrillation in four of five pigs. Unlike intracoronary delivery of other potent coronary constrictors, intracoronary administration of endothelin did not lead to rapid escape from the peptide's deleterious influence. Coronary exposure to endothelin under pathophysiological circumstances could result in uniquely persistent decrements in myocardial perfusion and contractile function.

Myocardial adrenergic changes at two stages of heart failure due to adriamycin treatment in rats

1991 ◽  
Vol 260 (3) ◽  
pp. H909-H916 ◽  
Author(s):  
J. Tong ◽  
P. K. Ganguly ◽  
P. K. Singal
Keyword(s):  
Heart Failure ◽  
Congestive Heart Failure ◽  
Structural Changes ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Ventricular Systolic Pressure ◽  
Two Stages

Changes in myocardial norepinephrine (NE) levels, turnover, uptake, and release in rats were examined at two stages of cardiac dysfunction induced by adriamycin (ADR) given intraperitoneally in six equal doses over a period of 2 wk for a cumulative dose of 15 mg/kg. At 3 wk posttreatment, ADR-treated animals showed no changes in left ventricular systolic pressure (LVSP), aortic systolic pressure (ASP), and aortic diastolic pressure (ADP) but left ventricular end-diastolic pressure (LVEDP) was significantly higher. At 6 wk posttreatment, LVSP, ASP, and ADP were significantly lower and LVEDP remained elevated. Animals in both ADR-treated groups showed signs of congestive heart failure as indicated by ascites, congestive liver, and elevated LVEDP. Structural changes typical of ADR cardiomyopathy were more pronounced in the 6-wk group. In vivo hemodynamic as well as in vitro muscle function response to different concentrations of epinephrine was depressed in its duration as well as extent in both 3- and 6-wk ADR-treated groups. Myocardial NE levels were increased in the 3-wk group but were depressed in the 6-wk group. NE turnover was faster in both 3- and 6-wk ADR groups, uptake was increased only in the 6-wk group, and release was unchanged. These data show increased cardiac sympathetic tone at both stages of ADR-induced congestive heart failure.

Ventricular-specific expression of angiotensin II type 2 receptors causes dilated cardiomyopathy and heart failure in transgenic mice

2003 ◽  
Vol 285 (5) ◽  
pp. H2179-H2187 ◽  
Author(s):  
Xinhua Yan ◽  
Robert L. Price ◽  
Masaharu Nakayama ◽  
Kenta Ito ◽  
Adam J. T. Schuldt ◽  
...  
Keyword(s):  
Heart Failure ◽  
Angiotensin Ii ◽  
Dilated Cardiomyopathy ◽  
Diastolic Pressure ◽  
Systolic Pressure ◽  
Left Ventricular ◽  
Specific Expression ◽  
Protein Levels

The angiotensin II type 2 (AT2) receptor is upregulated in the left ventricle in heart failure, but its pathophysiological roles in vivo are not understood. In the present study, AT2 receptors were expressed in transgenic (TG) mice using the ventricular-specific myosin light-chain (MLC-2v) promoter. In TG compared with nontransgenic (NTG) mice, in vivo left ventricular (LV) systolic pressure and peak +dP/d t were depressed while LV diastolic pressure was elevated ( P < 0.05). Echocardiography showed severely depressed LV fractional shortening, increased systolic and diastolic dimensions, and wall thinning ( P < 0.05). Confocal and electron microscopy studies revealed an increase in the size of myocytes and interstitial spaces as well as an increase in interstitial collagen, disruption of the Z-band, and changes in cytochrome c localization. The changes were most prominent in the highest-expressing TG line, which implies a dose-response relationship. AT2 overexpression was also directly associated with the increase of phosphorylated protein levels of PKC-α, PKC-β, and p70S6 kinase. These data demonstrate that ventricular myocyte-specific expression of AT2 receptors promotes the development of dilated cardiomyopathy and heart failure in vivo.

Sign in / Sign up

Export Citation Format

Share Document