Targeting Cardiac Myocyte Na
            +
            -K
            +
            Pump Function With β3 Adrenergic Agonist in Rabbit Model of Severe Congestive Heart Failure

Background: Abnormally high cytosolic Na + concentrations in advanced heart failure impair myocardial contractility. Stimulation of the membrane Na + -K + pump should lower Na + concentrations, and the β3 adrenoceptor (β3 AR) mediates pump stimulation in myocytes. We examined if β3 AR-selective agonists given in vivo increase myocyte Na + -K + pump activity and reverse organ congestion in severe heart failure (HF). Methods: Indices for HF were lung-, heart-, and liver: body weight ratios and ascites after circumflex coronary artery ligation in rabbits. Na + -K + pump current, I p , was measured in voltage-clamped myocytes from noninfarct myocardium. Rabbits were treated with the β3 AR agonists CL316,243 or ASP9531, starting 2 weeks after coronary ligation. Results: Coronary ligation caused ascites in most rabbits, significantly increased lung-, heart-, and liver: body weight ratios, and decreased I p relative to that for 10 sham-operated rabbits. Treatment with CL316,243 for 3 days significantly reduced lung-, heart-, and liver: body weight ratios and prevalence of ascites in 8 rabbits with HF relative to indices for 13 untreated rabbits with HF. It also increased I p significantly to levels of myocytes from sham-operated rabbits. Treatment with ASP9531 for 14 days significantly reduced indices of organ congestion in 6 rabbits with HF relative to indices of 6 untreated rabbits, and it eliminated ascites. β3 AR agonists did not significantly change heart rates or blood pressures. Conclusions: Parallel β3 AR agonists-induced reversal of Na + -K + pump inhibition and indices of congestion suggest pump inhibition is a useful target for treatment with β3 AR agonists in congestive HF.

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Effects of Dantrolene on Arrhythmogenicity in Isolated Regional Ischemia-Reperfusion Rabbit Hearts with or without Pacing-Induced Heart Failure

BioMed Research International ◽

10.1155/2015/532820 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 2

Author(s):

Chung-Chuan Chou ◽

Hui-Ling Lee ◽

Po-Cheng Chang ◽

Hung-Ta Wo ◽

Ming-Shien Wen ◽

...

Keyword(s):

Heart Failure ◽

Ischemia Reperfusion ◽

Rabbit Model ◽

Control Group ◽

Ventricular Premature Beat ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Regional Ischemia ◽

Intracellular Ca

Dantrolene was reported to suppress ventricular fibrillation (VF) in failing hearts with acute myocardial infarction, but its antiarrhythmic efficacy in regional ischemia-reperfusion (IR) hearts remains debatable. Heart failure (HF) was induced by right ventricular pacing. The IR rabbit model was created by coronary artery ligation for 30 min, followed by reperfusion for 15 min in vivo in both HF and non-HF groups (n= 9 in each group). Simultaneous voltage and intracellular Ca2+(Cai) optical mapping was then performed in isolated Langendorff-perfused hearts. Electrophysiological studies were conducted and VF inducibility was evaluated by dynamic pacing. Dantrolene (10 μM) was administered after baseline studies. The HF group had a higher VF inducibility than the control group. Dantrolene had both antiarrhythmic (prolonged action potential duration (APD) and effective refractory period) and proarrhythmic effects (slowed conduction velocity, steepened APD restitution slope, and enhanced arrhythmogenic alternans induction) but had no significant effects on ventricular premature beat (VPB) suppression and VF inducibility in both groups. A higher VF conversion rate in the non-HF group was likely due to greater APD prolonging effects in smaller hearts compared to the HF group. The lack of significant effects on VPB suppression by dantrolene suggests that triggered activity might not be the dominant mechanism responsible for VPB induction in the IR model.

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Inhibition of N-type calcium channels in cardiac sympathetic neurons attenuates ventricular arrhythmogenesis in heart failure

Cardiovascular Research ◽

10.1093/cvr/cvaa018 ◽

2020 ◽

Author(s):

Dongze Zhang ◽

Huiyin Tu ◽

Chaojun Wang ◽

Liang Cao ◽

Wenfeng Hu ◽

...

Keyword(s):

Heart Failure ◽

Coronary Artery ◽

Ventricular Arrhythmias ◽

Sympathetic Neurons ◽

Coronary Artery Ligation ◽

Channel Blockers ◽

Artery Ligation ◽

Cell Excitability ◽

Ventricular Arrhythmogenesis

Abstract Aims Cardiac sympathetic overactivation is an important trigger of ventricular arrhythmias in patients with chronic heart failure (CHF). Our previous study demonstrated that N-type calcium (Cav2.2) currents in cardiac sympathetic post-ganglionic (CSP) neurons were increased in CHF. This study investigated the contribution of Cav2.2 channels in cardiac sympathetic overactivation and ventricular arrhythmogenesis in CHF. Methods and results Rat CHF was induced by surgical ligation of the left coronary artery. Lentiviral Cav2.2-α shRNA or scrambled shRNA was transfected in vivo into stellate ganglia (SG) in CHF rats. Final experiments were performed at 14 weeks after coronary artery ligation. Real-time polymerase chain reaction and western blot data showed that in vivo transfection of Cav2.2-α shRNA reduced the expression of Cav2.2-α mRNA and protein in the SG in CHF rats. Cav2.2-α shRNA also reduced Cav2.2 currents and cell excitability of CSP neurons and attenuated cardiac sympathetic nerve activities (CSNA) in CHF rats. The power spectral analysis of heart rate variability (HRV) further revealed that transfection of Cav2.2-α shRNA in the SG normalized CHF-caused cardiac sympathetic overactivation in conscious rats. Twenty-four-hour continuous telemetry electrocardiogram recording revealed that this Cav2.2-α shRNA not only decreased incidence and duration of ventricular tachycardia/ventricular fibrillation but also improved CHF-induced heterogeneity of ventricular electrical activity in conscious CHF rats. Cav2.2-α shRNA also decreased susceptibility to ventricular arrhythmias in anaesthetized CHF rats. However, Cav2.2-α shRNA failed to improve CHF-induced cardiac contractile dysfunction. Scrambled shRNA did not affect Cav2.2 currents and cell excitability of CSP neurons, CSNA, HRV, and ventricular arrhythmogenesis in CHF rats. Conclusions Overactivation of Cav2.2 channels in CSP neurons contributes to cardiac sympathetic hyperactivation and ventricular arrhythmogenesis in CHF. This suggests that discovering purely selective and potent small-molecule Cav2.2 channel blockers could be a potential therapeutic strategy to decrease fatal ventricular arrhythmias in CHF.

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Importance of the coronary circulation for cardiac and metabolic performance in rainbow trout ( Oncorhynchus mykiss )

Biology Letters ◽

10.1098/rsbl.2018.0063 ◽

2018 ◽

Vol 14 (7) ◽

pp. 20180063 ◽

Cited By ~ 5

Author(s):

Andreas Ekström ◽

Michael Axelsson ◽

Albin Gräns ◽

Jeroen Brijs ◽

Erik Sandblom

Keyword(s):

Heart Rate ◽

Rainbow Trout ◽

Oncorhynchus Mykiss ◽

Metabolic Rate ◽

Oxygen Supply ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Coronary Ligation ◽

Metabolic Performance

Cardiac oxygenation is achieved via both coronary arterial and luminal venous oxygen supply routes in many fish species. However, the relative importance of these supplies for cardiac and aerobic metabolic performance is not fully understood. Here, we investigated how coronary artery ligation in rainbow trout ( Oncorhynchus mykiss ), implanted with heart rate loggers, affected cardiorespiratory performance in vivo . While coronary ligation significantly elevated resting heart rate, the standard metabolic rate was unchanged compared to sham-treated controls. However, coronary ligation reduced the maximum metabolic rate while heart rate remained unchanged following enforced exercise. Thus, coronary ligation reduced metabolic and heart rate scopes by 29% and 74%, respectively. Our findings highlight the importance of coronary oxygen supply for overall cardiorespiratory performance in salmonid fish, and suggest that pathological conditions that impair coronary flow (e.g. coronary arteriosclerosis) constrain the ability of fish to cope with metabolically demanding challenges such as spawning migrations and environmental warming.

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Integrative System Biology Analyses Identify Seven MicroRNAs to Predict Heart Failure

Non-Coding RNA ◽

10.3390/ncrna5010022 ◽

2019 ◽

Vol 5 (1) ◽

pp. 22 ◽

Cited By ~ 2

Author(s):

Henri Charrier ◽

Marie Cuvelliez ◽

Emilie Dubois-Deruy ◽

Paul Mulder ◽

Vincent Richard ◽

...

Keyword(s):

Heart Failure ◽

Systems Biology ◽

Ventricular Remodeling ◽

Left Ventricular Remodeling ◽

Left Ventricular ◽

Coronary Artery Ligation ◽

Mirna Signature ◽

Artery Ligation ◽

Proteomic Data

Heart failure (HF) has several etiologies including myocardial infarction (MI) and left ventricular remodeling (LVR), but its progression remains difficult to predict in clinical practice. Systems biology analyses of LVR after MI provide molecular insights into this event such as modulation of microRNA (miRNA) that could be used as a signature of HF progression. To define a miRNA signature of LVR after MI, we use 2 systems biology approaches, integrating either proteomic data generated from LV of post-MI rat induced by left coronary artery ligation or multi-omics data (proteins and non-coding RNAs) generated from plasma of post-MI patients from the REVE-2 study. The first approach predicted that 13 miRNAs and 3 of these miRNAs would be validated to be associated with LVR in vivo: miR-21-5p, miR-23a-3p and miR-222-3p. The second approach predicted that 24 miRNAs among 1310 molecules and 6 of these miRNAs would be selected to be associated with LVR in silico: miR-17-5p, miR-21-5p, miR-26b-5p, miR-222-3p, miR-335-5p and miR-375. We identified a signature of 7 microRNAs associated with LVR after MI that support the interest of integrative systems biology analyses to define a miRNA signature of HF progression.

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

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00440.2011 ◽

2011 ◽

Vol 301 (4) ◽

pp. H1438-H1446 ◽

Cited By ~ 12

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.

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Targeting cardiac myocyte Na+-K+ pump function with β3 adrenergic agonist in rabbits and patients with severe congestive heart failure

10.1101/804245 ◽

2019 ◽

Author(s):

Natasha AS Fry ◽

Chia-Chi Liu ◽

Alvaro Garcia ◽

Elisha J Hamilton ◽

Keyvan Karimi Galougahi ◽

...

Keyword(s):

Heart Failure ◽

Cardiac Myocyte ◽

Oral Treatment ◽

Nyha Class ◽

Signs And Symptoms ◽

Pump Current ◽

Severe Congestive Heart Failure ◽

Post Discharge ◽

Treatment Target ◽

Coronary Ligation

AbstractBackgroundReported one- and two-year mortality for patients with advanced heart failure (HF) treated medically are ~75% and nearly 100%. In such patients, reversible cellular abnormalities are potential treatment targets and a raised cytosolic Na+ concentration that impairs their myocardial contractility is one potential target. β3 adrenoceptor (β3 AR) agonists stimulate the myocyte Na+-K+ pump.MethodsWe induced severe HF in rabbits by coronary ligation and measured indices of organ congestion after treatment with β3 AR agonists. Na+-K+ pump current was measured in voltage-clamped myocytes isolated from non-infarct myocardium. To assess if β3 ARs might add benefit to optimised guideline-directed medical treatment we report outcomes of giving the β3 AR agonist mirabegron to patients hospitalized with advanced, treatment-refractory stage D HF.ResultsTreatment of rabbits after coronary ligation with β3 AR agonist reversed a decreased myocyte Na+-K+ pump current and significantly reduced organ congestion and prevalence of ascites. Oral treatment with mirabegron rapidly improved signs and symptoms of 9 patients with advanced HF and improvement of ≥1 NYHA Class was maintained early post-discharge with continued treatment. One patient died from HF at 16 months, 4 died from other causes at 2 – 30 months and 4 remain alive at 38 ± 4 months with NYHA Class II symptoms.ConclusionsParallel β3 AR agonist-induced reversal of Na+-K+ pump inhibition and severe HF in rabbits identify pump inhibition as a treatment target, and changed in-hospital clinical trajectory and post-discharge course more favorable than expected suggest efficacy of mirabegron in advanced human HF.

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Abstract 18592: Anti-arrhythmic Effect of a Novel Rycal, S44121 / Arm036, in a Post-myocardial Infarction Mouse Model of Heart Failure

Circulation ◽

10.1161/circ.130.suppl_2.18592 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Jerome Thireau ◽

Charlotte Farah ◽

Muriel Bouly ◽

Jerome Roussel ◽

Alain Lacampagne ◽

...

Keyword(s):

Myocardial Infarction ◽

Heart Failure ◽

Mouse Model ◽

Ryanodine Receptors ◽

Left Ventricular ◽

Cardiac Contraction ◽

Post Myocardial Infarction ◽

Coronary Artery Ligation ◽

Artery Ligation

Introduction: Targeting leaky cardiac ryanodine receptors (RyR2) to prevent diastolic Ca2+ release from the sarcoplasmic reticulum (SR) is a promising pharmacological approach, to rescue the impaired cardiac contraction and prevent Ca2+-dependent arrhythmias in heart failure (HF) and disease. Hypothesis: Based on prior work from the Marks group, the Rycal S44121 (also known as ARM036) is an experimental small molecule stabilizer of RyR. We investigated the effects of S44121 in a post-myocardial infarction (PMI) mouse model of HF. Methods and results: Mice were randomly assigned to 3 groups: Sham, PMI (subjected to left coronary artery ligation), and PMI-S (treated for 3 weeks with S44121 by subcutaneous osmotic pumps on day 7 post-MI, 10 mg/kg/day). Intracellular Ca2+ was measured on single left ventricular myocytes. PMI mice exhibited a 4-fold increase in the frequency of spontaneous Ca2+ release events, Ca2+ sparks, as measured in quiescent cells using the fluorescent Ca2+ indicator Fluo-4. PMI mice also exhibited higher global diastolic Ca2+, measured with the ratiometric fluorescent probe, Indo-1 AM, and increased the occurrence of ectopic diastolic Ca2+ waves. Acute application of S44121 (10 μM for 15 min) reduced Ca2+ sparks frequency. Chronic treatment of mice with S44121 also normalized the frequency of Ca2+ sparks and of ectopic Ca2+ waves, and corrected diastolic cellular Ca2+ overload. Effects were maximal at 20 mg/kg/day. Furthermore, treatment with S44121 abolished Ca2+ waves promoted by β-adrenergic challenge (acute application of isoproterenol, 10 nM). The potential anti-arrhythmic benefit of S44121 was assessed in vivo using telemetric surface electrocardiograms. S44121 had no effect on ECG intervals and did not alter the heart rate. However, anti-arrhythmic effects were confirmed by observation of a dose-dependent reduction of spontaneous ventricular extrasystoles and ventricular tachycardia. Near maximum benefits were observed at 10 mg/kg/day, both in basal conditions or following a challenge with acute treatment of isoproterenol (0.5 mg/kg, dosed ip). Conclusion: In mice with post-ischemic HF, treatment with S44121 prevented the abnormal diastolic SR Ca2+ leak and ectopic Ca2+ waves, and reduced ventricular arrhythmias.

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In vivo genetic profiling and cellular localization of apelin reveals a hypoxia-sensitive, endothelial-centered pathway activated in ischemic heart failure

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.00935.2007 ◽

2008 ◽

Vol 294 (1) ◽

pp. H88-H98 ◽

Cited By ~ 105

Author(s):

Ahmad Y. Sheikh ◽

Hyung J. Chun ◽

Alexander J. Glassford ◽

Ramendera K. Kundu ◽

Ingo Kutschka ◽

...

Keyword(s):

Heart Failure ◽

Endothelial Cells ◽

Cardiac Failure ◽

Cellular Localization ◽

Hypoxic Exposure ◽

Peptide Ligand ◽

Coronary Artery Ligation ◽

Artery Ligation

Signaling by the peptide ligand apelin and its cognate G protein-coupled receptor APJ has a potent inotropic effect on cardiac contractility and modulates systemic vascular resistance through nitric oxide-dependent signaling. In addition, there is evidence for counterregulation of the angiotensin and vasopressin pathways. Regulatory stimuli of the apelin-APJ pathway are of obvious importance but remain to be elucidated. To better understand the physiological response of apelin-APJ to disease states such as heart failure and to elucidate the mechanism by which such a response might occur, we have used the murine model of left anterior descending coronary artery ligation-induced ischemic cardiac failure. To identify the key cells responsible for modulation and production of apelin in vivo, we have created a novel apelin-lacZ reporter mouse. Data from these studies demonstrate that apelin and APJ are upregulated in the heart and skeletal muscle following myocardial injury and suggest that apelin expression remains restricted to the endothelium. In cardiac failure, endothelial apelin expression correlates with other hypoxia-responsive genes, and in healthy animals both apelin and APJ are markedly upregulated in various tissues following systemic hypoxic exposure. Experiments with cultured endothelial cells in vitro show apelin mRNA and protein levels to be increased by hypoxia, through a hypoxia-inducible factor-mediated pathway. These studies suggest that apelin-expressing endothelial cells respond to conditions associated with heart failure, possibly including local tissue hypoxia, and modulate apelin-APJ expression to regulate cardiovascular homeostasis. The apelin-APJ pathway may thus provide a mechanism for systemic endothelial monitoring of tissue perfusion and adaptive regulation of cardiovascular function.

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Abstract 14553: Mitochondrial Calcium Uptake via Mitochondrial Calcium Uniporter Suppress Ventricular Arrhythmia in the Ischemic Heart Failure Mice

Circulation ◽

10.1161/circ.142.suppl_3.14553 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Hikaru Hagiwara ◽

Masaya Watanabe ◽

Yoichiro Fujioka, ◽

Taro Koya ◽

Motoki Nakao ◽

...

Keyword(s):

Heart Failure ◽

Left Ventricular ◽

Epifluorescence Microscopy ◽

Mitochondrial Calcium ◽

Coronary Artery Ligation ◽

Sham Operation ◽

Artery Ligation ◽

Mitochondrial Calcium Uniporter ◽

Calcium Uniporter

Background: Delayed after depolarization by calcium (Ca 2+ ) leak from sarcoplasmic reticulum (SR) via Ryanodine receptor is one of the causes of ventricular arrhythmias (VAs) in heart failure (HF). Ca 2+ uptake into mitochondria via mitochondrial calcium uniporter (MCU) is participated in Ca 2+ handling, but the relationship between VAs in HF and Ca 2+ uptake into mitochondria is unclear. Purpose: We sought to investigate whether increased Ca 2+ uptake into mitochondria via MCU reduces diastolic Ca 2+ leak and suppresses VAs in ischemic HF mice. Methods: Ten-week-old male C57BL/6J mice were divided into 2 groups; sham operation mice (Sham) or HF mice (HF) in which myocardial infarction was induced by left coronary artery ligation. After 4-6 weeks, cardiomyocyte or mitochondria were isolated respectively from the myocardium of Sham and the non-infarct myocardium of HF. Ca 2+ waves (CaWs) were measured on an epifluorescence microscopy. Calcium transients and calcium sparks were measured on a confocal microscope in linescan mode. Mitochondrial Ca 2+ uptake were measured by estimating the extra-mitochondrial Ca 2+ reduction with Fluo-5N on a spectrofluoro-photometer. VAs was induced in the Langendorff perfused hearts. Left ventricular (LV) pressure was measured using a microtip transducer catheter . Results: HF mice showed left ventricular dysfunction and increased heart and lung weights compared to Sham. Kaempferol, a MCU activator, increased mitochondrial Ca 2+ uptake in the isolated mitochondria both in Sham and HF. CaWs and Ca spark frequency in the presence of isoproterenol was attenuated by 10 μM Kaempferol. Kaempferol did not show significant changes in Ca 2+ transient amplitude, however increased the time to 50% decay significantly. The incidence of induced VAs was suppressed by Kaempferol. In vivo measurements, intravenous administration of Kaempferol (5mg/kg) did not show significant changes in hemodynamic parameters in HF mice. Conclusions: Ca 2+ uptake into mitochondria via MCU suppresses VAs in HF. Despite the adverse influence of the traditional antiarrhythmic drugs for HF condition, a novel strategy that promotes Ca 2+ uptake into mitochondria might be a potential therapeutic approach for VA treatment in HF patients.

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Temporary fatigue and altered extracellular matrix in skeletal muscle during progression of heart failure in rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90617.2008 ◽

2009 ◽

Vol 297 (1) ◽

pp. R26-R33 ◽

Cited By ~ 6

Author(s):

Tommy A. Rehn ◽

Bengt Å. Borge ◽

Per K. Lunde ◽

Morten Munkvik ◽

Marianne Lunde Sneve ◽

...

Keyword(s):

Heart Failure ◽

Skeletal Muscle ◽

Extracellular Matrix ◽

Muscle Fatigue ◽

Hind Limb ◽

Collagen Content ◽

Coronary Artery Ligation ◽

Artery Ligation ◽

Skeletal Muscle Fatigue

Patients with congestive heart failure (CHF) experience increased skeletal muscle fatigue. The mechanism underlying this phenomenon is unknown, but a deranged extracellular matrix (ECM) might be a contributing factor. Hence, we examined ECM components and regulators in a rat postinfarction model of CHF. At various time points during a 3.5 mo-period after induction of CHF in rats by left coronary artery ligation, blood, interstitial fluid (IF), and muscles were sampled. Isoflurane anesthesia was employed during all surgical procedures. IF was extracted by wicks inserted intermuscularly in a hind limb. We measured cytokines in plasma and IF, whereas matrix metalloproteinase (MMP) activity and collagen content, as well as the level of glycosaminoglycans and hyaluronan were determined in hind limb muscle. In vivo fatigue protocols of the soleus muscle were performed at 42 and 112 days after induction of heart failure. We found that the MMP activity and collagen content in the skeletal muscles increased significantly at 42 days after induction of CHF, and these changes were time related to increased skeletal muscle fatigability. These parameters returned to sham levels at 112 days. VEGF in IF was significantly lower in CHF compared with sham-operated rats at 3 and 10 days, but no difference was observed at 112 days. We conclude that temporary alterations in the ECM, possibly triggered by VEGF, are related to a transient development of skeletal muscle fatigue in CHF.

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