Animal Models Of Heart Failure Research Articles

T-Tubule Remodeling Causes Ca 2+ Cycling Defects during the Progression to Heart Failure in the Intact Spontaneously Hypertensive Rat Heart

Severe disruption of the t-tubule network in cardiac myocytes has been found in nearly all animal and human models of heart failure. T-tubule disorganization would be expected to cause alterations in the EC coupling because of a separation of junctional SR from trigger Ca entry and the increase in orphaned ryanodine receptors. However, little is currently known about changes in t-tubules during the early stages of disease development, before heart failure (HF) develops. The goal of this study was to measure the relationship between cardiac function, t-tubule organization and Ca2+ cycling defects in whole hearts during the progression to HF.

Improved cardiac function after sarcoplasmic reticulum Ca2+-ATPase gene transfer in a heart failure model induced by chronic myocardial ischaemia

Objective Chronic myocardial ischaemia (CMI) has become an important cause of heart failure (HF). The aim of this study was to examine the eff ects of sarco-endoplasmic reticulum calcium ATPase (SERCA2a) gene transfer in large HF animal models induced by CMI.Methods and results HF was induced in mini pigs by proximal left anterior descending coronary (LAD) ameroid constrictors. After confi rmation of myocardial perfusion defects and cardiac function impairment, animals were divided into 4 groups (each including 4 animals): the HF group; the HF+enhanced green fl uorescent protein (EGFP) group; the HF+SERCA2a group; and sham animals as a control group. rAAV1-EGFP and rAAV1-SERCA2a were injected intramyocardially to animals of the HF+EGFP and HF+SERCA2a groups separately. Sixty days after gene transfer, expressions of SERCA2a were examined, cardiac functions and changes of serum infl ammatory and neuro-hormonal factors were determined. The results demonstrated that 60 days after gene transfer, LVEF, Ev/Av and ± dp/dtmax of the HF+SERCA2a group increased signifi cantly (P < 0.05), along with an increase in SERCA2a protein expression (P < 0.05) compared with the HF/HF+EGFP groups. Serum concentrations of infl ammatory and neuro-hormonal factors were also decreased in the HF+SERCA2a group (P < 0.05).Conclusions Restoration of SERCA2a in myocardium of HF model induced by CMI could signi fi cantly improve cardiac function, suggesting its potential therapeutic signifi cance in CMI-related heart failure.

Gene therapy with iNOS enhances regional contractility and reduces delayed contrast enhancement in a model of postischemic congestive heart failure

The purpose of this study was to evaluate the effect of transient local myocardial gene transfer of iNOS on cardiac function in a large mammal animal model of heart failure induced by chronic ischemia. Chronic myocardial ischemia was induced using a minimally invasive model in 16 landrace pigs. Upon demonstration of heart failure, eight animals were treated with liposome-mediated iNOS-gene-transfer by local intramyocardial injection; eight animals received a sham procedure to serve as control. The transmurality of late enhancement (control: 46.4%, iNOS: 35.9%; p < 0.05) was significantly decreased in the ischemic area in the iNOS-treated group. Wall thickness at end-systole (6.8 mm vs. 5.9 mm, p < 0.001) and at end-diastole (5.4 mm vs. 4.2 mm, p < 0.001) were significantly higher in the therapy group. Additionally, the regional wall motion at the level of the ischemic region was 3.5 mm in the therapy group while it was significantly less (3.0 mm, p < 0.001) in the control group. Our findings demonstrate that transient iNOS overexpression potentially leads to a significant decrease of regional late enhancement with a positive effect on regional cardiac function in the ischemic area in a large animal model of postischemic heart failure.

Vagal stimulation for heart failure

On the very solid background of experimental and clinical studies pointing to the cardiovascular risks associated with depressed vagal reflexes and supported by specific experiments in animal models of heart failure, we are witnessing a rapidly growing interest in the very untraditional approach to the management of heart failure represented by chronic vagal stimulation. Additional studies have been performed using vagal stimulation in animal models of heart failure showing that benefit can occur even in the absence of heart rate changes. The first in-man studies of chronic vagal stimulation have been performed, first as a single center and then as a small multicenter study with favorable results in terms of feasibility, safety, and efficacy. The initial observations with chronic vagal stimulation in man, though limited by very small numbers, are very encouraging and seem to open new paths, or perhaps avenues, for the management of symptomatic heart failure. This transition between experimental and clinical approaches represents an exciting example of translational research.

Cardiac Resynchronization and Electrophysiological Reverse-Remodeling in the Failing Heart

The electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. In human studies and a number of animal models of heart failure, functional downregulation of K+ currents and alterations in depolarizing Na+ and Ca2+ currents and transporters are demonstrated. Alterations in intercellular ion channels and matrix contribute to heterogeneity of APD and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the heart failure with dyssynchronous LV contraction (DHF). Furthermore, β-adrenergic signaling and modulation of ionic currents is blunted in heart failure. Cardiac resynchronization therapy (CRT) partially reversed the DHF-induced downregulation of K+ current and improved Na+ channel gating. CRT significantly improved Ca2+ homeostasis especially in myocytes from late-activated, lateral wall, and restores the DHF-induced blunted β-adrenergic receptor responsiveness. CRT abbreviated DHF-induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD, and suppressed development of early afterdepolarizations. In conclusion, CRT partially restores the DHF-induced ion channel remodeling, abnormal Ca2+ homeostasis, blunted β-adrenergic response and regional heterogeneity of APD, thus may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

Vagal Stimulation for Heart Diseases: From Animals to Men - An Example of Translational Cardiology -

An autonomic imbalance with a reduction in vagal activity and an increase in sympathetic activity is present in heart failure. The same type of imbalance, when present in patients with a myocardial infarction, is associated with increased risk for cardiac mortality. Experimental studies have demonstrated that vagal stimulation has an antifibrillatory effect and has proven to be beneficial in animal models of heart failure. Given this background, the potential value of chronic vagal stimulation was explored in humans with an implantable neuro-stimulator capable of delivering low current pulses with adjustable parameters to stimulate the right vagus. A small multicenter feasibility and safety study exploring efficacy has recently been completed. A total of 32 patients with left ventricular ejection fraction (LVEF) <35% and a history of chronic heart failure in symptomatic NYHA class II-III were included in the study. The results indicate feasibility and safety. Interestingly, there are also very encouraging results for the efficacy on the NYHA class, quality of life, 6-min walk test, left ventricular end-systolic volume and LVEF. The latter, at the 1-year follow up, had increased from 21 ± 7% to 34 ± 12% (P<0.0001). Finally, vagal stimulation in heart failure patients has a strong rationale and the preliminary data suggests that it is likely to be of value to these patients. It is now appropriate to move toward a randomized controlled clinical trial of adequate size.

Validation of a Mimic Heart Failure Model

Introduction: Animal models which mimic the clinical characteristics of heart failure (HF) with dyssynchrony play a critical role in development of new therapies. Existing HF animal models created by left bundle branch block (LBBB), rapid pacing, or microembolization alone or in combinations only mimic partial HF characteristics and are time-costuming and expensive. The microembolization model creates a stable reduction in left ventricular ejection fraction (LVEF) with minimal change in QRS. Methods: Ten dogs were implanted with two epicardial leads on the left ventricle (LV) and LBBB ablation increased QRS width by 2×. After 4 weeks, HF was induced by microembolization procedures every 1–3 weeks by injecting microspheres into one or both of the coronary arteries (LAD and Left Circumflex) until LVEF decreased to <35% by echocardiography. Results: Two dogs (20%) died during the microembolization procedure. All surviving canines developed severe ischemic cardiomyopathy with dyssynchrony. QRS width significantly increased after LBBB and was stable throughout multiple microembolizations. LVEF significantly decreased after multiple microembolizations but not after LBBB. The pathological examination was performed in the failed hearts at end of the study. Conclusion: This viable and reproducible canine model can mimic heart failure characteristics and serve as a useful tool to evaluate new HF therapies.

Past, present, and future of CRT

Cardiac resynchronization therapy is a key non-pharmacological treatment strategy for drug-refractory moderate-to-severe symptomatic heart failure in the presence of compromised left ventricular function and ventricular conduction delay. Because not all patients with conventional criteria benefit from CRT, continuous efforts have been directed toward improving patient selection; in particular, emerging echocardiographic criteria such as regional and global myocardial strains are being investigated to better predict CRT response. In the meantime, growing evidence from large randomized controlled trials (RCTs, REVERSE, and MADIT-CRT) has demonstrated that even mildly symptomatic patients may benefit from CRT. The role of CRT in heart failure patients with narrow QRS, however, remains to be defined in the scheme of larger RCTs (such as EchoCRT) as the ones carried out thus far (RethinQ and ESTEEM-CRT). Important experimental data derived from animal heart failure models are gradually elucidating the complex pathophysiological basis of cardiac dyssynchrony, which involves diffuse alterations from genome to structure. At the same time, technological breakthroughs, such as wireless endocardial cardiac pacing, will render the prospect of delivering CRT more precisely and more effectively, a reality in the near future.

EDITORIAL: Insights Into the Development and Treatment of Cardiovascular Disease: A Role for Animal Models

Approximately one-third of the total deaths worldwide per annum, amounting to 16.6 million people, is due to cardiovascular disease [1], making it the number one cause of death [2]. Cardiovascular disease also has a major impact on morbidity [1]. Thus, reducing the incidence of deaths due to vascular disease/complications and developing better treatment strategies, remains a central goal for national economies worldwide [3, 4]. Consequently, several animal models have been developed to replicate human vascular diseases, in order to study the pathophysiology of disease progression and novel therapeutic options. This issue of The Open Cardiovascular Medicine Journal discusses some of these models. In this Editorial, each review article for the Special Issue will be briefly outlined, with consideration given to a few additional models. Tsui describes genetically predisposed, chemical and physical animal models of abdominal aortic aneurysms (AAAs) [5]. This review focuses on the pathophysiological mechanisms that underlie the development and progression of AAAs and the different treatment modalities for their management. Ou et al. discusses the development of animal models of myocardial infraction, dilated cardiomyopathy, heart failure, myocarditis and cardiac hypertrophy, emphasising the usefulness of stem cell therapy [6]. Karasu describes abnormal cardiac contractility and impaired vascular reactivity in animal models of diabetes mellitus and highlights the role of antioxidant therapy in preventing or delaying diabetic cardiovascular complications [7]. Grossman explores the use of the renal hypertension-Goldblatt kidney and uraemic cardiomyopathy animal models to look at the relationship between cardiovascular disease and renal pathophysiology [8]. Ameen and Robson describe the relationship between Duchenne Muscular Dystrophy and cardiovascular disease in spontaneous and transgenic animal models, outlining new treatment options [9]. Price et al. discusses the use of magnetic resonance imaging to follow the pathophysiology of myocardial ischaemia and atherosclerosis in animal models. Attention has also been given to imaging the rodent developing heart to assess the influence of genes and congenital diseases [10]. In addition, several other models have been developed for the study of vascular disease. This Editorial briefly addresses some of them.

Enhancing the metabolic substrate: PPAR-alpha agonists in heart failure

The prognosis for patients diagnosed with heart failure has significantly improved over the past three decades; however, the disease still confers a high degree of morbidity and mortality. Current treatments for chronic heart failure have focused primarily on blocking neurohormonal signaling and optimizing hemodynamic parameters. Although significant resources have been devoted toward the development of new pharmaceutical therapies for heart failure, few new drugs have been designed to target myocardial metabolic pathways despite growing evidence that on a fundamental level chronic heart failure can be characterized as an imbalance between myocardial energy demand and supply. Disruptions in myocardial energy pathways are evident as the myocardium is unable to generate sufficient amounts of ATP with advancing stages of heart failure. Down-regulation of fatty acid oxidation likely contributes to the phenotype of the "energy starved" heart. Fibrates are small molecule agonists of PPARα pathways that have been used to treat dyslipidemia. Although never used therapeutically in clinical heart failure, PPARα agonists have been shown to enhance fatty acid oxidation, improve endothelial cell function, and decrease myocardial fibrosis and hypertrophy in animal models of heart failure. In light of their excellent clinical safety profile, PPARα agonists may improve outcomes in patients suffering from systolic heart failure by augmenting myocardial ATP production in addition to targeting maladaptive hypertrophic pathways.

The Role of Phospho‐Adenosine Monophosphate‐Activated Protein Kinase and Vascular Endothelial Growth Factor in a Model of Chronic Heart Failure

We established a stable and reproducible animal model of chronic heart failure (CHF) in sheep to investigate biomolecular changes. Therefore, two biomarkers, adenosine monophosphate-activated protein kinase (AMPK) and vascular endothelial growth factor-A (VEGF-A) were examined to reveal their role during chronic ischemic conditions of the heart. AMPK was studied because it plays an important role in cellular energy homeostasis and its upregulation is associated with myocardial ischemia, whereas VEGF-A was studied because it acts as an important signaling protein for neoangiogenesis. We examined 15 juvenile sheep (mean weight, 78±4kg; control, n=3; ShamOP, n=2; coronary microembolization [CME], n=10). CHF was induced under fluoroscopic guidance by multiple sequential microembolizations (MEs) through bolus injection of polysterol microspheres (90µm, n=25.000) into the left main coronary artery. CME was repeated up to three times at 2- to 3-week intervals until animals started to develop stable signs of CHF. All animals were followed for 3 months. Phosphorylation of AMPK, marking the activated protein form, was detected by Western blotting. VEGF-A and vascular endothelial growth factor-receptor 2 (VEGF-R2) mRNA were detected by real-time polymerase chain reaction. Glyceraldehyde-3-phosphate-dehydrogenase (GAPDH) was used as a reference housekeeping gene. All 10 CHF animals developed clinical signs of CHF as indicated by a significant decrease of cardiac output, decreased ejection fraction, as well as occurrence of tachycardia and tachypnoea. Western blots showed significant phosphorylation of AMPK in CME animals compared to the control group (phospho-adenosine monophosphate-activated protein kinase α) (GAPDH control: 0.0, CME left ventricle [LV]: 0.39±0.20, CME right ventricle [RV]: 0.53±0.30; P<0.05). VEGF-A and VEGF-R2 expression in CME animal myocardium was within the range of the control group, but this data did not reach statistical significance due to the small size of this group. While microinjection was performed into the left main coronary artery, phosphorylation of AMPK and expression of VEGF-A and VEGF-R2 were significantly higher in the RV than in the LV. Multiple sequential intracoronary MEs can effectively induce myocardial dysfunction with clinical and biomolecular signs of chronic ischemic cardiomyopathy. Quantitative analysis of biomolecular markers showed a significantly higher phosphorylation of AMPK in CHF animals compared with control myocardium.

Attenuated β-Adrenergic Response and Reduced Repolarization Reserve in Rabbit Model of Chronic Heart Failure

Background: Existing animal models of pacing-induced heart failure are often associated with high acute (1-3 weeks) mortality secondary to very high pacing frequencies. We speculated whether lower frequency pacing for longer time intervals (11 weeks) would produce a chronic heart failure model with reduced acute mortality, and displaying pronounced structural, functional, and electrical remodeling.

Erythropoietin Receptor Signaling Mitigates Renal Dysfunction-Associated Heart Failure by Mechanisms Unrelated to Relief of Anemia

We examined the effect of asialoerythropoietin (asialoEPO), a nonerythrogenic derivative of erythropoietin (EPO), on renal dysfunction-associated heart failure. Although EPO is known to exert beneficial effects on cardiac function, the clinical benefits in patients with chronic kidney disease are controversial. It remains to be addressed whether previously reported outcomes were the result of relief of the anemia, adverse effects of EPO, or direct cardiovascular effects. Mice underwent 5/6 nephrectomy to cause renal dysfunction. Eight weeks later, when renal dysfunction was established, anemia and cardiac dysfunction and remodeling were apparent. Mice were then assigned to receive saline (control), recombinant human erythropoietin (rhEPO) at 5,000 IU (714 pmol)/kg, or asialoEPO at 714 pmol/kg, twice/week for 4 weeks. Although only rhEPO relieved the nephrectomy-induced anemia, both rhEPO and asialoEPO significantly and similarly mitigated left ventricular dilation and dysfunction. The hearts of rhEPO- or asialoEPO-treated mice showed less hypertrophy, reflecting decreases in cardiomyocyte hypertrophy and degenerative subcellular changes, as well as significant attenuation of fibrosis, leukocyte infiltration, and oxidative deoxyribonucleic acid damage. These phenotypes were accompanied by restored expression of GATA-4, sarcomeric proteins, and vascular endothelial growth factor and decreased inflammatory cytokines and lipid peroxidation. Finally, myocardial activation was observed of extracellular signal-regulated protein kinase and signal transducer and activator of transcription pathways in the treated mice. EPO receptor signaling exerts direct cardioprotection in an animal model of renal dysfunction-associated heart failure, probably by mitigating degenerative, pro-fibrosis, inflammatory, and oxidative processes but not through relief of anemia.

Performance of Echocardiographic Parameters in Sequential Monitoring of Left Ventricular Function in an Animal Model of Acute Heart Failure

Numerous newer parameters have been established for sensitive and reproducible evaluation of left ventricular (LV) dysfunction. We assessed the performance of these parameters in sequential monitoring of LV function in an animal model of controllable drug-induced LV dysfunction. To establish predictable aggravating LV dysfunction, seven male beagle dogs were anesthetized and received intermittent injection of esmolol and propofol of gradually increasing dosage. Parameters reflecting LV function were measured after each drug infusion. These included LV ejection fraction (LVEF) measured by both two-dimensional (2D) and three-dimensional (3D) echocardiography, Tei index, ratio of early diastolic transmitral flow velocity to early diastolic mitral annular velocity (E/e') and 2D strain-derived parameters. Changes in these parameters over time were compared with the baseline value. Changes in 2D and 3D LVEF were observed after infusion with propofol (5 mg/kg) and esmolol (3.5 mg/kg). Doppler-derived parameters including E/e' and the Tei index failed to detect LV dysfunction prior to 2D LVEF. Significant changes in 2D strains and strain rates (SRs) could be induced by relatively small anesthetic dosages (∼4 mg propofol/kg and 2.5 mg esmolol/kg). Strain-derived parameters were generally highly reproducible and longitudinal strain had the best intraobserver and interobserver reproducibility. The 2D strain parameters provide accurate identification of subclinical impairment of LV function earlier than all other echocardiographic indices.

CaMKII Inhibition in Heart Failure Makes Jump to Human

See related article, pages 1150–1161 In this issue of Circulation Research , Sossalla et al1 show that acute inhibition of Ca2+/calmodulin-dependent protein kinase (CaMK)II in failing human myocardium causes functional improvement in contractility by restoring a positive force–frequency relationship (FFR) in cardiac trabeculae. The loss of this normal positive FFR (and often an induction of a negative FFR) is a functional hallmark of failing human myocardium2 and has been seen as an intrinsic limitation of the failing heart to enhance contractility appropriately at higher heart rates. This failure of positive FFR also constitutes a reduction in functional cardiac reserve. So, why might CaMKII inhibition be beneficial in heart failure (HF)? For several years, evidence has been accumulating that CaMKII is increased in both expression level and activity in both animal models of HF and in failing human hearts.3,–,9 It has also come to light that CaMKII has many different functional effects in cardiac myocytes, including alterations in ion channels, Ca2+ handling proteins, myofilaments, and transcriptional regulation.10,–,12 Moreover, many of these CaMKII effects on myocyte properties have been implicated in hypertrophy, HF, and arrhythmias in animal models. Indeed, CaMKII inhibition (or knockout of the dominant cardiac isoform CaMKIIδ) can improve cardiac function and delay the onset of maladaptive aspects of the hypertrophic/HF phenotype in animal models, resulting in beneficial functional effects.13,–,15 Sossalla et al1 provide important novel data that acute CaMKII inhibition in human HF myocardium causes functional improvement. This is an important validation step with respect to consideration of cardiac CaMKII inhibition as therapeutic strategy in human HF. So, what are some key acute functional effects of CaMKII that can alter cardiac Ca2+ handling and excitability? CaMKII phosphorylates …

Electrophysiological Remodeling in Heart Failure Dyssynchrony vs. Resynchronization

The electrophysiological hallmark of cells and tissues isolated from failing hearts is prolongation of action potential duration (APD) and conduction slowing. In human studies and a number of animal models of heart failure, functional downregulation of K currents and alterations in depolarizing Na and Ca currents and transporters are demonstrated. Alterations in intercellular ion channels and matrix contribute to heterogeneity of APD and conduction slowing. The changes in cellular and tissue function are regionally heterogenous particularly in the heart failure with dyssynchronous LV contraction (DHF). Furthermore, β‐adrenergic signaling and modulation of ionic currents is blunted in heart failure.Cardiac resynchronization therapy (CRT) partially reversed the DHF‐induced downregulation of K current and improved Na channel gating. CRT significantly improved Ca homeostasis especially in myocytes from late‐activated, lateral wall, and restores the DHF‐induced blunted β‐adrenergic receptor responsiveness. CRT abbreviated DHF‐induced prolongation of APD in the lateral wall myocytes and reduced the LV regional gradient of APD, and suppressed development of early afterdepolarizations.In conclusion, CRT partially restores DHF‐induced ion channel remodeling, abnormal Ca homeostasis, blunted β‐adrenergic response and regional heterogeneity of APD, thus may suppress ventricular arrhythmias and contribute to the mortality benefit of CRT as well as improve mechanical performance of the heart.

Novel Large Animal Model of Acute Experimental Hypertensive Heart Failure

Background: Systolic hypertension especially in women and blacks is increasingly recognized and present in approximately 50% of subjects with acute decompensated heart failure (ADHF). Importantly, an abrupt increase in blood pressure may indeed be the mechanism for ADHF in such subjects. To date there is a lack of a large animal model of ADHF with hypertension to allow detailed characterization of the hemodynamic and neurohumoral phenotype and to test potential therapeutic agents. Objectives: Develop a novel large animal model of pacing induced ADHF and angiotensin II (ANG II) induced hypertension and characterize its cardiorenal and neurohumoral phenotype.

Acute effects of urocortin 2 on cardiac function and propensity for arrhythmias in an animal model of hypertension‐induced left ventricular hypertrophy and heart failure

To test acute effects of the corticotropin-releasing factor-related peptide urocortin 2 (Ucn2) on left ventricular (LV) function and the propensity for ventricular arrhythmias in the isolated heart of an animal model of hypertension-induced heart failure. Hearts from Dahl salt-sensitive rats with severe LV dysfunction were perfused according to Langendorff. Left ventricular developed pressure and the positive and negative derivatives of LV pressure were analysed before and after perfusion with Ucn2 (n = 15) or normal perfusion solution (control, n = 9). Intracellular calcium cycling parameters were assessed by surface fluorometry. Furthermore, monophasic action potential duration (MAPD) and ventricular fibrillation threshold (VFT) were determined, the latter by a train-of-pulses method at increasing voltage to scan the vulnerable period of repolarization. Urocortin 2 significantly affected intracellular calcium cycling and improved LV contractile function and relaxation. Compared with baseline values, Ucn2 significantly decreased MAPD at 30, 50, and 90% repolarization and significantly increased VFT compared with baseline values. No changes were observed in control experiments. Administration of Ucn2 rapidly improves LV function and increases VF threshold in failing, isolated rat hearts with increased propensity for ventricular arrhythmias. These observations suggest a potential use of Ucn2 as a safe and novel agent for the treatment of acute heart failure.

S100A1: A Multifaceted Therapeutic Target in Cardiovascular Disease

Cardiovascular disease is the leading cause of death worldwide, showing a dramatically growing prevalence. It is still associated with a poor clinical prognosis, indicating insufficient long-term treatment success of currently available therapeutic strategies. Investigations of the pathomechanisms underlying cardiovascular disorders uncovered the Ca2+ binding protein S100A1 as a critical regulator of both cardiac performance and vascular biology. In cardiomyocytes, S100A1 was found to interact with both the sarcoplasmic reticulum ATPase (SERCA2a) and the ryanodine receptor 2 (RyR2), resulting in substantially improved Ca2+ handling and contractile performance. Additionally, S100A1 has been described to target the cardiac sarcomere and mitochondria, leading to reduced pre-contractile passive tension as well as enhanced oxidative energy generation. In endothelial cells, molecular analyses revealed a stimulatory effect of S100A1 on endothelial NO production by increasing endothelial nitric oxide synthase activity. Emphasizing the pathophysiological relevance of S100A1, myocardial infarction in S100A1 knockout mice resulted in accelerated transition towards heart failure and excessive mortality in comparison with wild-type controls. Mice lacking S100A1 furthermore displayed significantly elevated blood pressure values with abrogated responsiveness to bradykinin. On the other hand, numerous studies in small and large animal heart failure models showed that S100A1 overexpression results in reversed maladaptive myocardial remodeling, long-term rescue of contractile performance, and superior survival in response to myocardial infarction, indicating the potential of S100A1-based therapeutic interventions. In summary, elaborate basic and translational research established S100A1 as a multifaceted therapeutic target in cardiovascular disease, providing a promising novel therapeutic strategy to future cardiologists.

Changes in metabolic profile and population of skeletal muscle fibers of mice overexpressing calsequestrin: Influence of losartan

In heart failure, exertional fatigue of skeletal muscles can occur. A transgenic mouse overexpressing calsequestrin can be regarded as an animal model of heart failure. The aims of the present study were to investigate, whether at the time of cardiac failure the composition of fiber types of skeletal muscles was altered, what kind of alterations in glycolytic and oxidative enzyme activities occurred in different muscle fiber types and whether these were affected by the administration of the angiotensin II receptor blocker, losartan. Hemodynamic parameters were determined using a working heart preparation. Four groups of mice were investigated: wild-type (WT) mice and transgenic (TG) mice overexpressing calsequestrin, with and without losartan treatment. Enzyme activities were measured in homogenates of Rectus femoris muscle and in muscle fibers, which were typed by their metabolic profile. Calcineurin expression was measured by Western blotting. Succinate dehydrogenase activity was increased by 275% in R. femoris muscle homogenates of TG compared to WT mice. This was due to a 57% increase in slow oxidative fibers, which was accompanied by an increased calcineurin expression in TG muscles. This increase was attenuated by losartan treatment. With respect to glycerol-3-phosphate-dehydrogenase (GPDH), no difference was evident comparing WT and TG. Treatment with losartan resulted in a down-regulation of GPDH in WT and TG. In conclusion, changes in skeletal muscles occur in this mouse model of heart failure and these changes were antagonized by losartan. In contrast to heart failure patients, in the mouse model a shift to the oxidative phenotype of skeletal muscle was noted, possibly due to enhanced calcineurin expression.