Animal Model Of Chronic Heart Failure Research Articles

Advances in animal models of chronic heart failure and its applications in traditional Chinese medicine

Chronic heart failure(CHF) is a series of clinical syndromes in which various heart diseases progress to their end stage. Its morbidity and mortality are increasing year by year, which seriously threatens people's life and health. The diseases causing CHF are complex and varied, such as coronary heart disease, hypertension, diabetes, cardiomyopathy and so on. It is of great significance to establish animal models of CHF according to different etiologies to explore the pathogenesis of CHF and develop drugs to prevent and treat CHF induced by different diseases. Therefore, based on the classification of the etiology of CHF, this paper summarizes the animal models of CHF widely used in recent 10 years, and the application of these animal models in traditional Chinese medicine(TCM) research, in order to provide ideas and strategies for studying the pathogenesis and treatment of CHF, and provide ideas for TCM modernization research.

AIM2-driven inflammasome activation in chronic heart failure

Abstract Background Inflammation and cytokine release have been implicated in the pathogenesis of chronic heart failure (CHF). Of particular interest, Canakinumab, a monoclonal antibody against interleukin-1b (IL-1β), had provided benefit against cardiovascular events, suggesting that blockade of IL-1β secretion and signaling might be a promising new therapeutic target. Although, recent studies have provided evidence that inflammasome activation is the main contributor to IL-1β maturation, the role of inflammasome activation in CHF remains unknown. Objective Therefore, we aimed to assess inflammasome activation in myocardial samples from end-stage failing hearts. Methods Inflammasome activation was assessed by immunoblotting in left ventricular myocardial specimens harvested from patients with end-stage CHF. Furthermore, immunoblot measurements were also performed on translational animal models of CHF (e.g. rat models of permanent coronary artery ligation and transverse aortic constriction). Left ventricular monocyte and macrophage infiltration was detected by immunohistochemistry. To investigate the molecular background of inflammasome activation, a series of cell culture experiments were performed on AC16 human cardiomyocytes and THP-1 human monocytic cell lines. Results Out of the 4 major inflammasome sensors tested, expression of the inflammasome protein absent in melanoma 2 (AIM2) and NLR family CARD domain-containing protein 4 (NLRC4) increased in human CHF while the NLRP1 and NLRP3 (NLR family, pyrin domain containing 1 and 3) inflammasome showed no change. A similar expression pattern in AIM2 and NLRC4 was also noted in CHF animal models. Furthermore, robust infiltration of Iba1+ monocytes/macrophages was observed in human failing hearts as well as in different animal models of CHF. In vitro AIM2 inflammasome activation, as induced by transfection with double-stranded DNA [poly(deoxyadenylic-deoxythymidylic)] was reduced significantly by the pharmacological blockade of pannexin-1 channels. Conclusions AIM2 and NLRC4 inflammasome activation might contribute to chronic inflammation in CHF. Our findings suggest that pannexin-1 channels might be a promising novel target to reduce inflammasome activation. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): NVKP_16-1-2016-0017

Evaluation of nine active components of Lu-Jiao Fang in normal and hypertrophic rat myocardia via LC-MS/MS.

Lu-Jiao Fang (LJF), a traditional Chinese medicine prescription, can improve the cardiac function of chronic heart failure (CHF) patients; however, knowledge about the cardiac distribution of LJF, especially in CHF animal models, is rather limited. This work aimed to explore the cardiac distribution of LJF in pressure overload-induced CHF rats at the last gavage administration of LJF after 30 weeks of treatment. LC-MS/MS methods for analyzing nine active components (i.e. loganin, hesperidin, epimedin C, icariin, psoralen, isopsoralen, baohuoside I, morroniside and specnuezhenide) of LJF in cardiac tissue samples were established, and the components were then analyzed in left ventricular wall (LVW) and right ventricular wall (RVW) in parallel at same time point postdose for three dose groups. The results showed that most analytical component levels in LVW (hypertrophic myocardium) were only 39-74% of those in RVW (normal myocardium); however, psoralen and isopsoralen levels in LVW were equal to or even greater than the levels in RVW, suggesting that the hypertrophic myocardium tissue affinity of psoralen and isopsoralen might overcome the negative effect of decreased blood flow on distribution. This study indicated that the pathological state may influence drug distribution, and the efficacy of psoralen and isopsoralen for improving CHF deserves further investigation.

Abstract 710: Quality of Life Assessment in Yucatan Mini Swine after Myocardial Infarction

Introduction: Quality of life assessments (QOL) measurements are valuable in assessing functional class in patients with chronic heart failure (CHF). Yet, limited quantifiable QOL measures are available in pre-clinical animal models of CHF. To address this issue, we developed methods of QOL assessments in mini swine after myocardial infarction (MI). Methods: Quality of life activity was continuously monitored in Yucatan mini-swine using collar-mounted activity monitors (Fitbark 2) and by performing treadmill exercise tests. Activity treadmill data were obtained for 1 month before and 1 month following MI. Myocardial infarction was created by 90-minute occlusion-reperfusion of the left anterior descending coronary artery. Infarct size and ventricular volumes were measured with Magnetic Resonance Imaging prior to and 1 month after MI. Results: The swine had an average MI size of 20±3%, with increases in LV end-diastolic volume from 62.8±7.8 to 72.1±7.4 ml, LV end-systolic volume from 22.1±2.7 to 36.6±4.8 ml and a decrease in EF from 65±3% to 49±4%, N=5-6 (P<0.05). The 24/7 total FitBark Activity Scores using area under the curve decreased post MI from 184.5±16.8 to 159.4±19.5, N=7-8 (P<0.01). Conclusions: These data demonstrate the feasibility of measuring quality of life in mini swine after myocardial infarction defined by activity level and treadmill exercise testing. This work establishes the potential basis for presenting quality of life measurements in animals as adjunctive assessment of new treatments for chronic heart failure after myocardial infarction.

Sympathoexcitation in response to cardiac and pulmonary afferent stimulation of TRPA1 channels is attenuated in rats with chronic heart failure.

Excessive sympathoexcitation characterizes the chronic heart failure (CHF) state. An exaggerated cardiac sympathetic afferent reflex (CSAR) contributes to this sympathoexcitation. Prior studies have demonstrated that the CSAR to capsaicin [transient receptor potential (TRP) vanilloid 1 agonist] is exaggerated in CHF animal models. We recently discovered that capsaicin application to the lung visceral pleura in anesthetized, vagotomized, open-chested rats increases mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA). We named this response the pulmonary spinal afferent reflex (PSAR). Due to the similarities between TRP vanilloid 1 and TRP ankyrin 1 (TRPA1) channels as well as the excessive sympathoexcitation of CHF, we hypothesized that stimulation of the CSAR and PSAR with a specific TRPA1 agonist would result in an augmented response in CHF rats (coronary ligation model) compared with sham control rats. In response to a TRPA1 agonist, both CSAR and PSAR in sham rats resulted in biphasic changes in MAP and increases in HR and RSNA 10-12 wk postmyocardial infarction (post-MI). These effects were blunted in CHF rats. Assessment of TRPA1 expression levels in cardiopulmonary spinal afferents by immunofluorescence, quantitative RT-PCR, and Western blot analysis 10-12 wk post-MI all indicates reduced expression in CHF rats but no reduction at earlier time points. TRPA1 protein was reduced in a dorsal root ganglia cell culture model of inflammation and simulated tissue ischemia, raising the possibility that the in vivo reduction of TRPA1 expression was, in part, caused by CHF-related tissue ischemia and inflammation. These data provide evidence that reflex responses to cardiopulmonary spinal afferent TRPA1 stimulation may be attenuated in CHF rather than enhanced. NEW & NOTEWORTHY Excessive sympathoexcitation characterizes chronic heart failure (CHF). The contribution of transient receptor potential ankyrin 1 (TRPA1) channel-mediated reflexes to this sympathoexcitation is unknown. We found that application of TRPA1 agonist to the heart and lung surface resulted in increased heart rate and sympathetic output and a biphasic change in mean arterial pressure in control rats. These effects were attenuated in CHF rats, decreasing the likelihood that TRPA1 channels contribute to cardiopulmonary afferent sensitization in CHF.

Electrical and mechanical alternans during ventricular tachycardia with moderate chronic heart failure

A chronic heart failure (CHF) rat underwent epicardial programmed electrical stimulation (PES). Ventricular tachycardia (VT) developed during PES. Mechanical alternans was noted despite fixed tachycardia cycle length. Anti-tachycardia pacing attempts initiated a second VT that generated pulse intermittently and then degenerated into pulseless VT with electrical alternans.To our knowledge electrical and mechanical alternans have not been recorded in animal models of CHF during VT. The distinct events of mechanical alternans and electrical alternans may be indicative of progressively worsened calcium handling in the compromised cardiomyocytes.Although ion channel differences between rodents and humans exist, this work attempts to demonstrate this rat model's usefulness in understanding cardiac electrophysiology in CHF.

Abstract 412: Galectin-3 Promotes Pro-Hypertrophic Communication Between Fibroblasts and Cardiomyocytes

Galectin-3 (gal-3) is a β-galactoside-binding protein used as a prognostic biomarker in chronic heart failure (CHF) patients. Genetic and pharmacologic studies show that gal-3 is required for cardiac remodeling in animal models of CHF, suggesting an active role for gal-3 in the progression of the disease, but the mechanism involved is largely unknown. We assessed the hypothesis that gal-3 induces cardiac remodeling, causing both cardiomyocyte hypertrophy and fibroblasts activation through a mechanism involving intercellular communication. As a model, we used neonatal rat ventricular cardiomyocytes (NRVM), and fibroblasts (NRVF) stimulated with recombinant gal-3. We assessed cell death and proliferation by flow cytometry and MTT assays. To elucidate the signaling pathways involved, we quantified relative changes in protein levels by Western blot. To determine cell size and sarcomerization, we used confocal microscopy. Changes in mRNA and microRNA expression were analyzed by qPCR. Our results show that gal-3 does not induce hypertrophy or sarcomerization on isolated NRVM culture. On the other hand, NRVF treated with gal-3 exhibit an increase in ERK1/2 (n=3, p<0.05) and AKT (n=3, p<0.05) phosphorylation, as well as a marked increase in cell proliferation (n=4, p<0.05), without changes in αSMA and collagen. Interestingly, gal-3 increased tgfb1 expression in cardiac fibroblasts (n=5, p<0.05) and induced an increase of miR-21 and miR-23a levels in the culture media (15- and 6-folds over basal, respectively, n=4, p<0.05). To test a possible paracrine communication between cardiomyocytes and fibroblasts, we stimulated NRVM with fibroblast-derived, gal-3-stimmulated conditioned medium. Our results show that in this condition there is an increase in both cardiac remodeling markers (Nppa and Myh7), as well as cardiomyocyte area. In conclusion, gal-3 activates pro-survival and proliferation signaling pathways in cardiac fibroblasts without a direct effect on cardiomyocytes. However, gal-3 can induce cardiomyocyte hypertrophy by a mechanism involving paracrine communication between fibroblasts and myocytes, which likely includes TGFβ1 and the hypertrophy-related miR-21 and miR-23a.

Gene Expressions Underlying Mishandled Calcium Clearance and Elevated Generation of Reactive Oxygen Species in the Coronary Artery Smooth Muscle Cells of Chronic Heart Failure Rats.

Background:The calcium clearance and reactive oxygen species (ROS) generations in the coronary artery smooth muscle cells in chronic heart failure (HF) have not been fully investigated. Therefore, we attempted to understand the gene expressions underlying the mishandling of calcium clearance and the accumulations of ROS.Methods:We initially established an animal model of chronic HF by making the left anterior descending coronary artery ligation (CAL) in rats, and then isolated the coronary artery vascular smooth muscle cells from the ischemic and the nonischemic parts of the coronary artery vessels in 12 weeks after CAL operation. The intracellular calcium concentration and ROS level were measured using flow cytometry, and the gene expressions of sarco/endoplasmic reticulum Ca2+-ATPase (SERCA2a), encoding sarcoplasmic reticulum Ca2+-ATPase 2a, encoding sodium-calcium exchanger (NCX), and p47phox encoding a subunit of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were examined using real-time quantitative reverse transcription polymerase chain reaction and Western blotting, respectively.Results:We found that the calcium accumulation and ROS generation in the coronary artery smooth muscle cells isolated from either the ischemic or the nonischemic part of the CAL coronary artery vessel were significantly increased irrespective of blood supply (all P < 0.01). Moreover, these were accompanied by the increased expressions of NCX and p47phox, the decreased expression of SERCA2a, and the increased amount of phosphorylated forms of p47phox in NADPH oxidase (all P < 0.05).Conclusions:Our results demonstrated that the disordered calcium clearance and the increased ROS generation occurred in the coronary artery smooth muscle cells in rats with chronic HF produced by ligation of the left anterior descending coronary artery (CAL), and which was found to be disassociated from blood supply, and the increased generation of ROS in the cells was found to make concomitancy to the increased activity of NADPH oxidase in cytoplasm.

The effect of non-xanthine adenosine receptor antagonist on ventricular remodeling and RAAS in chronic heart failure

Objective To analyze the effect of non-xanthine adenosine receptor antagonist(SLV320) on the ventricular remodeling and renin-angiotensin-aldosterone system(RAAS)in animal experimental models of chronic heart failure(CHF). Methods The 40 healthy male New Zealand rabbits were received adriamycin by intravenous injection to establishing the experimental animal models and were randomly divided into 4 groups, which were high-dosage group(injected with SLV320,10.0μg·kg-1·d-1),medium-dosage group(injected with SLV320,5.0μg·kg-1·d-1),low-dosage group(injected with SLV320,2.5μg·kg-1· d-1)and furosemide group(fed with furosemide,2.0mg·kg-1·d-1).Each group had 10 rabbits and continuous treated for one week. The indexes of plasma renin activity(PRA),angiotensinⅡ(AngⅡ),aldosterone (ALD)and beta ntriuretic peptide(BNP)were detected at pre-and post-treatment,and compared among 4 groups. The indexes of left ventricular end-systolic dimension(LVESD), left ventricular end-diastolic dimension(LVEDD),left ventricular posterior wall(LVPW),left ventricle ejection fraction(LVEF),left ventricular fractional shortening(LVFS)and E/A at pre-and post-treatment were detected by echocardiography and compared among 4 groups. The wet weigh of the left and right ventricle were weigh accurately. And the indexes of left ventricle weight index(LVWI)and the body weight index(BWI)were calculated and compared among 4 groups. Results The plasma levels of PRA, Ang Ⅱ,ALD and BNP were no different among 4 groups before study(all P>0.05). The sequence of 4 groups on the plasma levels of RAASindexes was highdosage group 0.05). The sequence of 4 groups on the levels of LVEF and LVFS was high-dosage group>medium-dosage group>low-dosage group>furosemide group, and the sequences of LVESD,LVEDD,LVPW and E/A were high-dosage group<medium-dosage group<low -dosage group<furosemide group(all P<0.05). The sequences of 4 groups on the LVWI and RVWI were high-dosage group<medium-dosage group<low-dosage group<furosemide group(all P<0.05). Conclusion SLV320 can regulate the ventricular remodeling and RAAS in animal model of CHF and this effect was dose dependent. Key words: Non-xanthine adenosine receptor antagonist; Heart failure; Ventricular remodeling; Renin-angiotensin-aldosterone system

Short-term vagal nerve stimulation improves left ventricular function following chronic heart failure in rats

Increasing numbers of animal and clinical investigations have demonstrated the effectiveness of long-term electrical vagal nerve stimulation (VNS) on chronic heart failure (CHF). The present study investigated the effects of short-term VNS on the hemodynamics of cardiac remodeling and cardiac excitation-contraction coupling (ECP) in an animal model of CHF following a large myocardial infarction. At 3 weeks subsequent to ligation of the left coronary artery, the surviving rats were randomized into vagal and sham-stimulated groups. The right vagal nerve of the CHF rats was stimulated for 72 h. The vagal nerve was stimulated with rectangular pulses of 40 ms duration at 1 Hz, 5 V. The treated rats, compared with the untreated rats, had significantly higher left ventricular ejection fraction (54.86±9.73, vs. 45.60±5.51%; P=0.025) and left ventricular fractional shortening (25.31±6.30, vs. 15.42±8.49%; P=0.013), and lower levels of brain natriuretic peptide (10.07±2.63, vs. 19.95±5.22 ng/ml; P=0.001). The improvement in cardiac pumping function was accompanied by a decrease in left ventricular end diastolic volume (1.11±0.50, vs. 1.54±0.57 cm3; P=0.032) and left ventricular end systolic volume (0.50±0.28, vs. 0.87±0.36 cm3; P=0.007). Furthermore, the expression levels of ryanodine receptor type 2 (RyR2) and sarcoplasmic reticulum calcium adenosine triphosphatase (SERCA2) were significantly higher in the treated rats compared with the untreated rats (P=0.011 and P=0.001 for RyR2 and SERCA2, respectively). Therefore, VNS was beneficial to the CHF rats through the prevention of cardiac remodeling and improvement of cardiac ECP.

Role of the Carotid Body Chemoreflex in the Pathophysiology of Heart Failure: A Perspective from Animal Studies.

The treatment and management of chronic heart failure (CHF) remains an important focus for new and more effective clinical strategies. This important goal, however, is dependent upon advancing our understanding of the underlying pathophysiology. In CHF, sympathetic overactivity plays an important role in the development and progression of the cardiac and renal dysfunction and is often associated with breathing dysregulation, which in turn likely mediates or aggravates the autonomic imbalance. In this review we will summarize evidence that in CHF, the elevation in sympathetic activity and breathing instability that ultimately lead to cardiac and renal failure are driven, at least in part, by maladaptive activation of the carotid body (CB) chemoreflex. This maladaptive change derives from a tonic increase in CB afferent activity. We will focus our discussion on an understanding of mechanisms that alter CB afferent activity in CHF and its consequence on reflex control of autonomic, respiratory, renal, and cardiac function in animal models of CHF. We will also discuss the potential translational impact of targeting the CB in the treatment of CHF in humans, with relevance to other cardio-respiratory diseases.

Cardioprotective effects of the YiQiFuMai injection and isolated compounds on attenuating chronic heart failure via NF-κB inactivation and cytokine suppression

Ethnopharmacological relevanceThe YiQiFuMai injection (YQFM) is a traditional Chinese medicine for the treatment of chronic heart failure (CHF). The present study not only evaluated the cardioprotective effect and anti-inflammatory mechanism of the YQFM injection in an experimental model of CHF but also investigated its bioactive constituents in vitro. Materials and methodsThe left anterior descending coronary artery (LAD) in rats was ligated to make an animal model of CHF. From this, electrocardiographic parameters and exterior signs of rat hearts were recorded. Additionally, the histopathology of heart tissues was examined, and parameters of inflammatory stress were measured. Experiments were performed over two months in LAD-ligation rats treated with YQFM or vehicle. Treatment with Captopril was used as a positive control, which has previously been shown to prevent CHF, and rats without LAD-ligation were used as a negative control. Furthermore, we screened and identified potential anti-inflammatory constituents by ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC/Q-TOF-MS) combined with NF-κB activity luciferase reporter assay systems. Further cytokine detection confirmed the anti-inflammatory effects of the potential NF-κB inhibitors from YQFM. ResultsThe administration of YQFM significantly improved cardiac function and ameliorated the activity level of inflammatory mediators (such as tumor necrosis factor-alpha, interleukin-6, and interleukin-1β) in CHF rats. Eight potential anti-inflammatory ingredients, ginsenosides Rb1, Rg1, Rf, Rh1, Rc, Rb2, Ro, and Rg3, were characterized and confirmed. Among these compounds, ginsenoside Ro was revealed as a new NF-κB inhibitor. ConclusionThe results suggested that NF-κB inactivation and cytokine suppression might be one of the main mechanisms of YQFM that caused ameliorative effects in CHF rats, and the major constituents of ginsenosides were identified playing a key role in the treatment of CHF.

S37 Can the Lung Reverse Remodel? Gene Therapy For Cardiac Failure Alters Pulmonary Gene Expression

IntroductionIrreversible alveolar capillary membrane (ACM) remodelling accompanies chronic heart failure (CHF), contributing to dyspnoea, the predominant symptom that limits quality of life in CHF. Gene therapy is aimed at improving...

Effect of ghrelin and its analogues, BIM‐28131 and BIM‐28125, on the expression of myostatin in a rat heart failure model

BackgroundIn chronic heart failure (CHF), cachexia is a hallmark of the terminal stage of this disease and is associated with a severely reduced quality of life and poor prognosis. Therapeutic options are currently not available. Ghrelin and its analogues BIM-28125 and BIM-28131 (now known as RM-131) have been shown to increase weight in a rat model of CHF. It has been further demonstrated that the expression of myostatin, a negative regulator of skeletal muscle mass, is increased in CHF. The aim of the study was to investigate the influence of ghrelin or its analogues on myostatin in CHF.MethodsIn an animal model of CHF, Sprague–Dawley rats received either ghrelin or two ghrelin analogues BIM-28125 and BIM-28131 in two different concentrations (50 and 500 nmol/kg/day) compared to placebo. The compounds were delivered using osmotic mini pumps. The expression of myostatin was analyzed in skeletal muscle by RT-PCR and Western blot, and muscle mass of gastrocnemius muscle was measured. The plasma levels of tumor necrosis factor alpha (TNF-α) were measured.ResultsThe relative weight of the gastrocnemius muscle of the sham-operated group was significantly increased compared to placebo-treated CHF rats. The application of ghrelin analogue BIM-28125 and BIM-28131 in their higher concentrations led to a significant reduction in myostatin mRNA expression in comparison to placebo. Myostatin protein expression was significantly reduced in both concentrations of ghrelin and BIM-28131 and in the lower concentration of BIM-28125. The increase of TNF-α plasma concentration in the CHF-animals could be abolished by all used substances.ConclusionsIn an animal model of CHF, the expression of myostatin is significantly reduced in the skeletal muscle after application of ghrelin and most concentrations of its analogues BIM-28125 and BIM-28131 possibly due to anti-inflammatory effects.

Muscle oxygen transport and utilization in heart failure: implications for exercise (in)tolerance.

The defining characteristic of chronic heart failure (CHF) is an exercise intolerance that is inextricably linked to structural and functional aberrations in the O(2) transport pathway. CHF reduces muscle O(2) supply while simultaneously increasing O(2) demands. CHF severity varies from moderate to severe and is assessed commonly in terms of the maximum O(2) uptake, which relates closely to patient morbidity and mortality in CHF and forms the basis for Weber and colleagues' (167) classifications of heart failure, speed of the O(2) uptake kinetics following exercise onset and during recovery, and the capacity to perform submaximal exercise. As the heart fails, cardiovascular regulation shifts from controlling cardiac output as a means for supplying the oxidative energetic needs of exercising skeletal muscle and other organs to preventing catastrophic swings in blood pressure. This shift is mediated by a complex array of events that include altered reflex and humoral control of the circulation, required to prevent the skeletal muscle "sleeping giant" from outstripping the pathologically limited cardiac output and secondarily impacts lung (and respiratory muscle), vascular, and locomotory muscle function. Recently, interest has also focused on the dysregulation of inflammatory mediators including tumor necrosis factor-α and interleukin-1β as well as reactive oxygen species as mediators of systemic and muscle dysfunction. This brief review focuses on skeletal muscle to address the mechanistic bases for the reduced maximum O(2) uptake, slowed O(2) uptake kinetics, and exercise intolerance in CHF. Experimental evidence in humans and animal models of CHF unveils the microvascular cause(s) and consequences of the O(2) supply (decreased)/O(2) demand (increased) imbalance emblematic of CHF. Therapeutic strategies to improve muscle microvascular and oxidative function (e.g., exercise training and anti-inflammatory, antioxidant strategies, in particular) and hence patient exercise tolerance and quality of life are presented within their appropriate context of the O(2) transport pathway.

Exercise training normalizes ACE and ACE2 in the brain of rabbits with pacing-induced heart failure

Exercise training (EX) normalizes sympathetic outflow and plasma ANG II in chronic heart failure (CHF). The central mechanisms by which EX reduces this sympathoexcitatory state are unclear, but EX may alter components of the brain renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) may mediate an increase in sympathetic nerve activity (SNA). ACE2 metabolizes ANG II to ANG-(1-7), which may have antagonistic effects to ANG II. Little is known concerning the regulation of ACE and ACE2 in the brain and the effect of EX on these enzymes, especially in the CHF state. This study aimed to investigate the effects of EX on the regulation of ACE and ACE2 in the brain in an animal model of CHF. We hypothesized that the ratio of ACE to ACE2 would increase in CHF and would be reduced by EX. Experiments were performed on New Zealand White rabbits divided into the following groups: sham, sham + EX, CHF, and CHF + EX (n = 5 rabbits/group). The cortex, cerebellum, medulla, hypothalamus, paraventricular nucleus (PVN), nucleus tractus solitarii (NTS), and rostral ventrolateral medulla (RVLM) were analyzed. ACE protein and mRNA expression in the cerebellum, medulla, hypothalamus, PVN, NTS, and RVLM were significantly upregulated in CHF rabbits (ratio of ACE to GAPDH: 0.3 +/- 0.03 to 0.8 +/- 0.10 in the RVLM, P < 0.05). EX normalized this upregulation compared with CHF (0.8 +/- 0.1 to 0.4 +/- 0.1 in the RVLM). ACE2 protein and mRNA expression decreased in CHF (ratio of ACE2 to GAPDH: 0.3 +/- 0.02 to 0.1 +/- 0.01 in the RVLM). EX increased ACE2 expression compared with CHF (0.1 +/- 0.01 to 0.8 +/- 0.1 in the RVLM). ACE2 was present in the cytoplasm of neurons and ACE in endothelial cells. These data suggest that the activation of the central RAS in animals with CHF involves an imbalance of ACE and ACE2 in regions of the brain that regulate autonomic function and that EX can reverse this imbalance.

Impact of exercise training on myostatin expression in the myocardium and skeletal muscle in a chronic heart failure model

In late-stage chronic heart failure (CHF), elevated cytokines and cachexia are often observed. Several studies have shown that exercise training exerts beneficial effects on skeletal muscle in this setting. Furthermore, it has been shown that the expression of myostatin, a key regulator of skeletal muscle mass, is increased in a variety of cachectic states. This study aimed to investigate the expression of myostatin in CHF, the influence of exercise training on myostatin levels, and regulation of myostatin by tumour necrosis factor-alpha (TNF-alpha). In an animal model of CHF (LAD-ligation model), protein expression of myostatin was elevated 2.4-fold in the skeletal muscle and more than four-times in the myocardium, compared with control (Co). Exercise training on a treadmill over 4 weeks led to a significant reduction in myostatin protein expression in the skeletal muscle and the myocardium of CHF animals, with values returning to baseline levels. In differentiated C2C12 cells, TNF-alpha induced the expression of myostatin through a p38MAPK-dependent pathway involving nuclear factor kappa-B (NF-kappaB). The increased TNF-alpha mRNA levels in the skeletal muscle of CHF animals correlated significantly with myostatin expression. These alterations in myostatin expression in the skeletal and heart muscle following exercise training could help to explain the beneficial anti-catabolic effects of exercise training in CHF.

Experimental Rat Models of Chronic Heart Failure

Chronic heart failure (CHF) is an end stage of all cardiovascular diseases and associated with multiple pathophysiological alterations and adaptations, such as marked anatomic and biochemical changes of the myocardium including left ventricular dysfunction and dilation, increased systemic vascular resistance, and activation of neurohumoral system. The use of animal models has provided a new mechanism of the complex pathogenesis of this syndrome and the effects of drug intervention. However, all of the animal models used have advantages as well as disadvantages. The species and interventions used to create chronic heart failure depend on the scientific question as well as on factors such as ethical and economical considerations, accessibility and reproducibility of the models. Rat animal models of CHF are induced by surgical techniques (coronary ligation, aortic banding, or aortacaval shunts), genetic manipulation (spontaneously hypertensive rat, hypertensive heart failure rat, or Dahl salt-sensitive rat), and toxic drugs (adriamycin, ethanol, or streptozotocin, etc.). They are frequently used because rats are inexpensive and many techniques have been developed to measure functional parameters. The current review will focus upon the characteristics of rat models of CHF.

Arterial Chemoreceptors and Sympathetic Nerve Activity

Chronic elevation in sympathetic nerve activity (SNA) is associated with the development and maintenance of certain types of hypertension1 and contributes to the progression of chronic heart failure (CHF).2 The mechanisms involved in sympathetic dysfunction in these disorders appear to be complex and multifactorial. A unified hypothesis is likely to encompass alterations in multiple autonomic reflex pathways, central integratory sites, and chemical mediators that control sympathetic outflow. For example, tonic restraint of sympathetic outflow by arterial and cardiopulmonary baroreflexes is depressed in CHF2 and depressed or reset in hypertension.3 Moreover, maladaptive changes also occur in the central nervous system at integrative sites for autonomic control in both disease processes.4,5 It is also clear that sympathoexcitatory cardiac,6 somatic,7 and central/peripheral chemoreceptor reflexes8 are enhanced in CHF and hypertension. Arterial chemoreceptors serve an important regulatory role in the control of alveolar ventilation, but they also exert a powerful influence on cardiovascular function.9 Activation of arterial chemoreceptors by hypoxemia increases sympathetic outflow to systemic vascular beds to compensate for the direct vasodilating effects of hypoxia on these vessels and to redistribute blood flow to essential organs. In this review, we highlight relevant information that implicates the arterial chemoreflex as a contributory mechanism for the sympathetic hyperactivity in CHF and hypertension and illustrate proposed mechanisms for this altered function. Arterial chemoreceptors located in the aortic and carotid bodies (CBs) respond to hypoxemia and hypercapnia. Because central chemoreceptors also respond to hypercapnia, hypoxia is typically used as a specific stimulus to arterial chemoreceptors. In some mammals, such as rats and rabbits, reflex responses to hypoxemia arise solely from the CB, whereas in other species, the aortic chemoreceptor contribution can be significant. However, it is not possible to experimentally separate the relative contribution of the aortic and …

Carotid body function in heart failure.

In this review, we summarize the present state of knowledge of the functional characteristics of the carotid body (CB) chemoreflex with respect to control of sympathetic nerve activity (SNA) in chronic heart failure (CHF). Evidence from both CHF patients and animal models of CHF has clearly established that the CB chemoreflex is enhanced in CHF and contributes to the tonic elevation in SNA. This adaptive change derives from altered function at the level of both the afferent and central nervous system (CNS) pathways of the reflex arc. At the level of the CB, an elevation in basal afferent discharge occurs under normoxic conditions in CHF rabbits, and the discharge responsiveness to hypoxia is enhanced. Outward voltage-gated K(+) currents (I(K)) are suppressed in CB glomus cells from CHF rabbits, and their sensitivity to hypoxic inhibition is enhanced. These changes in I(K) derive partly from downregulation of nitric oxide synthase (NOS)/NO signaling and upregulation of angiotensin II (Ang II)/Ang II receptor (AT(1)R) signaling in glomus cells. At the level of the CNS, interactions of the enhanced input from CB chemoreceptors with altered input from baroreceptor and cardiac afferent pathways and from central Ang II further enhance sympathetic drive. In addition, impaired function of NO in the paraventricular nucleus of the hypothalamus participates in the increased SNA response to CB chemoreceptor activation. These results underscore the principle that multiple mechanisms involving Ang II and NO at the level of both the CB and CNS represent complementary and perhaps redundant adaptive mechanisms to enhance CB chemoreflex function in CHF.