Prevention Of Cardiac Remodeling Research Articles

Pyroptosis is a drug target for prevention of adverse cardiac remodeling: The crosstalk between pyroptosis, apoptosis, and autophagy.

Acute myocardial infarction (AMI) is one of the main reasons of cardiovascular disease-related death. The introduction of percutaneous coronary intervention to clinical practice dramatically decreased the mortality rate in AMI. Adverse cardiac remodeling is a serious problem in cardiology. An increase in the effectiveness of AMI treatment and prevention of adverse cardiac remodeling is difficult to achieve without understanding the mechanisms of reperfusion cardiac injury and cardiac remodeling. Inhibition of pyroptosis prevents the development of postinfarction and pressure overload-induced cardiac remodeling, and mitigates cardiomyopathy induced by diabetes and metabolic syndrome. Therefore, it is reasonable to hypothesize that the pyroptosis inhibitors may find a role in clinical practice for treatment of AMI and prevention of cardiac remodeling, diabetes and metabolic syndrome-triggered cardiomyopathy. It was demonstrated that pyroptosis interacts closely with apoptosis and autophagy. Pyroptosis could be inhibited by nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 inhibitors, caspase-1 inhibitors, microRNA, angiotensin-converting enzyme inhibitors, angiotensin Ⅱ receptor blockers, and traditional Chinese herbal medicines.

Resolvin-D1 attenuation of angiotensin II-induced cardiac inflammation in mice is associated with prevention of cardiac remodeling and hypertension

AimsDespite the broad pharmacological arsenal to treat hypertension, chronic patients may develop irreversible cardiac remodeling and fibrosis. Angiotensin II, the main peptide responsible for the Renin-Angiotensin-Aldosterone-System, has been closely linked to cardiac remodeling, hypertrophy, fibrosis, and hypertension, and some of these effects are induced by inflammatory mediators. Resolvin-D1 (RvD1) elicits potent anti-inflammatory and pro-resolving effects in various pathological models. In this study, we aimed to examine whether RvD1 ameliorates cardiac remodeling and hypertension triggered by angiotensin II. Methods and resultsAlzet® osmotic mini-pumps filled with angiotensin II (1.5 mg/kg/day) were implanted in male C57BL/6 J mice for 7 or 14 days. RvD1 (3 μg/kg/day, i.p) was administered one day after the surgery and during the complete infusion period. Blood pressure and myocardial functional parameters were assessed by echocardiography. At the end of the experimental procedure, blood and heart tissue were harvested, and plasma and histological parameters were studied. After 7 and 14 days, RvD1 reduced the increase of neutrophil and macrophage infiltration triggered by angiotensin II, and also reduced ICAM-1 and VCAM-1 expression levels. RvD1 also reduced cytokine plasma levels (IL-1β, TNF-α, IL-6, KC, MCP-1), cardiac hypertrophy, interstitial and perivascular fibrosis, and hypertension. ConclusionsThis study unveils novel cardioprotective effects of RvD1 in angiotensin II-induced hypertension and cardiac remodeling by attenuating inflammation and provides insights into a potential clinical application.

Intracerebroventricular infusion of donepezil prevents cardiac remodeling and improves the prognosis of chronic heart failure rats

Oral administration of donepezil, a centrally acting acetylcholinesterase inhibitor, improves the survival of rats with chronic heart failure (CHF). The mechanisms of cardioprotective effects of donepezil, however, remain totally unknown. To elucidate potential mechanisms, we examined whether central microinfusion of donepezil would exert cardioprotection. Intracerebroventricular microinfusion pumps with cerebroventricular cannula were implanted in rats with myocardial infarction. The rats were randomly divided into central saline treatment (CST) and central donepezil treatment (CDT) groups. We evaluated cardiac remodeling and function after a 6-week treatment and examined the 160-day survival rate. Compared to the CST, the CDT markedly improved the 160-day survival rate (68% vs. 32%, P = 0.002) through the prevention of cardiac remodeling and the lowering of plasma catecholamine, brain natriuretic peptide, and angiotensin II. These results suggest that the central mechanism plays an important role in the cardioprotective effects of donepezil.

METFORMIN EXERTS CARDIOPROTECTION IN ISOPROTERENOL-INDUCED CARDIOMYOPATHY IN RATS

Introduction. Due to neuropathy in diabetic patients, the dysfunction of the autonomic nervous system occurs, and cardiac activity undergone excess sympathetic stimulation which is named cardiac autonomic neuropathy. Patients with cardiac autonomic neuropathy are at higher risk of left ventricular hypertrophy and are predisposed to cardiovascular events. It was established that metformin, a first-line agent for the initial pharmacotherapy of type 2 diabetes mellitus, poses significant cardioprotective effects. Nevertheless, its activity in the myocardium, subjecting the increased sympathetic tone, remains poorly investigated.
 The aim of the study – to explore the effects of metformin on cardiac remodeling after prolonged isoproterenol administration at a low dose.
 Research Methods. To induce cardiomyopathy, Wistar rats were injected intraperitoneally with isoproterenol (Iso – 5 mg/kg) in the continuous presence of metformin (М – 100 mg/kg) or vehicle only for 7 consecutive days. Tissue samples were stained with Hematoxylin&Eosin using standard method. The serum level of brain natriuretic peptide was estimated using the Rat BNP ELISA Kit. Statistical comparison of multiple groups was performed by one-way ANOVA followed by Bonferroni Test using GraphPad Prism version 5.00.
 Results and Discussion. The results of investigation demonstrate that metformin treatment significantly aboli­shed cardiac hypertrophy in rats induced by isoproterenol administration at the daily dose 5 mg/kg for 7 days. Anti­hypertrophic effect of the drug was confirmed by its ability to diminish the serum level of brain natriuretic peptide. Structural fibrotic reorganization was prevented as well.
 Conclusions. Metformin exerts cardioprotection after prolonged isoproterenol administration at a low dose preventing hypertrophic and fibrotic remodeling and fetal genes reprogramming. Thus, it might be a potential tool in the prevention of cardiac remodeling in patients with sympathetic overactivity.

P629Voluntary exercise associated with myokine production ameliorates cardiac remodeling and inflammation in a myocardial infarction mouse model

Abstract Background Left ventricular (LV) remodeling, through excessive inflammation, leads to heart failure. Exercise (Ex) training is associated with a risk reduction in heart failure through direct and indirect mechanisms by which Ex contributes an anti-inflammatory effect. During Ex, contracting muscle fibers release myokines, including interleukins (ILs), tumor necrosis factor α (TNF-α), follistatin-like protein 1 (FSTL-1), and fibroblast growth factor 21 (FGF-21), into the bloodstream. These myokines may have beneficial effects on other damaged organs, such as an infarcted myocardium, through anti-inflammatory effects. However, the exact mechanisms of the anti-inflammatory effects of voluntary Ex in myocardial infarction (MI) are poorly understood. Therefore, we investigated the effect of voluntary Ex on cardiac remodeling and inflammation, the relationship between cardiac remodeling and skeletal muscle (SKM) response, and circulating myokine levels in a mouse model of MI. Methods Twelve-week-old male C57BL/6J mice were used and divided into the following 4 groups: sham operation (Sham), MI, Sham+Ex, and MI+Ex. MI was induced by ligation of the left anterior descending coronary artery. Ex groups began voluntary wheel running for 4 weeks after the operation. An echocardiography was performed at baseline and 4 weeks after the operation. The mRNA levels in the LV infarcted area and SKM were measured with RT-PCR and western blot analysis. Plasma levels of myokines were also measured with immunoassays. Results Four weeks after MI induction, echocardiographic evaluation showed that the MI mice had a larger LV end-diastolic diameter (LVEDD) and end-systolic diameter (LVESD) than the Sham mice. The MI mice also showed higher mRNA levels of TNF-α, IL-1β, IL-6, and IL-10 in the LV tissue when compared to the Sham mice. These changes were significantly ameliorated in the MI+Ex mice. Interestingly, in the MI+Ex mice, mRNA levels of IL-6, IL-1β, FSTL-1, and FGF-21 in the SKM were significantly higher than in the MI mice, while there were no significant differences in TNF-α and IL-10 levels in all groups. Similarly, protein expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha, sirtuin-1, and mitochondrial transcriptional factor A of mitochondrial function markers in SKM were also significantly higher in the MI+Ex mice than in the MI mice. Furthermore, there were significant correlations between plasma levels of IL-1β, but not other myokines, and LVEDD, and LVESD. In addition, there was also a significant correlation between the SKM IL-1β level and LVESD in the Sham+Ex mice (all, P<0.05). Conclusions Amelioration of cardiac remodeling and inflammation by voluntary Ex is associated with increased myokines, especially IL-1β, in a MI mouse model. These results suggest that increased myokine levels, through voluntary exercise, may play an important role in the prevention of cardiac remodeling after MI.

SCIENTIFIC ACHIEVEMENTS OF THE DEPARTMENT OF INTERNAL MEDICINE, PHYSICAL REHABILITATION AND SPORTS MEDICINE

The article shows the results of a study conducted within the framework of the scientific research "Neurohormonal disorders in acute myocardial infarction against the background of hypertension and renal dysfunction, optimizing treatment and prevention of complications" at the department of internal medicine, physical rehabilitation and sports medicine for 3 years. A new multipurpose and pathogenetic method was developed for optimization of medical treatment in patients with acute myocardial infarction combined with hypertension and different stages of chronic kidney disease, and prevention of cardiac remodeling under conditions of using aldosterone antagonists – eplerenone and spironolactone.

PREVENTION OF COMPLICATIONS CAUSED BY MYOCARDIAL ISCHEMIA-REPERFUSION IN NONCARDIAC SURGICAL PROCEDURES

In the next 20 years, the aging population will be a major factor affecting the characteristics of perioperative anesthesia tactics. Domestic researchers have reported that the incidence of cardiac complications after general surgical procedures in patients with middle and old age is 9.1%, and mortality in these complications reached 45.5%. Analyzed current data on myocardial ischemia-reperfusion, the etiopathogenesis of perioperative cardiac complications, recurrence of their development and the possible consequences. It is concluded that prevention and timely treatment of complications resulting from ischemia-reperfusion of the myocardium, with noncardiac surgical interventions is an important tactical (prevention of perioperative myocardial infarction, arrhythmias, cardiac death) and policy (prevention of cardiac remodeling and post-hospital disability of patients) anaesthesiological tasks. Research carried out in the Nrgovsky Research Institute of General Reanimatology showed that in the real practice Detsky index, Lee index and echocardiographic left ventricular ejection fraction did not provide high accuracy prediction of cardiac events. More informative proved preoperative determination of blood N-terminal part of the pro-brain natriuretic peptide (NT-proBNP). In assessing the predictive ability of NT-proBNP area under the ROC-curve achieved 0.86. NT-proBNP value 358 pg/ml and above provided 77% sensitivity and 85% specificity. The comparative assessment and recommendations on the use to reduce the risk of cardiac complications of β-blockers, statins, calcium channel blockers, nitrates, clonidine, dexmedetomidine, levosimendan and phosphocreatine. Phosphocreatine, introduced in practice domestic cardiac surgery and transplantology more than 20 years ago, continues to be studied and used at the moment. Recently demonstrated that perioperative phosphocreatine usage appointment in older oncological patients with a high risk of cardiac complications reduces the incidence of acute ischemia and delirium, shortens the length of stay the intensive care unit and hospital stay. It was concluded that the reduction in the incidence of cardiac events has undoubted relevance with noncardiac operations.

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.

EGCG Blocked Phenylephrin-Induced Hypertrophy in H9C2 Cardiomyocytes, by Activating AMPK-Dependent Pathway.

AMP-activated protein kinase (AMPK) is a key regulator of energy metabolism. Previous studies have shown that activation of AMPK results in suppression of cardiac myocyte hypertrophy via inhibition of the p70S6 kinase (p70S6K) and eukaryotic elongation factor-2 (eEF2) signaling pathways. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac hypertrophy. However, the molecular mechanisms has not been well investigated. In this study, we found that EGCG could significantly reduce natriuretic peptides type A (Nppa), brain natriuretic polypeptide (BNP) mRNA expression and decrease cell surface area in H9C2 cardiomyocytes stimulated with phenylephrine (PE). Moreover, we showed that AMPK is activated in H9C2 cardiomyocytes by EGCG, and AMPK-dependent pathway participates in the inhibitory effects of EGCG on cardiac hypertrophy. Taken together, our findings provide the first evidence that the effect of EGCG against cardiac hypertrophy may be attributed to its activation on AMPK-dependent signaling pathway, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.

Вплив кверцетину на протеасомну активність в аорті та серці щурів зі спонтанною гіпертензією

To determine the role of proteasome proteolysis in the pathogenesis of hypertension, we have studied the proteolytic activity of the proteasome in the aorta and heart tissues of rats with spontaneous hypertension (line SHR), and used quercetin, the drug that can inhibit the activity of this multicatalytic complex. In the aorta of SHR, the activities of the proteasome were not significantly different from that observed in Wistar rats. At the same time, in the heart tissues the trypsin-like (at 40%, P > 0.05), and chymotrypsin-like (by 1.7 times, P < 0.03) activities were significantly less in SHR. Significant morphological changes (fibrosis of the left ventricle was 4.7%, aorta intima width was increased and heart weight index was higher by 21.6% (3.7 +/- 0.6 mg/g) compared with Wistar rats (2.9 +/- 0,4 mg/g, P < 0.004) were observed in these animals functional disorders (reduced stroke volume by 3 times (P < 0.0001), ejection fraction by 2.5 times (P < 0.0001), increased end diastolic pressure by 6.5 times (P < 0.005), end systolic pressure by 15% (P < 0.004)) were revealed. Pharmacological drug "Qvercetin" effectively inhibited trypsin-like and chymotrypsin-like proteasome activities in the aorta (2.7-fold (P < 0.005) and 2-fold (P < 0.003), correspondingly) and trypsin-like, and peptidyl-glutamyl peptide-hydrolyzing-like activities (2.4-fold, P > 0.05 and 9.3-fold, P < 0.02, correspondingly) activities in the heart, leading to a significant improvement of morphological and functional parameters of the heart. Whereas the drug "Qvercetin" that is widely used in clinical practice (especially in therapy of acute myocardial infarction) it could be recommended for the use in prevention of cardiac remodeling with high level of blood pressure.

ASSA13-06-6 Prevention of Cardiac Remodelling by Gene Silencing of Toll-Like Receptor-4 in Mice with Diabetic Cardiomyopathy

<h3>Objective</h3> Left ventricular (LV) remodelling contributes to the development of cardiac dysfunction and is considered as a key determinant of morbidity, mortality and prognosis in patients who developed diabetic cardiomyopathy (DCM). Stimulation of toll-like receptor 4 (TLR4) can lead to impairment of myocyte contractility and activation of several intracellular mediators such as kinases, which are known as critical regulators of myocardial remodelling. Up-regulation of TLR4 expression has been shown in myocardial tissue of diabetic mice. This work is aimed to investigate whether TLR4 has influences on cardiac function and remodelling in a mouse model of DCM. <h3>Methods</h3> Diabetes was induced in C57/B16 mice by the intraperitoneal injection of streptozotocin. Diabetic mice were treated with TLR4 siRNA or scrambled siRNA as control once a week. After treatment for 6 weeks, echocardiographic parameters and invasive cardiac function detection were performed. LV tissues were collected for the assessment of collagen density and cardiomyocyte hypertrophy. Meanwhile, the expression of myeloid differentiation factor 88 (MyD88) and c-Jun N-terminal kinases (JNK) were also detected by real- time PCR and western blot. <h3>Results</h3> Compared with diabetic mice and scrambled siRNA treated diabetic mice, TLR4 siRNA treated diabetic mice showed improved systolic and diastolic LV functions and decreased LV remodelling as evidenced by reduced collagen density and levels of plasma atrial natriuretic peptide. Interstitial fibrosis and myocardial hypertrophy were also reduced by TLR4 siRNA treatment. These were associated with down- regulations of intracellular TLR4 adapter MyD88 and significantly increased expression of the anti-hypertrophic JNK, suggesting the JNK pathway may be also involved in TLR4 triggered LV remodelling in DCM. <h3>Conclusions</h3> In summary, we present direct evidence that TLR4 plays a critical role in cardiac remodelling in DCM. TLR4 may be a novel therapeutic target in the treatment of DCM.

EGCG inhibits CTGF expression via blocking NF-κB activation in cardiac fibroblast

Connective tissue growth factor (CTGF) has been reported to play an important role in tissue fibrosis and presents a promising therapeutic target for fibrotic diseases. In heart, inappropriate increase in level of CTGF promotes fibroblast proliferation and extracellular matrix (ECM) accumulation, thereby exacerbating cardiac hypertrophy and subsequent failure. Epigallocatechin-3-gallate (EGCG), the major polyphenol found in green tea, possesses multiple protective effects on the cardiovascular system including cardiac fibrosis. However, the molecular mechanism by which EGCG exerts its anti-fibrotic effects has not been well investigated. In this study, we found that EGCG could significantly reduce collagen synthesis, fibronectin (FN) expression and cell proliferation in rat cardiac fibroblasts stimulated with angiotensinII (AngII). It also ameliorated cardiac fibrosis in rats submitted to abdominal aortic constriction (AAC). Moreover, EGCG attenuated the excessive expression of CTGF induced by AAC or AngII, and reduced the nuclear translocation of NF-κB p65 subunit and degradation of IκB-α. Subsequently, we demonstrated that in cardiac fibroblasts NF-κB inhibition could suppress AngII-induced CTGF expression. Taken together, these findings provide the first evidence that the effect of EGCG against cardiac fibrosis may be attributed to its inhibition on NF-κB activation and subsequent CTGF overexpression, suggesting the therapeutic potential of EGCG on the prevention of cardiac remodeling in patients with pressure overload hypertrophy.

Cardoguard, an Ayurvedic antihypertensive formulation, prevents cardiac remodeling in spontaneously hypertensive rats by inhibition of ERK and PKCε signaling pathways

Ayurveda is an Indian system of medicine. Despite clinical efficacy, lack of scientific validation has limited the effective use of Ayurvedic drugs. Cardoguard is an Ayurvedic antihypertensive drug formulated by Nagarjuna Herbal Concentrates Ltd., Kerala, India. Left ventricular hypertrophy (LVH) is a modifiable risk factor, and regression of LVH reduces the propensity for adverse cardiovascular events. This study was taken up with the objective of evaluating the efficacy of Cardoguard in the prevention of cardiac remodeling. Cardoguard was administered orally to 2-month-old spontaneously hypertensive rats for 4 months at a dose of 5 mg·day(-1). The dose corresponds to the therapeutic dose calculated on the basis of body surface area. Lower hypertrophy index, decrease in cardiomyocyte area, and reduction of interstitial fibrosis in treated spontaneously hypertensive rats indicate amelioration of cardiac hypertrophy by Cardoguard. Cardiac output increased in response to treatment. Immunostaining for the phosphorylated components of major signaling pathways associated with hypertrophy suggests that prevention of LVH by Cardoguard is possibly mediated through inhibition of extracellular signal-regulated kinases and protein kinase C-ε signaling pathways. Reduced expression of 3-nitrotyrosine in response to the treatment suggests that prevention of cardiac remodeling by Cardoguard is mediated by reduction of oxidative stress.

100 Renin: A new therapeutic target in the prevention of cardiac remodeling in patients with abdominal obesity?

100 Renin: A new therapeutic target in the prevention of cardiac remodeling in patients with abdominal obesity?

Role of kallistatin in prevention of cardiac remodeling after chronic myocardial infarction

Oxidative stress causes cardiomyocyte death and subsequent ventricular dysfunction and cardiac remodeling after myocardial infarction (MI), thus contributing to high mortality in chronic heart failure patients. We investigated the effects of kallistatin in cardiac remodeling in a chronic MI rat model and in primary cardiac cells. Human kallistatin gene was injected intramyocardially 20 min after ligation of the left coronary artery. At 4 weeks after MI, expression of human kallistatin in rat hearts was identified by reverse transcription–polymerase chain reaction, immunohistochemistry and ELISA. Kallistatin administration improved cardiac performance, increased mean arterial pressure, decreased myocardial infarct size and restored left ventricular wall thickness. Kallistatin treatment significantly attenuated cardiomyocyte size and atrial natriuretic peptide expression. Kallistatin also reduced collagen accumulation, collagen fraction volume and expression of collagen types I and III, transforming growth factor-β1 (TGF-β1) and plasminogen activator inhibitor-1 in the myocardium. Inhibition of cardiac hypertrophy and fibrosis by kallistatin was associated with increased cardiac nitric oxide (NO) levels and decreased superoxide formation, NADH oxidase activity and p22-phox expression. Moreover, in both primary cultured rat cardiomyocytes and myofibroblasts, recombinant kallistatin inhibited intracellular superoxide formation induced by H2O2, and the antioxidant effect of kallistatin was abolished by Nω-nitro-L-arginine methyl ester (L-NAME), indicating a NO-mediated event. Kallistatin promoted survival of cardiomyocytes subjected to H2O2 treatment, and inhibited H2O2-induced Akt and ERK phosphorylation, as well as NF-κB activation. Furthermore, kallistatin abrogated TGF-β-induced collagen synthesis and secretion in cultured myofibroblasts. This is the first study to demonstrate that kallistatin improves cardiac performance and prevents post-MI-induced cardiac hypertrophy and fibrosis through its antioxidant action.

OPTIMIZATION OF THE TREATMENT OF ELDERLY PATIENTS WITH MYOCARDIAL INFARCTION BY REVASCULARIZATION IN COMBINATION WITH INOTROPIC STIMULATION AND MYOCARDIAL UNLOADING

Aim. To study effect of coronary revascularization in combination with inotropic stimulation and myocardial unloading on prognosis in elderly patients with myocardial infarction (MI) complicated with heart failure (HF). Material and methods. 149 elderly patients with ECG picture of acute MI with ST segment elevation and HF symptoms were included into the study. All patients received standard therapy. According to the additional therapeutic maneuvers patients were split into four groups: 18 patients treated with percutaneous transluminal coronary angioplasty (PTCA) combined with inotropic levosimendan (LS) therapy; 20 patients with PTCA only; 22 patients treated with levosimendan (LS) only; control group - 89 patients with standard therapy without PTCA or LS. Results. Combination of PTCA and LS in elderly patients with acute MI complicated by HF had advantages in comparison with PTCA or LS applied separately or not applied at all. Combined therapy with PTCA and LS resulted in more prominent improvement of left ventricle systolic function, increase in exercise tolerance and more effective prevention of cardiac remodeling and was safe. Conclusion. Combined therapy with PTCA and LS is more effective than separate usage of these methods in elderly patients with MI complicated with HF.

Chronic chymase inhibition preserves cardiac function after left ventricular repair in rats☆

Although left ventricular repair (LVR) has been widely performed, the initial improvement of LV function does not last because of LV remodeling. Recent studies have demonstrated that chymase, a local enzyme in the heart, promotes angiotensin II formation as well as activation of transforming growth factor (TGF)-beta, both of which facilitate myocardial fibrosis. Therefore, chymase blockade may play an important role in the prevention of cardiac remodeling after LVR. In this study, the effects of chronic chymase inhibition (Chy-I) after LVR were evaluated in a rat LV aneurysm model. Rats that developed LV aneurysms 4 weeks after coronary artery ligation underwent LVR by plicating the LV aneurysm, and were randomized into two groups, the LVR group and the LVR + Chy-I group that received an oral chymase inhibitor (10 mg/kg/day) for 4 weeks. Echocardiography revealed better LV function in the LVR + Chy-I group than in the LVR group at 4 weeks. Four weeks after LVR, LV end-diastolic pressure and the time constant of LV isovolumic pressure decay, were significantly lower in the LVR+Chy-I group. The end-systolic pressure-volume relationship was higher in the LVR+Chy-I group. In the LVR+Chy-I group, mRNA expressions of TGF-beta1 and BNP significantly decreased in the LV myocardium. Histology showed reduced interstitial fibrosis in the LVR+Chy-I group. Chronic chymase inhibition prevented myocardial fibrosis and preserved cardiac function after LVR. A chymase inhibition could be an important strategy for management after LV repair surgery.

Abstract 3294: Superoxide-Dependent Cathepsin Activation System is Associated with Hypertensive Myocardial Remodeling and Represents a Target for Angiotesin II Type 1 Receptor Blocker Therapy

Objective: Cathepsin (Cat) activation contributes to tissue remodeling, and increased Cat activity and superoxide production has been observed in the left ventricle (LV) during heart failure (HF). In the present study we tested the hypothesis that superoxide-dependnet Cat activation inhibition prevents LV remodeling and dysfunction in the development of HF associated with hypertension. Methods and Results: We treated 8% salt-loaded Dahl salt-sensitive hypertensive rats (n=10 for each group) with vehicle hydralazine (5 mg/kg/d) E64d (a synthesis Cat inhibitor, 10 mg/kg/d), or olmesartan (OLM, 5 mg/kg/d) for 8 weeks. The rats fed 0.3% salt served as age-matched controls. The abundance of Cat mRNAs and proteins localized in cardiac myocytes (CMCs) and Cat-dependent activities were increased in the LV of HF rats and/or humans, and were reduced by OLM treatment. OLM suppressed the elastic lamina degradation by 56% (n=6, p&lt;0.01) concomitant with decreased local Cat S expression in intracoronary smooth muscle cells (SMCs) and restored the balance of elastin to collagen in the LV tissue of HF rats (HF 4.6 ± 0.9% vs. OLM 15.5 ± 2.1% elastin content/collagen content (%), n=6, P=0.031; control 22 ± 2.1%). Furthermore, OLM suppressed not only angiotensin converting enzyme and angiotensin II type 1 receptor (AT 1 R) and macrophage infiltration but also levels of NADPH oxidase components (p22 phox , gp91 phox , and p47 phox) concomitant with decreased NADPH activity and O 2 − production in LV tissues of HF rats and humans. These changes were accompanied by improved cardiac fibrosis, stiffness, and dysfunction. Interestingly, LV remodeling and dysfunction were partially improved by treatment with E64d. In vitro, H 2 O 2 stimulated Cat S mRNA and protein expression and activity, and these increases were abolished by pretreatment with MnTmPyp (50 μ mol/L) and N-acetylcysteine (5 mmol/L) as well as apocynin (100 μ mol/L) in culture CMCs (n=6, p&lt;0.01). Conclusions: This is the first report showing that Cats are likely to trigger and promote LV remodeling, and that AT 1 R inhibition exerts inhibitory effect on Cat activation system by the inhibition of NADPH oxidase-dependent superoxide anion production, leading to the prevention of cardiac remodeling and dysfunction.

27. Prevention of Cardiac Remodeling and Heart Failure in Dahl-Salt Sensitive Rats by AAV Vector-Mediated Interleukin-10 Expression

Background: Inflammation plays a crucial role in the pathogenesis of congestive heart failure (CHF). Enhanced plasma levels of proinflammatory cytokines in patients with CHF have been demonstrated by many other groups. TNF-α targeted approach was not sufficient to disrupt the activated network of inflammatory mediators in CHF. IL-10 exerts pleiotropic cardioprotective effects, such as anti-inflammatory effect, and improvement of the endothelial cell function. Previously, we reported that systemic expression of IL-10 ameliorated hypertension as well as cardiac hypertrophy in the Dahl salt-sensitive (DS) rats.

Chymase inhibition prevents cardiac fibrosis and improves diastolic dysfunction in the progression of heart failure.

Angiotensin (Ang) II, which plays a crucial role in the cardiac remodeling process, is generated via angiotensin-converting enzyme (ACE); however, an alternative generation pathway, chymase, which is stored in the mast cells, also exists in the heart. Cardiac chymase is insensitive to ACE inhibitors (ACEIs), and heart chymase promotes interstitial fibrosis by affecting collagen metabolism via transforming growth factor-beta in vitro. Therefore, selective chymase blockade seems to be an important strategy in the prevention of cardiac remodeling We evaluated the effects of a specific chymase inhibitor, SUNC8257 (Chy I; 10 mg/kg twice a day; n=7), on changes in cardiac structures, Ang II levels, and gene expressions, which are characterized as molecular markers for fibrosis, in dogs with tachycardia induced heart failure (HF). In HF, the number of chymase enzyme-positive mast cells increased in the left ventricle (LV) compared with the normal group; however, Chy I significantly decreased the mast cell density and cardiac Ang II levels. Despite no significant differences in LV systolic function compared with the vehicle group, Chy I decreased LV end-diastolic pressure and shortened the prolongation of tau. Chy I suppressed collagen-type I and III and transforming growth factor-beta mRNA levels and decreased fibrosis in the LV compared with the vehicle. The chymase pathway may be critical for cardiac diastolic dysfunction accompanied with fibrosis. Chronic chymase inhibition may therefore become an important strategy in the prevention of cardiac remodeling in HF.