Anti-remodeling Effects Research Articles

Angiotensin II Receptor Blockade Prevented Left Ventricular Hypertrophy and Heart Failure Induced by Chronic Beta-adrenergic Receptor Stimulation

Angiotensin II receptor blockade (ARB) prevents left ventricular (LV) remodeling. The anti-remodeling effect of ARB was mediated from, at least in part, pressure reduction. In addition, the effect of ARB on diastolic heart failure (DHF) is still unclear. Therefore We investigated whether ARB prevents LV hypertrophy (H) and HF in chronic isoproterenol (ISO) treated mice, which model revealed LVH and DHF without hypertension. Osmotic minipump was implanted in male mice and ISO was chronically administrated for 4 weeks (30 μg/kg/day).

Melatonin as a potential antihypertensive treatment

The number of patients with well-controlled hypertension is alarmingly low worldwide and new approaches to treatment of increased blood pressure (BP) are being sought. Melatonin has a role in blood pressure regulation. The nighttime production of melatonin is found to be reduced in hypertensive individuals. Administration of melatonin decreased BP in several animal models of hypertension, in healthy men and women, and in patients with arterial hypertension. Most promising results were achieved in patients with non-dipping nighttime pressure, in which the circadian rhythm of BP variation is disturbed. Several potential mechanisms of BP reduction are considered. Melatonin can, via its scavenging and antioxidant nature, improve endothelial function with increased availability of nitric oxide exerting vasodilatory and hypotensive effects. Melatonin seems to interfere with peripheral and central autonomic system, with a subsequent decrease in the tone of the adrenergic system and an increase of the cholinergic system. Melatonin may act on BP also via specific melatonin receptors localized in peripheral vessels or in parts of central nervous system participating in BP control. With a large clinical trial using melatonin in hypertension treatment, many important questions could be answered, such as the dose of melatonin and regimen of its application, the choice of patients with greatest possible benefit from melatonin treatment, the potential of anti-remodeling effect of melatonin and the interaction of melatonin with other antihypertensive drugs.

Physical training in patients with chronic heart failure of ischemic origin: effect on exercise capacity and left ventricular remodeling

Physical training is a well-known complementary treatment for chronic heart failure (CHF); however, many aspects require further studies. One of them is the impact on remodeling of the left ventricle (LV). The purpose of this study was to evaluate the effect of 6 months of training on LV, exercise capacity and safety issues in patients with ischemic CHF. Fifty patients (mean age 60.1+/-9.2 years) with ischemic CHF, New York Heart Association (NYHA) classification class II and III and left ventricular ejection fraction (LVEF) <or=35% were randomized into groups: undergoing 6-month training (25 patients) and not trained (25 patients). In both groups at baseline and at 6 months a cardiopulmonary exercise test and magnetic resonance imaging (MRI) with evaluation of LV were performed. Training was limited by the achievement of 80% of the predicted heart rate at VO2peak achieved at the baseline cardiopulmonary exercise test. All patients completed the 6-month observation. No serious adverse events were found in either group. Exercise capacity improved only in the trained group (VO2peak increased by 31%). At 6 months in the trained group there was a tendency towards an improvement in some LV parameters: ejection fraction, end-diastolic volume and wall motion score index (WMSI), whereas an opposite trend was seen in the controls (P<0.05, P<0.05 and P<0.01 for comparison of LVEFs, end-diastolic volumes and WMSIs, respectively). Six-month training in ischemic CHF patients is a safe modality. Training improves exercise capacity. There was no negative impact on LV morphology, and a trend towards improvement of functional parameters on MRI may suggest an anti-remodeling effect of training in patients with ischemic CHF.

Thalidomide attenuates the development of fibrosis during post‐infarction myocardial remodelling in rats

Inflammation plays a pathogenic role in the development of heart failure (HF). The aim of this study was to examine the effect of treatment with the immunomodulating drug thalidomide in a rat model for post-myocardial infarction (MI) HF. Rats were subjected to MI by left coronary artery ligation or sham-operated. Seven days after surgical intervention rats were randomised to treatment with thalidomide or vehicle for 8 weeks. Our main findings were: (i) thalidomide treatment did not affect cardiac function or the hypertrophic response, as determined by haemodynamic measurements and heart chamber weights, respectively. (ii) HF rats treated with thalidomide had a minor reduction in septum and relative wall thickness (p<0.05), indicating an anti-remodelling effect. (iii) Thalidomide appeared to have immunostimulatory effects on the myocardium as evident by increased MIP-1alpha gene expression (p<0.05). (iv) Treating HF rats with thalidomide reduced myocardial collagen content, as assessed by markedly decreased levels of hydroxyproline ( approximately 40% reduction; p<0.05), accompanied by lower TGF-beta(1) gene expression (p<0.05). Although thalidomide had no effect on cardiac function, our results suggest that intervention with thalidomide may have beneficial effects in post-MI HF by attenuating collagen accumulation and development of myocardial fibrosis.

Prevention of angiotensin II-induced cardiac remodeling by angiotensin-(1–7)

Cardiac remodeling, which typically results from chronic hypertension or following an acute myocardial infarction, is a major risk factor for the development of heart failure and, ultimately, death. The renin-angiotensin system (RAS) has previously been established to play an important role in the progression of cardiac remodeling, and inhibition of a hyperactive RAS provides protection from cardiac remodeling and subsequent heart failure. Our previous studies have demonstrated that overexpression of angiotensin-converting enzyme 2 (ACE2) prevents cardiac remodeling and hypertrophy during chronic infusion of angiotensin II (ANG II). This, coupled with the knowledge that ACE2 is a key enzyme in the formation of ANG-(1-7), led us to hypothesize that chronic infusion of ANG-(1-7) would prevent cardiac remodeling induced by chronic infusion of ANG II. Infusion of ANG II into adult Sprague-Dawley rats resulted in significantly increased blood pressure, myocyte hypertrophy, and midmyocardial interstitial fibrosis. Coinfusion of ANG-(1-7) resulted in significant attenuations of myocyte hypertrophy and interstitial fibrosis, without significant effects on blood pressure. In a subgroup of animals also administered [d-Ala(7)]-ANG-(1-7) (A779), an antagonist to the reported receptor for ANG-(1-7), there was a tendency to attenuate the antiremodeling effects of ANG-(1-7). Chronic infusion of ANG II, with or without coinfusion of ANG-(1-7), had no effect on ANG II type 1 or type 2 receptor binding in cardiac tissue. Together, these findings indicate an antiremodeling role for ANG-(1-7) in cardiac tissue, which is not mediated through modulation of blood pressure or altered cardiac angiotensin receptor populations and may be at least partially mediated through an ANG-(1-7) receptor.

Efeitos do tartarato de metoprolol em pacientes portadores de insuficiência cardíaca

To study the effects of metoprolol tartrate therapy in patients with heart failure. Fifty patients (36 males) aged 52+/-14.8 yrs, with functional class II to IV heart failure (HF) and left ventricular ejection fraction (LVFE) < 45%, assessed by radionuclide ventriculography, were evaluated in a retrospective study. Metoprolol tartrate was added to the usual therapy, with a starting dose of 12.5 mg, which was increased weekly to a maximum of 200 mg/day, according to patients tolerance. Clinical evaluation, electrocardiogram, Doppler echocardiogram, 24-h Holter monitoring and radionuclide ventriculography were carried out in the pre-treatment phase and repeated three and six months after the start of therapy. At the end of six months, there was functional class (NYHA) improvement with a reduction from 3.04+/-0.11 to 1.66+/-0.06(p<0.001). Ejection fraction increased from 29.84+1.61% to 38.56+/-1.95% (p< 0.001). The left ventricular diastolic diameter showed a reduction from 67.70+/-1.31 mm to 63.96+/-1.29 mm (p<0.001), and the left ventricular systolic diameter showed a reduction from 54.80+/-1.67 mm to 48.58+/-1.38 (p<0.001). There was no alteration in noradrenaline levels during the six-month follow-up period (p>0.05). Cardiac frequency decreased from 78.84+/-1.68 to 67.48+/-1.86 b.p.m. (p<0.001). The adding of metoprolol tartrate to the usual heart failure therapy is followed by an increase of ejection fraction, functional class improvement, and decrease of ventricular diameters and cardiac frequency. These results suggest anti-remodeling effects in patients with HF who utilize metoprolol tartrate in addition to the usual therapy.

Cardiac resynchronization therapy and adrenergic mechanisms

cardiac resynchronization therapy (CRT) is a major advance in the treatment of heart failure (HF), and thus far the most important HF therapeutic modality identified in the 21st century. When applied to patients with left ventricular dyssynchrony, CRT immediately improves chamber contractile

Effects of Selective Matrix Metalloproteinase Inhibitor (PG-116800) to Prevent Ventricular Remodeling After Myocardial Infarction: Results of the PREMIER (Prevention of Myocardial Infarction Early Remodeling) Trial

We sought to determine whether matrix metalloproteinase (MMP) inhibitor, PG-116800, reduced left ventricular (LV) remodeling after myocardial infarction (MI). PG-116800 is an oral MMP inhibitor with significant antiremodeling effects in animal models of MI and ischemic heart failure. In an international, randomized, double-blind, placebo-controlled study, 253 patients with first ST-segment elevation MI and ejection fraction between 15% and 40% were enrolled 48+/- 24 h after MI and treated with placebo or PG-116800 for 90 days. Major efficacy end points were changes in LV volumes as determined by serial echocardiography, and clinical and safety outcomes were also collected. In total, 203 patients (80%) completed 90 days of treatment and had evaluable baseline and 90-day echocardiograms. The proportion of patients with anterior MI (78% vs. 81%) and primary percutaneous coronary intervention (90% vs. 91%) along with baseline LV ejection fraction (35.5% vs. 36.8%) did not differ between PG-116800-treated and placebo-treated patients. There was no difference in the change in LV end-diastolic volume index from days 0 to 90 with PG-116800 versus placebo (5.09 +/- 1.45 ml/m(2) vs. 5.48 +/- 1.41 ml/m2, p = 0.42). Changes in LV diastolic volume, LV systolic volume, LV ejection fraction, sphericity index, plus rates of death or reinfarction were not significantly improved with PG-116800. PG-116800 was well tolerated; however, there was increased incidence of arthralgia and joint stiffness without significant increase in overall musculoskeletal adverse events (21% vs. 15%, p = 0.33). Matrix metalloproteinase inhibition with PG-116800 failed to reduce LV remodeling or improve clinical outcomes after MI.

765 Age effect in mild to moderate heart failure: baseline echocardiographic data from the AntiRemodeling Effect of CAnrenone IN Patients With Mild Chronic Heart Failure (AREA-IN-CHF) study

765 Age effect in mild to moderate heart failure: baseline echocardiographic data from the AntiRemodeling Effect of CAnrenone IN Patients With Mild Chronic Heart Failure (AREA-IN-CHF) study

792 Antiremodeling effect of canrenone in patients with mild chronic heart failure: AREA IN CHF study. Baseline data of patients

792 Antiremodeling effect of canrenone in patients with mild chronic heart failure: AREA IN CHF study. Baseline data of patients

Olmesartan Is an Angiotensin II Receptor Blocker with an Inhibitory Effect on Angiotensin-Converting Enzyme

Angiotensin II receptor blockers (ARBs) are widely used for the treatment of hypertension. It is believed that treatment with an ARB increases the level of plasma angiotensin II (Ang II) because of a lack of negative feedback on renin activity. However, Ichikawa (Hypertens Res 2001; 24: 641-646) reported that long-term treatment of hypertensive patients with olmesartan resulted in a reduction in plasma Ang II level, though the mechanism was not determined. It has been reported that angiotensin 1-7 (Ang-(1-7)) potentiates the effect of bradykinin and acts as an angiotensin-converting enzyme (ACE) inhibitor. It is known that ACE2, which was discovered as a novel ACE-related carboxypeptidase in 2000, hydrolyzes Ang I to Ang-(1-9) and also Ang II to Ang-(1-7). It has recently been reported that olmesartan increases plasma Ang-(1-7) through an increase in ACE2 expression in rats with myocardial infarction. We hypothesized that over-expression of ACE2 may be related to a reduction in Ang II level and the cardioprotective effect of olmesartan. Administration of 0.5 mg/kg/day of olmesartan for 4 weeks to 12-week-old stroke-prone spontaneously hypertensive rats (SHRSP) significantly reduced blood pressure and left ventricular weight compared to those in SHRSP given a vehicle. Co-administration of olmesartan and (D-Ala7)-Ang-(1-7), a selective Ang-(1-7) antagonist, partially inhibited the effect of olmesartan on blood pressure and left ventricular weight. Interestingly, co-administration of (D-Ala7)-Ang-(1-7) with olmesartan significantly increased the plasma Ang II level (453.2+/-113.8 pg/ml) compared to olmesartan alone (144.9+/-27.0 pg/ml, p<0.05). Moreover, olmesartan significantly increased the cardiac ACE2 expression level compared to that in Wistar Kyoto rats and SHRSP treated with a vehicle. Olmesartan significantly improved cardiovascular remodeling and cardiac nitrite/ nitrate content, but co-administration of olmesartan and (D-Ala7)-Ang-(1-7) partially reversed this anti-remodeling effect and the increase in nitrite/nitrate. These findings suggest that olmesartan may exhibit an ACE inhibitory action in addition to an Ang II receptor blocking action, prevent an increase in Ang II level, and protect cardiovascular remodeling through an increase in cardiac nitric oxide production and endogenous Ang-(1-7) via over-expression of ACE2.

767 Gender-related echocardiographic characteristics in mild to moderate heart failure: baseline data from the AntiRemodeling Effect of CAnrenone IN Patients With Mild Chronic Heart Failure study

767 Gender-related echocardiographic characteristics in mild to moderate heart failure: baseline data from the AntiRemodeling Effect of CAnrenone IN Patients With Mild Chronic Heart Failure study

Potential of Gene Therapy Strategy for the Treatment of Hypertension

Hypertension is one of the most important risk factors for cardiovascular diseases (CVDs). CVD extends across all populations and represents the leading cause of morbidity and mortality in industrialized countries. Hypertension increases the risk of peripheral arterial disease, cardiomyopathy, stroke, and renal failure. The disease affects &50 million Americans and goes undetected in at least one third of the population. In spite of the tremendous progress made by pharmacotherapy in the management and control of hypertension, there has been a steady escalation in its prevalence during the last decade. This has led many to conclude that traditional pharmacotherapy has reached an intellectual plateau and that novel and innovative approaches must be sought for the treatment, control, and possible cure of hypertension. As a result, efforts of our group and those of many others have been diverted to explore the use of gene transfer and gene therapy strategies for a long-term control of hypertension. We have argued that gene therapy offers potentially significant improvements and benefits over the use of traditional pharmacotherapy: (1) noncompliance by patients can be significantly reduced or even eliminated because of the fact that a single treatment involving gene transfer could remain effective for months or even years; (2) side effects associated with pharmacotherapy can be minimized as a result of specific targeting of a therapeutic gene in a given tissue and optimally influencing cardiovascular pathophysiology on an individual patient basis; and (3) with its potential to produce long-term beneficial outcomes in end-organ damage, the gene therapy strategy could lead to a cure of hypertension and its related pathophysiology. It is noteworthy to mention that current pharmacotherapies are often unable to reverse end-organ damage associated with hypertension. In order for the gene therapy for hypertension to be successful, one must provide conceptual support of its efficacy in …

Fixed-Dose Combination of Isosorbide Dinitrate and Hydralazine Inhibits Left Ventricular Remodeling in Well-Treated Severe Heart Failure in African-Americans: A-HeFT

Background: Slowing or regression of progressive left ventricular (LV) remodeling has been an important contributor to favorable outcomes in response to ACE inhibitors and beta blockers in treatment of chronic heart failure. Isosorbide dinitrate (ISDN) plus hydralazine (H) exerted an antiremodeling effect in V-HeFT I and II when given to patients receiving only digoxin plus diuretic. A-HeFT was carried out in African-Americans with severe heart failure, most of whom were treated with ACE inhibitors and beta blockers. This drug combination produced a 47 percent reduction in mortality compared to placebo.

Inhaled tolafentrine reverses pulmonary vascular remodeling via inhibition of smooth muscle cell migration.

BackgroundThe aim of the study was to assess the chronic effects of combined phosphodiesterase 3/4 inhibitor tolafentrine, administered by inhalation, during monocrotaline-induced pulmonary arterial hypertension (PAH) in rats.MethodsCD rats were given a single subcutaneous injection of monocrotaline to induce PAH. Four weeks after, rats were subjected to inhalation of tolafentrine or sham nebulization in an unrestrained, whole body aerosol exposure system. In these animals (i) the acute pulmonary vasodilatory efficacy of inhaled tolafentrine (ii) the anti-remodeling effect of long-term inhalation of tolafentrine (iii) the effects of tolafentrine on the expression profile of 96 genes encoding cell adhesion and extracellular matrix regulation were examined. In addition, the inhibitory effect of tolafentrine on ex vivo isolated pulmonary artery SMC cell migration was also investigated.ResultsMonocrotaline injection provoked severe PAH (right ventricular systolic pressure increased from 25.9 ± 4.0 to 68.9 ± 3.2 after 4 weeks and 74.9 ± 5.1 mmHg after 6 weeks), cardiac output depression and right heart hypertrophy. The media thickness of the pulmonary arteries and the proportion of muscularization of small precapillary resistance vessels increased dramatically, and the migratory response of ex-vivo isolated pulmonary artery smooth muscle cells (PASMC) was increased. Micro-arrays and subsequent confirmation with real time PCR demonstrated upregulation of several extracellular matrix regulation and adhesion genes, such as matrixmetalloproteases (MMP) 2, 8, 9, 10, 11, 12, 20, Icam, Itgax, Plat and serpinb2. When chronically nebulized from day 28 to 42 (12 daily aerosol maneuvers), after full establishment of severe pulmonary hypertension, tolafentrine reversed about 60% of all hemodynamic abnormalities, right heart hypertrophy and monocrotaline-induced structural lung vascular changes, including the proportion of pulmonary artery muscularization. The upregulation of extracellular matrix regulation and adhesion genes was reduced by nearly 80% by inhalation of the tolafentrine. When assessed in vitro, tolafentrine blocked the enhanced PASMC migratory response.ConclusionIn conclusion, we demonstrate for the first time that inhalation of combined PDE3/4 inhibitor reverses pulmonary hypertension fully developed in response to monocrotaline in rats. This "reverse-remodeling" effect includes structural changes in the lung vascular wall and key molecular pathways of matrix regulation, concomitant with 60% normalization of hemodynamics.

IN VITRO INHIBITORY EFFECTS OF ATORVASTATIN ON CARDIAC FIBROBLASTS: IMPLICATIONS FOR VENTRICULAR REMODELLING

1. Hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (statins) reduce mortality after myocardial infarction (MI). Although this may be predominantly due to their known anti-ischaemic actions, these drugs are known to have other beneficial effects. 2. Because pathological deposition of extracellular matrix (ECM) material is a key component of remodelling after MI, we sought to determine whether atorvastatin could inhibit ECM production in vitro. 3. The addition of atorvastatin to rat cardiac fibroblasts stimulated with either transforming growth factor (TGF)-beta1 (TGF-beta1) or angiotensin (Ang) II reduced collagen synthesis in a dose-dependent manner (3.7-fold reduction (95% confidence interval (CI) 1.8-15; P < 0.01) and 5.3-fold reduction (95% CI 1.8-7.7; P < 0.01), respectively, compared with stimulant alone). Similar observations were made in human cardiac fibroblast cell culture. Atorvastatin also dose-dependently reduced TGF-beta1 and AngII-induced increases in alpha(I)-procollagen mRNA (P < 0.01 for both), as well as gene expression of the profibrotic peptide connective tissue growth factor. 4. Atorvastatin appears to directly inhibit collagen production by cardiac fibroblasts. This antifibrotic action may contribute to the antiremodelling effect of statins.

The effect and safety of carvedilol on the patients with chronic congestive heart failure

目的 观察β受体阻滞剂卡维地洛治疗慢性心力衰竭的临床疗效.方法采用随机和多中心研究方法,将60例心力衰竭患者随机平均分为两组,两组均给予心力衰竭常规治疗,A组加用卡维地洛.6个月随访其好转率,并比较治疗前后左室收缩内径(LVDs)、左室舒张内径(LVD)、左室射血分数(LVEF)变化.结果6个月后A组好转率(治愈率+好转率)为88%,B组好转率82.7%.两组LVDs、LVD、LVEF较治疗前均有显著改善(P＜0.05).结论卡维地洛在心力衰竭标准用药基础上治疗慢性心力衰竭是有效及安全的,可显著改善左室重塑。

Anti-remodelling effects of short-term high-intensity exercise training in patients with stable post-infarction heart failure

Anti-remodelling effects of short-term high-intensity exercise training in patients with stable post-infarction heart failure

Inhaled Iloprost Reverses Vascular Remodeling in Chronic Experimental Pulmonary Hypertension

Inhaled iloprost is an effective therapy for pulmonary arterial hypertension (PAH). However, no study to date has addressed the effects of inhaled iloprost on changes to pulmonary vascular structure that occur in PAH. The present study was designed to investigate chronic antiremodeling effects of inhaled iloprost in monocrotaline (MCT)-induced PAH in rats. Four weeks after a single injection of MCT, after full establishment of PAH, rats were nebulized with iloprost at a dose of 6 microg . kg(-1) . day(-1), or underwent sham nebulization with saline. After 2 weeks of inhalation therapy, right ventricular pressure and pulmonary vascular resistance were reversed in rats treated with iloprost, but not in sham-treated control animals. Systemic arterial pressure was unaffected. In addition, right heart hypertrophy, the degree of pulmonary artery muscularization, and the medial wall thickness of intraacinar pulmonary arteries regressed in response to iloprost. Furthermore, the MCT-induced increase in matrix metalloproteinase-2 and -9 activities and tenascin-C expression was suppressed. We conclude that the inhalation of iloprost reverses PAH and vascular structural remodeling in MCT-treated rats. This regimen suggests the possibility of an antiremodeling therapy in PAH.

Therapeutic administration of Budesonide ameliorates allergen-induced airway remodelling.

Airway inflammation and remodelling are important pathophysiologic features of chronic asthma. Although current steroid use demonstrates anti-inflammatory activity, there are limited effects on the structural changes in the lung tissue. We have used a mouse model of prolonged allergen challenge that exhibits many of the salient features of airway remodelling in order to investigate the anti-remodelling effects of Budesonide. Treatment was administered therapeutically, with dosing starting after the onset of established eosinophilic airway inflammation and hyper-reactivity. Budesonide administration reduced airway hyper-reactivity and leukocyte infiltration in association with a decrease in production of the Th2 mediators, IL-4, IL-13 and eotaxin-1. A reduction in peribronchiolar collagen deposition and mucus production was observed. Moreover, our data show for the first time that, Budesonide treatment regulated active transforming growth factor (TGF)-beta signalling with a reduction in the expression of pSmad 2 and the concomitant up-regulation of Smad 7 in lung tissue sections. Therefore, we have determined that administration of Budesonide modulates the progression of airway remodelling following prolonged allergen challenge via regulation of inflammation and active TGF-beta signalling.