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At least 19 recordsLinked to original sources
PubMed2001

Effects of combination of ACE inhibitor and angiotensin receptor blocker on cardiac remodeling, cardiac function, and survival in rat heart failure.

BACKGROUND: The mechanism and treatment of diastolic heart failure are poorly understood. We compared the effects of an ACE inhibitor, an angiotensin receptor blocker (ARB), and their combination on diastolic heart failure in Dahl salt-sensitive (DS) rats. METHODS AND RESULTS: DS rats fed an 8% NaCl diet from 7 weeks of age were treated with benazepril 10 mg/kg alone, valsartan 30 mg/kg alone, or combined benazepril and valsartan at 5 and 15 mg/kg, respectively, or at 1 and 3 mg/kg, respectively. At 16 weeks of age, DS rats exhibited prominent concentric left ventricular (LV) hypertrophy and diastolic dysfunction with preserved systolic function, as estimated by echocardiography. Despite comparable hypotensive effects among all drug treatments, the combination of benazepril 5 mg/kg and valsartan 15 mg/kg improved diastolic dysfunction and survival in DS rats more effectively than ACE inhibitor or ARB alone. Furthermore, the increase in LV endothelin-1 levels and hydroxyproline contents in DS rats was significantly suppressed only by combined benazepril and valsartan, and LV atrial natriuretic peptide mRNA upregulation in DS rats was suppressed to a greater extent by the combination therapy than monotherapy. CONCLUSIONS: The combination of ACE inhibitor and ARB, independently of the hypotensive effect, improved LV phenotypic change and increased LV endothelin-1 production and collagen accumulation, diastolic dysfunction, and survival in a rat heart failure model more effectively than either agent alone, thereby providing solid experimental evidence that the combination of these 2 agents is more beneficial than monotherapy for treatment of heart failure.

Angiotensin Receptor Antagonists↗
PubMedDate not supplied

[Effects of aldosterone receptor blocker therapy on cardiac remodeling].

Cardiac remodeling is a physiologic or pathologic condition that occurs after myocardial infarction, pressure overload, myocardial inflammatory diseases, idiopathic dilated cardiomyopathy or volume overload. In spite of different etiologies, molecular, biochemical and mechanical processes are the same. The change in left ventricular function brings about a complex neuro-hormonal disorder, and disease progression is due to the combined action of several biological factors with toxic effects on the heart and vessels. The renin-angiotensin-aldosterone system (RAAS) is very important in this process, through the effects on hydro-saline balance or through direct processes on myocardium. A direct effect of aldosterone in myocardial fibrosis after the detection of heart tissue aldosterone production has been demonstrated. In the past, the attention of physicians and researchers was focused on angiotensin II inhibition; and therefore, on angiotensin-converting enzyme (ACE) inhibitors, considering them sufficient to antagonize the effects of aldosterone. Nevertheless, this theory has been confuted in recent studies, with the evidence of elevated plasmatic aldosterone levels in patients treated with ACE-inhibitors and angiotensin receptor blockers. This phenomenon probably is due to the activation of secondary ACTH mediated pathways of trial aldosterone production. It has been demonstrated that aldosterone receptor inhibition is effective in reducing cardiac remodeling and mortality. AREA-IN CHF is the first multicentric, double blind, randomized, placebo control study to compare canrenone, an aldosterone receptor blocker, with placebo. The primary end point is the echocardiographic evaluation of left ventricular remodeling. Secondary end points are left ventricular end-systolic volume, ejection fraction, diastolic filling patterns, NYHA functional class, and mortality and hospitalizations of cardiac origin. In addition, bio-humoral effects of aldosterone receptor blocker therapy will be investigated. The study results will be available at the end of 2006.

Heart Failure↗
PubMed2002

Extracellular matrix and cardiac remodelling.

Cardiac remodelling associated with primitive and secondary cardiomyopathy is generally associated with changes in the expression in extracellular matrix (ECM) proteins as well as their transmembrane receptors, the integrins. It emerges now that the ECM provides a structural, chemical, and mechanical substrate that is essential in cardiac function and responses to pathophysiological signals. This review will describe the various elements of the ECM, its modifications that are associated with cardiac hypertrophy and heart failure, and the molecular basis bringing a better insight into the dynamics of the ECM.

Cardiomyopathy, Hypertrophic↗
PubMed1996

The role of the renin-angiotensin system in the pathophysiology of cardiac remodeling.

Cardiac hypertrophy of diverse etiologies is associated with two remodeling events: an increase in cardiac muscle mass, and the abnormal accumulation of fibrillar collagen, which results in increased myocardial stiffness and eventual ventricular dysfunction. Clinical and animal studies have implicated angiotensin II (A II) as a growth promoter of both cardiac myocytes and fibroblasts during the cardiac remodeling that occurs with hypertension and myocardial infarction. The growth-promoting effects of A II occur, in part, independent of effects on hemodynamic load. Tissue culture studies have shown that cardiac myocytes and fibroblasts are targets for the actions of A II. In these cells. A II activates phospholipases C, D, and A2, leading in turn to the activation of multiple, conventional second-messenger pathways. By an undefined process. A II also increases the tyrosine phosphorylation of cytosolic proteins, and activates the STAT family of transcription factors, which may mediate an inflammatory or stress response. A II has been shown to affect gene expression of cultured cardiac myocytes and fibroblasts, induce either cellular hyperplasia or hypertrophy, and increase expression of other growth factors. Cardiac fibroblasts have been shown to respond to A II with increased expression of integrins and the extracellular matrix proteins, collagen and fibronectin. Recently, stretch of cardiac myocytes was shown to induce hypertrophy, through an autocrine release of A II. All of the aforementioned actions of A II are mediated by the AT1 receptor.

Angiotensin II↗
PubMed2000

Cardiac remodeling--concepts and clinical implications: a consensus paper from an international forum on cardiac remodeling. Behalf of an International Forum on Cardiac Remodeling.

Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Defined as genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation and other factors still under investigation. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. Mechanisms other than remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling. Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality. Although measurement of ejection fraction can reliably guide initiation of treatment in HF, opinions differ regarding the value of ejection fraction data in guiding ongoing therapy. The role of echocardiography or radionuclide imaging in the management and monitoring of HF is as yet unclear. To fully appreciate the potential benefits of HF therapies, clinicians should understand the relationship between remodeling and HF progression. Their patients may then, in turn, acquire an improved understanding of their disease and the treatments they are given.

Adrenergic beta-Antagonists↗
PubMed2006

Pediatric cardiac remodeling after cardiac resynchronization therapy.

A 1.8-year-old male required a conventional DDD pacemaker for an atrioventricular block after congenital heart surgery. Five years later, heart failure due to left ventricular (LV) dyssynchrony progressed and we performed cardiac resynchronization therapy (CRT). Long-term echocardiographic follow-up showed that LV shortening fraction had improved within the first year after CRT, and LV end diastolic dimension had decreased after the first year. During LV remodeling (1-24 months after CRT), the QRS duration shortened without a change in the JT and T (peak-end) interval. The New York Heart Association class improved from III to I during the 2.3-year follow-up.

Cardiac Pacing, Artificial↗
PubMed2003

Effects of therapeutic beta blockade on myocardial function and cardiac remodelling in congenital cardiac disease.

BACKGROUND: Cardiac remodelling is now recognised as an important aspect of cardiovascular disease progression and is, therefore, emerging as a therapeutic target in cardiac failure due to different etiologies. Little is known about the influence of different therapies for cardiac failure on the remodelling seen in infants with congenital cardiac disease. METHODS: During follow-up of a prospective and randomized trial, we investigated therapeutic effects on neurohormonal activation, ventricular function, and myocardial gene expression. We compared the data from 8 infants with severe congestive heart failure due to left-to-right shunts, who received digoxin and diuretics alone, to 9 infants who received additional treatment with propranolol. RESULTS: In these infants, beta-adrenergic blockade significantly reduced highly elevated levels of renin, from 284 +/- 319 microU/ml compared to 1061 +/- 769 microU/ml. Systolic ventricular function was normal in both groups, but diastolic ventricular function was improved in those receiving propranolol, indicated by significantly lower left atrial pressures, lower end-diastolic pressures, and less pronounced ventricular hypertrophy, the latter estimated by lower ratios of myocardial wall to ventricular cavity areas on average of 42%. Further hemodynamic parameters showed no significant differences between the groups, except for the lower heart rate in infants treated with propranolol. In those treated with digoxin and diuretics, there was a significant downregulation of beta2-receptor and angiotensin-2 receptor genes, and up-regulation of endothelin A receptor and connective tissue growth factor genes, that were partially prevented by additional treatment with propranolol. CONCLUSIONS: Beta-blockade is a new therapeutic approach for congestive heart failure in infants with congenital cardiac disease, producing with significant benefits on neurohormonal activation, diastolic ventricular function, and cardiac remodelling.

Adrenergic beta-Antagonists↗
PubMed2001

Calcium channel blockade limits cardiac remodeling and improves cardiac function in myocardial infarction-induced heart failure in rats.

Calcium channel antagonists (CCAs) have been proposed to prevent cardiac events after myocardial infarction (MI). However, unwanted effects, such as negative inotropy, limit their use in many cases. The aim of this study was to compare the effects of long-term treatment with the CCAs, mibefradil, verapamil, and amlodipine, administered before and after chronic MI on myocardial remodeling and cardiac function. MI was induced by permanent ligation of the left coronary artery in male Wistar rats. Infarcted animals were treated with placebo, mibefradil (10 mg/kg/d po), verapamil (8 mg/kg bid po), or amlodipine (4 mg/kg/d po). Treatment was started 7 days before or 3 h after MI induction. Six weeks after MI, mean arterial blood pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), and cardiac contractility (dP/dt(max)) were measured. Morphometric parameters such as infarct size (IS), left ventricular dilation (LVD), septal thickness (ST), and cardiac fibrosis were determined in picrosirius red-stained hearts. Six weeks after MI, MAP and dP/dt(max) were decreased, whereas LVEDP and HR were increased in placebo-treated controls. The hearts featured an IS of 45%, left ventricular dilation, cardiac fibrosis, and septal thinning. MAP of all CCA-treated animals was increased, whereas LVEDP was decreased and dP/dt(max) increased 7-day pre- and 3-h post-MI started in mibefradil- and amlodipine-treated animals, but not in verapamil-treated animals. In contrast to amlodipine treatment, before and after MI started mibefradil and verapamil treatment decreased HR. Pretreatment with all CCA reduced IS and increased ST, whereas only mibefradil and amlodipine pretreatment prevented LVD and cardiac fibrosis. After MI started treatment with mibefradil and amlodipine reduced IS and cardiac fibrosis, and increased ST. Long-term treatment with the CCAs mibefradil, verapamil, and amlodipine reduced myocardial remodeling and improved cardiac function in MI-induced heart failure in rats.

Amlodipine↗
PubMed2006

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.

Analysis of Variance↗
PubMedDate not supplied

Matrix is the site of indirect effects of propranolol on the ion channelopathies in cardiac remodeling by L-thyroxine.

Cardiac remodeling by chronic L-thyroxine medication causes exaggerated cardiac arrhythmias in relation to ion channelopathies that involve multichannels. The matrix of lipid membrane is likely the key site where channel lesions, possibly will develop and be benefitted by drug intervention. Cardiac remodeling in rats and guinea pigs was developed by L-thyroxine 0.5 mg/kg SC for 10 days. Propranolol was instituted on days 8-10. Whole cell holding was applied to measure ion currents. An increase in HR, dispersion of QTc, mitochondrial Na+/K+ ATPase, Ca2+/Mg2+ ATPase, and LPO production were found in the model. T3 and T4 levels in plasma were high. Propranolol was effective in regressing cardiac remodeling, together with lowering all the parameters and the enhanced I(Ca.L),I(KS), and I(KR) currents, but T3 and T4 remained basically unchanged. The changes in ion channels are likely the consequence of the cardiac remodeling that is formed by oxidative stress and increased energy consumption provoked by L-thyroxine. The benefit of propranolol on the disordered ion channels is mediated by its ability to ameliorate lesions of the matrix.

Algorithms↗
PubMed2006

Long-term stimulation of adenosine A2b receptors begun after myocardial infarction prevents cardiac remodeling in rats.

BACKGROUND: Adenosine inhibits proliferation of cardiac fibroblasts and hypertrophy of cardiomyocytes, both of which may play crucial roles in cardiac remodeling. In the present study, we investigated whether chronic stimulation of adenosine receptors begun after myocardial infarction (MI) prevents cardiac remodeling. METHODS AND RESULTS: MI was produced in Wistar rats by permanent ligation of the left anterior descending coronary artery. One week after the onset of MI, animals were randomized into 8 groups: vehicle, dipyridamole (DIP; the adenosine uptake inhibitor, 50 mg/kg), 2-chroloadenosine (CADO; the stable analogue of adenosine, 2 mg/kg), and CADO in the presence of the nonselective adenosine receptor antagonist 8-sulfophenyltheophylline (8-SPT) or the selective antagonist for adenosine A1, A2a, A2b, or A3 receptor. Three weeks after treatment, hemodynamic and echocardiographic parameters in the DIP and CADO groups were significantly improved compared with the vehicle group. These hemodynamic and echocardiographic improvements were blunted by either 8-SPT or the selective adenosine A2b antagonist MRS1754 but not by the selective antagonists for other subtypes of adenosine receptors. The collagen volume fraction was smaller, and gene expression of the molecules associated with cardiac remodeling such as matrix metalloproteinase in noninfarcted areas was reduced in the DIP and CADO groups compared with the vehicle group, both of which were attenuated by either 8-SPT or MRS1754. CONCLUSIONS: Long-term stimulation of adenosine A2b receptors begun after MI attenuates cardiac fibrosis in the noninfarcted myocardium and improves cardiac function. Drugs that stimulate adenosine A2b receptors or increase adenosine levels are new candidates for preventing cardiac remodeling after MI.

2-Chloroadenosine↗
PubMed2006

Undernutrition in utero augments systolic blood pressure and cardiac remodeling in adult mouse offspring: possible involvement of local cardiac angiotensin system in developmental origins of cardiovascular disease.

Evidence has emerged that undernutrition in utero is a risk factor for cardiovascular disorders in adulthood, along with genetic and environmental factors. Recently, the local expression of angiotensinogen and related bioactive substances has been demonstrated to play a pivotal role in cardiac remodeling, i.e. fibrosis and hypertrophy. The aim of the present study was to clarify the possible involvement of the local cardiac angiotensin system in fetal undernutrition-induced cardiovascular disorders. We developed a mouse model of undernutrition in utero by maternal food restriction, in which offspring (UN offspring) showed an increase in systolic blood pressure (8 wk of age, P < 0.05; and 16 wk, P < 0.01), perivascular fibrosis of the coronary artery (16 wk, P < 0.05) and cardiac cardiomegaly (16 wk, P < 0.01), and cardiomyocyte enlargement, concomitant with a significant augmentation of angiotensinogen (P < 0.05) and endothelin-1 (P < 0.01) mRNA expression and a tendency to increase in immunostaining for both angiotensin II and endothelin-1 in the left ventricles (16 wk). These findings suggest that fetal undernutrition activated the local cardiac angiotensin system-associated bioactive substances, which contributed, at least partly, to the development of cardiac remodeling in later life, in concert with the effects of increase in blood pressure.

Angiotensin II↗
PubMed2002

Regulation of cardiac remodeling by nitric oxide: focus on cardiac myocyte hypertrophy and apoptosis.

Cardiac hypertrophy occurs in pathological conditions associated with chronic increases in hemodynamic load. Although hypertrophy can initially be viewed as a salutary response, ultimately, it often enters a phase of pathological remodeling that may lead to heart failure and premature death. A prevailing concept predicts that changes in gene expression in hypertrophied cardiac myocytes and cardiac myocyte loss by apoptosis contribute to the transition from hypertrophy to failure. In recent years, nitric oxide (NO) has emerged as an important regulator of cardiac remodeling. Specifically, NO has been recognized as a potent antihypertrophic and proapoptotic mediator in cultured cardiac myocytes. Studies in genetically engineered mice have extended these findings to the in vivo situation. It appears that low levels and transient release of NO by endothelial NO synthase exert beneficial effects on the remodeling process by reducing cardiac myocyte hypertrophy, cavity dilation and mortality. By contrast, high levels and sustained production of NO by inducible NO synthase seem to be maladaptive by reducing ventricular contractile function, and increasing cardiac myocyte apoptosis, and mortality. In the future, these novel insights into the role of NO in cardiac remodeling should allow the development of novel therapeutic strategies to treat cardiac remodeling and failure.

Animals↗
PubMed2003

Implication of cardiac remodeling in heart failure: mechanisms and therapeutic strategies.

The concept and clinical implication of left ventricular remodeling have been gradually extended. Cardiac remodeling plays important roles in the progression of cardiovascular diseases including myocardial infarction, valvular heart diseases, myocarditis, and dilated cardiomyopathy. In addition to cardiac myocytes, fibroblasts, extracellular matrix proteins and coronary vasculature are also involved in the remodeling process. Cardiac remodeling is associated with alterations of many mediators such as neurohumoral factors, cytokines, enzymes, ion channels, oxidative stress and mechanical stress. Although remodeling is initially an adaptive response to maintain normal cardiac function, it gradually becomes maladaptive and leads to progressive decompensation. Recent research has attempted to elucidate underlying molecular mechanisms of cardiac remodeling and to develop novel therapeutic strategies for heart failure. The modulation of remodeling process is effective for preventing the progression of heart failure.

Adaptation, Physiological↗
PubMed2003

[Alterations of Axin protein expression during cardiac remodeling in rats].

The purpose of the present study was to observe the expression of Axin protein during cardiac remodeling in rats. Cardiac remodeling animal models were prepared with the methods of jugular venous norepinephrine (NE)-infusion or arterial-vein fistula (AVF). The ultrasonic parameters of rat hearts were recorded before sacrifice. The expressions of Axin protein were determined by Western blot in rat hearts from different remodeling models as well as cultured cardiac fibroblasts from adult rats. Cardiac concentric hypertrophy and fibrosis was induced by 3-day jugular vein infusion of NE in rats. The expression of Axin in the left ventricles increased significantly compared with that of the control group. Cardiac eccentric hypertrophy without fibrosis was induced by A-V fistula for one week in rats, and no change in Axin protein expression in the left ventricles was observed. In cultured adult rat cardiac fibroblasts, NE treatment for 24 h increased significantly the Axin protein level. It is therefore concluded that Axin protein was expressed in rat heart and increased significantly in left ventricles during NE-induced rat cardiac remodeling, which may be relevant to cardiac fibrosis.

Animals↗
PubMed2004

Protective role of mast cells in homocysteine-induced cardiac remodeling.

Recent reports including those from our laboratories indicate that hyperhomocysteinemia (Hhe) is an independent risk factor for cardiac dysfunction and clinical heart failure. Mast cell accumulation is a prominent feature in our model of Hhe-induced cardiac dysfunction. Because mast cell-derived mediators can potentially attenuate cardiac remodeling, we investigated the possible protective role of mast cells in Hhe-induced cardiac remodeling using a mast cell-deficient rat model that in our recent report did not demonstrate any adverse cardiac function at younger age (6 mo) than mast cell-competent control animals. Mast cell-deficient (Ws/Ws) rats and mast cell-competent (+/+) littermate control animals (3 mo of age) were treated with a Hhe-inducing diet for 10 wk. Cardiac remodeling was assessed structurally utilizing histomorphometric methods and functionally using an isolated Langendorff-perfused heart preparation. The Hhe-inducing diet caused similar elevations of homocysteine levels in the two groups. Compared with Hhe +/+ rats, the Hhe Ws/Ws rats demonstrated strikingly exacerbated adverse cardiac remodeling and myocardial fibrosis. Cardiac function measurement showed worsened diastolic function in Hhe Ws/Ws rats compared with Hhe +/+ rats. The absence of mast cells strikingly exacerbates Hhe-induced adverse cardiac remodeling and diastolic dysfunction. These findings indicate a potential dual rather than sole deleterious role for mast cells in cardiac injury.

Animals↗
PubMedDate not supplied

Pharmacologic effects on cardiac remodeling.

Clinical research during the past several decades has shown the importance of cardiac remodeling as a basic mechanism in the progression of heart failure. Changes in cardiac remodeling have high concordance with long-term clinical outcomes. Cardiac remodeling should be regarded as a primary target for treatment and also can serve as a reliable surrogate for clinical outcomes. Neurohormonal blockade with combination treatments that inhibit the renin-angiotensin-aldosterone and sympathetic systems has proven effective in improving cardiac remodeling and clinical outcomes. Such treatment should be standard therapy for patients with left ventricular dysfunction after myocardial infarction and patients with chronic heart failure.

Adrenergic beta-Antagonists↗
PubMed2004

Critical role of CNS effects of aldosterone in cardiac remodeling post-myocardial infarction in rats.

BACKGROUND: Oral administration of spironolactone improves cardiac remodeling and its central infusion prevents the increase in sympathetic drive post-myocardial infarction (MI). We hypothesized that central actions of aldosterone contribute to cardiac remodeling post-MI. OBJECTIVE: To compare the effects of intracerebroventricular (icv) infusion and oral administration of spironolactone on cardiac remodeling and left ventricle (LV) dysfunction post-MI in rats. METHODS: Spironolactone was administered orally (80 mg/kg/day) or by icv infusion (100 ng/h), starting 1-3 days post-MI in Wistar rats and continued for 6 weeks. RESULTS: At 6 weeks post-MI, in the rats treated with vehicle, LV peak systolic pressure (LVPSP) and LV dP/dt max were clearly decreased and LV end diastolic pressure (LVEDP) and plasma catecholamines and serum aldosterone increased. All these parameters improved with both oral and icv spironolactone. The MI-induced increases in internal circumferences of LV and right ventricle (RV), and in interstitial and perivascular fibrosis, in both the LV and RV were significantly prevented/inhibited by both oral and icv spironolactone. Laminin, fibronectin and fibrillar collagen (visualized by scanning electron microscopy, SEM) increased in the non-infarcted part of the LV post-MI in the vehicle group, but not/less in rats on oral or icv spironolactone. CONCLUSIONS: Since the magnitude of beneficial effects of icv spironolactone at low doses was largely equal to that achieved with its oral administration at much higher doses, we propose that in addition to other sites of action, aldosterone appears to activate central nervous system (CNS) pathways and thereby influences peripheral mechanisms involved in cardiac remodeling.

Administration, Oral↗