Pathological Myocardial Remodeling Research Articles

P6344Volume overload-triggered pathological myocardial remodeling occurs in the absence of calcium/calmodulin-dependent protein kinase type II delta

Abstract Background Calcium/calmodulin-dependent protein kinase type II delta (CamKIIδ), the predominant cardiac CaMKII isoform, has been implicated in the progression of myocardial infarction- and pressure overload-induced pathological remodeling and heart failure, but its role in volume overload (VO) has not been defined. We have previously reported an activation of CamKII during transition to HF in VO. Purpose Here, we analyzed the impact of CamKIIδ deletion in VO-triggered myocardial remodeling and heart failure development. Methods CaMKIIδ knockout (CaMKIIδ-KO) and wild-type (WT) littermates were exposed to aorto-caval shunt-induced VO, and the progression of myocardial remodeling was assessed by serial echocardiography, histological and molecular analyses. Results CaMKIIδ-KO and WT littermates exhibited similar mortality pattern in response to VO. Serial echocardiographic measurements showed a comparable eccentric myocardial remodeling, altered left ventricle geometry and perturbed ventricular function after shunt. At 12 weeks post-shunt both CaMKIIδ-KO and WT mice experienced comparable increases in relative heart weight, cardiomyocyte diameter, cardiac apoptosis, and hypertrophic genes expression. Conclusion We therefore conclude that CaMKIIδ signaling is dispensable for the progression of pathological cardiac remodeling induced by VO. This should be considered before CaMKII inhibition is approved therapeutically for HF treatment.

Oral pharmacological inhibition of calpains attenuates isoproterenol-induced myocardial hypertrophy and fibrosis

Background: Myocardial remodeling is an important cause of heart failure and a major medical and social problem. Our group has demonstrated that pharmacological inhibition of the Ca2+-dependent proteases calpains attenuates post-infarction remodeling and heart failure. Recent data suggest that calpain activity is elevated in non-ischemic cardiomyopathies and that G-protein coupled receptor kinase 2 (GRK2) promotes cardiac hypertrophy. Objective: To determine the therapeutic benefit and mechanism of inhibiting calpain activity in pathological myocardial remodeling of non-ischemic cause.

Activation of Cardiac Stem Cells in Myocardial Infarction

The development of heart failure caused by acute myocardial infarction is accompanied by massive necrotic death of cardiomyocytes in lesion areas and subsequent pathological myocardial remodeling. Traditionally, the possibility of heart reparation has been considered to be severely limited or absent in the postnatal period. Endogenous cardiac stem cells with a regenerative potential have recently been described, but the mechanisms of activation of these cells remain poorly understood. The aim of our work was to obtain cardiac stem cells from the ischemic area of the myocardium and compare their functional properties with stem cells isolated from the healthy area of the myocardium. RT-PCR was used to quantify the gene expression in cardiac stem cells. In addition, differentiated cells were stained for specific markers using immunocytochemical method. Cardiac stem cells originating from the infarction area had a higher proliferative potential and a greater propensity to migrate in comparison to the cells originated from a healthy myocardial area. The expression level of several specific markers of cardiogenic, osteogenic and adipogenic differentiation upon induction of corresponding differentiation was higher in the cells from the infarction area than in cells from the healthy myocardium. We conclude that myocardial ischemia activates the internal regenerative potential of cardiac stem cells.

Relationship of the liver fibrous formation processes and cardiosclerosis in patients with stable coronary heart disease combined with non-alcoholic fatty liver disease.

Aim of the study was to determine the features of myocardial remodeling in patients with postinfarction cardiosclerosis combined with non-alcoholic fatty liver disease (NAFLD) and identify the dependence of the liver fibrogenesis processes and cardiosclerosis depending on the liver fibrosis stage. Material and methods. The study included 300 patients with postinfarction cardiosclerosis with and without NAFLD. Patients with NAFLD were divided depending on the liver fibrosis stage. Among them patients with non-alcoholic steatosis and non-alcoholic steatohepatitis (NASH) were observed. General clinical examination, electrocardiography, coronary angiography, echocardiography, elastography, assessment of the liver functional state, serum type IV collagen were conducted. Results. Formation of pathological myocardial remodeling types dependent on the fibrosis liver stage and grew along with the progression of NAFLD (р<0.05). Analysis of the elastography results showed a significant increase of the liver stiffness in all patients (р<0.05). The greatest value of shear wave velocity was observed in patients with severe fibrosis of the liver parenchyma of F4 stage (р<0.05). The level of type IV collagen increased according to the stages of liver fibrosis progression and was the highest in patients with NASH of IVB and VB groups (p<0.05). The direct correlation relationships between stage of fibrosis, level of type IV collagen and myocardial left ventricle mass index in patients with coronary heart disease and NAFLD were revealed. Conclusions. Intensity of fibrotic changes in the liver and myocardium depends on the NAFLD progression and fibrosis stage, and the presence of direct correlative relationship between the liver parenchyma stiffness, level of type IV collagen and myocardial left ventricle mass index indicates mutual aggravating influence of the coronary heart disease and NAFLD on the course of one another, which generally promotes activation of fibrogenesis in liver and myocardium.

Cell therapy for heart disease: current status and future directions.

Treatment of ischemic heart disease has evolved considerably over time, seeing a technological impetus in recent times. Prompt diagnosis and progressively earlier reperfusion of the infarct artery have become the cornerstone of the early myocardial ischemia management. However, treatment of post-infarction sequelae resulting from ischemic damage sustained within the myocardium remains a considerable challenge. In this setting, stem cell therapy has emerged as an exciting regenerative modality with a promise to arrest or even reverse the pathological myocardial remodeling. Multiple preclinical and clinical studies have thereafter reported use of various types of stem cells delivered through varying routes. While most of these studies reported positive results, some appropriate concerns were raised in others. This has resulted in considerable uncertainty regarding cell therapy and an inability to formulate therapeutic recommendations. Though there has been a considerable improvement in our understanding of stem cell properties, there is a need to identify specific mechanisms of actions in order to maximize the benefits of stem cell therapy in ischemic heart disease. With this review, we attempt to highlight some of the salient features of stem cell research, focusing on understanding the predominant types of stem cells, proposed mechanisms of action, routes of administration, and application of this exciting and innovative regenerative therapy offered by stem cells.

Purinergic Antagonist Suramin Aggravates Myocarditis and Increases Mortality by Enhancing Parasitism, Inflammation, and Reactive Tissue Damage in Trypanosoma cruzi-Infected Mice.

Suramin (Sur) acts as an ecto-NTPDase inhibitor in Trypanosoma cruzi and a P2-purinoceptor antagonist in mammalian cells. Although the potent antitrypanosomal effect of Sur has been shown in vitro, limited evidence in vivo suggests that this drug can be dangerous to T. cruzi-infected hosts. Therefore, we investigated the dose-dependent effect of Sur-based chemotherapy in a murine model of Chagas disease. Seventy uninfected and T. cruzi-infected male C57BL/6 mice were randomized into five groups: SAL = uninfected; INF = infected; SR5, SR10, and SR20 = infected treated with 5, 10, or 20 mg/kg Sur. In addition to its effect on blood and heart parasitism, the impact of Sur-based chemotherapy on leucocytes myocardial infiltration, cytokine levels, antioxidant defenses, reactive tissue damage, and mortality was analyzed. Our results indicated that animals treated with 10 and 20 mg/kg Sur were disproportionally susceptible to T. cruzi, exhibiting increased parasitemia and cardiac parasitism (amastigote nests and parasite load (T. cruzi DNA)), intense protein, lipid and DNA oxidation, marked myocarditis, and mortality. Animals treated with Sur also exhibited reduced levels of nonprotein antioxidants. However, the upregulation of catalase, superoxide dismutase, and glutathione-S-transferase was insufficient to counteract reactive tissue damage and pathological myocardial remodeling. It is still poorly understood whether Sur exerts a negative impact on the purinergic signaling of T. cruzi-infected host cells. However, our findings clearly demonstrated that through enhanced parasitism, inflammation, and reactive tissue damage, Sur-based chemotherapy contributes to aggravating myocarditis and increasing mortality rates in T. cruzi-infected mice, contradicting the supposed relevance attributed to this drug for the treatment of Chagas disease.

Ультрасоноґрафічна характеристика структури і функції серця у хворих із синтропічною кардіоміопатією на ґрунті цирозу печінки та їх особливості залежно від тяжкості основної хвороби

Liver cirrhosis is usually accompanied by extrahepatic syntropic lesions, among which cardiomyopathy is one of the most common. To date, both the definition and the criteria of syntropic cirrhotic cardiomyopathy have been formulated. However, information on the exploration of the relationship between the changes of the heart in these patients and the class of severity of cirrhosis in is not found in the available literature. Aim. To describe the ultrasound features of the heart in patients with syntropic cardiomyopathy and to find out their features related to the severity of the main liver disease. Material and Methods. After receiving the consent on conduction of the complex examination in randomized way with the previous stratification on the presence of the cirrhosis there were selected 603 patients (445 men, 158 women, age 49,2±10,6 years). The patients were stratified into two subgroups: 113 patients with cirrhosis and without circulatory system disorder of which 23 patients were randomly included in the comparison group; 490 patients with cirrhosis and extrahepatic circulatory system disorder from which, in a randomized manner we chose the patients for the experimental group - 66 patients with cirrhosis and cardiomyopathy). The cirrhotic patients in the experimental group were classified according to the criteria of C. G. Child and R. N. Pugh (23 patients in class A, 22 - in B and 21 - in C). The control group consisted of 19 healthy volunteers of the same gender and age. Ultrasound was conducted according to the standard procedure - lying on the left side using the "SAMSUNG H-60" Device. The obtained material was processed using the EViews program (Quantitative Micro Software). Results and Discussion. Our analysis made it possible to reveal a number of structural characteristics of cardiomyopathy: significantly lower end-diastolic volume of the right ventricle and significantly higher end-diastolic left ventricular volume; sizes of right and left ventricle in the systole; sizes of the left ventricle and interventricular septum, which was manifested by pathological myocardial remodeling; normal systolic function at rest in patients of the experimental group achieved due to high stroke volume and, accordingly, high minute blood volume and cardiac indices; diastolic dysfunction and the high C. Tei index. we also found that the structure and function of the heart varied along with the increase of the cirrhosis severity. Namely, the interventricular septum and the left ventricle were found to be hypertrophied and subsequently dilated; systolic function in all classes - within normal ranges, and diastolic - sharply decreased in case of the cirrhosis exacerbation. All this is as a result of the overload of the heart with increasing blood volume and disturbance of metabolic processes in the myocardium. Conclusions.  Patients with liver cirrhosis and syntropic cardiomyopathy have specific changes in the structure of the myocardium resulting in the occurrence of pathologic variants of heart remodeling, normal systolic function at rest and diastolic dysfunction. The structure and function of the heart is related to the liver cirrhosis severity  - the revealed structural and functional disturbances increase along with exacerbation of the underlying liver disease. The obtained information will help to optimize the diagnosis and treatment of patients with liver cirrhosis and syntropic cardiomyopathy.

Anatomical Substrates and Ablation of Reentrant Atrial and Ventricular Tachycardias in Repaired Congenital Heart Disease.

Advances in surgical repair techniques for various types of congenital heart disease have improved survival into adulthood over the past decades, thus exposing these patients to a high risk of atrial and ventricular arrhythmias later in life. These arrhythmias arise from complex arrhythmogenic substrates. Substrate formation may depend on both pathological myocardial remodelling and variable anatomical boundaries, determined by the type and timing of prior corrective surgery. Accordingly, arrhythmogenic substrates after repair have changed as a result of evolving surgical techniques. Radiofrequency catheter ablation offers an important therapeutic option but remains challenging due to the variable anatomy, surgically created obstacles and the complex arrhythmogenic substrates. Recent technical developments including electroanatomical mapping and image integration for delineating the anatomy facilitate complex catheter ablation procedures. The purpose of this review is to provide an update on the changing anatomical arrhythmogenic substrates and their potential impact on catheter ablation in patients with repaired congenital heart disease and tachyarrhythmias.

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control β-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation.

Acute stimulation of cardiac β-adrenoceptors is crucial to increasing cardiac function under stress; however, sustained β-adrenergic stimulation has been implicated in pathological myocardial remodeling and heart failure. Here, we have demonstrated that export of cAMP from cardiac myocytes is an intrinsic cardioprotective mechanism in response to cardiac stress. We report that infusion of cAMP into mice averted myocardial hypertrophy and fibrosis in a disease model of cardiac pressure overload. The protective effect of exogenous cAMP required adenosine receptor signaling. This observation led to the identification of a potent paracrine mechanism that is dependent on secreted cAMP. Specifically, FRET-based imaging of cAMP formation in primary cells and in myocardial tissue from murine hearts revealed that cardiomyocytes depend on the transporter ABCC4 to export cAMP as an extracellular signal. Extracellular cAMP, through its metabolite adenosine, reduced cardiomyocyte cAMP formation and hypertrophy by activating A1 adenosine receptors while delivering an antifibrotic signal to cardiac fibroblasts by A2 adenosine receptor activation. Together, our data reveal a paracrine role for secreted cAMP in intercellular signaling in the myocardium, and we postulate that secreted cAMP may also constitute an important signal in other tissues.

Hepatocyte growth factor regulates the TGF-β1-induced proliferation, differentiation and secretory function of cardiac fibroblasts.

Cardiac fibroblast (CF) proliferation and transformation into myofibroblasts play important roles in cardiac fibrosis during pathological myocardial remodeling. In this study, we demonstrate that hepatocyte growth factor (HGF), an antifibrotic factor in the process of pulmonary, renal and liver fibrosis, is a negative regulator of cardiac fibroblast transformation in response to transforming growth factor-β1 (TGF-β1). HGF expression levels were significantly reduced in the CFs following treatment with 5 ng/ml TGF-β1 for 48 h. The overexpression of HGF suppressed the proliferation, transformation and the secretory function of the CFs following treatment with TGF-β1, as indicated by the attenuated expression levels of α-smooth muscle actin (α-SMA) and collagen I and III, whereas the knockdown of HGF had the opposite effect. Mechanistically, we identified that the phosphorylation of c-Met, Akt and total protein of TGIF was significantly inhibited by the knockdown of HGF, but was significantly enhanced by HGF overexpression. Collectively, these results indicate that HGF activates the c-Met-Akt-TGIF signaling pathway, inhibiting CF proliferation and transformation in response to TGF-β1 stimulation.

Myocardial gene expression of T-bet, GATA-3, Ror-γt, FoxP3, and hallmark cytokines in chronic Chagas disease cardiomyopathy: an essentially unopposed TH1-type response.

Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence of Trypanosoma cruzi infection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples. Methods and Results. Quantitative PCR showed markedly upregulated expression of IFN-γ and transcription factor T-bet, and minor increases of GATA-3; FoxP3 and CTLA-4; IL-17 and IL-18 in CCC as compared with NIC samples. Conversely, cytokines expressed by TH2 cells (IL-4, IL-5, and IL-13) or associated with Treg (TGF-β and IL-10) were not upregulated in CCC myocardium. Expression of TH1-related genes such as T-bet, IFN-γ, and IL-18 correlated with ventricular dilation, FoxP3, and CTLA-4. Conclusions. Results are consistent with a strong local TH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+ Treg cell population, which is unable to completely curb IFN-γ production in CCC myocardium, therefore fueling inflammation.

ОсОбеннОсти пеРинА тАЛьнОгО АнАМнеЗА и ВАРиАбеЛьнОсти сеРДеЧнОгО РитМА У неДОнОШеннЫх ДетеЙ пеРВОгО гОДА жиЗни, РОжДеннЫх с экстРеМАЛьнО ниЗкОЙ МАссОЙ теЛА и ОЧень ниЗкОЙ МАссОЙ теЛА

Aim. To study the heart rate variability and autonomic regulation features in preterm infants with an analysis of adverse perinatal factors. Matherial and methods. Current study included preterm infants during infancy. We assessed thoroughly history, physical examination of patients, electrocardiography findings, ambulatory ECG Holter monitoring results. Results and discussion. We analyzed of the most significant perinatal risk factors for cardiovascular diseases such as burdened obstetric history, chronic fetoplacental insufficiency, preeclampsia, viral infections during the first trimester of pregnancy. There was a reduction of circadian index in the children with ELBW and VLBW, that is, the presence of the rigidity of the circadian profile of heart rate (HR). According to ECG Holter monitoring, preterm infants had such cardiac disorders as cardiac arrhythmia supraventricular and ventricular, conduction disturbances in the form of AV block, daily rhythm structure changes in the form of the rigidity of the circadian profile of HR. We found decreased temporal parameters of heart rate variability, which indicates a weakening of parasympathetic effects on the heart and relative sympathicotonia. Conclusion. The presence of autonomic imbalance with a predominance of sympathetic tone, reduced heart rate variability in conjunction with anatomical defects, overloading of the heart chambers volume or pressure and hypoxia may predispose the development of pathological myocardial remodeling in infants with extremely and very low birth weight.

Correlation between ECG and coronary angiography in patients with a sudden obstruction of the right coronary artery (RCA)—physiological and pathological myocardial remodeling

Correlation between ECG and coronary angiography in patients with a sudden obstruction of the right coronary artery (RCA)—physiological and pathological myocardial remodeling

Cardiokines

The sets of proteins secreted from cells, ie, secretomes, play crucial roles in intercellular and intertissue communication during tissue development and growth and in response to various pathological stresses. The secretomes produced by the heart encompass a group of proteins that have been referred to as cardiokines. In today's era of molecular sophistication, the number of identified cardiokine candidates is steadily increasing as a result of the desire to identify new biomarkers and targets for cardiovascular disease treatment. It is widely recognized that the cells of the heart, including myocytes, fibroblasts, vascular cells, and progenitor cells, secrete various subsets of regulatory proteins in response to changes in the cardiac environment.1–5 These secreted proteins are required for the maintenance of normal cardiac function, and they control pathological remodeling of the myocardium in response to injury through their ability to modulate myocyte death, fibroblast activation, inflammation, and vascular growth and regression. In addition, some of these factors function systematically, influencing kidney function or cachectic processes. Examples of well-known cardiokines include atrial natriuretic peptide and brain natriuretic peptide, which are synthesized mainly in the myocardium and upregulated in response to myocardial stretching.6,7 Both atrial natriuretic peptide and brain natriuretic peptide exert beneficial actions on cardiac remodeling by directly affecting cardiac cells in an autocrine and/or paracrine manner. In addition, atrial natriuretic peptide and brain natriuretic peptide influence electrolyte and water excretion in the kidney and regulate vascular tone and vascular cell growth via endocrine mechanisms.7 Cardiac cells produce tumor necrosis factor-α and transforming growth factor-β1 in pathological states, and these factors can promote pathological myocardial remodeling by promoting the recruitment of inflammatory cells or by facilitating hypertrophic growth and fibrosis.8,9 Under conditions of stress, the heart also produces angiotensin II, contributing to cardiac …

In Vitro Effects of Pirfenidone on Cardiac Fibroblasts: Proliferation, Myofibroblast Differentiation, Migration and Cytokine Secretion

Cardiac fibroblasts (CFs) are the primary cell type responsible for cardiac fibrosis during pathological myocardial remodeling. Several studies have illustrated that pirfenidone (5-methyl-1-phenyl-2-[1H]-pyridone) attenuates cardiac fibrosis in different animal models. However, the effects of pirfenidone on cardiac fibroblast behavior have not been examined. In this study, we investigated whether pirfenidone directly modulates cardiac fibroblast behavior that is important in myocardial remodeling such as proliferation, myofibroblast differentiation, migration and cytokine secretion. Fibroblasts were isolated from neonatal rat hearts and bioassays were performed to determine the effects of pirfenidone on fibroblast function. We demonstrated that treatment of CFs with pirfenidone resulted in decreased proliferation, and attenuated fibroblast α-smooth muscle actin expression and collagen contractility. Boyden chamber assay illustrated that pirfenidone inhibited fibroblast migration ability, probably by decreasing the ratio of matrix metalloproteinase-9 to tissue inhibitor of metalloproteinase-1. Furthermore, pirfenidone attenuated the synthesis and secretion of transforming growth factor-β1 but elevated that of interleukin-10. These direct and pleiotropic effects of pirfenidone on cardiac fibroblasts point to its potential use in the treatment of adverse myocardial remodeling.

PKCβII inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses

Protein kinase C βII (PKCβII) levels increase in the myocardium of patients with end-stage heart failure (HF). Also targeted overexpression of PKCβII in the myocardium of mice leads to dilated cardiomyopathy associated with inflammation, fibrosis and myocardial dysfunction. These reports suggest a deleterious role of PKCβII in HF development. Using a post-myocardial infarction (MI) model of HF in rats, we determined the benefit of chronic inhibition of PKCβII on the progression of HF over a period of 6 weeks after the onset of symptoms and the cellular basis for these effects. Four weeks after MI, rats with HF signs that were treated for 6 weeks with the PKCβII selective inhibitor (βIIV5-3 conjugated to TAT47–57 carrier peptide) (3 mg/kg/day) showed improved fractional shortening (from 21% to 35%) compared to control (TAT47–57 carrier peptide alone). Formalin-fixed mid-ventricle tissue sections stained with picrosirius red, haematoxylin and eosin and toluidine blue dyes exhibited a 150% decrease in collagen deposition, a two-fold decrease in inflammation and a 30% reduction in mast cell degranulation, respectively, in rat hearts treated with the selective PKCβII inhibitor. Further, a 90% decrease in active TGFβ1 and a significant reduction in SMAD2/3 phosphorylation indicated that the selective inhibition of PKCβII attenuates cardiac remodelling mediated by the TGF-SMAD signalling pathway. Therefore, sustained selective inhibition of PKCβII in a post-MI HF rat model improves cardiac function and is associated with inhibition of pathological myocardial remodelling.

Myocardial Reverse Remodeling

Despite an extensive literature defining the mechanisms and significance of pathological myocardial remodeling, there has been no comprehensive review of the inverse process, often labeled reverse remodeling. Accordingly, the goal of this review is to overview the varied settings in which clinically significant reverse remodeling has been well documented. When available, we reviewed relevant randomized, controlled clinical trials, and meta-analyses with sufficient cardiac imaging data to permit conclusions about reverse remodeling. When these types of studies were not available, relevant case-control studies and case series that employed appropriate methodology were reviewed. Regression of pathological myocardial hypertrophy, chamber shape distortions, and dysfunction occurs in a wide variety of settings. Although reverse remodeling occurs spontaneously in some etiologies of myocardial dysfunction and failure, remodeling is more commonly observed in response to medical, device-based, or surgical therapies, including β-blockers, revascularization, cardiac resynchronization therapy, and valve surgery. Indeed, reverse remodeling following pathophysiologically targeted interventions helps validate that the targeted mechanisms are propelling and/or sustaining pathological remodeling. The diverse clinical settings in which reverse remodeling has been observed demonstrates that myocardial remodeling is bidirectional and occurs across the full spectrum of myocardial disease severity, duration, and etiology. Observations in several settings suggest that recovered hearts are not truly normal despite parallel improvements at organ, tissue, and cellular level. Nevertheless, the link between reverse remodeling and improved outcomes should inspire further research to better understand the mechanisms responsible for both reverse remodeling and persistent deviations from normalcy.

Effects of interleukin-18 on cardiac fibroblast function and gene expression

Fibroblasts are the primary cell type responsible for synthesis and remodeling of the extracellular matrix in the heart. A number of factors including growth factors, hormones and mechanical forces have been identified that modulate the production of extracellular matrix by cardiac fibroblasts. Inflammatory mediators including pro-inflammatory cytokines and chemokines also impact fibrosis of the heart. Recent studies have illustrated that interleukin-18 promotes a pro-fibrotic response in cardiac fibroblasts; however the effects of this cytokine on other aspects of fibroblast function have not been examined. While fibroblasts have long been known for their role in production and remodeling of the extracellular matrix, other functions of these cells are only now beginning to be appreciated. We hypothesize that exposure to interleukin-18 will stimulate other aspects of fibroblast behavior important in myocardial remodeling including proliferation, migration and collagen reorganization. Fibroblasts were isolated from adult male rat hearts and bioassays performed to determine the effects of interleukin-18 on fibroblast function. Treatment of fibroblasts with interleukin-18 (1–100ng/ml) resulted in increased production of extracellular matrix components and remodeling or contraction of three-dimensional collagen scaffolds by these cells. Furthermore, exposure to interleukin-18 stimulated fibroblast migration and proliferation. Treatment of heart fibroblasts with interleukin-18 resulted in the rapid activation of the c-Jun N-terminal kinase (JNK) and phosphoinositide 3-kinase (PI3-kinase) pathways. Studies with pharmacological inhibitors illustrated that activation of these pathways is critical to interleukin-18 mediated alterations in fibroblast function. These studies illustrate that interleukin-18 plays a role in modulation of cardiac fibroblast function and may be an important component of the inflammation-fibrosis cascade during pathological myocardial remodeling.

Remodelling of the heart and vessels in experimental hypertension: advances in protection

Left ventricular hypertrophy (LVH), despite its adaptive nature, increases cardiovascular morbidity and mortality. Novel approaches for protection against pathological heart remodelling are presented in this supplement. Melatonin diminishes myocardial fibrosis in rats exposed to continuous light and N-nitro-L-arginine-methyl ester (L-NAME) treatment and reduces production of endothelium-derived constricting factors in L-NAME-induced hypertension. Melatonin, because of its extraordinary antioxidant and scavenging properties, benefits for endothelium and sympatholytic action, may prove to be a useful protective drug against heart remodelling. In hypertension induced by relative aldosteronism, the correction of macro and micronutrient dyshomeostasis appears to act beneficially within pathological myocardial remodelling. Alterations in the signal cascade of pathological myocardial growth, including humoral stimuli, receptors, intracellular messengers or transcriptional factors, may be favourably modified at different levels. Inhibition of nuclear factor kappa B (NF-kappaB) potentiates hypertension development, enhances oxidative load, increases the cross-sectional area of the aorta and reduces nitric oxide (NO) synthase activity in L-NAME hypertension. It is suggested that NF-kappaB may play a protective rather than a deleterious role in the haemodynamically overloaded circulation. Compound 21, a recently developed peptide angiotensin II type 2 (AT2) receptor agonist, offers a novel approach in investigating the role of AT2 receptors in the protection of the hypertensive heart. A novel NO donor, L-419, with its intrinsic protection of NO, improves the entire NO signalling cascade and thus favourably influencing the response of the left ventricle to haemodynamic overload. LVH prevention or regression should be considered a therapeutic success only when, along with hypertrophied mass reduction, an improvement of the heart structure, function, metabolism and electrical stability is achieved.