Differences in inflammation, MMP activation and collagen damage account for gender difference in murine cardiac rupture following myocardial infarction

Cardiac rupture remains a fatal complication of acute myocardial infarction (MI) with its mechanism partially understood. We hypothesized that damage to the collagen matrix of infarcted myocardium is the central mechanism of rupture and therefore responsible for the difference in the incidence of rupture between genders. We examined left ventricular (LV) remodeling during the acute phase post-MI in 129sv mice. Following induction of MI, we monitored rupture events and assessed the extent of LV remodeling by echocardiography. Muscle tensile strength, content of insoluble and soluble collagen, expression and activity of matrix metalloproteinases (MMPs) and density of inflammatory cells were determined in the infarcted and non-infarcted myocardium. We then tested the effects of MMP inhibition on rupture. Compared to female mice, males with MI displayed greater extent of LV remodeling, reduced muscle tensile strength, loss of insoluble collagen, local inflammatory response and MMP-9 activation, changes associated with a 3 times higher incidence of rupture than in females. MMP-9 expression by circulating blood mononuclear cells was also increased in male mice with acute MI. Treatment of male mice with an MMP inhibitor reduced MMP activity and halved rupture incidence. Our findings demonstrate that the differences in the severity of inflammation, MMP activation and damage to collagen matrix account for gender difference in cardiac rupture. Our study illustrates the breakdown of fibril collagen as a central mechanism of cardiac rupture.     

Role of osteopontin in heart failure associated with aging

Cardiovascular disease is one of the leading causes of death in the elderly. Much of the morbidity and mortality in the elderly is attributable to acute ischemic events leading to myocardial infarction (MI) and death of cardiac myocytes. Evidence has been provided that aging associated with adverse remodeling post MI as demonstrated by less effective myocardial repair, greater infarct expansion, and septal hypertrophy. Expression of osteopontin (OPN) increases in the heart post MI. Transgenic mice studies suggest that increased expression of OPN plays a protective role in post-MI LV remodeling by modulating collagen deposition and fibrosis. OPN, a multifunctional protein, has the potential to influence the molecular and cellular changes associated with infarct healing. The post-MI infarct healing process involves temporarily overlapping phases that include the following—(1) inflammation with migration and adhesion of neutrophils and macrophages, phagocytosis and inflammatory gene expression; (2) tissue repair with fibroblast adhesion and proliferation, myofibroblast differentiation, extracellular matrix deposition and scar formation; and (3) structural and functional remodeling of infarcted and non-infarcted myocardium through cardiac myocyte apoptosis, hypertrophy and myocardial angiogenesis. This review is focused on the expression of OPN in the heart post MI and its role in various phases of infarct healing.     

Loss of fibulin-2 protects against progressive ventricular dysfunction after myocardial infarction

Remodeling of the cardiac extracellular matrix (ECM) is an integral part of wound healing and ventricular adaptation after myocardial infarction (MI), but the underlying mechanisms remain incompletely understood. Fibulin-2 is an ECM protein upregulated during cardiac development and skin wound healing, yet mice lacking fibulin-2 do not display any identifiable phenotypic abnormalities. To investigate the effects of fibulin-2 deficiency on ECM remodeling after MI, we induced experimental MI by permanent coronary artery ligation in both fibulin-2 null and wild-type mice. Fibulin-2 expression was up-regulated at the infarct border zone of the wild-type mice. Acute myocardial tissue responses after MI, including inflammatory cell infiltration and ECM protein synthesis and deposition in the infarct border zone, were markedly attenuated in the fibulin-2 null mice. However, the fibulin-2 null mice had significantly better survival rate after MI compared to the wild-type mice as a result of less frequent cardiac rupture and preserved left ventricular function. Up-regulation of TGF-β signaling and ECM remodeling after MI were attenuated in both ischemic and non-ischemic myocardium of the fibulin-2 null mice compared to the wild type counterparts. Increase in TGF-β signaling in response to angiotensin II was also lessened in cardiac fibroblasts isolated from the fibulin-2 null mice. The studies provide the first evidence that absence of fibulin-2 results in decreased up-regulation of TGF-β signaling after MI and protects against ventricular dysfunction, suggesting that fibulin-2 may be a potential therapeutic target for attenuating the progression of ventricular remodeling.     

Phenytoin can accelerate the healing process after experimental myocardial infarction?

BACKGROUND: Over-degradation and/or inadequate accumulation of extracellular matrix after myocardial infarction (MI) may lead to adverse ventricular remodeling, even ventricular aneurysm or rupture. Phenytoin can increase gingival overgrowth by stimulating the proliferation of connective tissue, which implies a novel way to hasten the healing process after MI. METHODS: Experimental MI was induced by permanent coronary ligation. Surviving rats after MI were randomly divided into phenytoin, captopril, phenytoin plus captopril, operation control and sham operation group. Picrosirius red staining plus polarized microscopy was used for collagen analysis. Left ventricular passive pressure-volume relationship was determined ex vivo. The effects of phenytoin concentration gradient (0, 1.25, 2.5, 5.0, 10.0, and 20.0 microg/mL) on transforming growth factor-beta1 (TGF-beta1) mRNA and protein expression by neonatal rat cardiac fibroblast were determined using semi-quantitative RT-PCR and ELISA, respectively. Peritoneal macrophage was incubated with same gradient of phenytoin concentration. Then the supernatant was harvested to stimulate another 6 groups of cardiac fibroblast, to investigate possible role mediated by macrophage. RESULTS: Phenytoin treatment could promote type I collagen cross-linking level and ratio of type I/III collagen in the infarcted region and had no obvious side effect on interstitial collagen volume fraction, subtype ratio and distribution in non-infarcted region. Phenytoin-treated hearts exhibited attenuation of global ventricular dilation. Phenytoin alone had no direct effects on rat cardiac fibroblast proliferation and collagen production in vitro, but phenytoin-stimulated macrophage could exert a positive influence on cardiac fibroblast TGF-beta1 mRNA and protein production, which exhibited a dose-dependent manner. CONCLUSIONS: Phenytoin can accelerate the healing process in the infarcted region and has no obviously detrimental influence on collagen accumulation in non-infarcted region, which implies a potential benefit to patients undergoing early post-infarction ventricular remodeling process.     

Temporal and Spatial Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases Following Myocardial Infarction

Following a myocardial infarction (MI), the homeostatic balance between matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is disrupted as part of the left ventricle (LV) response to injury. The full complement of responses to MI has been termed LV remodeling and includes changes in LV size, shape and function. The following events encompass the LV response to MI: (1) inflammation and LV wall thinning and dilation, (2) infarct expansion and necrotic myocyte resorption, (3) accumulation of fibroblasts and scar formation, and (4) endothelial cell activation and neovascularization. In this review, we will summarize MMP and TIMP roles during these events, focusing on the spatiotemporal localization and MMP and TIMP effects on cellular and tissue‐level responses. We will review MMP and TIMP structure and function, and discuss specific MMP roles during both the acute and chronic phases post‐MI, which may provide insight into novel therapeutic targets to limit adverse remodeling in the MI setting.     

Regulatory T cells ameliorate cardiac remodeling after myocardial infarction

Persistent inflammatory responses participate in the pathogenesis of adverse ventricular remodeling after myocardial infarction (MI). We hypothesized that regulatory T (Treg) cells modulate inflammatory responses, attenuate ventricular remodeling and subsequently improve cardiac function after MI. Acute MI was induced by ligation of the left anterior descending coronary artery in rats. Infiltration of Foxp3(+) Treg cells was detected in the infarcted heart. Expansion of Treg cells in vivo by means of adoptive transfer as well as a CD28 superagonistic antibody (JJ316) resulted in an increased number of Foxp3(+) Treg cells in the infarcted heart. Subsequently, rats with MI showed improved cardiac function following Treg cells transfer or JJ316 injection. Interstitial fibrosis, myocardial matrix metalloproteinase-2 activity and cardiac apoptosis were attenuated in the rats that received Treg cells transfer. Infiltration of neutrophils, macrophages and lymphocytes as well as expression of tumor necrosis factor (TNF)-α and interleukin (IL)-1β were also significantly decreased, and the CD8(+) cardiac-specific cytotoxic T lymphocyte response was inhibited. Expression of interleukin (IL)-10 in the heart, however, was increased. Additional studies in vitro indicated that Treg cells directly protect neonatal rat cardiomyocytes against LPS-induced apoptosis, and this protection depends on the cell-cell contact and IL-10 expression. Furthermore, Treg cells inhibited proinflammatory cytokines production by cardiomyocytes. These data demonstrate that Treg cells serve to protect against adverse ventricular remodeling and contribute to improve cardiac function after myocardial infarction via inhibition of inflammation and direct protection of cardiomyocytes.     

Vascular remodeling during healing after myocardial infarction in the dog model: effects of reperfusion, amlodipine and enalapril

OBJECTIVES: We sought to determine whether reperfusion and the calcium channel blocker amlodipine or the angiotensin-converting enzyme inhibitor enalapril, during healing over six weeks after myocardial infarction (MI), limit structural vascular remodeling in the noninfarct zone (NIZ). BACKGROUND: The effect of reperfusion and amlodipine or enalapril on structural vascular remodeling during healing of MI has not been determined. METHODS: We randomly assigned 54 dogs to reperfused or nonreperfused MI, followed by twice-daily doses of oral placebo, amlodipine (5 mg) or enalapril (5 mg) for six weeks and three days off treatment, or to three matching sham groups. We measured in vivo hemodynamic data and left ventricular (LV) function and remodeling (by echocardiography) over the six weeks, as well as ex vivo structural vascular, ventricular and collagen remodeling in the hearts after six weeks. RESULTS: Compared with placebo and sham groups, both amlodipine and enalapril with or without reperfusion produced LV unloading and limited structural LV remodeling and dysfunction over six weeks in vivo, and also decreased the NIZ resistance vessel media/lumen area ratio at six weeks ex vivo. In addition, amlodipine, but not enalapril, preserved infarct scar collagen and increased the border zone collagen volume fraction and perivascular fibrosis, as well as NIZ resistance vessel media thickness. Enalapril, but not amlodipine, decreased transforming growth factor-beta in the border zone and NIZ. CONCLUSIONS: The results indicate that therapy with amlodipine and enalapril during healing after reperfused MI limits structural vascular remodeling in the NIZ, probably by different mechanisms.     

Matrix metalloproteinase therapy in heart failure

Opinion statement  Milestones in the progression to heart failure following myocardial infarction (MI) are changes in left ventricular (LV) geometry and function, termed post-MI remodeling. Critical to this adverse remodeling process are changes in the expression, synthesis, and degradation of myocardial extracellular matrix (ECM) proteins. The myocardial ECM is not a passive entity but a complex and dynamic microenvironment that represents an important structural and signaling system within the myocardium. In particular, basic and clinical studies have provided conclusive evidence that abnormal and persistent activation of the ECM degradation pathway, notably through the matrix metalloproteinases (MMPs), contribute to adverse post-MI remodeling. This review examines recent clinical studies that provide further support to the hypothesis that a specific portfolio of MMPs are diagnostic and likely contributory to LV remodeling and the progression to heart failure after MI. Future translational and clinical research focused on the molecular and cellular mechanisms regulating ECM structure and function likely will contribute to an improved understanding of post-MI LV remodeling and yield novel therapeutic targets.     

Wound healing following myocardial infarction

A wound-healing response that eventuates in fibrous tissue formation appears at the site of myocardial infarction (MI) in the affected ventricle. Fibrosis can likewise appear remote to the MI and cause an extensive structural remodeling of the myocardium of infarcted and noninfarcted ventricles. Substances involved in promoting healing at and remote to MI are of considerable interest and an important clinical issue, given that the healing response is subject to pharmacologic intervention. Angiotensin-converting enzyme (ACE) is expressed by wound-healing fibroblast-like cells; it likely serves to regulate local concentrations of angiotensin II and bradykinin involved in healing and matrix remodeling. Wound healing following MI and its regulation are addressed in this review.     

Transforming growth factor beta inhibition increases mortality and left ventricular dilatation after myocardial infarction

BACKGROUND: Transforming growth factor (TGF)-beta is a locally generated cytokine involved in healing processes and tissue fibrosis, all relevant for cardiac remodeling and the development of heart failure after myocardial infarction (MI). However, data regarding the function of TGF-beta after ischemic injury are inconclusive. METHODS AND RESULTS: We tested the effect of TGF-beta inhibition by application of a blocking antibody in mice with MI. Starting 1 week before or 5 days after coronary artery ligation mice were treated with intraperitoneal injections of an anti-TGF-beta (5 mg/kg bodyweight 1D11, Genzyme) or control antibody. Mortality over 8 weeks was significantly higher in the groups treated with the anti-TGF-beta antibody. Both, pre or post MI treatments were associated with increased left ventricular dilatation after MI as determined by serial echocardiography. In anti-TGF-beta treated mice collagen production decreased and matrix-metalloproteinase expression increased. However, the expression of TGF pro-inflammatory cytokine TNF-alpha was not altered by the treatment. Anti-TGF-beta treatment before or after coronary artery ligation increases mortality and worsens left ventricular remodeling in mice with non-reperfused MI. The detrimental effects of TGF-beta inhibition may be mediated by alterations in extracellular matrix remodeling.     

Cardiac rupture complicating myocardial infarction

Rupture of the ventricular free wall is a leading cause of death in patients with acute myocardial infarction (MI). There are a number of risk indicators that are associated with cardiac rupture, such as female gender, old age, hypertension, and first MI. Typical symptoms of cardiac rupture are recurrent or persistent chest pain, syncope, and distension of jugular veins. Electrocardiographic signs may include sinus tachycardia, new Q-waves in 2 or more leads, persistent or recurrent ST segment elevation, deviation of expected evolutionary T-wave pattern, and electromechanical dissociation in end-stage cases. Once patients at risk have been identified using clinical symptoms and electrocardiographic signs, a fast and sensitive diagnostic test to confirm cardiac rupture is transthoracic echocardiography (TTE). New insights in the etiology of subacute myocardial rupture suggests that defective cardiac remodeling may predispose the heart for rupture. The matrix metalloproteinase (MMP) system has been shown to play an important role in cardiac extracellular matrix (ECM) remodeling and cardiac rupture. Current therapy of cardiac rupture consists mainly of surgery, and conservative management with hemodynamic monitoring, prolonged bed rest, beta-blockers, and angiotensin-converting enzyme (ACE) inhibitors in selected cases.     

Effects of the calcineurin dependent signaling pathway inhibition by cyclosporin A on early and late cardiac remodeling following myocardial infarction

BACKGROUND: The calcineurin-mediated signaling pathway has been implicated as one of the crucial pathways in cardiac hypertrophy. However, the role of calcineurin pathway on cardiac remodeling after myocardial infarction (MI) has not been well defined. METHODS: Infarcted rats (n = 45) were randomized into calcineurin inhibitor, cyclosporin A (CsA) or vehicle groups, 3 days after MI and treated for 2 weeks (early post-MI cardiac remodeling stage), or randomized 17 days after MI and treated for 2 weeks (late remodeling stage). RESULTS: Calcineurin pathway inhibition during the early cardiac remodeling stage attenuated the myocardial hypertrophy after MI (P < 0.05). However, left ventricular dimensions were further increased and fractional shortening deteriorated with calcineurin inhibition during this stage (P < 0.05, each). During late remodeling stage, CsA treatment did not affect myocardial hypertrophy and cardiac dilation following MI. CONCLUSION: Our results strongly support the hypothesis that calcineurin pathway mediates compensatory myocardial hypertrophy during the early remodeling stage after MI. However, the calcineurin pathway does not seem to affect the late remodeling after MI.     

Non-fibrillar collagens: Key mediators of post-infarction cardiac remodeling?

Cardiac remodeling is accelerated during pathological conditions and several anabolic and catabolic regulators work in concert to repair the myocardium and maintain its functionality. The fibroblasts play a major role in this process via collagen deposition as well as supplying the degradative matrix metalloproteinases. During the more acute responses to a myocardial infarction (MI) the heart relies on a more aggressive wound healing sequence that includes the myofibroblasts, specialized secretory cells necessary for infarct scar formation and thus, rescue of the myocardium. The activated fibroblasts and myofibroblasts deposit large amounts of fibrillar collagen during the post-MI wound healing phase, type I and III collagen are the most abundant collagens in the heart and they maintain the structural integrity under normal and disease states. While collagen I and III have been the traditional focus of the myocardial matrix, recent studies have suggested that the non-fibrillar collagens (types IV and VI) are also deposited during pathological wound healing and may play key roles in myofibroblast differentiation and organization of the fibrillar collagen network. This review highlights the potential roles of the non-fibrillar collagens and how they work in concert with the fibrillar collagens in mediating myocardial remodeling.     

Role of nitrates after acute myocardial infarction.

Apart from their ability to relieve myocardial ischemia, nitrates have an important role to play on preservation of left ventricular (LV) geometry and function after acute myocardial infarction (MI). In the first 48 hours after acute MI, intravenous nitroglycerin infusion titrated to a low-dose regimen produces multiple benefits, including smaller infarct size, better regional and global LV function, less remodeling, fewer in-hospital complications, and fewer deaths in-hospital and up to 1 year. This regimen might be an effective adjunct during reperfusion therapy for salvaging ischemic myocardium, LV geometry, and function. Recent studies indicate that prolonged therapy with nitrates during the healing phase after acute MI can effectively further limit progressive LV remodeling (less LV dilation, expansion, thinning, and aneurysm formation) and preserve LV function. Tolerance with chronic therapy is avoided by an eccentric dose regimen to provide a nitrate-free interval.     

不同月龄鼠急性心肌梗死后心室重构和心脏破裂的观察

目的 探讨老龄对小鼠急性心肌梗死(AMI)后心室重构心脏破裂的影响. 方法 老龄和低龄C57BL/6小鼠,随机分为假手术组、心肌梗死组.建立AMI模型后,观察心脏破裂发生率,并于AMI后第7天行超声和血流动力学检查;应用酶谱法、病理染色及免疫组化方法 ,分别于AMI后第3、7天检测基质金属蛋白酶-2、-9(MMP-2、MMP-9)活性表达,炎性细胞浸润程度,心肌间质胶原含量(CVF)和类型的变化. 结果 AMI后老龄组心脏破裂率高于低龄组(38.0%与16.0%,X2=6.139,P＜0.05);第7天时,较低龄组出现明显的梗死区扩张、左心室重构、心功能障碍及血流动力学变化(t=5.754,P＜0.05).与低龄组比较,老龄AMI组AMI后第3天炎性细胞浸润程度、MMP-9表达明显增加(P＜0.05).与低龄组比较,老龄组心肌间质胶原含量、Ⅲ型胶原表达增加(P＜0.05). 结论 老龄是小鼠AMI后心脏破裂的高危因素,其原因可能与AMI早期炎性细胞浸润程度增加、MMP-9、Ⅲ型胶原过度表达和早期左心室重构恶化有关.     

Targeting the Wnt/frizzled signaling pathway after myocardial infarction: A new tool in the therapeutic toolbox?

Wnt/frizzled signaling in the adult heart is quiescent under normal conditions; however it is reactivated after myocardial infarction (MI). Any intervention at the various levels of this pathway can modulate its signaling. Several studies have targeted Wnt/frizzled signaling after MI with the majority of them indicating that the inhibition of the pathway is beneficial since it improves infarct healing and prevents heart failure. This suggests that blocking the Wnt/frizzled signaling pathway could be a potential novel therapeutic target to prevent the adverse cardiac remodeling after MI.     

Peroxisome proliferator-activated receptor alpha-independent actions of fenofibrate exacerbates left ventricular dilation and fibrosis in chronic pressure overload

Progressive cardiac remodeling is characterized by subsequent chamber hypertrophy, enlargement, and pump dysfunction. It is also associated with increased cardiac fibrosis and matrix turnover. Interestingly, peroxisome proliferator-activated receptor (PPAR) alpha activators reduce cardiac hypertrophy, inflammation, and fibrosis. Little is known about the role of fenofibrates in mediating PPARalpha-independent effects in response to chronic pressure overload (PO). Wild-type and PPARalpha-deficient mice were subjected to chronic PO caused by ascending aortic constriction to test the role of fenofibrates in chronic, progressive cardiac remodeling by a PPARalpha-independent mechanism. Mice were randomized to regular chow or chow-containing fenofibrate (100 mg/kg of body weight per day) for 1 week before and 8 weeks after ascending aortic constriction. In the presence of PPARalpha, wild-type chronic PO mice, treated with fenofibrate, had improved cardiac remodeling. However, PO PPARalpha-deficient mice treated with fenofibrate had increased mortality, significantly adverse left ventricular end diastolic (3.4+/-0.1 versus 4.2+/-0.1 mm) and end systolic (1.5+/-0.2 versus 2.5+/-0.2 mm) dimensions, and fractional shortening (57+/-3% versus 40+/-3%). Fenofibrate also increased myocardial hypertrophy, cardiac fibrosis, and the ratio of matrix metalloproteinase-2/tissue inhibitor of matrix metalloproteinase-2 in PO PPARalpha-deficient mice. Fenofibrate inhibited matrix metalloproteinase activity in vitro and aldosterone-induced increases in extracellular signal-regulated kinase phosphorylation. Thus, fenofibrate improved cardiac remodeling in chronic PO mice. However, in PPARalpha-deficient mice, this chronic PO was exacerbated and associated with increased myocardial fibrosis and altered matrix remodeling. In the absence of PPARalpha, fenofibrates exerts deleterious, pleiotropic myocardial actions. This is an important observation, because PPARalpha agonists are considered possible inhibitory regulators of cardiac remodeling in the remodeled heart.     

Intravascular ultrasound assessment of the association between spatial orientation of ruptured coronary plaques and remodeling morphology of culprit plaques in ST-elevation acute myocardial infarction

The aim of this study was to assess the association between the spatial location of plaque rupture and remodeling pattern of culprit lesions in acute anterior myocardial infarction (MI). Positive remodeling suggests a potential surrogate marker of plaque vulnerability, whereas plaque rupture causes thrombus formation followed by coronary occlusion and MI. Intravascular ultrasound (IVUS) can determine the precise spatial orientation of coronary plaque formation. We studied 52 consecutive patients with acute anterior MI caused by plaque rupture of the culprit lesion as assessed by preintervention IVUS. The plaques were divided into those with and without positive remodeling. We divided the plaques into three categories according to the spatial orientation of plaque rupture site: myocardial (inner curve), epicardial (outer curve), and lateral quadrants (2 intermediate quadrants). Among 52 plaque ruptures in 52 lesions, 27 ruptures were oriented toward the epicardial side (52%), 18 toward the myocardial side (35%), and 7 in the 2 lateral quadrants (13%). Among 35 plaques with positive remodeling, plaque rupture was observed in 21 (52%) on the epicardial side, 12 (34%) on the myocardial side, and 2 (6%) on the lateral side. However, among 17 plaques without positive remodeling, plaque rupture was observed in 6 (35%), 6 (35%), and 5 (30%), respectively (p?=?0.047). Atherosclerotic plaques with positive remodeling showed more frequent plaque rupture on the epicardial side of the coronary vessel wall in anterior MI than those without positive remodeling.     

Oxidative stress and cardiac repair/remodeling following infarction

Extensive cardiac remodeling after myocardial infarction (MI) contributes significantly to ventricular dysfunction. Factors regulating left ventricular remodeling at different stages after MI are under investigation. There is growing recognition and experimental evidence that oxidative stress mediated by reactive oxygen species plays a role in the pathogeneses of myocardial repair/remodeling in various cardiac diseases. After acute MI, oxidative stress is developed in both infarcted and noninfarcted myocardium. Accumulating evidence has demonstrated that oxidative stress participates in several aspects of cardiac repair/remodeling after infarction that include cardiomyocyte apoptosis, inflammatory/fibrogenic responses, and hypertrophy. The exact pathways on reactive oxygen species-mediated myocardial remodeling are under investigation. The therapeutic potential of oxidative stress-directed drugs in myocardial remodeling after infarction has not been fully realized.     

Growth hormone improves bioenergetics and decreases catecholamines in postinfarct rat hearts

The aims of this study were to examine, in vivo, the effects of GH treatment on myocardial energy metabolism, function, morphology, and neurohormonal status in rats during the early postinfarct remodeling phase. Myocardial infarction (MI) was induced in male Sprague Dawley rats. Three different groups were studied: MI rats treated with saline (n = 7), MI rats treated with GH (MI + GH; n = 11; 3 mg/kg x day), and sham-operated rats (sham; n = 8). All rats were investigated with 31P magnetic resonance spectroscopy and echocardiography at 3 days after MI and 3 weeks later. After 3 weeks treatment with GH, the phosphocreatine/ATP ratio increased significantly, compared with the control group (MI = 1.69 +/- 0.09 vs. MI + GH = 2.42 +/- 0.05, P < 0.001; sham = 2.34 +/- 0.08). Treatment with GH significantly attenuated an increase in left ventricular end systolic volume and end diastolic volume. A decrease in ejection fraction was prevented in GH-treated rats (P < 0.05 vs. MI). Myocardial and plasma noradrenaline levels were significantly lower in MI rats treated with GH. These effects were accompanied by normalization of plasma brain natriuretic peptide levels (sham = 124.1 +/- 8.4; MI = 203.9 +/- 34.7; MI + GH = 118.3 +/- 8.4 ng/ml; P < 0.05 vs. MI). In conclusion, GH improves myocardial energy reserve, preserves left ventricular function, and attenuates pathologic postinfarct remodeling in the absence of induction of left ventricular hypertrophy in postinfarct rats. The marked decrease in myocardial content of noradrenaline, after GH treatment, may protect myocardium from adverse effects of catecholamines during postinfarct remodeling.