This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sutton, M. G. St. J. Articles by Sharpe, N. Search for Related Content PubMed PubMed Citation Articles by Sutton, M. G. St. J. Articles by Sharpe, N. Related Collections Structure Remodeling Cardiovascular Pharmacology Cell signalling/signal transduction Acute myocardial infarction

(Circulation. 2000;101:2981.)
© 2000 American Heart Association, Inc.

Clinical Cardiology: New Frontiers

Left Ventricular Remodeling After Myocardial Infarction

Pathophysiology and Therapy

Martin G. St. John Sutton, MBBS, FRCP; Norman Sharpe, MD, FRACP

From the University of Pennsylvania Medical Center, Philadelphia, Pa (M.G.S.J.S.), and the Department of Medicine, University of Auckland, Auckland, New Zealand (N.S.).

Correspondence to Norman Sharpe, MD, FRACP, FACC, Department of Medicine, University of Auckland, 4th Floor, Auckland Hospital, Grafton, Private Bag 92-019, Auckland, New Zealand. E-mail n.sharpe{at}auckland.ac.nz

Key Words: myocardial infarction • remodeling • signal transduction • structure • pharmacology

Left ventricular remodeling is the process by which ventricular size, shape, and function are regulated by mechanical, neurohormonal, and genetic factors.^{1 2} Remodeling may be physiological and adaptive during normal growth or pathological due to myocardial infarction, cardiomyopathy, hypertension, or valvular heart disease (Figure 1). This article will review postinfarction remodeling, pathophysiological mechanisms, and therapeutic intervention.

View larger version (46K): [in this window] [in a new window]   Figure 1. Diagrammatic representation of the many factors involved in the pathophysiology of ventricular remodeling. ECM indicates extracellular matrix; RAAS, renin-angiotensin-aldosterone system; CO, cardiac output; SVR, systemic vascular resistance; LV, left ventricular; and AII, angiotensin II.

Pathophysiology

Postinfarction Left Ventricular Remodeling
The acute loss of myocardium results in an abrupt increase in loading conditions that induces a unique pattern of remodeling involving the infarcted border zone and remote noninfarcted myocardium. Myocyte necrosis and the resultant increase in load trigger a cascade of biochemical intracellular signaling processes that initiates and subsequently modulates reparative changes, which include dilatation, hypertrophy, and the formation of a discrete collagen scar. Ventricular remodeling may continue for weeks or months until the distending forces are counterbalanced by the tensile strength of the collagen scar. This balance is determined by the size, location, and transmurality of the infarct, the extent of myocardial stunning, the patency of the infarct-related artery, and local tropic factors.^{1 3}

The myocardium consists of 3 integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. Consideration of all 3 components provides important insights into the remodeling process and a rationale for future therapeutic strategies. The cardiomyocyte is terminally differentiated and develops tension by shortening. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of type I and type III collagen that couples myocytes and maintains the spatial relations between the myofilaments and their capillary microcirculation.^{4 5} The collagen framework couples adjacent myocytes by intercellular struts that align myofilaments to optimize force development, distribute force evenly to the ventricular walls, and prevent sarcomeric deformation.⁵

Myocardial infarction results in the migration of macrophages, monocytes, and neutrophils into the infarct zone; this initiates intracellular signaling and neurohormonal activation, which localizes the inflammatory response. Changes in circulatory hemodynamics are determined primarily by the magnitude of myocyte loss, the stimulation of the sympathetic nervous system and renin-angiotensin-aldosterone system, and the release of natriuretic peptides.

Postinfarction remodeling has been arbitrarily divided into an early phase (within 72 hours) and a late phase (beyond 72 hours). The early phase involves expansion of the infarct zone,⁵ which may result in early ventricular rupture or aneurysm formation. Late remodeling involves the left ventricle globally and is associated with time-dependent dilatation, the distortion of ventricular shape, and mural hypertrophy. The failure to normalize increased wall stresses results in progressive dilatation, recruitment of border zone myocardium into the scar, and deterioration in contractile function.^{1 6}

Early Remodeling
Infarct expansion results from the degradation of the intermyocyte collagen struts by serine proteases and the activation of matrix metalloproteinases (MMPs) released from neutrophils.⁷ Infarct expansion occurs within hours of myocyte injury,³ results in wall thinning and ventricular dilatation, and causes the elevation of diastolic and systolic wall stresses. Early ventricular dilatation due to infarct expansion has been unequivocally demonstrated in man. Increased wall stress is a powerful stimulus for hypertrophy mediated by mechanoreceptors and transduced to intracellular signaling, partly via angiotensin II (Ang II) release, which initiates the increased synthesis of contractile assembly units.⁸ Wall stress is also a major determinant of ventricular performance.

Adaptive responses are invoked that preserve stroke volume by involving the noninfarcted remote myocardium.⁹ Infarct expansion causes the deformation of the border zone and remote myocardium, which alters Frank/Starling relations and augments shortening.⁹ Perturbations in circulatory hemodynamics trigger the sympathetic adrenergic system, which stimulates catecholamine synthesis by the adrenals and spillover from sympathetic nerve terminals, activates the renin-angiotensin-aldosterone system, and stimulates the production of atrial and brain natriuretic peptides (ANP and BNP).¹⁰ Augmented shortening and increased heart rate from sympathetic stimulation result in hyperkinesis of the noninfarcted myocardium and temporary circulatory compensation. In addition, the natriuretic peptides reduce intravascular volume and systemic vascular resistance, normalize ventricular filling, and improve pump function.

Late Remodeling
Remodeling involves myocyte hypertrophy and alterations in ventricular architecture to distribute the increased wall stresses more evenly as the extracellular matrix forms a collagen scar to stabilize the distending forces and prevent further deformation. Myocyte hypertrophy is demonstrable microscopically, with an up to 70% increase in cell volume¹¹ and mural hypertrophy by in-series sarcomeric replication, without a change in sarcomere length.

Remodeling and Hypertrophy
Hypertrophy is an adaptive response during postinfarction remodeling that offsets increased load, attenuates progressive dilatation, and stabilizes contractile function.¹ Genes for transcriptional factors, such as c-fos, c-jun, c-myc, Egr-1, natriuretic peptides (ANP, BNP), sarcomeric proteins (ß-myosin heavy chain [ßMyHC] in rodents, smooth muscle and skeletal -actins, and myosin light chains 1a and 2a), enzymes (angiotensin-converting enzyme [ACE], ßARK), and growth factors (endothelin-1 [ET-1], insulin-like growth factor-1, transforming growth factor [TGF]-ß1), are induced and regulated by hypertrophic stimuli.^{12 13 14}

Myocyte hypertrophy is initiated by neurohormonal activation, myocardial stretch, the activation of the local tissue renin-angiotensin system (RAS), and paracrine/autocrine factors. Hypotension after infarction activates the RAS-aldosterone axis, catecholamine production by adrenal medulla, the spillover from sympathetic nerve terminals, and the secretion of natriuretic peptides. Enhanced norepinephrine (NE) release contributes directly and indirectly to the hypertrophic response. Stimulation of 1 adrenoreceptors by NE leads to myocyte hypertrophy via the Gq-dependent signaling pathway.¹⁵ The activation of ß1 adrenoreceptors in the juxtaglomerular apparatus induces renin release, which enhances the production of Ang II. Increased Ang II production, induced by the diminished stretch activation of vascular smooth muscle cells in the juxtaglomerular apparatus, promotes the presynaptic release of NE and blocks its reuptake, increases catecholamine synthesis, and potentiates the postsynaptic action of NE.¹⁶ In addition, Ang II and NE may augment ET-1 release, which is another stimulus for myocyte hypertrophy and stimulates the secretion of ANP. ANP, in turn, inhibits the production of catecholamines, Ang II, ET-1, and aldosterone.¹⁷

Serine proteases activate the local RAS in the noninfarcted myocardium, leading to the up-regulation of angiotensinogen gene expression and increased local ACE activity. These changes enhance local Ang II production, which is the likely stimulus for hypertrophy in noninfarcted myocardium.¹⁸ In addition to the activation of the RAS and adrenergic receptors locally, small mechanical strains induced by elevated wall stresses sensed by infarcted and noninfarcted myocardium have been implicated in hypertrophy.¹² Small mechanical stretches of myocytes demonstrate a tight bidirectional relationship between wall stress and myocyte hypertrophy,⁸ which resembles that between stress and hypertrophy in the intact heart. Stretch-induced hypertrophy in cardiomyocytes mimics hemodynamic load–induced hypertrophy, occurs in the absence of neurohormonal stimulation, and does not require active tension development.¹² These noninjurious strains are of similar magnitude to the increased wall stress from ventricular dilatation after infarction.⁸

Mechanical stretch results in the secretion of Ang II from cytoplasmic granules, and this stretch-induced hypertrophic response is mediated by AT1 receptors.^{12 13 14} Through the activation of this G-protein–coupled receptor, multiple signaling pathways are potentially activated. These include the calcium-dependent activation of tyrosine kinase and the activation of protein kinase C (PKC) via inositide signaling (phospholipase Cß), mitogen-activated protein (MAP) kinase, and S6 kinase.¹⁵ PKC further induces the secretion of Ang II and, by autocrine/paracrine action, secreted Ang II amplifies the signals evoked by mechanical stress. Mechanical stretch from increased wall stress may induce rapid, transient activation of immediate early genes (ie, jun, fos, myc, and Egr-1), followed by the activation of fetal gene program (ie, -actin, ß-MyHC, and ANP) and a time-dependent increase in protein synthesis.^{8 12} The role of immediate early genes in hypertrophy is not clear; however, in vitro studies have shown that Egr-1 may be involved in the transcriptional regulation of the -MyHC gene.¹⁹

Cardiac hypertrophy is stimulated by a variety of biochemical and physical stimuli and transduced through a common mechanism involving the activation of protein kinase cascades. The receptors for NE, ET-1, and Ang II are similar and are coupled to Gq proteins.¹⁵ The activation of Gq stimulates phospholipase Cß, which in turn leads to the production of 1, 2 diacylglycerol and the activation of PKC.¹⁵ Growth factors, including fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, insulin, and insulin-like growth factor, activate receptor tyrosine kinase, p21 ras, and MAP kinase (extracellular regulated kinase or Jun N-terminal kinase). The activation of MAP kinase is a prerequisite for the transcriptional and morphological changes of myocyte hypertrophy.²⁰ Ang II may also activate p21 ras through the activation of the nonreceptor tyrosine kinase of the src family.²¹ Intracellular calcium seems critical for the activation of protein kinases in cardiomyocytes by Ang II and other hypertrophic stimuli before the fetal gene program can be switched on to increase protein synthesis.

Collagen Degradation
The triple-helical structure of collagen renders it resistant to proteolytic degradation, except by MMPs, which are secreted into the extracellular matrix in their latent proenzyme form.²² The activation of MMPs requires the proteolytic cleavage of a propeptide sequence. MMP1 (collagenase) cleaves collagen into 3/4 and 1/4 fragments, which are unfolded and degraded by MMP2, MMP9 (gelatinases), and MMP3 (stromelysin).²² The regulation of the MMPs occurs at 3 levels: transcription, activation, and inhibition.²²

The temporal sequence of collagen degradation by the MMPs is species-specific.^{7 23} Collagen breakdown begins within 3 hours of infarction and is induced by serine proteases such as plasmin and the release of MMP8 from neutrophils.⁷ The initial digestion of collagen intercellular struts is responsible for the slippage of the necrotic myofilaments that causes infarct expansion.^{5 24} In the rat heart, MMP1 activity is not detectable until day 2 postinfarction, and it peaks at day 7.⁷ Activation of MMP1 augments MMP2 activity, which peaks at day 7, whereas MMP9 activity is only detectable by day 4.⁷ MMP3 activity is a regulatory step in the activation of the family of MMPs. PKC has been implicated in the induction of MMP transcription in that Ang II, ET-1, tumor necrosis factor-, and catecholamines, which cause receptor-mediated increases in PKC, are associated with an increase in MMPs.²⁵

Collagenolytic activity is confined to regions of injury by tissue inhibitors of the metalloproteinases (TIMPs). These low-molecular-weight proteins (TIMPs) form high-affinity complexes with activated MMPs and neutralize collagen degradation by blocking the catalytic domain of MMPs.²² TIMPs are induced in the infarct zone within 6 hours, peak by day 2, and return to normal by 14 days.⁷ The synthesis of TIMPs is modulated by the levels of activated MMPs, such that collagen degradation reflects the dysequilibrium between MMPs and TIMPs.

Triggers for Tissue Repair
Myocardial repair is triggered by cytokines released from injured myocytes. The cytokine TGF-ß1 increases early in the infarct zone, stimulating macrophage and fibroblast chemotaxis and fibroblast proliferation.²⁶ An increase in -interferon activates macrophages to produce nitric oxide, which increases vascular permeability and confines the cellular inflammatory response to the infarct zone.²⁷ Activated macrophages are genetically transformed to express ACE, which provides a local source of Ang II that is regulated independently of plasma Ang II but plays a pivotal role in reparative fibrosis.²⁶ The early release of TGF-ß1 from necrotic myocytes and macrophages is also important in the phenotypic transformation of interstitial fibroblasts to myofibroblasts, which elaborate receptors to Ang II, TGF-ß1, and ET-1.^{26 28} Myofibroblasts express genes encoding for procollagen types 1 and 3, generate Ang I and II and receptors for Ang II and TGF-ß1 and ET-1; this enables the autoregulation of collagen turnover.^{4 26} Synthesis of collagen types 1 and 3 by myofibroblasts is modulated by several factors, including Ang II–related mechanical deformation, fibroblast growth factor, platelet-derived growth factor, ANP, and bradykinin-mediated prostaglandin E2 and nitric oxide release.⁴ By inhibiting fibroblast growth, ANP may retard collagen synthesis and limit proliferative remodeling.¹⁷ Mechanical strains also determine the degree of collagen cross-linking and the strength of the mature scar.²⁹

Tissue repair is initiated by the formation of a fibrin-fibronectin matrix, which precedes collagen synthesis,³⁰ to which myofibroblasts become adherent. A complex costimulatory relationship exists between aldosterone, ANP, endothelin, bradykinin, and TGF-ß1 in the regulation of collagen synthesis. Aldosterone is synthesised by myofibroblasts and has a concentration in the heart that is >17-fold greater than that in plasma.³¹ Aldosterone, which is regulated by nitric oxide, ANP, and Ang II, stimulates the transcription of collagen type I and type III mRNA. This action is blocked by spironolactone, which implicates the mineralocorticoid receptor in collagen synthesis. The aldosterone-mineralocorticoid receptor complex activates the Ang1 receptor gene to increase the number of Ang1 receptors. Reciprocal stimulation of aldosterone and Ang II amplifies the proliferative and fibrogenic responses of Ang II to up-regulate type I and type III collagen mRNAs, both of which are prevented by Ang1 receptor blockade.^{32 33}

Deposition of type III and type I collagen occurs predominantly in the infarct zone; however, it also occurs in noninfarcted myocardium when intercellular signaling is potentiated by extensive myocyte necrosis. Type III collagen mRNA increases by day 2 and remains elevated for 3 weeks; type I collagen mRNA increases by day 4 and may remain elevated for up to 3 months.⁷ Collagen is detectable microscopically by day 7 and then increases dramatically, such that by 28 days, the necrotic myocytes are entirely replaced by fibrous tissue.⁷ After the formation of a scar that equilibrates distending and restraining forces, collagen formation is down-regulated and most myofibroblasts undergo apoptosis.

Therapeutic Intervention

The effects of therapies designed to prevent or attenuate postinfarction left ventricular remodeling are best considered with reference to the pathophysiological mechanisms involved. Thrombolysis limits infarct size, transmurality, and infarct expansion and is of proven benefit in eligible patients. Beyond the acute phase, ventricular remodeling is influenced most by infarct artery patency, ventricular loading conditions, neurohormonal activation, and local tissue growth factors.

Infarct Artery Patency
Although infarct size is a major determinant of ventricular remodeling, late patency of the infarct-related artery or collateral flow to the infarct may confer survival benefit. In a study of patients who did not receive thrombolysis, the degree of perfusion of the infarct-related artery was a more important predictor of left ventricular volume change from 48 hours to 1 month after infarction than infarct size.³⁴ Reperfusion may salvage endocardial tissue and restore stunned myocardium in the infarct border zone. Reperfused infarcts with contraction-band necrosis may have greater tensile strength and less propensity to expansion. However, infarct size, location, and collateral flow determine the likelihood of late remodeling. A large autopsy series confirmed the association of infarct expansion with large transmural infarcts.³⁵ Infarct expansion occurred more frequently in the left anterior descending coronary artery than in the right coronary artery, and increased heart weight correlated inversely with expansion. Differences in regional wall thickness, the radius of curvature, and intramural tension also influence infarct expansion and remodeling.

Several studies have demonstrated a benefit from myocardial reperfusion, with reduced infarct size and associated improvement in later regional and global ventricular function.^{36 37} The independent prognostic importance of infarct-related artery patency has emerged from studies in which patency has correlated closely with changes in left ventricular volume and function.³⁸ The Total Occlusion Study of Canada trial³⁹ recently demonstrated the benefit of primary stenting compared with angioplasty alone in improving late patency, restenoses, and the need for revascularization in a large group of patients with nonacute coronary occlusions. However, the benefit of the acute percutaneous revascularization of occluded infarct-related arteries on remodeling is unknown.

Pharmacological Intervention
Thrombolysis is of proven value in the acute infarction, in which the primary objectives are limiting infarct size and salvaging ischemic myocardium. Once infarct evolution has occurred, pharmacological intervention may minimize infarct expansion and ventricular dilatation and improve the long-term prognosis.

Nitroglycerin
Intravenous nitroglycerin limits infarct size, infarct expansion, infarct-related complications, and mortality for up to 1 year.⁴⁰ The long-term beneficial effects of transdermal nitroglycerin on left ventricular remodeling after myocardial infarction have also been reported.⁴¹ Despite these positive results, the large GISSI-3 trial (Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico)⁴² and the Fourth International Study of Infarct Survival (ISIS 4)⁴³ failed to show a significant mortality benefit in patients treated with nitrates after acute myocardial infarction. This may have been due to a null bias related to extensive use of nonstudy nitrates and also to the limited efficacy of the nitrate regimens used. However, there may be a true lack of efficacy of routine nitrate therapy when used concurrently with thrombolysis, aspirin, ACE inhibitors, and ß-blockers. Although routine intravenous nitroglycerin may be used during the first 24 hours after myocardial infarction, nitrates are not recommended routinely beyond this time except for specific indications, which include persistent ischemia, hypertension, or heart failure.

ACE Inhibition
The efficacy of ACE inhibitors in attenuating left ventricular dilatation after infarction was first demonstrated in the rat, and this effect on remodeling was associated with improved survival. The effects of captopril, furosemide, and placebo were studied in patients with asymptomatic left ventricular dysfunction (ejection fraction <45%) 1 week after a Q-wave myocardial infarction⁴⁴ (Figure 2). Captopril treatment resulted in a significant reduction in left ventricular end-systolic volume index, with increases in stroke volume index and ejection fraction, whereas treatment with furosemide and placebo was associated with significant increases in echocardiographic left ventricular volumes at 1 year. Another study⁴⁵ randomized patients with an ejection fraction <45% and without heart failure to receive captopril or placebo at a mean of 18 days after a first anterior myocardial infarction. End-diastolic volume increased in the placebo group at 1 year but not in the captopril group, although the difference between groups was not significant. Although left ventricular dysfunction can be improved with ACE inhibition commenced 1 week after infarction, earlier intervention seems to provide greater benefit⁴⁶ (Figure 3).

View larger version (83K): [in this window] [in a new window]   Figure 2. Left ventricular (LV) remodeling after transmural anteroseptal myocardial infarction (MI): 2D echocardiographic evaluation at 1 week and 3 months. Extensive anteroapical akinesis, progressive dilatation, and dysfunction with increased sphericity are evident, as is the development of apical thrombus. EDV indicates end-diastolic volume; ESV, end-systolic volume; and EF, ejection fraction.

View larger version (33K): [in this window] [in a new window]   Figure 3. Left ventricular (LV) function plot derived from quantitative 2D echocardiographic data from 2 intervention studies44 46 using ACE inhibition after myocardial infarction (MI). Postinfarction left ventricular dilatation is greater at 1 week than at 24 to 48 hours after Q-wave infarction. Intervention with captopril (cap, light arrows) prevents or reverses progressive remodeling compared with placebo (plac, dark arrows), with a greater benefit after earlier intervention (from 24 to 48 hours) than after 1 week. SVI indicates stroke volume index, LVEDVI, left ventricular end-diastolic volume index; and EF, ejection fraction.

The mechanism of improvement with ACE inhibition is related in part to peripheral vasodilatation, ventricular unloading, and the attenuation of ventricular dilatation. There may be additional beneficial effects on the coronary circulation⁴⁷ and intrinsic plasminogen-activating system. Although coronary hemodynamic data have suggested a balanced effect of ACE inhibitors on the coronary circulation, one study in patients with heart failure and angina indicated that such treatment may worsen ischemia, because of the hypotension that compromises myocardial perfusion.⁴⁸ Importantly, ACE inhibition may have a direct effect on myocardial tissue,^{4 8 18} preventing the inappropriate growth and hypertrophy stimulated by Ang II and other growth factors.

A number of large studies have demonstrated a survival benefit when ACE inhibitors have been used in all patients with myocardial infarction^{42 43} and selectively in patients with left ventricular dysfunction or heart failure.^{49 50} The consistent survival benefit of ACE inhibitors compared with other vasodilators and a comparison of short- and long-term effects implicates biological tissue effects in addition to vasodilatation.

Evaluation of ACE inhibitor treatment with captopril given 2 hours after the commencement of streptokinase therapy showed the most benefit on regional wall motion in patients with anterior infarction with reduced infarct-related artery flow.⁵¹ This finding is concordant with the retrospective analysis of the Survival and Ventricular Enlargement study,⁵² which showed a reduction in a composite end point in captopril-treated patients with occluded arteries but no such effect in those with patent arteries.

It is recommended that patients with left ventricular dysfunction or heart failure be treated with ACE inhibitors without delay after infarction. Alternatively, all patients should be treated with ACE inhibitors initially, with a review of the need for continuation later on the basis of left ventricular function assessment.

ß-Blockade
The effects of ß-blockade on postinfarction left ventricular remodeling have been little studied. Preliminary data suggest that carvedilol may attenuate remodeling, an effect associated with a significant reduction in subsequent adverse cardiac events.⁵³ Whether ß-blocking agents provide a benefit additional to ACE inhibitor treatment in patients with left ventricular dysfunction or heart failure after acute myocardial infarction remains unknown. Although the rationale for combination treatment is strong when extrapolating from clinical trials with ß-blockers after myocardial infarction generally and after heart failure, definitive data are lacking.

The effects of ACE inhibition and ß-blockade seem complementary. After myocardial infarction and in chronic heart failure, ACE inhibition improves remodeling and primarily reduces deaths from progressive heart failure. In chronic heart failure caused by ischemia, ß-blockade with carvedilol can reverse remodeling, which may progress despite standard treatment, including ACE inhibition.⁵⁴ The mortality benefit from ß-blockade in chronic heart failure, which is now clearly established, is due to a reduction in both progressive heart failure and sudden death. Thus, in patients with significant left ventricular dysfunction or heart failure after myocardial infarction, combination neurohormonal blockade may be optimal, although occasionally limited by hypotension.

Future Clinical Research and Management
Ventricular remodeling can be considered a primary target for treatment and a reliable surrogate for long-term outcomes. Noninvasive imaging has provided insights into the mechanisms by which biochemical and cellular changes are translated into alterations in ventricular architecture and function during remodeling. Clinical outcome analyses and reliable, objective, noninvasive measurements of ventricular structure and function currently provide a template for assessing new therapies. Cardiac MRI offers even greater accuracy, reductions in sample size requirements for intervention studies, and reliable assessment of individual cases⁵⁵ (Figure 4).

View larger version (91K): [in this window] [in a new window]   Figure 4. Cardiac MRI of left ventricular remodeling after inferoposterior myocardial infarction: regional wall motion analysis. a, The infarcted basal segment shows akinesis and thinning from 11 days to 3 months compared with the compensatory increase in contraction and thickening anteriorly. b, Three-dimensional shaded endocardial surfaces in lateral projection with a color scale representing wall thickening and showing changes from 11 days to 3 months. Dark blue equates with 20% wall thickening; yellow 50%, and red 80%. Reproduced with permission from Reference 55 .

The future challenge must be the primary prevention of myocardial infarction in patients at a high risk for coronary disease. In addition, new therapeutic strategies should be targeted to limit remodeling by the controlled modulation of the molecular and cellular factors involved in tissue repair, including hypertrophy, fibrosis, and the capillary microcirculation.

Use of novel IIb/IIIa platelet inhibitors to preserve the capillary microcirculation and minimize plugging from the aggregation of platelets, monocytes, and macrophages, in combination with early restoration of flow to the infarct zone by primary angioplasty or thrombolysis (open artery hypothesis), might further improve myocyte salvage and limit remodeling.

Preventing the breakdown of the extracellular collagen scaffold with exogenous MMP inhibitors or increased activity of TIMPs could stiffen the infarct zone, arrest infarct expansion, and prevent ventricular dilatation and the increased wall stress that initiates the intracellular signaling for enzymatic degradation of collagen.

Pharmacological blockade of TGF-ß1, which plays a critical role in the development of fibrosis (Figure 1), may potentially reduce or even prevent fibrosis in the infarct and the noninfarct zones, thereby improving ventricular compliance.

The development of new agents that allow modulation of the hypertrophic response triggered by plasma and local neurohormones would include partial blockers of natriuretic peptides, endothelin, and aldosterone receptors that would be similar to current ACE and Ang II receptor-blocking agents or blockers at the second messenger level.

Gene therapy enabling adenoviral gene transfection with vascular endothelial growth factor can enhance intracellular calcium handling and improve the contractile function of cardiomyocytes by the over-expression of sarcoplasmic reticulum Ca²⁺ ATPase in vitro, suggesting that selective gene transfer into hypertrophied myocardium might normalize intracellular calcium handling and provide a means to promote the controlled regression of hypertrophy. Further novel genetic engineering may permit phenotypic transformation of embryonic stem cells into cardiomyocytes or facilitate cardiomyocyte regeneration and engraftment in regions of fibrosis and thinning to restore wall thickness and myocardial mass. Similarly, genetic approaches to modify vascular growth may well be amenable to clinical application in the future.

A more highly integrated, systematic, and focused research approach and increased clinician awareness of the importance of remodeling and opportunities for intervention should ensure more effective management and improved outcomes for patients.

Received August 17, 1999; revision received April 7, 2000; accepted April 13, 2000.

References

1. Pfeffer MA, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications. Circulation. 1990;81:1161–1172.[Abstract/Free Full Text]

2. Rouleau JL, de Champlain J, Klein M, et al. Activation of neurohumoral systems in postinfarction left ventricular dysfunction. J Am Coll Cardiol. 1993;22:390–398.[Abstract]

3. Warren SE, Royal HD, Markis JE, et al. Time course of left ventricular dilation after myocardial infarction: influence of infarct-related artery and success of coronary thrombolysis. J Am Coll Cardiol. 1988;11:12–19.[Abstract]

4. Weber KT. Extracellular matrix remodeling in heart failure: a role for de novo angiotensin II generation. Circulation. 1997;96:4065–4082.[Free Full Text]

5. Erlebacher JA, Weiss JL, Weisfeldt ML, et al. Early dilation of the infarcted segment in acute transmural myocardial infarction: role of infarct expansion in acute left ventricular enlargement. J Am Coll Cardiol. 1984;4:201–208.[Abstract]

6. White HD, Norris RM, Brown MA, et al. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation. 1987;76:44–51.[Abstract/Free Full Text]

7. Cleutjens JP, Kandala JC, Guarda E, et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol. 1995;27:1281–1292.[Medline] [Order article via Infotrieve]

8. Sadoshima J, Jahn L, Takahashi T, et al. Molecular characterization of the stretch-induced adaptation of cultured cardiac cells: an in vitro model of load-induced cardiac hypertrophy. J Biol Chem. 1992;267:10551–10560.[Abstract/Free Full Text]

9. Lew WYW, Chen Z, Guth B, et al. Mechanisms of augmented segment shortening in nonischemic areas during acute ischemia of the canine left ventricle. Circ Res. 1985;56:351–358.[Abstract/Free Full Text]

10. Hall C. Interaction and modulation of neurohormones on left ventricular remodelling. In: St. John Sutton MG, ed. Left Ventricular Remodelling After Acute Myocardial Infarction. London: Science Press Ltd; 1996:89–99.

11. Anversa P, Beghi C, Kikkawa Y, et al. Myocardial response to infarction in the rat: morphometric measurement of infarct size and myocyte cellular hypertrophy. Am J Pathol. 1985;118:484–492.[Abstract]

12. Yamazaki T, Komuro I, Kudoh S, et al. Angiotensin II partly mediates mechanical stress-induced cardiac hypertrophy. Circ Res. 1995;77:258–265.[Abstract/Free Full Text]

13. Bogoyevitch MA, Glennon PE, Andersson MB, et al. Endothelin-1 and fibroblast growth factors stimulate the mitogen-activated protein kinase signaling cascade in cardiac myocytes: the potential role of the cascade in the integration of two signaling pathways leading to myocyte hypertrophy. J Biol Chem. 1994;269:1110–1119.[Abstract/Free Full Text]

14. Sadoshima J, Izumo S. Molecular characterization of angiotensin II–induced hypertrophy of cardiac myocytes and hyperplasia of cardiac fibroblasts: critical role of the AT1 receptor subtype. Circ Res. 1993;73:413–423.[Abstract/Free Full Text]

15. Ju H, Zhao S, Tappia PS, et al. Expression of Gq alpha and PLC-beta in scar and border tissue in heart failure due to myocardial infarction. Circulation. 1998;97:892–829.[Abstract/Free Full Text]

16. Ball SG. The sympathetic nervous system and converting enzyme inhibition. J Cardiovasc Pharmacol. 1989;13(suppl 3):S17–S21.

17. Levin ER, Gardner DG, Samson WK. Mechanisms of disease: natriuretic peptide. N Engl J Med. 1998;339:321–328.[Free Full Text]

18. Lindpaintner K, Lu W, Neidermajer N, et al. Selective activation of cardiac angiotensinogen gene expression in post-infarction ventricular remodeling in the rat. J Mol Cell Cardiol. 1993;25:133–143.[Medline] [Order article via Infotrieve]

19. Gupta MP, Gupta M, Zak R, et al. Egr-1, a serum-inducible zinc finger protein, regulates transcription of the rat cardiac alpha-myosin heavy chain gene. J Biol Chem. 1991;266:12813–12816.[Abstract/Free Full Text]

20. Glennon PE, Daddoura S, Sale EM, et al. Depletion of mitogen-activated protein kinase using an antisense oligodeoxynucleotide approach down-regulates the phenylephrine-induced hypertrophic response in rat cardiac myocytes. Circ Res. 1996;78:954–961.[Abstract/Free Full Text]

21. Sadoshima J, Izumo S. The heterotrimeric G q protein-coupled angiotensin II receptor activates p21 ras via the tyrosine kinase-Shc-Grb2-Sos pathway in cardiac myocytes. EMBO J. 1996;15:775–787.[Medline] [Order article via Infotrieve]

22. Mann DL, Spinale FG. Activation of matrix metalloproteinases in the failing human heart: breaking the tie that binds. Circulation. 1998;98:1699–1702.[Free Full Text]

23. Cleutjens JP, Verluyten MJ, Smiths JF, et al. Collagen remodeling after myocardial infarction in the rat heart. Am J Pathol. 1995;147:325–338.[Abstract]

24. Olivetti G, Capasso JM, Sonnenblick EH, et al. Side-to-side slippage of myocytes participates in ventricular wall remodeling acutely after myocardial infarction in rats. Circ Res. 1990;67:23–34.[Abstract/Free Full Text]

25. Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997;378:151–160.

26. Desmouliere A, Geinoz A, Gabbiani F, et al. Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 1993;122:103–111.[Abstract/Free Full Text]

27. Sigusch HH, Campbell SE, Weber KT. Angiotensin II-induced myocardial fibrosis in rats: role of nitric oxide, prostaglandins and bradykinin. Cardiovasc Res. 1996;31:546–554.[Medline] [Order article via Infotrieve]

28. Guarda E, Katwa LC, Myers PR, et al. Effects of endothelins on collagen turnover in cardiac fibroblasts. Cardiovasc Res. 1993;27:2130–2134.[Abstract/Free Full Text]

29. McCormick RJ, Musch TI, Bergman BC, et al. Regional differences in LV collagen accumulation and mature cross-linking after myocardial infarction in rats. Am J Physiol. 1994;266:H354–H359.[Abstract/Free Full Text]

30. Knowlton AA, Connelly CM, Romo GM, et al. Rapid expression of fibronectin in the rabbit heart after myocardial infarction with and without reperfusion. J Clin Invest. 1992;89:1060–1068.

31. Sun Y, Cleutjens JP, Diaz-Arias AA, et al. Cardiac angiotensin converting enzyme and myocardial fibrosis in the rat. Cardiovasc Res. 1994;28:1423–1432.[Abstract/Free Full Text]

32. Silvestre JS, Heymes C, Oubenaissa A, et al. Activation of cardiac aldosterone production in rat myocardial infarction: effect of angiotensin II receptor blockade and role in cardiac fibrosis. Circulation. 1999;99:2694–2701.[Abstract/Free Full Text]

33. Robert V, Heymes C, Silvestre JS, et al. Angiotensin AT1 receptor subtype as a cardiac target of aldosterone: role in aldosterone-salt-induced fibrosis. Hypertension. 1999;33:981–986.[Abstract/Free Full Text]

34. Jeremy RW, Hackworthy RA, Bautovich G, et al. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol. 1987;9:989–995.[Abstract]

35. Pirolo JS, Hutchins GM, Moore GW. Infarct expansion: pathologic analysis of 204 patients with a single myocardial infarct. J Am Coll Cardiol. 1986;7:349–354.[Abstract]

36. Touchstone DA, Beller GA, Nygaard TW, et al. Effects of successful intravenous reperfusion therapy on regional myocardial function and geometry in humans: a topographic assessment using two-dimensional echocardiography. J Am Coll Cardiol. 1989;13:1506–1513.[Abstract]

37. Marino P, Zanolla L, Zardini P (GISSI). Effect of streptokinase on left ventricular modeling and function after myocardial infarction: the GISSI trial. J Am Coll Cardiol. 1989;14:1149–1158.[Abstract]

38. White HD, Cross DB, Elliott JM, et al. Long-term prognostic importance of patency of the infarct-related coronary artery after thrombolytic therapy for acute myocardial infarction. Circulation. 1994;89:61–67.[Abstract/Free Full Text]

39. Buller CE, Dzavik V, Carere RG, et al, for the TOSCA Investigators. Primary stenting versus balloon angioplasty in occluded coronary arteries: the Total Occlusion Study of Canada (TOSCA). Circulation. 1998;100:236–242.[Abstract/Free Full Text]

40. Jugdutt BI, Warnica JW. Intravenous nitroglycerin therapy to limit myocardial infarct size, expansion, and complications: effect of timing, dosage, and infarct location. Circulation. 1988;78:906–919.[Abstract/Free Full Text]

41. Mahmarian JJ, Moye LA, Chinoy DA, et al. Transdermal nitroglycerin patch therapy improves left ventricular function and prevents remodeling after acute myocardial infarction: results of a multicenter prospective, randomized, double-blind, placebo-controlled trial. Circulation. 1998;97:2017–2024.[Abstract/Free Full Text]

42. GISSI-3. Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6 week mortality and ventricular function after acute myocardial infarction: Gruppo Italiano per lo Studio della Sopravvivenza nell’infarto Miocardico. Lancet. 1994;343:1115–1122.[Medline] [Order article via Infotrieve]

43. ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: a randomized factorial trial assessing early oral captopril, oral mononitrate and intravenous magnesium sulphate in 58 050 patients with suspected acute myocardial infarction. Lancet. 1995;345:669–682.[Medline] [Order article via Infotrieve]

44. Sharpe N, Murphy J, Smith H, et al. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet. 1988;1:255–259.[Medline] [Order article via Infotrieve]

45. Pfeffer MA, Lamas GA, Vaughan DE, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med. 1988;319:80–86.[Abstract]

46. Sharpe N, Smith H, Murphy J, et al. Early prevention of left ventricular dysfunction after myocardial infarction with angiotensin-converting enzyme inhibition. Lancet. 1991;337:872–876.[Medline] [Order article via Infotrieve]

47. Magrini F, Shimizu M, Roberts N, et al. Converting-enzyme inhibition and coronary blood flow. Circulation. 1987;75:S1168–S1174.

48. Cleland JGF, Henderson E, McLenachen J, et al. Effect of captopril, an angiotensin-converting enzyme inhibitor, in patients with angina pectoris and heart failure. J Am Coll Cardiol. 1991;17:733–739.[Abstract]

49. Pfeffer MA, Braunwald E, Moyé LA, et al, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669–677.[Abstract]

50. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821–828.[Medline] [Order article via Infotrieve]

51. French JK, Amos DJ, Williams BF, et al. Effects of early captopril administration after thrombolysis on regional wall motion in relation to infarct artery blood flow. J Am Coll Cardiol. 1999;33:139–145.[Abstract/Free Full Text]

52. Lamas GA, Flaker GC, Mitchell G, et al, for the Survival and Ventricular Enlargement Investigators. Effect of infarct artery patency on prognosis after acute myocardial infarction. Circulation. 1995;92:1101–1109.[Abstract/Free Full Text]

53. Basu S, Senior R, Raval U, et al. Beneficial effects of intravenous and oral carvedilol treatment in acute myocardial infarction: a placebo-controlled, randomized trial. Circulation. 1997;96:183–191.[Abstract/Free Full Text]

54. Doughty RN, Whalley GA, Gamble G, et al. Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease: Australia-New Zealand Heart Failure Research Collaborative Group. J Am Coll Cardiol. 1997;29:1060–1066.[Abstract]

55. Cowan BR, Young AA. Regional analysis of left ventricular motion after myocardial infarction. Proc Int Soc Magn Reson. 1998;2:884.

This article has been cited by other articles:

				G. Dwivedi, R. Janardhanan, S. A. Hayat, T. K. Lim, and R. Senior Improved prediction of outcome by contrast echocardiography determined left ventricular remodelling parameters compared to unenhanced echocardiography in patients following acute myocardial infarction Eur J Echocardiogr, December 1, 2009; 10(8): 933 - 940. [Abstract] [Full Text] [PDF]

				S. K. Mani, S. Balasubramanian, J. A. Zavadzkas, L. B. Jeffords, W. T. Rivers, M. R. Zile, R. Mukherjee, F. G. Spinale, and D. Kuppuswamy Calpain inhibition preserves myocardial structure and function following myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2009; 297(5): H1744 - H1751. [Abstract] [Full Text] [PDF]

				T. Mihaljevic, A. M. Gillinov, and J. F. Sabik III Functional Ischemic Mitral Regurgitation: Myocardial Viability as a Predictor of Postoperative Outcome After Isolated Coronary Artery Bypass Grafting Circulation, October 13, 2009; 120(15): 1459 - 1461. [Full Text] [PDF]

				V. Schachinger, B. Assmus, S. Erbs, A. Elsasser, W. Haberbosch, R. Hambrecht, J. Yu, R. Corti, D. G. Mathey, C. W. Hamm, et al. Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial Eur J Heart Fail, October 1, 2009; 11(10): 973 - 979. [Abstract] [Full Text] [PDF]

				F.-L. Xiang, X. Lu, L. Hammoud, P. Zhu, P. Chidiac, J. Robbins, and Q. Feng Cardiomyocyte-Specific Overexpression of Human Stem Cell Factor Improves Cardiac Function and Survival After Myocardial Infarction in Mice Circulation, September 22, 2009; 120(12): 1065 - 1074. [Abstract] [Full Text] [PDF]

				A. GLUBA, M. BANACH, D. P. MIKHAILIDIS, and J. RYSZ Genetic Determinants of Cardiovascular Disease: The Renin-Angiotensin-Aldosterone System, Paraoxonases, Endothelin-1, Nitric Oxide Synthase and Adrenergic Receptors In Vivo, September 1, 2009; 23(5): 797 - 812. [Abstract] [Full Text] [PDF]

				S. Javadov, M. Karmazyn, and N. Escobales Mitochondrial Permeability Transition Pore Opening as a Promising Therapeutic Target in Cardiac Diseases J. Pharmacol. Exp. Ther., September 1, 2009; 330(3): 670 - 678. [Abstract] [Full Text] [PDF]

				Z. Kassiri, J. Zhong, D. Guo, R. Basu, X. Wang, P. P. Liu, J. W. Scholey, J. M. Penninger, and G. Y. Oudit Loss of Angiotensin-Converting Enzyme 2 Accelerates Maladaptive Left Ventricular Remodeling in Response to Myocardial Infarction Circ Heart Fail, September 1, 2009; 2(5): 446 - 455. [Abstract] [Full Text] [PDF]

				L. Ding, L. Dong, X. Chen, L. Zhang, X. Xu, A. Ferro, and B. Xu Increased Expression of Integrin-Linked Kinase Attenuates Left Ventricular Remodeling and Improves Cardiac Function After Myocardial Infarction Circulation, September 1, 2009; 120(9): 764 - 773. [Abstract] [Full Text] [PDF]

				M. Yousef, C. M. Schannwell, M. Kostering, T. Zeus, M. Brehm, and B. E. Strauer The BALANCE Study: clinical benefit and long-term outcome after intracoronary autologous bone marrow cell transplantation in patients with acute myocardial infarction. J. Am. Coll. Cardiol., June 16, 2009; 53(24): 2262 - 2269. [Abstract] [Full Text] [PDF]

				R. Bauer, V. Straub, A. Blain, K. Bushby, and G. A. MacGowan Contrasting effects of steroids and angiotensin-converting-enzyme inhibitors in a mouse model of dystrophin-deficient cardiomyopathy Eur J Heart Fail, May 1, 2009; 11(5): 463 - 471. [Abstract] [Full Text] [PDF]

				A. A. Young and A. F. Frangi Computational cardiac atlases: from patient to population and back Exp Physiol, May 1, 2009; 94(5): 578 - 596. [Abstract] [Full Text] [PDF]

				M. Remmelink, K. D. Sjauw, J. P.S. Henriques, M. M. Vis, R. J. van der Schaaf, K. T. Koch, J. G.P. Tijssen, R. J. de Winter, J. J. Piek, and J. Baan Jr Acute left ventricular dynamic effects of primary percutaneous coronary intervention from occlusion to reperfusion. J. Am. Coll. Cardiol., April 28, 2009; 53(17): 1498 - 1502. [Abstract] [Full Text] [PDF]

				H. J. Eisen Surgical Ventricular Reconstruction for Heart Failure N. Engl. J. Med., April 23, 2009; 360(17): 1781 - 1784. [Full Text] [PDF]

				R. H. Jones, E. J. Velazquez, R. E. Michler, G. Sopko, J. K. Oh, C. M. O'Connor, J. A. Hill, L. Menicanti, Z. Sadowski, P. Desvigne-Nickens, et al. Coronary Bypass Surgery with or without Surgical Ventricular Reconstruction N. Engl. J. Med., April 23, 2009; 360(17): 1705 - 1717. [Abstract] [Full Text] [PDF]

				R. Nishio and A. Matsumori Gelsolin and Cardiac Myocyte Apoptosis: A New Target in the Treatment of Postinfarction Remodeling Circ. Res., April 10, 2009; 104(7): 829 - 831. [Full Text] [PDF]

				J. Zhang, L. Ding, Y. Zhao, W. Sun, B. Chen, H. Lin, X. Wang, L. Zhang, B. Xu, and J. Dai Collagen-Targeting Vascular Endothelial Growth Factor Improves Cardiac Performance After Myocardial Infarction Circulation, April 7, 2009; 119(13): 1776 - 1784. [Abstract] [Full Text] [PDF]

				S. M. Hollenberg Heart Failure and Cardiac Pulmonary Edema ACCP Crit Care Med Brd Rev, January 1, 2009; 20(0): 117 - 128. [Full Text] [PDF]

				C. M. Kramer Insights into Myocardial Microstructure During Infarct Healing and Remodeling: Pathologists Need Not Apply Circ Cardiovasc Imaging, January 1, 2009; 2(1): 4 - 5. [Full Text] [PDF]

				M.-T. Wu, M.-Y. M. Su, Y.-L. Huang, K.-R. Chiou, P. Yang, H.-B. Pan, T. G. Reese, V. J. Wedeen, and W.-Y. I. Tseng Sequential Changes of Myocardial Microstructure in Patients Postmyocardial Infarction by Diffusion-Tensor Cardiac MR: Correlation With Left Ventricular Structure and Function Circ Cardiovasc Imaging, January 1, 2009; 2(1): 32 - 40. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, D. E. Sosnovik, B. A. French, F. K. Swirski, F. Bengel, M. M. Sadeghi, J. R. Lindner, J. C. Wu, D. L. Kraitchman, Z. A. Fayad, et al. Multimodality Cardiovascular Molecular Imaging, Part II Circ Cardiovasc Imaging, January 1, 2009; 2(1): 56 - 70. [Full Text] [PDF]

				R. S. Velagaleti, M. J. Pencina, J. M. Murabito, T. J. Wang, N. I. Parikh, R. B. D'Agostino, D. Levy, W. B. Kannel, and R. S. Vasan Long-Term Trends in the Incidence of Heart Failure After Myocardial Infarction Circulation, November 11, 2008; 118(20): 2057 - 2062. [Abstract] [Full Text] [PDF]

				R. Mukherjee, J. A. Zavadzkas, S. M. Saunders, J. E. McLean, L. B. Jeffords, C. Beck, R. E. Stroud, A. M. Leone, C. N. Koval, W. T. Rivers, et al. Targeted Myocardial Microinjections of a Biocomposite Material Reduces Infarct Expansion in Pigs Ann. Thorac. Surg., October 1, 2008; 86(4): 1268 - 1276. [Abstract] [Full Text] [PDF]

				M. Saeed, A. Martin, P. Ursell, L. Do, M. Bucknor, C. B. Higgins, and D. Saloner MR Assessment of Myocardial Perfusion, Viability, and Function after Intramyocardial Transfer of VM202, a New Plasmid Human Hepatocyte Growth Factor in Ischemic Swine Myocardium Radiology, October 1, 2008; 249(1): 107 - 118. [Abstract] [Full Text] [PDF]

				D. Fraccarollo, J. D. Widder, P. Galuppo, T. Thum, D. Tsikas, M. Hoffmann, H. Ruetten, G. Ertl, and J. Bauersachs Improvement in Left Ventricular Remodeling by the Endothelial Nitric Oxide Synthase Enhancer AVE9488 After Experimental Myocardial Infarction Circulation, August 19, 2008; 118(8): 818 - 827. [Abstract] [Full Text] [PDF]

				Meta-Analysis Research Group in Echocardiography ( Independent Prognostic Importance of a Restrictive Left Ventricular Filling Pattern After Myocardial Infarction: An Individual Patient Meta-Analysis: Meta-Analysis Research Group in Echocardiography Acute Myocardial Infarction Circulation, May 20, 2008; 117(20): 2591 - 2598. [Abstract] [Full Text] [PDF]

				D. D. Schocken, E. J. Benjamin, G. C. Fonarow, H. M. Krumholz, D. Levy, G. A. Mensah, J. Narula, E. S. Shor, J. B. Young, and Y. Hong Prevention of Heart Failure: A Scientific Statement From the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group Circulation, May 13, 2008; 117(19): 2544 - 2565. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, D. Sosnovik, J. W. Chen, P. Panizzi, J.-L. Figueiredo, E. Aikawa, P. Libby, F. K. Swirski, and R. Weissleder Activatable Magnetic Resonance Imaging Agent Reports Myeloperoxidase Activity in Healing Infarcts and Noninvasively Detects the Antiinflammatory Effects of Atorvastatin on Ischemia-Reperfusion Injury Circulation, March 4, 2008; 117(9): 1153 - 1160. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, E. Aikawa, J.-L. Figueiredo, L. Stangenberg, S. W. van den Borne, W. M. Blankesteijn, D. E. Sosnovik, F. A. Jaffer, C.-H. Tung, and R. Weissleder Transglutaminase activity in acute infarcts predicts healing outcome and left ventricular remodelling: implications for FXIII therapy and antithrombin use in myocardial infarction Eur. Heart J., February 2, 2008; 29(4): 445 - 454. [Abstract] [Full Text] [PDF]

				J.-Y. Qian, P. Harding, Y. Liu, E. Shesely, X.-P. Yang, and M. C. LaPointe Reduced Cardiac Remodeling and Function in Cardiac-Specific EP4 Receptor Knockout Mice With Myocardial Infarction Hypertension, February 1, 2008; 51(2): 560 - 566. [Abstract] [Full Text] [PDF]

				T. Soeki, I. Kishimoto, D. O. Schwenke, T. Tokudome, T. Horio, M. Yoshida, H. Hosoda, and K. Kangawa Ghrelin suppresses cardiac sympathetic activity and prevents early left ventricular remodeling in rats with myocardial infarction Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H426 - H432. [Abstract] [Full Text] [PDF]

				M. Nahrendorf, F. K. Swirski, E. Aikawa, L. Stangenberg, T. Wurdinger, J.-L. Figueiredo, P. Libby, R. Weissleder, and M. J. Pittet The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions J. Exp. Med., November 26, 2007; 204(12): 3037 - 3047. [Abstract] [Full Text] [PDF]

				W. D. Gilson, F. H. Epstein, Z. Yang, Y. Xu, K.-M. R. Prasad, M.-C. Toufektsian, V. E. Laubach, and B. A. French Borderzone Contractile Dysfunction Is Transiently Attenuated and Left Ventricular Structural Remodeling Is Markedly Reduced Following Reperfused Myocardial Infarction in Inducible Nitric Oxide Synthase Knockout Mice J. Am. Coll. Cardiol., October 30, 2007; 50(18): 1799 - 1807. [Abstract] [Full Text] [PDF]

				S. Sirivella and I. Gielchinsky Results of Coronary Bypass and Valve Operations for Mitral Valve Regurgitation Asian Cardiovasc Thorac Ann, October 1, 2007; 15(5): 396 - 404. [Abstract] [Full Text] [PDF]

				F. G. Spinale Myocardial Matrix Remodeling and the Matrix Metalloproteinases: Influence on Cardiac Form and Function Physiol Rev, October 1, 2007; 87(4): 1285 - 1342. [Abstract] [Full Text] [PDF]

				J. E. Ip, Y. Wu, J. Huang, L. Zhang, R. E. Pratt, and V. J. Dzau Mesenchymal Stem Cells Use Integrin beta1 Not CXC Chemokine Receptor 4 for Myocardial Migration and Engraftment Mol. Biol. Cell, August 1, 2007; 18(8): 2873 - 2882. [Abstract] [Full Text] [PDF]

				E. I. Dedkov, W. Zheng, L. P. Christensen, R. M. Weiss, F. Mahlberg-Gaudin, and R. J. Tomanek Preservation of coronary reserve by ivabradine-induced reduction in heart rate in infarcted rats is associated with decrease in perivascular collagen Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H590 - H598. [Abstract] [Full Text] [PDF]

				Y. Wang, M. C. de Waard, A. Sterner-Kock, H. Stepan, H.-P. Schultheiss, D. J. Duncker, and T. Walther Cardiomyocyte-restricted over-expression of C-type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice Eur J Heart Fail, June 1, 2007; 9(6-7): 548 - 557. [Abstract] [Full Text] [PDF]

				R. Mukherjee, J. T. Mingoia, J. A. Bruce, J. S. Austin, R. E. Stroud, G. P. Escobar, D. M. McClister Jr, C. M. Allen, M. A. Alfonso-Jaume, M. E. Fini, et al. Selective spatiotemporal induction of matrix metalloproteinase-2 and matrix metalloproteinase-9 transcription after myocardial infarction Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2216 - H2228. [Abstract] [Full Text] [PDF]

				B. Assmus, J. Honold, V. Schachinger, M. B. Britten, U. Fischer-Rasokat, R. Lehmann, C. Teupe, K. Pistorius, H. Martin, N. D. Abolmaali, et al. Transcoronary transplantation of progenitor cells after myocardial infarction. N. Engl. J. Med., September 21, 2006; 355(12): 1222 - 1232. [Abstract] [Full Text] [PDF]

				M. Gheorghiade, G. Sopko, L. De Luca, E. J. Velazquez, J. D. Parker, P. F. Binkley, Z. Sadowski, K. S. Golba, D. L. Prior, J. L. Rouleau, et al. Navigating the Crossroads of Coronary Artery Disease and Heart Failure Circulation, September 12, 2006; 114(11): 1202 - 1213. [Full Text] [PDF]

				M.-T. Wu, W.-Y. I. Tseng, M.-Y. M. Su, C.-P. Liu, K.-R. Chiou, V. J. Wedeen, T. G. Reese, and C.-F. Yang Diffusion Tensor Magnetic Resonance Imaging Mapping the Fiber Architecture Remodeling in Human Myocardium After Infarction: Correlation With Viability and Wall Motion Circulation, September 5, 2006; 114(10): 1036 - 1045. [Abstract] [Full Text] [PDF]

				S. Sulfi and A. D Timmis Review: Heart failure complicating acute myocardial infarction in patients with diabetes: pathophysiology and management strategies The British Journal of Diabetes & Vascular Disease, September 1, 2006; 6(5): 191 - 196. [Abstract] [PDF]

				O. Tenhunen, Y. Soini, M. Ilves, J. Rysa, J. Tuukkanen, R. Serpi, H. Pennanen, H. Ruskoaho, and H. Leskinen p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms FASEB J, September 1, 2006; 20(11): 1907 - 1909. [Abstract] [Full Text] [PDF]

				E. Roig Usefulness of neurohormonal markers in the diagnosis and prognosis of heart failure Eur. Heart J. Suppl., September 1, 2006; 8(suppl_E): E12 - E17. [Abstract] [Full Text] [PDF]

				J.-S. Choi, K.-B. Kim, W. Han, D. S. Kim, J. S. Park, J. J. Lee, and D. S. Lee Efficacy of Therapeutic Angiogenesis by Intramyocardial Injection of pCK-VEGF165 in Pigs Ann. Thorac. Surg., August 1, 2006; 82(2): 679 - 686. [Abstract] [Full Text] [PDF]

				S. Sirivella and I. Gielchinsky Clinical outcomes of surgery of mitral valve regurgitation and coronary artery bypass grafting Interactive CardioVascular and Thoracic Surgery, August 1, 2006; 5(4): 392 - 397. [Abstract] [Full Text] [PDF]

				E. Donal, C. Leclercq, C. Linde, and J.-C. Daubert Effects of cardiac resynchronization therapy on disease progression in chronic heart failure Eur. Heart J., May 1, 2006; 27(9): 1018 - 1025. [Abstract] [Full Text] [PDF]

				E. Carluccio, P. Biagioli, G. Alunni, A. Murrone, C. Giombolini, T. Ragni, P. N. Marino, G. Reboldi, and G. Ambrosio Patients With Hibernating Myocardium Show Altered Left Ventricular Volumes and Shape, Which Revert After Revascularization: Evidence That Dyssynergy Might Directly Induce Cardiac Remodeling J. Am. Coll. Cardiol., March 7, 2006; 47(5): 969 - 977. [Abstract] [Full Text] [PDF]

				M. Maczewski, M. Borys, P. Kacprzak, T. Gdowski, and D. Wojciechowski Angiotensin II AT1 receptor density on blood platelets predicts early left ventricular remodelling in non-reperfused acute myocardial infarction in humans Eur J Heart Fail, March 1, 2006; 8(2): 173 - 178. [Abstract] [Full Text] [PDF]

				D. Vanhoutte, M. Schellings, Y. Pinto, and S. Heymans Relevance of matrix metalloproteinases and their inhibitors after myocardial infarction: A temporal and spatial window Cardiovasc Res, February 15, 2006; 69(3): 604 - 613. [Abstract] [Full Text] [PDF]

				M. Matsumoto-Ida, Y. Takimoto, T. Aoyama, M. Akao, T. Takeda, and T. Kita Activation of TGF-{beta}1-TAK1-p38 MAPK pathway in spared cardiomyocytes is involved in left ventricular remodeling after myocardial infarction in rats Am J Physiol Heart Circ Physiol, February 1, 2006; 290(2): H709 - H715. [Abstract] [Full Text] [PDF]

				T. M. Kolettis Arrhythmogenesis after cell transplantation post-myocardial infarction. Four burning questions-And some answers Cardiovasc Res, February 1, 2006; 69(2): 299 - 301. [Full Text] [PDF]

				Y Abe, T Muro, Y Sakanoue, R Komatsu, M Otsuka, T Naruko, A Itoh, M Yoshiyama, K Haze, and J Yoshikawa Intravenous myocardial contrast echocardiography predicts regional and global left ventricular remodelling after acute myocardial infarction: comparison with low dose dobutamine stress echocardiography Heart, December 1, 2005; 91(12): 1578 - 1583. [Abstract] [Full Text] [PDF]

				B. Pitt, H. White, J. Nicolau, F. Martinez, M. Gheorghiade, M. Aschermann, D. J. van Veldhuisen, F. Zannad, H. Krum, R. Mukherjee, et al. Eplerenone Reduces Mortality 30 Days After Randomization Following Acute Myocardial Infarction in Patients With Left Ventricular Systolic Dysfunction and Heart Failure J. Am. Coll. Cardiol., August 2, 2005; 46(3): 425 - 431. [Abstract] [Full Text] [PDF]

				P. C. Meckert, H. G. Rivello, C. Vigliano, P. Gonzalez, R. Favaloro, and R. Laguens Endomitosis and polyploidization of myocardial cells in the periphery of human acute myocardial infarction Cardiovasc Res, July 1, 2005; 67(1): 116 - 123. [Abstract] [Full Text] [PDF]

				M Kato, K Dote, S Sasaki, K Goto, H Takemoto, S Habara, and D Hasegawa Myocardial performance index for assessment of left ventricular outcome in successfully recanalised anterior myocardial infarction Heart, May 1, 2005; 91(5): 583 - 588. [Abstract] [Full Text] [PDF]

				A. Schafer, D. Fraccarollo, M. Eigenthaler, P. Tas, A. Firnschild, S. Frantz, G. Ertl, and J. Bauersachs Rosuvastatin Reduces Platelet Activation in Heart Failure: Role of NO Bioavailability Arterioscler Thromb Vasc Biol, May 1, 2005; 25(5): 1071 - 1077. [Abstract] [Full Text] [PDF]

				T. Soeki, I. Kishimoto, H. Okumura, T. Tokudome, T. Horio, K. Mori, and K. Kangawa C-type natriuretic peptide, a novel antifibrotic and antihypertrophic agent, prevents cardiac remodeling after myocardial infarction J. Am. Coll. Cardiol., February 15, 2005; 45(4): 608 - 616. [Abstract] [Full Text] [PDF]

				Y. Sugano, T. Anzai, T. Yoshikawa, Y. Maekawa, T. Kohno, K. Mahara, K. Naito, and S. Ogawa Granulocyte colony-stimulating factor attenuates early ventricular expansion after experimental myocardial infarction Cardiovasc Res, February 1, 2005; 65(2): 446 - 456. [Abstract] [Full Text] [PDF]

				N. M. Albert, C. A. Eastwood, and M. L. Edwards Evidence-Based Practice for Acute Decompensated Heart Failure Crit. Care Nurse, December 1, 2004; 24(6): 14 - 29. [Full Text] [PDF]

				Y Sato, T Kita, Y Takatsu, and T Kimura Biochemical markers of myocyte injury in heart failure Heart, October 1, 2004; 90(10): 1110 - 1113. [Abstract] [Full Text] [PDF]

				A D McGavigan, J Moncrieff, M M Lindsay, P R Maxwell, and F G Dunn Time course of plasma markers of collagen turnover in patients with acute myocardial infarction Heart, September 1, 2004; 90(9): 1053 - 1054. [Full Text] [PDF]

				R. Ramani, M. Mathier, P. Wang, G. Gibson, S. Togel, J. Dawson, A. Bauer, S. Alber, S. C. Watkins, C. F. McTiernan, et al. Inhibition of tumor necrosis factor receptor-1-mediated pathways has beneficial effects in a murine model of postischemic remodeling Am J Physiol Heart Circ Physiol, September 1, 2004; 287(3): H1369 - H1377. [Abstract] [Full Text] [PDF]

				L.G Melo, M Gnecchi, A.S Pachori, K Wang, and V.J Dzau Gene- and cell-based therapies for cardiovascular diseases: current status and future directions Eur. Heart J. Suppl., September 1, 2004; 6(suppl_E): E24 - E35. [Abstract] [Full Text]

				M. Cirillo, A. Amaducci, F. Brunelli, M. Dalla Tomba, P. Parrella, G. Tasca, G. Troise, and E. Quaini Determinants of postinfarction remodeling affect outcome and left ventricular geometry after surgical treatment of ischemic cardiomyopathy J. Thorac. Cardiovasc. Surg., June 1, 2004; 127(6): 1648 - 1656. [Abstract] [Full Text] [PDF]

				S. Janssens, P. Pokreisz, L. Schoonjans, M. Pellens, P. Vermeersch, M. Tjwa, P. Jans, M. Scherrer-Crosbie, M. H. Picard, Z. Szelid, et al. Cardiomyocyte-Specific Overexpression of Nitric Oxide Synthase 3 Improves Left Ventricular Performance and Reduces Compensatory Hypertrophy After Myocardial Infarction Circ. Res., May 14, 2004; 94(9): 1256 - 1262. [Abstract] [Full Text] [PDF]

				R. Mukherjee, A. M. Parkhurst, J. T. Mingoia, S. E. Sweterlitsch, J. S. Leiser, G. P. Escobar, F. G. Spinale, and J. P. Saul Myocardial remodeling after discrete radiofrequency injury: effects of tissue inhibitor of matrix metalloproteinase-1 gene deletion Am J Physiol Heart Circ Physiol, April 1, 2004; 286(4): H1242 - H1247. [Abstract] [Full Text] [PDF]

				F. Eefting, B. Rensing, J. Wigman, W. J. Pannekoek, W. M. Liu, M. J. Cramer, D. J Lips, and P. A Doevendans Role of apoptosis in reperfusion injury Cardiovasc Res, February 15, 2004; 61(3): 414 - 426. [Abstract] [Full Text] [PDF]

				G. A. Whalley, G. D. Gamble, H. J. Walsh, S. P. Wright, S. Agewall, N. Sharpe, and R. N. Doughty Effect of tissue harmonic imaging and contrast upon between observer and test-retest reproducibility of left ventricular ejection fraction measurement in patients with heart failure Eur J Heart Fail, January 1, 2004; 6(1): 85 - 93. [Abstract] [Full Text] [PDF]

				R. E. Chapman and F. G. Spinale Extracellular protease activation and unraveling of the myocardial interstitium: critical steps toward clinical applications Am J Physiol Heart Circ Physiol, January 1, 2004; 286(1): H1 - H10. [Full Text] [PDF]

				W. M. Yarbrough, R. Mukherjee, G. P. Escobar, J. T. Mingoia, J. A. Sample, J. W. Hendrick, K. B. Dowdy, J. E. McLean, A. S. Lowry, T. P. O'Neill, et al. Selective Targeting and Timing of Matrix Metalloproteinase Inhibition in Post-Myocardial Infarction Remodeling Circulation, October 7, 2003; 108(14): 1753 - 1759. [Abstract] [Full Text] [PDF]

				T. Tsuda, E. Gao, L. Evangelisti, D. Markova, X. Ma, and M.-L. Chu Post-ischemic myocardial fibrosis occurs independent of hemodynamic changes Cardiovasc Res, October 1, 2003; 59(4): 926 - 933. [Abstract] [Full Text] [PDF]

				K. Christopher, T. F. Mueller, R. DeFina, Y. Liang, J. Zhang, R. Gentleman, and D. L. Perkins The graft response to transplantation: a gene expression profile analysis Physiol Genomics, September 29, 2003; 15(1): 52 - 64. [Abstract] [Full Text] [PDF]

				T. J. Wang, D. Levy, E. J. Benjamin, and R. S. Vasan The Epidemiology of "Asymptomatic" Left Ventricular Systolic Dysfunction: Implications for Screening Ann Intern Med, June 3, 2003; 138(11): 907 - 916. [Abstract] [Full Text] [PDF]

				M. Jessup and S. Brozena Heart Failure N. Engl. J. Med., May 15, 2003; 348(20): 2007 - 2018. [Full Text] [PDF]

				P Garot, O Pascal, M Simon, J L Monin, E Teiger, J Garot, P Gueret, and J L Dubois-Rande Impact of microvascular integrity and local viability on left ventricular remodelling after reperfused acute myocardial infarction Heart, April 1, 2003; 89(4): 393 - 397. [Abstract] [Full Text] [PDF]

				W. M. Yarbrough, R. Mukherjee, T. A. Brinsa, K. B. Dowdy, A. A. Scott, G. P. Escobar, C. Joffs, D. G. Lucas, F. A. Crawford Jr, and F. G. Spinale Matrix metalloproteinase inhibition modifies left ventricular remodeling after myocardial infarction in pigs J. Thorac. Cardiovasc. Surg., March 1, 2003; 125(3): 602 - 610. [Abstract] [Full Text] [PDF]

				Y. Oishi, R. Ozono, Y. Yano, Y. Teranishi, M. Akishita, M. Horiuchi, T. Oshima, and M. Kambe Cardioprotective Role of AT2 Receptor in Postinfarction Left Ventricular Remodeling Hypertension, March 1, 2003; 41(3): 814 - 818. [Abstract] [Full Text] [PDF]

				R. Mukherjee, T. A. Brinsa, K. B. Dowdy, A. A. Scott, J. M. Baskin, A. M. Deschamps, A. S. Lowry, G. P. Escobar, D. G. Lucas, W. M. Yarbrough, et al. Myocardial Infarct Expansion and Matrix Metalloproteinase Inhibition Circulation, February 4, 2003; 107(4): 618 - 625. [Abstract] [Full Text] [PDF]

				F. Rademakers, F. Van de Werf, L. Mortelmans, G. Marchal, and J. Bogaert Evolution of regional performance after an acute anterior myocardial infarction in humans using magnetic resonance tagging J. Physiol., February 1, 2003; 546(3): 777 - 787. [Abstract] [Full Text] [PDF]

				H. El-Adawi, L. Deng, A. Tramontano, S. Smith, E. Mascareno, K. Ganguly, R. Castillo, and N. El-Sherif The functional role of the JAK-STAT pathway in post-infarction remodeling Cardiovasc Res, January 1, 2003; 57(1): 129 - 138. [Abstract] [Full Text] [PDF]

				E. O. Weinberg, M. Shimpo, G. W. De Keulenaer, C. MacGillivray, S.-i. Tominaga, S. D. Solomon, J.-L. Rouleau, and R. T. Lee Expression and Regulation of ST2, an Interleukin-1 Receptor Family Member, in Cardiomyocytes and Myocardial Infarction Circulation, December 3, 2002; 106(23): 2961 - 2966. [Abstract] [Full Text] [PDF]

				M. Saeed, N. Watzinger, G. A. Krombach, G. K. Lund, M. F. Wendland, M. Chujo, and C. B. Higgins Left Ventricular Remodeling after Infarction: Sequential MR Imaging with Oral Nicorandil Therapy in Rat Model Radiology, September 1, 2002; 224(3): 830 - 837. [Abstract] [Full Text] [PDF]

				A. Deten, H. C. Volz, W. Briest, and H.-G. Zimmer Cardiac cytokine expression is upregulated in the acute phase after myocardial infarction. Experimental studies in rats Cardiovasc Res, August 1, 2002; 55(2): 329 - 340. [Abstract] [Full Text] [PDF]

				N. Ohte, K. Kurokawa, A. Iida, H. Narita, S. Akita, K. Yajima, H. Miyabe, J. Hayano, and G. Kimura Myocardial Oxidative Metabolism in Remote Normal Regions in the Left Ventricles with Remodeling After Myocardial Infarction: Effect of {beta}-Adrenoceptor Blockers J. Nucl. Med., June 1, 2002; 43(6): 780 - 785. [Abstract] [Full Text] [PDF]

				J. McMurray and M. A. Pfeffer New Therapeutic Options in Congestive Heart Failure: Part I Circulation, April 30, 2002; 105(17): 2099 - 2106. [Full Text] [PDF]

				M. K. Pasque Mathematic modeling and cardiac surgery J. Thorac. Cardiovasc. Surg., April 1, 2002; 123(4): 617 - 620. [Full Text] [PDF]

				N. Watzinger, G. K. Lund, C. B. Higgins, M. Chujo, and M. Saeed Noninvasive assessment of the effects of nicorandil on left ventricular volumes and function in reperfused myocardial infarction Cardiovasc Res, April 1, 2002; 54(1): 77 - 84. [Abstract] [Full Text] [PDF]

				D. Fraccarollo, J. Bauersachs, M. Kellner, P. Galuppo, and G. Ertl Cardioprotection by long-term ETA receptor blockade and ACE inhibition in rats with congestive heart failure: mono- versus combination therapy Cardiovasc Res, April 1, 2002; 54(1): 85 - 94. [Abstract] [Full Text] [PDF]

This Article Extract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sutton, M. G. St. J. Articles by Sharpe, N. Search for Related Content PubMed PubMed Citation Articles by Sutton, M. G. St. J. Articles by Sharpe, N. Related Collections Structure Remodeling Cardiovascular Pharmacology Cell signalling/signal transduction Acute myocardial infarction