Heart failure is a chronic disease with high morbidity and mortality, which represents a growing challenge in medicine. A major risk factor for heart failure with reduced ejection fraction is a history of myocardial infarction. The expansion of a large infarct scar and subsequent regional ventricular dilatation can cause postinfarct remodelling, leading to significant enlargement of the left ventricular chamber. It has a negative prognostic value, because it precedes the clinical manifestations of heart failure. The characteristics of the infarcted myocardium predicting postinfarct remodelling can be studied with cardiac magnetic resonance and experimental imaging modalities such as diffusion tensor imaging can identify the changes in the architecture of myocardial fibers. This review discusses all the aspects related to postinfarct left ventricular remodelling: definition, pathogenesis, diagnosis, consequences, and available therapies, together with experimental interventions that show promising results against postinfarct remodelling and heart failure.
The number of persons surviving an acute coronary syndrome has increased in the last decade [
In the United States, it is estimated that about 860.000 persons survive a first or recurrent heart attack every year [
The American Heart Association and the American College of Cardiology jointly released a classification of chronic heart failure based on four stages, with disease severity increasing from the first to the fourth stage [
It is known that chronic
The knowledge of mechanical and molecular factors leading to ventricular remodelling could guide the development of new targeted therapies against heart failure.
Postinfarct ventricular remodelling develops in about 30% patients with a history of myocardial infarction [
Ventricular remodelling is a predictor of heart failure, and for this reason it assumes a negative prognostic value [
An arbitrary definition of ventricular remodelling, but widely adopted in follow-up studies [
Left ventricular remodelling is characterized by a progressive increase in both end-diastolic (LVEDV) and end-systolic volumes (LVESV). The increase in LVESV can precede the increase in LVEDV, as a consequence of an impaired systolic function that causes a reduction in stroke volume [
The imaging modalities used to noninvasively assess ventricular volumes and function are echocardiography, radionuclide ventriculography, and cardiac magnetic resonance (CMR) [
Ventricular volumes are best expressed as volume indices, which are obtained by dividing the volumes by the body surface area. Normal values for LVEDVI and LVESVI are
A reduction in left ventricular ejection fraction (LVEF) is often observed during postinfarct remodelling, predicting heart failure and increased mortality. Normal values of LVEF are
Ventricular remodelling accompanies different heart diseases, such as dilatative nonischemic cardiomyopathy and cardiac hypertrophy in chronic hypertension and implies a change in myocardial anatomical structure [
In infarcted myocardium, ventricular contraction is not symmetrical, because the necrotic segments have lost their contractility [
In a normal ventricle, the force generated by myocardial contraction is balanced (a and c). When there is an infarct scar (white), the infarcted segment is stretched by the force generated by the remote normal myocardium (b and d). As a result, the infarct scar expands and the infarcted wall becomes thinner, while the remote myocardium becomes hypertrophic to maintain a normal global cardiac function (d). Arrows indicate the vectors of forces generated by opposite left ventricular segments during systole.
It is likely that some segments might recover a normal or near normal contractility in the months after myocardial infarction [
To maintain a normal stoke volume with a reduced number of normally working myocardial segments, the healthy myocardium has to produce a greater pressure [
Diffusion CMR is capable of detecting the direction of H2O molecules diffusing in solution. Direction of myocardial fibers can thus be identified, because water mainly diffuses along the major axis of cardiomyocytes [
The ventricular wall is composed of three layers of fibers with different orientation that rotate from the subepicardial to the subendocardial layer by almost 180° [
The external layer is composed of left-handed helical fibers that constitute the anterior basal and the posterior apical portions of the left ventricle and encircle the ventricular chamber with an orientation between −90° and −30°, having its long axis as 0° [
After a myocardial infarction, diffusion CMR tractography evidences the disappearance of subendocardial fibers and a hypertrophy of the subepicardial layer in the infarcted segments [
In postinfarct ventricular remodelling, hypertrophic cardiomyocytes are longer than normal cardiac cells. In an animal model, postinfarct ventricular remodelling was characterized by a lengthening of cardiomyocytes especially in the area surrounding the infarct scar, but also in remote myocardium [
Cardiomyocytes modify their transcriptional activity during remodelling, reactivating the expression of fetal genes that are normally silenced during adult life [
HDAC inhibitors (HDACi) are a class of anticancer drugs designed to modulate gene expression in cancer cells [
As heart has poor, if not absent, regenerative capacity, cardiac hypertrophy that occurs during postinfarct remodelling is accompanied by an increase in extracellular matrix, which is mainly constituted by collagen [
It is probable that the increase in wall stress in the infarcted heart that becomes dilated during remodelling [
Remodelling is a pathologic process that involves the entire ventricle, leading to a change in its global structure [
Chronic volume overload and increased adrenergic tone promote metalloproteinases activity [
Cardiomyocytes become hypertrophic in response to integrin-mediated mechanotransduction [
Molecular pathways of ventricular remodelling. Many mediators have either an adaptive role (in bold) at low doses or a maladaptive role, with chronic/intense stimulation.
Molecular pathways activated by interaction with receptor | Effects on cardiomyocytes | |
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Angiotensin II [ |
JNK |
Apoptosis |
ROS [ |
Cell damage |
Apoptosis |
TNF- |
NF- |
Apoptosis |
Growth factors (IGF-1, PDGF, GDF-15, HGF, and NRG-1) [ |
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Cell survival and growth |
Cardiotrophin-1 [ |
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Cell survival and growth |
Cytosolic calcium [ |
Calpains (calcium-activated proteases) |
Apoptosis |
Catecholamines [ |
PKA |
Apoptosis |
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Integrins [ |
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Cell survival and growth |
JNK: Jun N-terminal kinase; ERK: extracellular-regulated kinase; JAK/STAT: Janus kinase/signal transducers and activators of transcription; ROS: reactive oxygen species; TNF-
Ventricular remodelling usually develops in patients with a history of ST segment elevation myocardial infarction (STEMI), which produces an infarct scar with a transmural extent [
During an acute myocardial infarction, plasma levels of cardiac troponins and creatine kinase-MB positively correlate with infarct size determined by CMR, and very high levels predict an increase in ventricular volumes and a reduction in LVEF [
It is believed that heart failure develops when at least 25% of the left ventricular myocardial mass is lost [
Other predictors of ventricular remodelling are the irreversible forms of ischemia-reperfusion injury of the cardiac microvasculature, which are microvascular obstruction (MVO) and intramyocardial hemorrhage (IMH) [
MVO is identified as a hypointense area within the infarcted myocardium on CMR images of early and late gadolinium enhancement (Figure
Microvascular obstruction (arrow) as shown by early gadolinium enhancement in a patient with acute myocardial infarction (CMR study).
IMH is associated with a large infarct size and a large area of MVO [
MVO and IMH are also independent predictors of major adverse cardiac events (MACE), including cardiac death, stroke, myocardial infarction, and hospitalization for heart failure: hazard ratio (HR) for MVO is 2.79 (95% CI: 1.25–6.25,
After a myocardial infarction, the most frequent of the posterior basal segments, a dysfunction of a papillary muscle can occur, leading to a mitral regurgitation [
The presence of an aortic stenosis or hypertension may worsen postinfarct left ventricular remodelling [
Cardiac magnetic resonance, which is the preferred imaging modality for the assessment of ventricular volumes and function, has been used to validate several putative biomarkers of ventricular remodelling. However, the clinical role of these biomarkers in predicting postinfarct remodelling needs further investigation.
A positive correlation has been found between ventricular remodelling and plasma levels of some enzymes that contribute to extracellular matrix remodelling, such as matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitors of metalloproteinases (TIMPs) [
Other plasma proteins whose levels positively correlate with ventricular remodelling are tissue plasminogen activator (t-PA) [
The atrial natriuretic peptide (ANP), the brain natriuretic peptide (BNP), and the N-terminal fragment of its precursor (NT-proBNP) are produced by cardiomyocytes, and their blood levels increase with increasing myocardial wall stretch. In addition to their well known prognostic value in patients with heart failure, high levels of natriuretic peptides or NT-proBNP after myocardial infarction predict an increase in ventricular volumes, which is postinfarct remodelling [
Parameters that define left ventricular remodelling are consolidated surrogate end points [
When a patient develops postinfarct left ventricular remodelling, he is at increased risk of heart failure or sudden death due to a lethal arrhythmia [
Eccentric hypertrophy, as that observed during post-infarct ventricular remodelling, is associated with a threefold increase in the risk of major adverse cardiac events, including death from cardiovascular causes, reinfarction, heart failure, stroke, and cardiac arrest (HR: 3.1; 95% CI: 1.9–4.8,
Infarct scar expansion during postinfarct remodelling sometimes causes a great regional dilatation of ventricular chamber, which is a ventricular aneurysm (Figure
The expansion of a wide anterior and transmural infarct scar often leads to the formation of an apical left ventricular aneurysm that predisposes to left ventricular thrombosis. In this case, postinfarct remodelling is characterized by a great apical dilatation of the left ventricular chamber, together with a thinning of the infarcted segments (arrow).
The slow blood flow in the cavity of the ventricular aneurysm can lead to the formation of an intracardiac thrombus. Among 100 patients with an anterior ST segment elevation myocardial infarction and LVEF <40%, 27 patients had a left ventricular thrombus, as assessed by contrast-enhanced CMR [
There are clinical evidences that postinfarct remodelling can be prevented or, in some cases, reversed [
Therapies capable of inducing reverse remodelling.
Mechanism of action | Notes | |
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ACE inhibitors/ARBs [ |
RAAS antagonism | |
Antialdosterone diuretics [ |
RAAS antagonism | |
Reduce cardiotoxic effects of chronic |
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NO donors plus hydralazine [ |
Increase cGMP and reduce preload | |
MMPs inhibitors [ |
Inhibit ECM remodelling | Experimental. No evidences in humans |
rNRG-1 [ |
Promotes cardiomyocyte survival pathways | Experimental |
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CRT [ |
Increases GSK-3 |
Eligibility: patients with symptomatic HF and LBBB |
LVAD [ |
Reduces LV workload | Eligibility: patients with severe HF as bridge to recovery or bridge to heart transplant |
Mitral valve surgery [ |
Reduces LV workload | Eligibility: patients with severe mitral regurgitation |
Diastolic cardiac restraint devices [ |
Reduce myocardial wall tension | Experimental |
ACE: angiotensin-converting enzyme; ARBs: angiotensin receptor blockers; RAAS: renin-angiotensin-aldosterone system; NO nitric oxide; cGMP: cyclic guanosine monophosphate; MMPs: matrix metalloproteinases; ECM: extracellular matrix; rNRG-1: recombinant human neuregulin-1; CRT: cardiac resynchronization therapy; GSK-3
Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) have consolidated efficacy as antiremodelling drugs [
The recent PARADIGM-HF multicenter randomized controlled trial [
Together with ACEi, ARBs and antialdosterone diuretics,
Adrenergic stimulation allows for the maintenance of an adequate global cardiac function after acute myocardial infarction, by increasing the contractility of viable myocardium. However, chronic
Nitric oxide (NO) donors such as nitrates have well known beneficial effects in patients with heart failure [
As the major risk factor for postinfarct remodelling is infarct size [
Other promising approaches are stem cells and gene therapy, which have shown interesting results in pilot trials on adjunctive therapy of myocardial infarction and heart failure, and that might reverse postinfarct remodelling [
Therapies with proven efficacy against postinfarct remodelling exist, and research is bringing new discoveries in the pathogenesis of postinfarct remodelling into the field of clinical practice and therapy. Heart failure is one of the most important causes of morbidity and mortality worldwide, and patients with postinfarct remodelling show the highest risk of symptomatic heart failure. For this reason, the battle of medicine against heart failure is against postinfarct remodelling, which means that the prevention is better than the cure.
The authors declare that there is no conflict of interests regarding the publication of this paper.
The authors thank Dr. Edgardo Bonacina, Director of the Anatomic Pathology Unit of Niguarda Ca’ Granda Hospital, for permission on Figure