Left Ventricular Remodeling After Myocardial Infarction—Pathophysiology, Diagnostic Approach and Management During Cardiac Rehabilitation

Abstract

Despite the improvement in prognosis in patients with acute myocardial infarction (AMI), a significant proportion of survivors still experience heart failure (HF)-related adverse outcomes. Adverse left ventricular remodeling (LVR), which refers to a progressive dilation of left ventricular (LV) end-diastolic and end-systolic volumes, usually accompanied by a deterioration in LV systolic function, occurs frequently and underlies most cases of HF development after AMI. In this review, we discuss the current definitions of post-AMI LVR, the most appropriate imaging modalities for its detection, and the pathophysiological mechanisms by which Cardiac Rehabilitation (CR) can improve LVR—including exercise interventions, cardiovascular risk factors control, and pharmacological therapy optimization. Finally, we provide up-to-date recommendations for the follow-up and management of LVR in post-AMI patients enrolled in CR and outline future prospects on this topic.

1. Contemporary Management of Acute Myocardial Infarction

Cardiovascular (CV) disease is the leading cause of mortality worldwide [1]. The World Health Organization estimates that nearly 20 million people died from CV disease in 2022, representing around one-third of all global deaths [2]. Among the entire spectrum of CV disease, ischemic heart disease accounts for most deaths and contributes substantially to morbidity. Acute myocardial infarction (AMI) represents one of its most severe manifestations, and substantial efforts have been made to improve its diagnosis, treatment and follow-up [2].

In recent decades, the prognosis of AMI patients has steadily improved [3]. Several factors have contributed to improved survival in the acute phase, such as the implementation of cardiopulmonary resuscitation, external defibrillation, coronary care units, and, more recently, thrombolysis and primary percutaneous coronary intervention (pPCI) [3]. Coronary angiography and revascularization are now standard procedures, tailored to clinical presentation and patient characteristics [4]. Patients meeting electrocardiographic or clinical criteria for ST-segment elevation or occlusion myocardial infarction (STEMI/OMI) require emergent coronary angiography (“AMI code”) [4].

The widespread adoption of pPCI in STEMI/OMI significantly improved short-term survival and reduced infarct size, leading to better long-term prognosis [3]. Pharmacological advances have also transformed care, establishing a comprehensive multidrug regimen as the current standard [5,6]. Post-AMI therapy should include antiplatelet agents to further prevent coronary thrombus formation; lipid-lowering therapy, including statins, to minimize or reverse atherosclerotic plaque progression; beta-blockers and renin–angiotensin–aldosterone system (RAAS) inhibitors to improve prognosis; and additional agents according to patient needs or the structural and functional consequences of AMI.

Given the importance of long-term CV risk factors control, current clinical practice guidelines emphasize the achievement of secondary prevention targets [7,8]. In this regard, Cardiac Rehabilitation (CR) is recommended as the most effective strategy to optimize risk factors control, improve quality of life, and enhance long-term prognosis [7,8]. Contrary to early 20th century recommendations of prolonged bed rest after AMI, one of the core components of CR is exercise training [9]. Beyond exercise, CR provides the ideal framework for pharmacological therapy optimization and dose titration, aimed at optimal secondary prevention achievement and prognostic improvement in patients with systolic dysfunction and/or heart failure (HF).

Improved acute-phase survival has, paradoxically, increased the prevalence of HF, which now represents a major contributor to adverse post-AMI outcomes [10,11]. Reduced left ventricular ejection fraction (LVEF) and adverse left ventricular remodeling (LVR) in the chronic phase are significant predictors of HF-related adverse events [12,13,14]. Identifying and treating patients with or at risk of LVR is therefore crucial to improving prognosis.

In this review, we discuss the contemporary diagnosis of LVR after AMI; the best imaging modalities and follow-up strategies in patients at risk of post-AMI LVR; and the pathophysiology and role of CR in modulating post-AMI LVR, from pharmacological, exercise-based, and CV risk factors perspectives. Our aim is to provide an up-to-date overview of the diagnosis and follow-up of LVR, while also addressing the implications of CR throughout this diagnostic and therapeutic process.

2. Search Strategy

For this narrative review, a comprehensive literature search was performed in PubMed/MEDLINE, Scopus, Google Scholar, and Web of Science databases for studies published up to October 2025. The following keywords and combinations were used: “myocardial infarction”, “ventricular remodeling”, “cardiac rehabilitation”, “exercise training”, “risk factor control”, and “pharmacological therapy”. Articles were limited to those published in English. We included original research articles, meta-analyses, and narrative or systematic reviews focusing on the definition, mechanisms, imaging assessment, and management of post-AMI LVR, as well as the role of CR interventions. Reference lists of relevant articles were also screened to identify additional publications. Given the narrative design of this review, no formal quality assessment or meta-analytic synthesis was performed.

3. Pathophysiology of Post-AMI Left Ventricular Remodeling

Cardiac remodeling is a dynamic and complex process that arises after cardiac injury, usually due to obstruction of the epicardial coronary arteries, and involves structural and functional changes, particularly at the ventricular level [15,16] (Figure 1). As previously mentioned, these modifications are known to influence the patient’s clinical course, significantly increasing the risk of subsequent HF [17,18,19].

Acute coronary occlusion interrupts oxygen supply to the affected myocardium, leading to anaerobic metabolism, cell membrane destabilization, and cell death by apoptosis, autophagy, or necrosis [20]. Cell death begins in the subendocardial layers and progresses toward the subepicardial layers if the coronary blockage continues. Endothelial disruption also contributes to vascular permeability and tissue injury [21,22,23].

Massive cell death triggers an inflammatory response and cytokine release, which recruit leukocytes to the injured area. Metabolic and epigenetic mechanisms further regulate cell growth and apoptosis [24,25,26]. Certain cell lineages, such as macrophages, phagocytize dead cells and extracellular matrix debris as an initial step towards tissue repair, although excessive inflammation can lead to further expansion of the infarcted area [16,27,28,29,30].

In a later stage, fibroblasts generate a collagen matrix that forms fibrotic scar tissue [31,32]. Unlike some species capable of myocardial regeneration [33], mammals respond to AMI mainly by scar formation. Scar formation is generally regarded as positive since it prevents cardiac rupture and death, although excessive scarring increases wall stiffness, and the optimal balance required to achieve good mechanical and electrical scar properties is not yet defined [34,35]. Angiogenesis is another key response after AMI that contributes to tissue repair and has been targeted in cardiac regeneration studies [36,37].

At the same time, other biochemical processes are activated, such as the RAAS system, which stimulates proteolytic enzymes [25]. These biochemical cascades, together with mechanical mechanisms such as wall stress—with increased preload and afterload—progressively lead to wall thinning and ventricular dilatation and remodeling, thereby increasing the risk of developing HF.

3.1. Stages of Post-AMI LVR

LVR includes two phases: an early phase, occurring within the first days after AMI, and a late phase, mainly starting around one month later [38,39]. In the early phase, the infarcted zone stretches and thins due to the lack of contractile function, leading to an expansion of the infarcted area into neighboring regions. During this period, processes such as myocyte hypertrophy, apoptosis, and modifications to the extracellular matrix are also observed [38,40]. In the late phase, or chronic remodeling, the myocardium not directly affected by necrosis undergoes hypertrophy and dilation as an adaptive mechanism to increased wall stress. This response is highly variable and potentially reversible [40,41,42].

3.2. Factors Involved in the Pathophysiology of Post-AMI LVR

3.2.1. Mechanical Alterations

Laplace’s law states ventricular wall tension is directly proportional to the pressure and ventricular radius, and inversely proportional to twice the wall thickness [18]. During early remodeling, stretching of the infarcted segment raises wall tension and promotes thinning. Additionally, the increase in left ventricular (LV) volume leads to volume and pressure overload in the non-infarcted areas. Initially compensated by the Frank–Starling mechanism, excessive dilation eventually leads to a self-perpetuating cycle of tension and expansion [38,42,43,44,45].

3.2.2. Neurohormonal Activation

The sympathetic nervous system and the RAAS system induce vasoconstriction, fluid retention, hypertrophy, and fibrosis, perpetuating remodeling and worsening prognosis [46,47]. Endothelin is a vasoconstrictive peptide that promotes inflammation through different signaling pathways, contributing to adverse remodeling. It also stimulates cardiomyocyte hypertrophy [48,49]. Natriuretic peptides exert a protective effect through natriuresis, vasodilation, and inhibition of the RAAS and sympathetic nervous system [49]. In addition, they may regulate hypertrophy and have a well-known prognostic role in HF [50]. Indeed, reducing the harmful effects of neurohormonal activation is one of the main goals of current pharmacological therapy for HF [51,52].

3.2.3. Extracellular Matrix Degradation and Fibrosis

After AMI, matrix metalloproteinases (MMPs) initially degrade the extracellular matrix, followed by collagen deposition from myofibroblasts [16,27,28,29,30]. Fibrosis can be reversible (interstitial) or irreversible (replacement), and its excess may compromise oxygen exchange [53]. Extensive scarring is detrimental, but several additional factors such as scar transmurality, collagen bundle orientation, and wall mechanical properties can also impact LVR beyond the extent of scarring [34,54].

3.2.4. Inflammation

AMI-induced cell death releases intracellular components that activate the immune system, triggering a significant inflammatory response. This initial response is beneficial and necessary for myocardial repair [25]. However, a chronic proinflammatory state can drive maladaptive remodeling. Several cytokines, such as interleukin-1β, interleukin-6, and tumor necrosis factor (TNF)-α, amplify tissue damage, thereby promoting adverse LVR [18,55].

3.2.5. Reperfusion Injury

Emergent coronary reperfusion is essential to reduce infarct size and improve long-term prognosis and LV systolic function. However, in some cases coronary reperfusion can worsen acute myocardial damage in a phenomenon known as ischemia–reperfusion injury [56]. One of the mechanisms involved is the production of reactive oxygen species (ROS) which, in addition to enhancing inflammation, can directly damage cell membrane lipids and deoxyribonucleic acid, leading to cell death [57,58].

3.2.6. Comorbidities

Post-infarction cardiac remodeling is aggravated by various comorbidities and contributing factors. Chronic kidney disease can promote adverse LVR through increased hemodynamic load, dysregulation of the RAAS system, uremic toxins, anemia, and pro-inflammatory states [59,60]. Hypercholesterolemia, hypertension, type 2 diabetes, obesity, and smoking can also impact post-AMI LVR. Please refer to Section 5 for further information.

4. Definition and Diagnosis of Post-AMI Left Ventricular Remodeling

4.1. Definition of Post-AMI LVR

Although post-AMI LVR is generally defined as a change in LV volumes over time, there is still no universally accepted definition [61]. The lack of clear and consistent criteria makes it difficult to precisely establish what is meant by LVR, when and how follow-up should be performed, which factors are associated with it, how often it occurs, and what its prognostic value is in patients with AMI. The absence of consensus has contributed to marked variability in study results and the abundance of research with diverse designs and definitions (Figure 2, Table 1).

Different cardiac imaging methods can be used for the diagnosis of LVR: echocardiography, cardiac magnetic resonance (CMR), and nuclear techniques. Echocardiography is widely available and serves as the first-line method, but it has limitations in spatial resolution and reproducibility [18]. CMR imaging, while less accessible and more complex, provides more accurate and reproducible measurements and is considered the gold standard for assessing LV volumes and systolic function [62,63]. For this reason, in recent years CMR has become the reference technique for quantifying LVR [64,65].

Studies published to date use different parameters and thresholds to define LVR [17,61,66,67,68,69]. The most common are the percentage changes in left ventricular end-diastolic volume (LVEDV) and left ventricular end-systolic volume (LVESV). However, the thresholds initially used were derived from echocardiographic studies conducted mostly before the era of pPCI and were not initially strongly linked to major clinical events [70,71]. Furthermore, the optimal timing for post-infarction imaging follow-up to assess LVR is still debated. Studies using serial CMR have shown that volumes can remain relatively stable during the first month after STEMI, with a significant increase in volumes occurring between the first and third month [72]. Published studies are highly heterogeneous in this regard. Some analyze the first 3–4 months after infarction, others focus on around 6 months, while some include longer follow-up periods [61].

Table 1. Echocardiographic and CMR definitions of post-AMI LVR.

Study	Year	n	Imaging Modality	LVR Criteria			Follow-Up Timing	Endpoint
				∆LVEDV	∆LVESV	∆LVEF
Bolognese et al. [17]	2002	284	TTE	>20%	-	-	6 months	Cardiac death and aHF
Mannaerts et al. [73]	2004	33	TTE	>20%	-	-	6 or 12 months	Prediction of LVR
van der Bijl et al. [67]	2020	1995	TTE	>20%	-	-	3, 6, or 12 months	aHF
Silveira et al. [74]	2021	50	TTE	≥15%	(and/or) ≥15%	-	6 months	Prediction of LVR
Logeart et al. [75]	2024	410	TTE	>20%	-	-	6 months	All-cause death or aHF
Bulluck et al. [76]	2017	40	CMR	≥12%	(and) ≥12%	-	5 months	Prediction of LVEF < 50%
Rodriguez-Palomares et al. [77]	2019	374	CMR	>15%	-	(and) ↓ > 3%	6 months	CV death, aHF or VA
Alonso Tello et al. [78]	2025	1067	CMR	>15%	-	(and) ↓ > 3%	6 months	CV death, aHF or VA
Reindl et al. [15]	2019	224	CMR	≥10%	-	-	4 months	All-cause death, AMI, stroke, or HF
Bulluck et al. [79]	2020	285	CMR	≥12%	(and) ≥12%	-	6 months	All-cause death or aHF
Shetelig et al. [80]	2018	240	CMR	≥10 mL/m2	-	-	4 months	Association with interleukin-8 levels
Garg et al. [81]	2017	50	CMR	-	>15%	-	3 months	Worsening of systolic function
Shetye et al. [82]	2017	65	CMR	≥20%	(and/or) ≥15%	-	4 months	Prediction of LVR
Sugano et al. [83]	2017	71	CMR	>5%	-	-	6 months	Prediction of LVR
Fabregat-Andrés et al. [84]	2015	31	CMR	>10%	-	-	6 months	Association with PGC-1α levels
Huttin et al. [85]	2017	121	CMR	>17.3 mL	-	(or) ↓ > 8.3%	6 months	Association with vascular function
Eitel et al. [86]	2011	154	CMR	-	Any ↑	Any ↓	6 months	Usefulness of intracoronary abciximab application

“↓” indicates reduction. Abbreviations: aHF = admission for heart failure. AMI = acute myocardial infarction. CMR = cardiac magnetic resonance. CV = cardiovascular. HF = heart failure. LVEDV = left ventricular end-diastolic volume. LVEF = left ventricular ejection fraction. LVESV = left ventricular end systolic volume. LVR = left ventricular remodeling. PGC-1α = peroxisome proliferator-activated receptor-gamma coactivator-1alpha VA = ventricular arrythmia.

Table 1. Echocardiographic and CMR definitions of post-AMI LVR.

Study	Year	n	Imaging Modality	LVR Criteria			Follow-Up Timing	Endpoint
				∆LVEDV	∆LVESV	∆LVEF
Bolognese et al. [17]	2002	284	TTE	>20%	-	-	6 months	Cardiac death and aHF
Mannaerts et al. [73]	2004	33	TTE	>20%	-	-	6 or 12 months	Prediction of LVR
van der Bijl et al. [67]	2020	1995	TTE	>20%	-	-	3, 6, or 12 months	aHF
Silveira et al. [74]	2021	50	TTE	≥15%	(and/or) ≥15%	-	6 months	Prediction of LVR
Logeart et al. [75]	2024	410	TTE	>20%	-	-	6 months	All-cause death or aHF
Bulluck et al. [76]	2017	40	CMR	≥12%	(and) ≥12%	-	5 months	Prediction of LVEF < 50%
Rodriguez-Palomares et al. [77]	2019	374	CMR	>15%	-	(and) ↓ > 3%	6 months	CV death, aHF or VA
Alonso Tello et al. [78]	2025	1067	CMR	>15%	-	(and) ↓ > 3%	6 months	CV death, aHF or VA
Reindl et al. [15]	2019	224	CMR	≥10%	-	-	4 months	All-cause death, AMI, stroke, or HF
Bulluck et al. [79]	2020	285	CMR	≥12%	(and) ≥12%	-	6 months	All-cause death or aHF
Shetelig et al. [80]	2018	240	CMR	≥10 mL/m2	-	-	4 months	Association with interleukin-8 levels
Garg et al. [81]	2017	50	CMR	-	>15%	-	3 months	Worsening of systolic function
Shetye et al. [82]	2017	65	CMR	≥20%	(and/or) ≥15%	-	4 months	Prediction of LVR
Sugano et al. [83]	2017	71	CMR	>5%	-	-	6 months	Prediction of LVR
Fabregat-Andrés et al. [84]	2015	31	CMR	>10%	-	-	6 months	Association with PGC-1α levels
Huttin et al. [85]	2017	121	CMR	>17.3 mL	-	(or) ↓ > 8.3%	6 months	Association with vascular function
Eitel et al. [86]	2011	154	CMR	-	Any ↑	Any ↓	6 months	Usefulness of intracoronary abciximab application

“↓” indicates reduction. Abbreviations: aHF = admission for heart failure. AMI = acute myocardial infarction. CMR = cardiac magnetic resonance. CV = cardiovascular. HF = heart failure. LVEDV = left ventricular end-diastolic volume. LVEF = left ventricular ejection fraction. LVESV = left ventricular end systolic volume. LVR = left ventricular remodeling. PGC-1α = peroxisome proliferator-activated receptor-gamma coactivator-1alpha VA = ventricular arrythmia.

Due to the variability of diagnostic tests and the lack of well-established criteria, multiple quantitative cut-off points have been proposed to define LVR, in some cases arbitrarily [61]. The most widely accepted definition is a >20% increase in LVEDV, which was first described by ventriculography in 1986 [17,66] and has been associated with adverse clinical outcomes [67].

4.2. Diagnosis of Post-AMI LVR

After the initial definition of LVR by ventriculography [66], subsequent studies primarily used echocardiography (Table 1). Bolognese et al. also used a > 20% increase in LVEDV as the cut-off, since it clearly exceeds intra-observer measurement variability as determined by the upper limit of the 95% confidence interval of the change (%Δ) in LVEDV [17]. Later studies linked this definition of LVR to an increased risk of hospitalization for HF [67]. In any case, other echocardiographic studies have used different cut-off points [74], highlighting the lack of uniformity and standardization in the research.

Regarding CMR-based studies (Table 1), several collaborative efforts have sought to unify criteria, taking advantage of CMR’s higher reproducibility and reliability. Bulluck et al. assessed LVR using lower thresholds, suggesting a 12% increase for both LVEDV and LVESV. These results were intended to predict a long-term LVEF < 50% but were not correlated with clinical events, and the sample size was small (n = 40) [76]. In a subsequent prospective study of 285 patients, the same authors confirmed that a ≥12% increase in both LVEDV and LVESV was associated with worse clinical outcomes, especially in the group with a concomitant ≥12% increase in both LVEDV and LVESV [79]. Reindl et al. studied 224 patients to determine the optimal cut-off value for predicting major events and proposed a 10% increase in LVEDV as the threshold [15]. Rodriguez-Palomares et al. suggested a 15% relative increase in LVEDV and a concomitant 3% relative decrease in LVEF as the cut-offs that best predicted clinical events such as CV mortality, admission for HF, or ventricular arrhythmia, in a sample of 374 patients with STEMI. These studies suggest that CMR, due to its higher spatial resolution and reproducibility, can predict an adverse prognosis even when smaller changes occur in LV volumes and LVEF.

In contrast to adverse LVR, many patients experience reverse LVR, characterized by decreased LV volumes and improved LVEF in the months following AMI. Definitions of reverse LVR also vary considerably regarding the metrics and thresholds used, although it is well established that it confers a more favorable prognosis [87,88,89].

As part of the diagnostic work-up, all AMI patients should undergo baseline imaging during the index admission (≤7 days post-AMI and before hospital discharge), preferably by echocardiography, or by CMR in complex or inconclusive cases [7,8]. Follow-up imaging during the chronic phase (3–6 months post-AMI) is recommended for patients at higher risk of LVR and/or with reduced LVEF. An increase of >20% in LVEDV is a reasonable echocardiographic threshold for defining LVR, whereas an increase of >10–15% in CMR-derived LVEDV may suffice to identify LVR, particularly when accompanied by a concomitant rise in LVESV and/or a reduction in LVEF.

4.3. Sex-Related Differences and Specific Populations

Women have a higher risk of mortality and HF after AMI [78,90,91,92,93]. However, evidence on sex-related differences in post-AMI LVR remains inconclusive. Some authors have reported a higher occurrence in women, while other studies have reported it in men, with some considering the remodeling process in women to be more favorable [17,94,95]. Nevertheless, recent studies report no significant differences between sexes after adjusting for confounding factors [71,78,96]. This likely indicates that sex differences in LVR and post-AMI prognosis are more attributable to variations in baseline characteristics than to intrinsic biological differences. For instance, women presenting with AMI are generally older and disproportionately affected by both traditional and non-traditional CV risk factors [97].

In elderly STEMI patients, the risk of major cardiac events and HF readmissions is markedly higher—even when LVEF reduction is modest [11,98]. Multiple causes of this worse prognosis have been described in this patient subgroup, but there is no solid evidence that this is due to a higher prevalence of adverse LVR [99]. Some studies even suggest that younger patients are more prone to adverse LVR [100]. Therefore, the mechanisms underlying the worse prognosis in elderly patients likely extend beyond structural and volumetric changes alone.

5. Cardiac Rehabilitation and Left Ventricular Remodeling

5.1. Cardiac Rehabilitation After AMI

Irrespective of LVEF and the risk of LVR, exercise-based CR is systematically recommended after AMI [7,8]. CR reduces total mortality [101], decreases the number of hospitalizations and the risk of subsequent AMI, lowers sociosanitary costs, and improves quality of life, even in contemporary cohorts [102,103].

CR is a multicomponent, multidisciplinary program that encompasses a number of interventions [104]. Perhaps the most visible part of CR is exercise training, which has traditionally been in a hospital-centered basis. However, the current trend favors individualized approaches, including ambulatory, home-based, and telerehabilitation programs for low-risk patients [105,106,107,108]. Nevertheless, CR must integrate several other interventions beyond exercise training.

AMI patients included in CR should achieve optimal CV risk factors control, facilitated by both lifestyle modification and pharmacological therapy optimization [109,110,111]. Lipid control, management of hypertension, metabolic and weight management in diabetic or overweight patients, and smoking cessation are considered core components of CR [112]. Mental health evaluation and therapy for affected individuals should be provided [113], as well as psychosocial support services [114].

Specifically in patients with mildly reduced or reduced LVEF and/or symptomatic HF after AMI, CR provides the ideal framework for initiating, up-titrating, or even de-escalating pharmacological therapy [115,116,117]. Diuretics, beta-blockers, RAAS inhibitors, sodium-glucose cotransporter-2 inhibitors (SGLT2-i), and other drugs can ameliorate symptoms, improve prognosis, and modulate LVR in patients with systolic dysfunction after AMI.

Thus, exercise training, CV risk factors control, and pharmacological optimization emerge as significant factors that could modulate LVR after AMI through CR (Figure 3).

5.2. Exercise Training and LVR

Many decades ago, exercise training was believed to be unsafe for AMI survivors, as it was thought to trigger ventricular tachyarrhythmias and promote LV dilation [118]. However, subsequent evidence has confirmed its safety, showing that exercise does not induce adverse LVR [119,120], and can even improve LVR in the long term [121]. Current recommendations encourage AMI survivors to engage in regular physical activity, particularly moderate-to-vigorous aerobic and resistance exercise [8,122,123].

As one of the core components of CR, exercise training should begin after appropriate evaluation. Exercise testing, which can be safely performed a few days after hospital discharge if there are no contraindications, provides information regarding exercise tolerance and training intensities. Patients must then be provided with clear guidance regarding the type, duration, frequency, and target intensity of exercise, following the FITT (frequency, intensity, time, type) model [104]. Supervised in-hospital training sessions, when available, should be complemented with ambulatory sessions after education on self-monitoring methods—mainly heart rate–based and perceived exertion–based approaches (talk test, Borg RPE scale, etc.).

Exercise training shows beneficial effects on LVR, especially when started soon after discharge and maintained for longer durations [121,124]. It can improve LVEF, end-diastolic volumes, and myocardial mechanics [125,126]. These beneficial effects have also been observed in patients without significant LV systolic dysfunction [127].

Post-AMI inflammation, although necessary and beneficial to some extent [128], can be modulated by exercise training [129]. Cardiac fibrosis occurs as a physiological response to cardiomyocyte injury and death and serves to prevent wall rupture in the infarcted area. However, excessive fibrosis can expand the myocardial scar and negatively affect LVEF and LVR. Physical exercise can attenuate this exaggerated response through a complex interaction between MMPs, tissue inhibitors of matrix metalloproteinases (TIMPs), transforming growth factor-β (TGF-β), and other signaling pathways [130,131].

Exercise can improve myocardial perfusion after AMI [132,133], potentially through enhanced angiogenesis via vascular endothelial growth factor (VEGF) [37,134] and hypoxia-inducible factor-1 α (HIF-1α) signaling [135]. Additional cardioprotective effects of post-AMI exercise include reduction in oxidative stress in cardiomyocytes by modulating endothelial nitric oxide synthase (eNOS) activity and signaling [136]; increased myocardial contractility and efficiency mediated by upregulation of sarco/endoplasmic reticulum Ca2+-ATPase 2alpha (SERCA2α) [137]; improvement of autonomic dysregulation [138]; and enhanced myocardial energy metabolism [137].

In summary, exercise training appears to provide significant structural and functional benefits that can favorably influence post-AMI LVR.

5.3. CV Risk Factors Control and LVR

Poor control of CV risk factors—such as elevated blood cholesterol, high arterial pressure, and poor weight and metabolic control—can negatively influence post-AMI LVR.

Elevated blood cholesterol, and specifically low-density lipoprotein cholesterol (LDL-C), is associated with higher LV volumes [139], thromboinflammation, and adverse LVR [140]. Accordingly, statin therapy and lowering LDL-C levels have been shown to attenuate adverse post-AMI LVR [141,142,143].

Uncontrolled hypertension ultimately leads to LV dilation through several pathophysiological mechanisms [144]. An increase in cardiac afterload promotes LV hypertrophy, which ultimately leads to TGF-β and angiotensin II activation, upregulation of lysyl oxidase, collagen crosslink formation, diffuse myocardial fibrosis, and wall stiffness. Since the AMI scar already increases systolic and diastolic pressure on a weakened LV [144], further overload in cases of uncontrolled hypertension can contribute to—and in fact is associated with—post-AMI adverse LVR [145,146].

Poor metabolic control in diabetic patients can lead to diabetic cardiomyopathy, a long-term complication caused by hyperglycemia and myocardial inflammation [147]. The accumulation of advanced glycation end products (AGE) promotes collagen crosslinking and myocardial fibrosis through angiotensin II, TGF-β and TNF signaling [148]. Persistent hyperglycemia also impairs vascular and autonomic function, increases oxidative stress, and alters myocardial metabolism by enhancing the utilization of free fatty acids as a consequence of impaired glucose uptake [148].

In AMI patients, abnormal glucose metabolism has been linked to remodeling severity. Elevated glycated hemoglobin (HbA1c) levels are associated with poorer LV strain in STEMI patients [149], and high glycemic variability increases the odds of post-AMI adverse LVR [150]. Even in non-diabetic post-STEMI patients the presence of insulin resistance and dysglycemia—assessed by fasting glucose, glucose tolerance and homeostasis model assessment-estimated insulin resistance—is associated with long-term LV dilation [151].

The interplay between obesity and post-AMI LVR is complex. Obesity can induce LVR in asymptomatic individuals [152,153], especially if combined with hypertension and diabetes mellitus [154]. Conversely, weight reduction, particularly after bariatric surgery, can normalize LV volumes and mechanics [155]. Interestingly, some studies describe an “obesity paradox,” where obese patients or those with higher epicardial fat may show preserved LVEF and less adverse remodeling after AMI [156,157]. Therefore, current interventions focus on moderate (5–10%) weight loss [104], maintaining metabolic health [158], and promoting regular physical activity [159]. In fact, excess weight and glucose intolerance induced by a high-fat diet in mice after AMI attenuated the positive effects of exercise on LVR [160].

Overall, data demonstrating that CV risk factors control positively affects post-AMI LVR are scarce. Still, adherence to secondary prevention recommendations is warranted given their well-established benefits on post-AMI prognosis [7,8].

5.4. Smoking Habits and LVR

Smoking is a major driver of atherosclerosis and CV disease and has a direct and indirect harmful effects on cardiac morphology and function through oxidative stress, inflammation, metabolic impairment, and cell death mechanisms [161]. It has been associated with incident HF with either reduced or preserved ejection fraction [162]. Nicotine exposure has also been associated with adverse remodeling and lower LVEF in preclinical models [163,164].

Some studies have suggested that STEMI patients who were former smokers have a reduced incidence of adverse LVR [165]. Unfortunately, these studies did not account for changes in smoking status after AMI, which may act as a confounding factor. The most accepted explanation for this apparently favorable pattern is ischemic preconditioning from prior exposure to smoking.

Nevertheless, smoking cessation after AMI significantly reduces the risk of subsequent CV events [166] and mitigates tobacco-mediated cardiac metabolic and structural damage [167]. Although smoking cessation must be strongly encouraged in all post-AMI patients [168,169], further research is warranted to confirm whether smoking cessation directly improves post-AMI LVR.

5.5. Pharmacological Therapy Optimization and LVR

Pharmacological therapy indicated for post-AMI systolic dysfunction has generally shown benefits in terms of LVR, mainly through blood pressure control, modulation of preload and afterload, RAAS inhibition, and regulation of cardiac metabolism, inflammation, and fibrosis [16,18]. As mentioned before, these therapies can be prescribed and up-titrated within the framework of CR.

Beta-adrenergic receptor activation by local norepinephrine activity can acutely enhance cardiac output through increased chronotropy and inotropy. However, chronic beta-adrenergic activation has a detrimental effect on LVR through mitogen-activated protein kinases (MAPK) signaling, Gs–AC–cAMP signaling, Ca²⁺-calcineurinNFAT/CaMKII-HDACs signaling, and PI3K signaling [16,170]. Thus, beta-blockers are generally indicated after AMI, especially in patients with reduced (≤40%) LVEF [7]. However, their effectiveness in patients with preserved LVEF—and consequently at lower risk of adverse LVR—is currently being questioned [171].

RAAS activation also has several beneficial effects shortly after AMI, as it increases preload and cardiac contractility and maintains blood pressure and perfusion. However, in the long term angiotensin II and aldosterone promote cardiac fibrosis, cardiomyocyte apoptosis, and endothelial dysfunction [39]. Thus, neurohormonal inhibition can prevent adverse LVR and improve LVEF. Angiotensin-converting enzyme inhibitors (ACEIs), or alternatively angiotensin receptor blockers (ARBs), are indicated in high-risk AMI patients [7], such as those with LVEF ≤ 40%, since they act at different points in the RAAS cascade and inhibit adverse LVR [16]. Mineralocorticoid receptor agonists (MRAs), such as eplerenone, are recommended in symptomatic and/or diabetic post-AMI patients with LVEF ≤ 40% [172] since they improve LVR through antifibrotic effects, particularly in STEMI patients [173].

Angiotensin receptor-neprilysin inhibitors (ARNI) have proved superior to ACEIs in HF patients with LVEF ≤ 40% to reduce the risk of CV death and HF hospitalization [174]. ARNI can also promote reverse LVR in HF patients [175] and in animal models of AMI [176,177]. Although the PARADISE-MI trial did not show a significant reduction in the HF-related primary endpoint versus ramipril [178], the echocardiographic substudy revealed favorable changes in remodeling parameters [179]. Given their mechanistic profile, ARNI may offer particular benefit in STEMI patients to prevent adverse LVR [180].

SGLT2-i are a first-line therapy in patients with diabetes, HF, and chronic kidney disease, owing to their broad cardioprotective and nephroprotective effects [181]. SGLT2-i reduce the risk of CV events, especially in secondary prevention, and lower the risk of HF hospitalization and progression of renal disease in several subset of patients [181]. Structurally, SGLT2-i therapy leads to favorable LVR: in patients with diabetes or prediabetes and reduced LVEF, empagliflozin produced greater reductions in LV volumes than placebo [182], and dapagliflozin showed similar results even in non-diabetic patients [183]. Specifically after AMI, empagliflozin improved LVR in nondiabetic pigs, increasing myocardial work efficiency through a metabolic shift toward the utilization of ketone bodies, free fatty acid, and branched-chain amino acid [184]. Consistently, in the EMMY trial, AMI patients treated with empagliflozin showed greater improvement in LVEF and greater reductions in LV volumes compared to placebo [185].

However, in the EMPA-MI and DAPA-MI trials treatment with empagliflozin or dapagliflozin failed to improve the composite major adverse CV events outcome in post-AMI patients at risk of HF, although empagliflozin reduced hospitalizations for HF and dapagliflozin improved cardiometabolic outcomes [186,187]. These results provide a reasonable basis for SGLT2-i therapy in post-AMI patients with diabetes and/or reduced LVEF to improve outcomes and potentially LVR, although treatment in other post-AMI populations remains under investigation [183].

6. Current Clinical Management and Future Directions

6.1. Management of LVR During Cardiac Rehabilitation

Adverse LVR can be targeted during each phase of CR at both the diagnostic and therapeutic levels (Figure 4,

Table 2. Recommendations for management of LVR after AMI during Cardiac Rehabilitation.

Phase 1 CRP-Admission for AMI
Diagnosis	Early risk stratification. Evaluate CV risk factors. Assessment of structural repercussions of AMI (LVEF, LVEDV, LVESV) *.
Treatment	Therapeutic planning for CV risk factors control. Initiation of low-intensity physical activity. Initiation of targeted therapy if LV dysfunction is present or there is risk of adverse LVR.
Phase 2 CRP-First months after discharge
Diagnosis	Individualized clinical follow-up according to patient risk. Reassessment of structural repercussions of AMI (LVEF, LVEDV, LVESV) in the chronic phase *.
Treatment	Aim for achievement of CV risk factors goals. Exercise testing and exercise interventions (in-hospital and/or ambulatory) at moderate- to high-intensity levels. Optimization and up-titration of targeted therapies for LV dysfunction or LVR.
Phase 3 CRP-Long-term follow-up
Diagnosis	Reassess achievement of CV risk factors goals. Follow-up (clinical, biomarkers, imaging *) for LVR monitoring.
Treatment	Maintenance of regular exercise training. Ensure therapeutic adherence (including lifestyle habits and pharmacological therapy).

* Advanced imaging (e.g., CMR) and a more detailed structural evaluation should be considered according to local availability, and especially in high-risk cases or when conflicting clinical/imaging results are present. Abbreviations: AMI = acute myocardial infarction. CMR = cardiac magnetic resonance. CRP = cardiac rehabilitation program. CV = cardiovascular. LV = left ventricular. LVEDV = left ventricular end-diastolic volume. LVEF = left ventricular ejection fraction. LVESV = left ventricular end systolic volume. LVR = left ventricular remodeling.

). Phase 1 CR takes place during AMI hospitalization. Assessment of CV risk factors and early risk stratification should be performed in this phase [7,8]. Specifically, risk factors for adverse LVR should be analyzed (Table 3).

Beyond routine echocardiography before discharge [7,8], advanced CMR imaging should be considered when more detailed structural assessment is required, for instance, in those with conflicting clinical and imaging results or at high risk of post-AMI complications. Echocardiography-derived LVEF can predict which patients will benefit from an early CMR for prognostic assessment [14], and a combination of pre-discharge clinical, ECG, and echocardiographic variables can stratify the risk of CMR-detected LV thrombus [188]. Universally available ECG variables during admission can also predict long-term adverse LVR [189]. Reliable evaluation of LVEF can translate into different therapeutic management, such as the prescription of specific drugs if reduced or mildly reduced LVEF is present.

During the first months after hospital discharge, patients should be enrolled in a Phase 2 CRP. Although universal participation is ideal [7,8], selecting higher-risk patients—those with severe AMI, lower LVEF, or higher risk of adverse LVR—may be reasonable in resource-limited settings. Early enrollment in CRP after AMI appears to yield better outcomes [104].

During this phase, exercise interventions are performed according to each patient’s individual intensity thresholds [104]. Regular exercising, as well as achieving target CV risk factors control, can positively influence post-AMI LVR. However, in patients with systolic dysfunction, prescription and up-titration of HF-indicated drugs should be ensured during follow-up. Structural reassessment of LVEF and LV volumes should be performed approximately 6 to 12 weeks after discharge, especially in patients with reduced LVEF [7,8], although in several patients serial imaging can be performed at a later time. CMR imaging in this context can have implications for implantable cardioverter-defibrillator indication [190].

During Phase 2 and Phase 3 CR, patients should maintain healthy lifestyle habits, including regular exercise and adequate CV risk factors control. Outpatient follow-up visits should aim to detect risk factors for adverse LVR (Table 3), especially in patients with suboptimal treatment, i.e., those without previous indication for HF-related pharmacological therapy. For instance, serial N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing can identify patients at higher risk of MACE [191], as well as sequential CMR imaging [12].

Table 3. Risk factors for LVR after AMI.

Categories	Risk Factor	Comments	References
Clinical factors	Age	Younger patients are more likely to experience adverse LVR, although elderly patients show a higher risk of incident HF across the full spectrum of LVEF ranges.	[11,100]
	Gender	Women have an increased risk of adverse LVR, although this association appears to be mediated by comorbidities and CV risk factors.	[78]
	Hypertension	Uncontrolled hypertension increases the risk of adverse LVR.	[145,146]
	Diabetes mellitus	Poor glycemic control is associated with adverse LVR.	[149,150,151]
	Chronic kidney disease	AMI patients with chronic kidney disease show increased risk of adverse LVR.	[59,60]
	Infarct location	Anterior location is associated with increased area at risk, larger infarct size, and adverse LVR.	[192]
	ECG parameters	Parameters such as the number of leads with Q waves and residual ST-segment elevation >1 mm have been associated with reduced LVEF, higher LV volumes, and increased infarct size during follow-up.	[189]
Imaging factors	LVEF	Although recovery from systolic dysfunction is possible, patients with initially lower LVEF have an increased risk of long-term reduced LVEF and higher LV volumes, which increases HF-related MACE.	[12,14]
	Myocardial strain	CMR-derived longitudinal and circumferential global strain, as well as strain in remote myocardium, predict adverse LVR and MACE after AMI.	[69,193,194,195]
	LVEDV and LVESV	More dilated LV volumes after AMI are associated with an increased risk of adverse LVR during follow-up.	[75,196]
	Infarct size	Larger infarct size predicts long-term risk of adverse LVR.	[197]
	MVO	Early detection of CMR-derived MVO is associated with adverse LVR and MACE. Long-term persistence of MVO is also associated with adverse structural outcomes.	[197,198,199]
Biomarkers	NT-proBNP	Higher NT-proBNP values are correlated with adverse LVR and can stratify the long-term risk of HF-related MACE.	[191,200]
	High-sensitivity troponin	Higher high-sensitivity troponin levels during admission predict lower LVEF and more extensive infarct size at long-term follow-up. Elevated levels are also associated with incident HF after AMI.	[200,201]
	sST2	Elevated sST2 levels after AMI are associated with more extensive infarctions, decreased LVEF, and higher LV volumes at follow-up.	[202]

Abbreviations: AMI = acute myocardial infarction. CMR = cardiac magnetic resonance. CV = cardiovascular. HF = heart failure. LV = left ventricular. LVEDV = left ventricular end-diastolic volume. LVEF = left ventricular ejection fraction. LVESV = left ventricular end systolic volume. LVR = left ventricular remodeling. MACE = major adverse cardiac events. MVO = microvascular obstruction. NT-proBNP = N-terminal pro-brain natriuretic peptide. sST2 = soluble suppression of tumorigenicity-2.

Table 3. Risk factors for LVR after AMI.

Categories	Risk Factor	Comments	References
Clinical factors	Age	Younger patients are more likely to experience adverse LVR, although elderly patients show a higher risk of incident HF across the full spectrum of LVEF ranges.	[11,100]
	Gender	Women have an increased risk of adverse LVR, although this association appears to be mediated by comorbidities and CV risk factors.	[78]
	Hypertension	Uncontrolled hypertension increases the risk of adverse LVR.	[145,146]
	Diabetes mellitus	Poor glycemic control is associated with adverse LVR.	[149,150,151]
	Chronic kidney disease	AMI patients with chronic kidney disease show increased risk of adverse LVR.	[59,60]
	Infarct location	Anterior location is associated with increased area at risk, larger infarct size, and adverse LVR.	[192]
	ECG parameters	Parameters such as the number of leads with Q waves and residual ST-segment elevation >1 mm have been associated with reduced LVEF, higher LV volumes, and increased infarct size during follow-up.	[189]
Imaging factors	LVEF	Although recovery from systolic dysfunction is possible, patients with initially lower LVEF have an increased risk of long-term reduced LVEF and higher LV volumes, which increases HF-related MACE.	[12,14]
	Myocardial strain	CMR-derived longitudinal and circumferential global strain, as well as strain in remote myocardium, predict adverse LVR and MACE after AMI.	[69,193,194,195]
	LVEDV and LVESV	More dilated LV volumes after AMI are associated with an increased risk of adverse LVR during follow-up.	[75,196]
	Infarct size	Larger infarct size predicts long-term risk of adverse LVR.	[197]
	MVO	Early detection of CMR-derived MVO is associated with adverse LVR and MACE. Long-term persistence of MVO is also associated with adverse structural outcomes.	[197,198,199]
Biomarkers	NT-proBNP	Higher NT-proBNP values are correlated with adverse LVR and can stratify the long-term risk of HF-related MACE.	[191,200]
	High-sensitivity troponin	Higher high-sensitivity troponin levels during admission predict lower LVEF and more extensive infarct size at long-term follow-up. Elevated levels are also associated with incident HF after AMI.	[200,201]
	sST2	Elevated sST2 levels after AMI are associated with more extensive infarctions, decreased LVEF, and higher LV volumes at follow-up.	[202]

Abbreviations: AMI = acute myocardial infarction. CMR = cardiac magnetic resonance. CV = cardiovascular. HF = heart failure. LV = left ventricular. LVEDV = left ventricular end-diastolic volume. LVEF = left ventricular ejection fraction. LVESV = left ventricular end systolic volume. LVR = left ventricular remodeling. MACE = major adverse cardiac events. MVO = microvascular obstruction. NT-proBNP = N-terminal pro-brain natriuretic peptide. sST2 = soluble suppression of tumorigenicity-2.

6.2. Future Directions

As the first step in the management of adverse LVR after an AMI, improved diagnostic approaches to confirm current or future LVR are being developed. Advanced echocardiography—including three-dimensional, contrast-enhanced, and strain analyses—can enhance the accuracy and reproducibility of LVEF measurements and improve risk stratification [18,203]. Nuclear molecular imaging can provide valuable information regarding several pathophysiological processes in the LVR process, such as inflammation, angiogenesis, fibrosis, and cardiac sympathetic activity [204]. However, CMR stands out as the most comprehensive imaging technique, offering detailed structural assessment, prognostic information, therapeutic guidance, and evaluation of novel interventions [205]. Determining which patients will benefit from a more detailed, CMR-based structural evaluation after AMI is likely one of the most relevant challenges in advancing precision medicine in this field [14,188,189,206].

From a therapeutic approach, novel strategies are being developed to modulate post-AMI adverse LVR. Inflammation modulation has shown positive results in animal models and AMI patients, although they have not yet been implemented in clinical practice [207]. Bone marrow-derived mesenchymal stem cell therapy and CD34+ cell transplantation could help in myocardial scar regeneration and neo-angiogenesis [208]. Non-coding RNA, protein and gene therapies can also modulate several pathways of the LVR process, although full implementation will require identification of specific targets in the complex process of post-AMI myocardial scarring [18]. As an example, the HF-REVERT trial will evaluate whether CDR132L, a synthetic antisense oligonucleotide that inhibits microRNA-132 (miR-132), can prevent or reverse adverse LVR after AMI [209]. In parallel, innovations in drug delivery—such as sustained-release platforms for MMP-9 inhibition—are opening the way to novel pharmacological strategies [210]. Lastly, surgical or transcatheter interventions to correct LV geometry could improve long-term LVR in selected patients [18].

In summary, future developments are likely to improve the detection of adverse LVR through more precise echocardiographic assessment and broader availability of advanced imaging techniques such as CMR. These advances may help identify patients at higher risk of LVR who could benefit from targeted therapies currently under investigation.

7. Conclusions

Adverse LVR affects a substantial proportion of post-AMI patients even in contemporary clinical practice. Although several criteria exist for LVR definition, serial imaging remains necessary for its accurate diagnosis, and CMR provides a more reliable assessment of LV volumes and systolic function. CR can favorably influence LVR not only through structured exercise interventions, but also by ensuring optimal control of CV risk factors and appropriate prescription and titration of HF-related pharmacological therapies. The identification of individuals at higher risk of adverse LVR should trigger an in-depth investigation of the structural consequences of AMI, to enable current and emerging therapies specifically targeted at modulating the LVR process.