Sage Journals: Discover world-class research

Abstract

Despite the widespread use of early revascularization and drugs to regulate the neuroendocrine system, the impact of such measures on alleviating the development of heart failure (HF) after myocardial infarction (MI) remains limited. Therefore, it is important to discuss the development of new therapeutic strategies to prevent or reverse HF after MI. This requires a better understanding of the potential mechanisms involved. HF after MI is the result of complex pathophysiological processes, with adverse ventricular remodeling playing a major role. Adverse ventricular remodeling refers to the heart’s adaptation in terms of changes in ventricular size, shape, and function under the influence of various regulatory factors, including the mechanical, neurohormonal, and cardiac inflammatory immune environments; ischemia/reperfusion injury; energy metabolism; and genetic correlation factors. Additionally, unique right ventricular dysfunction can occur secondary to ischemic shock in the surviving myocardium. HF after MI may also be influenced by other factors. This review summarizes the main pathophysiological mechanisms of HF after MI and highlights sex-related differences in the prognosis of patients with acute MI. These findings provide new insights for guiding the development of targeted treatments to delay the progression of HF after MI and offering incremental benefits to existing therapies.

Keywords

Myocardial infarction heart failure ventricular remodeling neurohormonal regulation ischemia/reperfusion injury pathophysiology

Introduction

Heart failure (HF) is usually the end stage of cardiovascular disease. Its prevalence is increasing, which is largely influenced by the increased survival rate of patients with myocardial infarction (MI).^1,2 For example, risk factors such as diabetes, chronic obstructive pulmonary disease, hypertension, and chronic kidney disease can accelerate the progression of HF. Patients with these risk factors can develop cardiac insufficiency or HF after MI, which can increase the risk of death or adverse outcomes including cardiac rupture, cardiac arrest, ventricular arrhythmias, recurrent MI, and even sudden death.^3,4 These adverse outcomes increase the economic pressure on the healthcare system and hinder effective medical management. Therefore, it is essential to understand the pathogenesis of HF after MI to improve its diagnosis and treatment, prolong patients’ lifespan, and decrease the risk of adverse outcomes.⁵

The myocardium is composed of cardiomyocytes (CMs), capillaries, and extracellular matrix (ECM), all of which help to maintain normal cardiovascular physiological function. HF after MI is caused by structural and functional abnormalities of the heart that occur following acute MI (AMI) (including ST-segment elevation MI and non-ST-segment elevation MI) during hospitalization or after discharge. The pathological changes in cardiac structure and function are commonly referred to as adverse ventricular remodeling (AVR). This process involves complex and progressive molecular and cellular transformations that markedly increase the risk of HF and reduce the survival rate.⁶

In this review, we summarize the main pathophysiological mechanisms of AVR after MI and examine the currently available diagnostic methods and treatments, particularly highlighting the sex-related differences in the prognosis of patients with AMI. We also discuss the direction of research in this field in the context of clinical applications.

AVR

In most cases, the development of HF after MI originates from AVR of the left ventricle (LV). This is likely explained by much higher stroke work of the LV than right ventricle (RV) because of the former’s dominance in cardiac pumping function. AVR after MI is characterized by the heart’s adaptations in terms of ventricular size, shape, and function in response to comprehensive regulatory factors such as the mechanical, neurohormonal, and cardiac inflammatory immune environments; ischemia/reperfusion (I/R) injury; energy metabolism; and genetic correlation factors.^7–9 The structure and function of CMs, capillaries, and ECM are maladaptive under the above regulatory mechanisms, ultimately leading to increased cardiac stiffness and deterioration of diastolic and systolic function (Figure 1).

Figure 1.

Mechanism of cardiac remodeling.

Mechanical agents

The geometric changes of the ventricle are the main stimulus for LV remodeling. Laplace’s law states that ventricular wall stress is directly related to the LV pressure and radius and inversely proportional to twice the LV wall thickness. In the early stage of MI, the cardiac load increases as a compensatory adaptive response to mechanical and physiological stress that damages cardiac output, causing CM hypertrophy and subsequent myocardial hypertrophy. Loss of cardiac systolic function and a secondary increase in LV volume can increase wall stress and oxygen consumption, which eventually results in maladaptive tissue remodeling and triggers the transition to HF.¹⁰ This transition to HF is triggered by attempts to compensate for the increased preload and afterload. The passive mechanical restraint of the surrounding normal myocardium also mediates a decrease in the systolic function of the infarcted area and even the overall ventricle.¹¹

Neurohormonal system regulation

The integrated regulation by the neurohormonal system plays an important role in maintaining the physiological balance of the cardiovascular system and is a critical link in the development of AVR leading to LV dysfunction. The cascade of cardiac regulatory hormones related to LV remodeling is comprehensively regulated by the sympathetic nervous system (SNS) and the renin–angiotensin–aldosterone system (RAAS), and the natriuretic peptide system provides a beneficial compensatory effect.⁸

Reduced cardiac output after MI due to acute decompensation can reflexively activate the SNS and provide β-adrenergic tone, resulting in compensatory enhancement of myocardial contractility, an increased heart rate, and increased myocardial oxygen consumption.¹² However, sustained sympathetic activation is detrimental to the LV, mainly because of the toxic effects of high concentrations of its downstream products (catecholamines such as norepinephrine and epinephrine) on CMs, as well as stimulation of fibroblast synthesis to promote myocardial interstitial fibrosis; these processes eventually lead to the development of HF.^13–18 Chronic SNS activation is a key promoter of RAAS activation, and reduced cardiac output also reflexively activates the RAAS, thereby mediating the adverse effects of angiotensin II. The binding of angiotensin II to angiotensin II type 1 receptors in the circulation causes increased aldosterone secretion, promoting AVR as well as leading to cell apoptosis and interstitial fibrosis, thus accelerating the development of HF.¹⁵ As aldosterone decreases the sensitivity of pressure receptors, the inhibition of sympathetic activity is reduced and norepinephrine release is increased. This suggests that attenuation of the pressure reflex by local aldosterone release may trigger sympathetic activation.¹⁹ In addition, the decrease in cardiac output activates the natriuretic peptide system to exert a beneficial compensatory effect. The three identified natriuretic peptide hormone subtypes are type A, B, and C natriuretic peptide. They can inhibit the SNS and RAAS to exert a beneficial compensatory effect.^20,21 These natriuretic peptides can dilate vessels while reducing pulmonary capillary wedge pressure, systemic arterial pressure, and RV pressure, and the resultant decrease in cardiac preload and afterload can improve cardiac remodeling.

The level of SNS and RAAS activation is correlated with the severity, outcome, and prognosis of HF. Thus, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers, β-blockers, mineralocorticoid receptor antagonists, and other drugs have been widely used in clinical practice to improve AVR. ACEI therapy has shown survival benefits after MI. Early initiation of ACEI therapy after MI improves short-term mortality, and administration of captopril after AMI can reduce the LV end-diastolic volume (LVEDV) and LV filling pressure.^22–24 The improvement in clinical outcomes using angiotensin receptor blockers and ACEIs is similar.^25,26 Use of β-blockers has consistently been shown to provide a survival advantage in patients with HF, and it plays a crucial role in β-adrenergic blockade in infarct remodeling.^27–29 Moreover, mineralocorticoid receptor antagonists are considered central molecules in ECM regulation, especially during collagen deposition.³⁰ Moreover, natriuretic peptides and nitric oxide (NO) can synchronously activate cyclic GMP-dependent protein kinases to exert anti-hypertrophic effects, and clinical studies of the cyclic GMP-phosphodiesterase inhibitor sildenafil, which can stimulate NO production, have shown its beneficial effects in the treatment of congestive HF.^31–33

Inflammatory immune activation

AMI triggers the inflammatory response, which aims to remove necrotic cellular debris and initiate anti-inflammatory repair. Cellular necrosis and apoptosis are essential for inflammatory immune system activation. Although these processes occur simultaneously, apoptosis is programmed cell death without the release of intracellular components whereas necrosis is an uncontrolled form of cell death with cell rupture. Later, the intracellular components released by the necrotic cells activate the immune system through innate immune receptors, resulting in infiltration of inflammatory cells. The differentiation and interaction of the various inflammatory cell subtypes are strictly regulated. By mediating inflammation or healing, inflammatory immune system activation plays a dual role: the chronic inflammatory state drives maladaptive remodeling, but infiltrating inflammatory cells can recruit leukocytes, remove tissue debris, and start the remedial response, thus allowing scar tissue formation.³⁴ However, inflammation can also mediate the release of damage-associated molecular patterns (DAMPS) from necrotic and apoptotic CMs after MI, continuously activating the innate immune system and triggering more severe and overactive inflammatory reactions.³⁵ The binding of DAMPs to pattern recognition receptors or Toll-like receptors is crucial for the activation of proinflammatory signaling pathways. Persistent dysregulated inflammation can promote CM death, impair the contractile function of surviving CMs, and promote interstitial tissue destruction.³⁶ Studies have shown that the inflammatory response is directly proportional to the degree of myocardial injury as evidenced by elevated levels of systemic inflammatory markers, such as C-reactive protein, being associated with a worse prognosis in patients with AMI and HF.^37–39

Different inflammatory cells and large numbers of cytokines and matrix metalloproteinases (MMPs) facilitate molecular coordination of the myocardial inflammatory response through extensive interactions, leading to expansion of the range of damage, aggravation of impaired tissue function, and acceleration of HF. Among these interactions, neutrophils and macrophages are major players in remodeling and are the primary leukocytes that infiltrate the infarcted LV.⁴⁰ Monocytes infiltrate first, after which neutrophils rapidly become the predominant leukocytes in the infarcted area. Although neutrophil infiltration reduces injury after AMI, it exacerbates the fibrotic response, promoting progression to HF.^41,42 Macrophages act as phagocytes to remove necrotic debris and apoptotic neutrophils, and their depletion can exacerbate LV remodeling and over-expansion.⁴³ The absence of polarization components of macrophages, such as CCR5 deficiency, does not limit the infiltration of these cells into the infarcted area; however, it hinders the healing process and increases the risk of rupture induced by proinflammatory and anti-inflammatory proteins.⁴⁴ Lymphocytes and mast cells also play an important role in the activation of fibroblasts and local inflammation within the myocardium.^45–48 Endothelial cells can also promote the formation of a pro-fibrotic inflammatory environment by activating a pro-inflammatory secretion phenotype.⁴⁹

Current studies are focusing on the use of different cytokines and chemokines as potential targets to improve cardiac function and the prognosis in patients with AMI or HF, such as inhibition of interleukins 1, 6, and 8; monocyte chemotactic protein 1; CC and CXC chemokines; and tumor necrosis factor α.⁵⁰ Because elevated MMPs after MI regulate remodeling by promoting ECM conversion and inflammatory signaling and are closely related to LV dysfunction in patients with HF, they may also serve as biomarkers of MI or HF and as future targets for preventing HF after MI.⁵¹

I/R injury, reactive oxygen species (ROS), and mitochondrial energy metabolism

Although emergency coronary intervention is beneficial for patients with AMI, reperfusion to restore myocardial blood flow allows the infarct size to expand, causing a series of harmful metabolic changes in CMs.⁵² This process is referred to as I/R injury and is characterized by a series of continuous and reciprocal processes. At the molecular level, reperfusion leads to sudden oxidization of succinate that accumulates during ischemia, mediating the production of ROS. The sustained increase in the oxygen free radical concentration can create a vicious circle through MMP activation followed by chronic mitochondrial remodeling, which reduces energy production and ultimately promotes the development of HF.^53,54

After MI, CMs are exposed to acute ischemic and hypoxic environments. Because anaerobic glycolysis becomes the only important source of newly generated adenosine triphosphate during coronary artery occlusion, a large amount of H⁺ can be generated simultaneously and accumulate intracellularly. Once perfusion is restored, H⁺ is transported to the extracellular space to ensure normal pH; this results in an increase in the intracellular Na⁺ concentration, which can eventually lead to Ca²⁺ overload.⁵⁵ High calcium concentrations induce opening of the mitochondrial permeability transition pore (mPTP), while the opening of nonselective channels in the inner mitochondrial membrane is a crucial determinant of lethal I/R injury. These channels open only in the first few minutes after myocardial reperfusion in response to mitochondrial Ca²⁺ overload, oxidative stress, physiological pH recovery, and adenosine triphosphate depletion. The formation and opening of mPTP during myocardial I/R can lead to outer membrane rupture because of the inner membrane potential depolarization and matrix expansion. Eventually, substances such as proteins and cytochrome C can be released into the cytoplasm to activate the cysteine cascade reaction, initiating cell death.⁵⁶ The accumulation of intracellular H⁺ and Ca²⁺ and destruction of the mitochondrial membrane potential can also lead to significant oxygen-derived free radical production during I/R injury. The chronic accumulation of oxyradicals in mitochondria can lead to a catastrophic cycle of mitochondrial DNA damage and decreased mitochondrial function, further generating ROS. These ROS can induce CM hypertrophy, CM apoptosis, and interstitial fibrosis through the activation of MMPs, forming a vicious circle of AVR and progression of HF.^7,54,57 MMP and tissue inhibitor of metalloproteinase are coordinately regulated at the transcriptional and translational levels through different transcription factors and enzymes, including the NF-κB and JAK-STAT pathways, and their regulation can also be influenced by neurohormonal activation.⁵⁸ High circulating levels of MMPs are associated with dilative AVR, systolic dysfunction, and an increased risk of progression to HF.^59,60 Progressive metabolic remodeling is a key driver of the transition to HF after MI, which will exacerbate the occurrence and development of AVR.⁶¹

Genetic regulation

In addition to the numerous above-described proven pathophysiological mechanisms leading to the development of HF after MI, genetically related regulatory mechanisms have been continuously revealed. Among these, epigenetic regulatory mechanisms play a major role.

Decreased CM contractility has been found to involve an altered cell phenotype. Pressure overload leads to a disproportionate increase in the ventricular wall thickness, and the expression of genes such as myosin and troponin can show embryonic alterations.⁶² This is widely related to the abnormal expression of certain microRNAs. For example, microRNA-208 encoded by the α-major histocompatibility complex gene plays a significant regulatory role in the production of myosin heavy chains, and its upregulation can lead to CM hypertrophy through negative regulation of SOX6.⁶³ Epigenetic regulation of non-coding RNAs, including long-stranded non-coding RNAs and microRNAs, play an essential role in I/R injury through endoplasmic reticulum (ER)–mitochondria microdomain interactions.⁶⁴ The sensitivity of CMs to death is fine-tuned by the intracellular calcium concentration. Therefore, when inositol 1,4,5-trisphosphate receptor (IP3R)-mediated I/R stress upregulates and leads to mitochondrial calcium overload, necrotic apoptosis signal pathways will be activated through the CaMKII-mPTP or XO-ROS-mPTP pathway in the reperfused heart. There is also evidence to suggest that receptor-interacting protein kinase 3 (Ripk3) manages IP3R located in the ER. Because genetic ablation of Ripk3 eliminates reperfusion-induced IP3R upregulation and ER stress confirms the necessity of ER–mitochondrial microdomains in stimulating Ripk3-induced necrotic apoptosis in cardiac I/R injury.⁶⁵ Additionally, the downstream event of necroptosis is the opening of Ripk3-activated mPTP, which mediates the swelling and rupture of organelles and cells due to energy generation obstacles. Interestingly, inhibition of certain genes also restores the adult heart to the metabolic state of the fetal gene pattern.⁶⁶

Multiple studies have focused on the susceptibility of individuals to I/R injury, which may be related to genes encoding angiotensin II, ACE, osteoprotegerin, transforming growth factor β, vascular endothelial growth factor, galactose lectin-3, ficolin-1, mitochondrial aldehyde dehydrogenase 2, and others.⁶⁷

Cardiac adaptive changes under integrated regulation

Cardiac adaptive changes mainly involve changes in ventricular size, shape, and function, which are primarily caused by CM changes and myocardial fibrosis in the infarct area, infarcted marginal area, and non-infarcted area. Physiological hypertrophy of CMs is often described as volume expansion of terminally differentiated CMs, a process that can resolve without causing any permanent damage. By contrast, the triggering of a series of pro-hypertrophic molecular pathways by MI often leads to overt myocardial damage. CMs may exhibit pathophysiological changes such as hypertrophy, necrosis, and apoptosis after MI. In the early stage of injury, the collagen scaffold is disrupted because inflammatory cells flow into the necrotic myocardium, making it challenging to maintain the ventricular shape and causing localized myocardial thinning and dilation in the infarcted region.^68,69 Because of the increased volume and pressure load, the surviving CMs in the non-infarcted region undergo stretching and compensatory eccentric hypertrophy,⁷⁰ which further leads to LV dilation. Compared with distal CMs, those in the infarcted marginal area are located closer to the hypertrophic infarcted myocardium and exhibit more severe differentiation, sarcomere depletion, and reduced mitochondrial volume. Additionally, myocardial fiber stretching and inflammation are essential triggers for myofibroblast activation. Necrotizing apoptosis of CMs after MI stimulates the development of myofibroblasts and results in collagen deposition, leading to progressive alternative fibrosis and eventually forming scars mainly composed of cross-linked collagen; these are considered irreversible changes.⁷¹ In the non-infarcted region, increased wall stress can also locally activate CMs, macrophages, and fibroblasts, causing chronic remodeling of the ECM network.^72,73 Excessive scarring increases the stiffness of the heart, hinders oxygen diffusion, and affects the heart’s diastolic function.

Notably, although the above-described process of AVR is a major factor in the development of HF in patients with MI, ventricular dysfunction may also result from other contributing or superimposed factors. Mechanical complications such as myocardial rupture, septal defects and ventricular free wall rupture, MI complicated by papillary muscle insufficiency, ventricular wall tumors, and septal perforation can aggravate the cardiac load and thus induce and worsen HF. Among these, septal rupture usually has the worst prognosis.⁷⁴ In addition, the development of HF after MI is closely related to previous myocardial damage. Long-term chronic myocardial ischemia can cause myocardial fibrosis, which increases the risk of HF after AMI. Patients with repair-induced scars in old infarcts or a history of HF are more likely to redevelop HF after MI, and the combination of other hereditary, metabolic, or toxic injury-related cardiomyopathies may also lead to AVR, LV dysfunction, and HF. Finally, patients who develop worsening of other systemic comorbidities such as anemia, chronic renal failure, and chronic obstructive pulmonary disease are also predisposed to HF after MI. Therefore, the deterioration of heart function in patients with MI and the final progression to HF is a multimechanistic pathway-related process influenced by multiple factors.

HF after MI: Beyond AVR

Although HF can be prevented by the use of reperfusion strategies and cardioprotective drugs as well as the implementation of strategies aimed at preventing LV dysfunction and remodeling, the risk of HF after MI has not been eliminated. One study showed no significant changes in the LVEDV or LV ejection fraction (LVEF) in patients with STEMI during follow-up, but up to 7.5% of patients required hospitalization because of HF during long-term follow-up.⁷⁵ In trials comparing colchicine, cyclosporine, and anabolic acid with a placebo, the common endpoint of HF or death still occurred in 13%, 10%, and 26% of patients, respectively, and was not associated with changes in the LVEDV and LVEF despite minimal changes in relative remodeling in patients with STEMI during follow-up.^76–78 This suggests that HF after MI can occur without systolic dysfunction and AVR. Additionally, the pathophysiological mechanisms leading to HF may be multifactorial and cannot be explained only by LV systolic dysfunction and ventricular remodeling. These mechanisms may be related to RV dysfunction or HF with a preserved ejection fraction (HFpEF) unrelated to an altered LVEF.⁷⁹

HF caused by RV infarction has unique hemodynamic characteristics (Table 1). Although acute proximal occlusion of the right coronary artery presents with typical symptoms of right HF, RV dysfunction may also occur after a larger infarction of the left coronary artery. RV function is an independent predictor of HF development and death in patients with LV dysfunction after MI, and reduced RV systolic function is also a major risk factor for death, sudden death, HF, and stroke after MI.^80,81 Compared with the LV, the RV has stronger resistance to permanent infarction. In addition, a series of optimal compensatory measures induced by RV infarction may lead to a greater potential for ischemic myocardial recovery.⁸² For example, the RV can maintain its function during moderate coronary artery hypoperfusion, possibly because the increased coronary blood flow from endogenous NO release reduces the myocardial oxygen demand.⁸³ The ischemic shock of the surviving myocardium usually mediates RV dysfunction. In cases of acute overload, the RV coronary artery perfusion pressure decreases, and the failure of the above compensatory measures leads to severe RV systolic dysfunction. This further reduces the blood flow to the LV, which ultimately manifests as reduced cardiac output and systemic hypotension. Meanwhile, elevated LV end-diastolic pressure reflected in the RV also leads to further expansion of the RV and a decline in systolic function.⁸⁴ However, because of the rarity of independent RV infarction, opinions regarding therapy (which are based on animal studies and observational evidence) mainly focus on underlying myocardial ischemia, end-organ perfusion, and potential arrhythmias, advocating that early revascularization may improve short-term and long-term patient outcomes.⁸⁵

Table 1.

Differences between RV infarction and LV infarction.

	RV infarction	LV infarction
Occlusive artery	Mostly mediated by RCA proximal occlusion before the branch site of the RV marginal branch	LAD occlusion or circumflex artery occlusion
Hemodynamics⁹⁸	i Lower RV systolic pressure(coronary blood flow during both systole and diastole, but more during diastole)ii Lower afterload and wall stress(connected to low pressure and high compliance of the pulmonary circulation)	High systolic pressure and wall stress
Pressure-capacity analysis	The RV only performs one-fourth of the stroke work of the LV(the RV wall thickness is only one-third that of the LV)⁹⁹	High stroke work
Energy consumption during insufficient perfusion	Low resting energy consumption and oxygen consumption¹⁰⁰	High energy consumption
Feature	LAD protects the RV through collateral blood flow in patients with proximal RCA occlusion¹⁰¹
Outcome	Higher chance of recovery from myocardial ischemia	Dominant infarction with irreversible myocardial necrosis

RV, right ventricle; LV, left ventricle; RCA, right coronary artery; LAD, left anterior descending artery.

HFpEF is defined as symptomatic HF with an LVEF of ≥50%. Although the resting systolic function is retained when the LVEF is preserved, patients may still experience symptoms during exercise because of the restricted diastolic reserve, which is affected by increased myocardial stiffness secondary to the elevated LV filling pressure, impaired cardiac output reserve, and persistent chronic ischemia.^86–88 Notably, silent MI also has a high incidence rate, although it is asymptomatic. Chronic ischemia may lead to myocardial hibernation and coma as well as a further decline in LV function. Moreover, HFpEF may also result from silent MI because myocardial ischemia is a main factor of HFpEF.⁸⁹ In addition, the incidence of HFpEF is strongly associated with hypertension, non-STEMI, and other etiologies such as atrial fibrillation, cardiomyopathy, myocarditis, heart valve disease, and diabetes.^80,90

Sex-related differences in prognosis

Women have been found to be at higher risk of new-onset HF after STEMI and to have worse survival rates than men. After correction, although women and men maintain a balance in baseline characteristics and early reperfusion treatment, women with MI still have a higher incidence of HF during hospitalization or after discharge than men.⁹¹ This phenomenon may have three main explanations. First, microcirculatory disorders, which are more common in women, may impair coronary blood flow reserve, making the myocardium more susceptible to ischemia.^92,93 Microcirculatory disorders are more prevalent in women than in men, and coronary microcirculatory disease or dysfunction may be a primary cause of angina symptoms in the presence of normal or near-normal coronary arteries. Coronary microvascular dysfunction may also coexist with atherosclerotic coronary artery disease and contribute to the occurrence and development of HF. Second, intrinsic biological differences in the manifestation of some diseases may lead to different prognoses after AMI between the two sexes, such as worse capillary formation and reduced cardiac adaptation to isolated systolic hypertension in women than in men, as well as different responses to treatment between women and men.^94,95 Third, other causes of STEMI may have different effects on new-onset HF and mortality after MI in women and men, such as spontaneous coronary artery dissection, plaque erosion, or coronary artery spasm.

Discussion

The development of HF after MI involves cardiac structural and functional changes under neurohormonal regulation, inflammatory immune regulation, and complex pathophysiological interactions between different signaling molecules and pathways. However, despite significant progress in elucidating the underlying mechanisms of HF after MI, many issues remain unresolved. First, the list of molecular factors leading to CM hypertrophy, necrosis, and apoptosis is growing. This makes it important to identify the mechanisms underlying structural and functional alterations in CMs using systematic analytical approaches, such as RNA sequencing and proteomic analysis, which could reveal higher-priority targets for preventing the development of HF after MI.⁹⁶ Second, the understanding of the dynamic cardiac matrix profiles in pathological cardiac remodeling remains limited, which may hinder exploration of the mechanisms of cardiac fibrosis to some degree. Therefore, determining the functional domains of ECM components and genetically tracing the myofibroblast lineage will provide an in-depth and comprehensive understanding of the pathogenesis of cardiac fibrosis. This is crucial for developing effective and safe therapies for cardiac fibrosis.⁹⁷ However, changes in cellular and tissue components alone may not be suitable as direct targets for HF therapy. Therefore, it is also necessary to develop a better understanding of the cross-regulatory role of neurohormonal system activation and inflammatory immunity in mediating cardiac adaptation and dysfunction after MI. Further investigation of the interactions between different mechanisms may be a future research direction. Although several types of drugs are available to prevent AVR after MI and treat LV dysfunction, individual differences in pathophysiological mechanisms may limit their clinical application. Therefore, the development of innovative drugs will depend on identifying new targets, and cardiac resynchronization therapy is a research hotspot. The gradual clarification of these pathophysiological mechanisms will provide new ideas for different means of treatment to delay the progression of HF after MI and may provide incremental benefits to existing therapies.

Footnotes

Declaration of conflicting interests

The authors declare no conflict of interest in preparing this article.

Ethics

The requirement for ethics approval was waived because of the nature of this study (review).

Funding

This work was supported by the Youth Fund of Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine (No. KYH2022093).

ORCID iD

Zeyi Cheng

References

Tsao

Aday

Almarzooq

, et al. Heart Disease and Stroke Statistics-2023 Update: a report from the American Heart Association. Circulation 2023; 147: e93–e621.

Virani

Alonso

Benjamin

, et al. Heart Disease and Stroke Statistics-2020 Update: a report from the American Heart Association. Circulation 2020; 141: e139–e596.

Gheorghiade

Fonarow

GC.

Management of post-myocardial infarction patients with left ventricular systolic dysfunction. Am J Med 2007; 120: 109–120.

Albert

Lewis

Recognizing and managing asymptomatic left ventricular dysfunction after myocardial infarction. Crit Care Nurse 2008; 28: 20–37; quiz 8.

Minicucci

Azevedo

Polegato

, et al. Heart failure after myocardial infarction: clinical implications and treatment. Clin Cardiol 2011; 34: 410–414.

Bolognese

Neskovic

Parodi

, et al. Left ventricular remodeling after primary coronary angioplasty: patterns of left ventricular dilation and long-term prognostic implications. Circulation 2002; 106: 2351–2357.

Bhatt

Ambrosy

Velazquez

EJ.

Adverse remodeling and reverse remodeling after myocardial infarction. Curr Cardiol Rep 2017; 19: 71.

Sackner-Bernstein

JD.

The myocardial matrix and the development and progression of ventricular remodeling. Curr Cardiol Rep 2000; 2: 112–119.

Swirski

Nahrendorf

Cardioimmunology: the immune system in cardiac homeostasis and disease. Nat Rev Immunol 2018; 18: 733–744.

10.

Harvey

Leinwand

LA.

The cell biology of disease: cellular mechanisms of cardiomyopathy. J Cell Biol 2011; 194: 355–365.

11.

Anzai

Post-infarction inflammation and left ventricular remodeling: a double-edged sword. Circ J 2013; 77: 580–587.

12.

Ciarka

Van de Borne

Pathak

Myocardial infarction, heart failure and sympathetic nervous system activity: new pharmacological approaches that affect neurohumoral activation. Expert Opin Investig Drugs 2008; 17: 1315–1330.

13.

Mladenka

Hrdina

Bobrovova

, et al. Cardiac biomarkers in a model of acute catecholamine cardiotoxicity. Hum Exp Toxicol 2009; 28: 631–640.

14.

Mann

Kent

Parsons

, et al. Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation 1992; 85: 790–804.

15.

Olivetti

Capasso

Meggs

, et al. Cellular basis of chronic ventricular remodeling after myocardial infarction in rats. Circ Res 1991; 68: 856–869.

16.

Olivetti

Abbi

Quaini

, et al. Apoptosis in the failing human heart. N Engl J Med 1997; 336: 1131–1141.

17.

Bohm

Ettelbruck

Flesch

, et al. Beta-adrenergic signal transduction following carvedilol treatment in hypertensive cardiac hypertrophy. Cardiovasc Res 1998; 40: 146–155.

18.

Osadchii

Norton

McKechnie

, et al. Cardiac dilatation and pump dysfunction without intrinsic myocardial systolic failure following chronic beta-adrenoreceptor activation. Am J Physiol Heart Circ Physiol 2007; 292: H1898–H1905.

19.

Wang

Chronic administration of aldosterone depresses baroreceptor reflex function in the dog. Hypertension 1994; 24: 571–575.

20.

Kasama

Furuya

Toyama

, et al. Effect of atrial natriuretic peptide on left ventricular remodelling in patients with acute myocardial infarction. Eur Heart J 2008; 29: 1485–1494.

21.

Chen

Redfield

Nordstrom

, et al. Subcutaneous administration of the cardiac hormone BNP in symptomatic human heart failure. J Card Fail 2004; 10: 115–119.

22.

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.

23.

ISIS-4: a randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction . ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. Lancet 1995; 345: 669–685.

24.

Pfeffer

Lamas

Vaughan

, et al. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med 1988; 319: 80–86.

25.

Solomon

Skali

Anavekar

, et al. Changes in ventricular size and function in patients treated with valsartan, captopril, or both after myocardial infarction. Circulation 2005; 111: 3411–3419.

26.

Antman

Anbe

Armstrong

, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction–executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004; 44: 671–719.

27.

Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353: 2001–2007.

28.

The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353: 9–13.

29.

Gaudron

Ertl

Long-term effects of beta-adrenergic blocking agent treatment on hemodynamic function and left ventricular remodeling in rats with experimental myocardial infarction: importance of timing of treatment and infarct size. J Am Coll Cardiol 1998; 31: 692–700.

30.

Pitt

Remme

Zannad

, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321.

31.

Schirone

Forte

Palmerio

, et al. A review of the molecular mechanisms underlying the development and progression of cardiac remodeling. Oxid Med Cell Longev 2017; 2017: 3920195.

32.

Pokreisz

Vandenwijngaert

Bito

, et al. Ventricular phosphodiesterase-5 expression is increased in patients with advanced heart failure and contributes to adverse ventricular remodeling after myocardial infarction in mice. Circulation 2009; 119: 408–416.

33.

Takimoto

Champion

, et al. Chronic inhibition of cyclic GMP phosphodiesterase 5A prevents and reverses cardiac hypertrophy. Nat Med 2005; 11: 214–222.

34.

Frantz

Falcao-Pires

Balligand

, et al. The innate immune system in chronic cardiomyopathy: a European Society of Cardiology (ESC) scientific statement from the Working Group on Myocardial Function of the ESC. Eur J Heart Fail 2018; 20: 445–459.

35.

Oliveira

Soares

Sposito

AC.

Inflammatory response during myocardial infarction. Adv Clin Chem 2018; 84: 39–79.

36.

Westman

Lipinski

Luger

, et al. Inflammation as a driver of adverse left ventricular remodeling after acute myocardial infarction. J Am Coll Cardiol 2016; 67: 2050–2060.

37.

Lindahl

Toss

Siegbahn

, et al. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000; 343: 1139–1147.

38.

Van Wezenbeek

Canada

Ravindra

, et al. C-reactive protein and N-terminal pro-brain natriuretic peptide levels correlate with impaired cardiorespiratory fitness in patients with heart failure across a wide range of ejection fraction. Front Cardiovasc Med 2018; 5: 178.

39.

Del Buono

Damonte

Trankle

, et al. Effect of interleukin-1 blockade with anakinra on leukocyte count in patients with ST-segment elevation acute myocardial infarction. Sci Rep 2022; 12: 1254.

40.

Soehnlein

Steffens

Hidalgo

, et al. Neutrophils as protagonists and targets in chronic inflammation. Nat Rev Immunol 2017; 17: 248–261.

41.

Horckmans

Ring

Duchene

, et al. Neutrophils orchestrate post-myocardial infarction healing by polarizing macrophages towards a reparative phenotype. Eur Heart J 2017; 38: 187–197.

42.

Huang

Frangogiannis

NG.

Anti-inflammatory therapies in myocardial infarction: failures, hopes and challenges. Br J Pharmacol 2018; 175: 1377–1400.

43.

Van Amerongen

Harmsen

Van Rooijen

, et al. Macrophage depletion impairs wound healing and increases left ventricular remodeling after myocardial injury in mice. Am J Pathol 2007; 170: 818–829.

44.

Zamilpa

Kanakia

Cigarroa

4th , et al. CC chemokine receptor 5 deletion impairs macrophage activation and induces adverse remodeling following myocardial infarction. Am J Physiol Heart Circ Physiol 2011; 300: H1418–H1426.

45.

Mortensen

RM.

Immune cell modulation of cardiac remodeling. Circulation 2012; 125: 1597–1600.

46.

Saxena

Dobaczewski

Rai

, et al. Regulatory T cells are recruited in the infarcted mouse myocardium and may modulate fibroblast phenotype and function. Am J Physiol Heart Circ Physiol 2014; 307: H1233–H1242.

47.

Levick

McLarty

Murray

, et al. Cardiac mast cells mediate left ventricular fibrosis in the hypertensive rat heart. Hypertension 2009; 53: 1041–1047.

48.

Zhang

Chancey

Tzeng

, et al. The development of myocardial fibrosis in transgenic mice with targeted overexpression of tumor necrosis factor requires mast cell-fibroblast interactions. Circulation 2011; 124: 2106–2116.

49.

Fujita

Shimojo

Terasaki

, et al. Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade. Heart Vessels 2013; 28: 646–657.

50.

DeLeon-Pennell

Meschiari

Jung

, et al. Matrix d. Prog Mol Biol Transl Sci 2017; 147: 75–100.

51.

Hartman

MHT

Groot

Leach

, et al. Translational overview of cytokine inhibition in acute myocardial infarction and chronic heart failure. Trends Cardiovasc Med 2018; 28: 369–379.

52.

Heusch

Myocardial ischaemia-reperfusion injury and cardioprotection in perspective. Nat Rev Cardiol 2020; 17: 773–789.

53.

Chouchani

Pell

Gaude

, et al. Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS. Nature 2014; 515: 431–435.

54.

Tsutsui

Kinugawa

Matsushima

Mitochondrial oxidative stress and dysfunction in myocardial remodelling. Cardiovasc Res 2009; 81: 449–456.

55.

Yellon

Hausenloy

DJ.

Myocardial reperfusion injury. N Engl J Med 2007; 357: 1121–1135.

56.

Heusch

Boengler

Schulz

Inhibition of mitochondrial permeability transition pore opening: the Holy Grail of cardioprotection. Basic Res Cardiol 2010; 105: 151–154.

57.

Frank

Bonney

, et al. Myocardial ischemia reperfusion injury: from basic science to clinical bedside. Semin Cardiothorac Vasc Anesth 2012; 16: 123–132.

58.

Chen

, et al. Angiotensin II regulation of collagen type I expression in cardiac fibroblasts: modulation by PPAR-gamma ligand pioglitazone. Hypertension 2004; 44: 655–661.

59.

Soejima

Ogawa

Sakamoto

, et al. Increased serum matrix metalloproteinase-1 concentration predicts advanced left ventricular remodeling in patients with acute myocardial infarction. Circ J 2003; 67: 301–304.

60.

Wagner

Delagardelle

Ernens

, et al. Matrix metalloproteinase-9 is a marker of heart failure after acute myocardial infarction. J Card Fail 2006; 12: 66–72.

61.

Peterzan

Lygate

Neubauer

, et al. Metabolic remodeling in hypertrophied and failing myocardium: a review. Am J Physiol Heart Circ Physiol 2017; 313: H597–H616.

62.

Kehat

Molkentin

JD.

Molecular pathways underlying cardiac remodeling during pathophysiological stimulation. Circulation 2010; 122: 2727–2735.

63.

Zhao

Wang

Sun

The functions of microRNA-208 in the heart. Diabetes Res Clin Pract 2020; 160: 108004.

64.

Marinescu

Lazar

Marta

, et al. Non-coding RNAs: prevention, diagnosis, and treatment in myocardial ischemia-reperfusion injury. Int J Mol Sci 2022; 23: 2728.

65.

Zhu

Jin

, et al. Ripk3 promotes ER stress-induced necroptosis in cardiac IR injury: a mechanism involving calcium overload/XO/ROS/mPTP pathway. Redox Biol 2018; 16: 157–168.

66.

Razeghi

Young

Alcorn

, et al. Metabolic gene expression in fetal and failing human heart. Circulation 2001; 104: 2923–2931.

67.

Berezin

AA.

Adverse cardiac remodelling after acute myocardial infarction: old and new biomarkers. Dis Markers 2020; 2020: 1215802.

68.

Cleutjens

Kandala

Guarda

, et al. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol 1995; 27: 1281–1292.

69.

Warren

Royal

Markis

, 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.

70.

Anversa

Beghi

Kikkawa

, 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.

71.

Frantz

Hundertmark

Schulz-Menger

, et al. Left ventricular remodelling post-myocardial infarction: pathophysiology, imaging, and novel therapies. Eur Heart J 2022; 43: 2549–2561.

72.

Chen

Frangogiannis

NG.

Macrophages in the remodeling failing heart. Circ Res 2016; 119: 776–778.

73.

Sager

Hulsmans

Lavine

, et al. Proliferation and recruitment contribute to myocardial macrophage expansion in chronic heart failure. Circ Res 2016; 119: 853–864.

74.

Matos

VA.

SHOCK Investigators . [Cardiogenic shock complicating acute myocardial infarction–etiologies, management and outcome: a report from the SHOCK Trial Registry]. Rev Port Cardiol 2001; 20: 349–350.

75.

Rodriguez-Palomares

Gavara

Ferreira-Gonzalez

, et al. Prognostic value of initial left ventricular remodeling in patients with reperfused STEMI. JACC Cardiovasc Imaging 2019; 12: 2445–2456.

76.

Mewton

Roubille

Bresson

, et al. Effect of colchicine on myocardial injury in acute myocardial infarction. Circulation 2021; 144: 859–869.

77.

Cung

Morel

Cayla

, et al. Cyclosporine before PCI in patients with acute myocardial infarction. N Engl J Med 2015; 373: 1021–1031.

78.

Abbate

Trankle

Buckley

, et al. Interleukin-1 blockade inhibits the acute inflammatory response in patients with ST-segment-elevation myocardial infarction. J Am Heart Assoc 2020; 9: e014941.

79.

Del Buono

Garmendia

Seropian

, et al. Heart failure after ST-elevation myocardial infarction: beyond left ventricular adverse remodeling. Curr Probl Cardiol 2022: 101215.

80.

Zornoff

Skali

Pfeffer

, et al. Right ventricular dysfunction and risk of heart failure and mortality after myocardial infarction. J Am Coll Cardiol 2002; 39: 1450–1455.

81.

Anavekar

Skali

Bourgoun

, et al. Usefulness of right ventricular fractional area change to predict death, heart failure, and stroke following myocardial infarction (from the VALIANT ECHO Study). Am J Cardiol 2008; 101: 607–612.

82.

Nagele

Flammer

AJ.

Heart failure after right ventricular myocardial infarction. Curr Heart Fail Rep 2022; 19: 375–385.

83.

Zong

Tune

Downey

HF.

Mechanisms of oxygen demand/supply balance in the right ventricle. Exp Biol Med (Maywood) 2005; 230: 507–519.

84.

Cresci

Goldstein

JA.

Hemodynamic manifestations of ischemic right heart dysfunction. Cathet Cardiovasc Diagn 1992; 27: 28–33; discussion-4.

85.

Lupi-Herrera

Gonzalez-Pacheco

Juarez-Herrera

, et al. Primary reperfusion in acute right ventricular infarction: an observational study. World J Cardiol 2014; 6: 14–22.

86.

Borlaug

Olson

Lam

, et al. Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction. J Am Coll Cardiol 2010; 56: 845–854.

87.

Del Buono

Iannaccone

Scacciavillani

, et al. Heart failure with preserved ejection fraction diagnosis and treatment: an updated review of the evidence. Prog Cardiovasc Dis 2020; 63: 570–584.

88.

Del Buono

Buckley

Abbate

Primary and secondary diastolic dysfunction in heart failure with preserved ejection fraction. Am J Cardiol 2018; 122: 1578–1587.

89.

Gheorghiade

Sopko

De Luca

, et al. Navigating the crossroads of coronary artery disease and heart failure. Circulation 2006; 114: 1202–1213.

90.

Slee

Saad

Saksena

Heart failure progression and mortality in atrial fibrillation patients with preserved or reduced left ventricular ejection fraction. J Interv Card Electrophysiol 2019; 55: 325–331.

91.

Cenko

Van der Schaar

Yoon

, et al. Sex-related differences in heart failure after ST-segment elevation myocardial infarction. J Am Coll Cardiol 2019; 74: 2379–2389.

92.

Taqueti

Shaw

Cook

, et al. Excess cardiovascular risk in women relative to men referred for coronary angiography is associated with severely impaired coronary flow reserve, not obstructive disease. Circulation 2017; 135: 566–577.

93.

Cenko

Bugiardini

Barriers to risk stratification accuracy in ischemic heart disease in women: the role of non-obstructive coronary artery disease. Curr Pharm Des 2016; 22: 3928–3934.

94.

Topel

Hayek

, et al. Sex differences in circulating progenitor cells. J Am Heart Assoc 2017; 6: e006245.

95.

Krumholz

Larson

Levy

Sex differences in cardiac adaptation to isolated systolic hypertension. Am J Cardiol 1993; 72: 310–313.

96.

Nakamura

Sadoshima

Mechanisms of physiological and pathological cardiac hypertrophy. Nat Rev Cardiol 2018; 15: 387–407.

97.

Zhao

Kong

Extracellular matrix remodeling and cardiac fibrosis. Matrix Biol 2018; 68–69: 490–506.

98.

Woulfe KC and Walker LA. Physiology of the right ventricle across the lifespan. Front Physiol 2021; 12: 642284.

99.

Cornwell WK, Tran T, Cerbin Let al. New insights into resting and exertional right ventricular performance in the healthy heart through real-time pressure-volume analysis. J Physiol 2020; 598: 2575–2587.

100.

Setty S, Tune JD and Downey HF. Nitric oxide contributes to oxygen demand-supply balance in hypoperfused right ventricle. Cardiovasc Res 2004; 64: 431–436.

101.

Haupt HM, Hutchins GM and Moore GW. Right ventricular infarction: role of the moderator band artery in determining infarct size. Circulation 1983; 67: 1268–1272.

Mechanism of heart failure after myocardial infarction

Abstract

Keywords

Introduction

AVR

Mechanical agents

Neurohormonal system regulation

Inflammatory immune activation

I/R injury, reactive oxygen species (ROS), and mitochondrial energy metabolism

Genetic regulation

Cardiac adaptive changes under integrated regulation

HF after MI: Beyond AVR

Sex-related differences in prognosis

Discussion

Footnotes

Declaration of conflicting interests

Ethics

Funding

ORCID iD

References