Roles of Autophagy, Mitophagy, and Mitochondria in Left Ventricular Remodeling after Myocardial Infarction

Abstract

This review examines the mechanisms of left ventricular dysfunction, focusing on the interplay between ventricular remodeling, autophagy, and mitochondrial dysfunction following myocardial infarction. Left ventricular dysfunction directly affects the heart’s pumping efficiency and can lead to severe clinical outcomes, including heart failure. After myocardial infarction, the left ventricle may suffer from weakened contractility, diastolic dysfunction, and cardiac remodeling, progressing to heart failure. Thus, this article discusses the pathophysiological processes involved in ventricular remodeling, including the injury and repair of infarcted and non-infarcted myocardia, adaptive changes, and specific changes in left ventricular systolic and diastolic functions. Furthermore, the role of autophagy in maintaining cellular energy homeostasis, clearing dysfunctional mitochondria, and the key role of mitochondrial dysfunction in heart failure is addressed. Finally, this article discusses therapeutic strategies targeting mitochondrial dysfunction and enhancing mitophagy, providing clinicians and researchers with the latest insights and future research directions.

Graphical abstract

Keywords

left ventricular dysfunction / myocardial infarction / autophagy / ventricular remodeling / heart failure / therapeutic strategies

1. Introduction

The left ventricle, as the primary pumping chamber of the heart, is responsible for delivering oxygen and nutrients throughout the body [1]. Its contractile and diastolic functions directly impact the heart’s pumping efficiency and are key indicators for assessing cardiac performance [2]. The normal function of the left ventricle is crucial for the health of the cardiovascular system and its dysfunction can lead to severe clinical consequences, including arrhythmias, heart failure, and sudden death. Therefore, maintaining and improving left ventricular function is essential for the management of cardiovascular diseases [3, 4].

Myocardial infarction (MI) is a severe disease caused by the acute occlusion of the coronary arteries, leading to ischemic necrosis of myocardial cells [5]. It causes local myocardial tissue damage and also triggers complex biological reactions that affect the infarcted area, the entire left ventricle [6, 7]. Consequently, left ventricular function may be severely compromised, characterized by weakened contractility, diastolic dysfunction, and cardiac remodeling [8]. These alterations can eventually progress to heart failure, severely affecting patients’ quality of life and prognosis [9]. The death of myocardial cells after myocardial infarction triggers a series of complex biological reactions, including inflammation, apoptosis, and ventricular remodeling, which collectively affect left ventricular function [10].

Autophagy, particularly mitophagy, is integral to maintaining cellular energy homeostasis and facilitating the removal of dysfunctional mitochondria [11]. Autophagy is a lysosome-mediated pathway that helps eliminate damaged organelles, and mitophagy specifically targets mitochondria, which is essential for optimizing cardiac function [12]. Enhancing autophagy and mitophagy can combat ischemic heart disease and improve cardiac function after myocardial infarction [13, 14]. For example, berberine promotes autophagy and reduces left ventricular remodeling and dysfunction after myocardial infarction [15]. Under hypoxic conditions, FUN14 domain-containing protein 1 (Fundc1)-mediated mitophagy helps restore mitochondrial function and protect cardiomyocytes from ischemic injury [16]. Therapeutically improving mitophagy may be an effective strategy for treating heart failure and improving outcomes after myocardial infarction. For instance, studies have shown that treatments inhibiting mitochondrial oxidative stress or promoting Fundc1-mediated mitophagy show promise in preventing heart failure and improving cardiac function [17, 18].

This review explores the mechanisms underlying left ventricular dysfunction following myocardial infarction, with a particular focus on ventricular remodeling, autophagy, and mitochondrial dysfunction. By integrating current scientific literature and recent research advancements, it offers clinicians and researchers the latest insights into the pathophysiology of left ventricular dysfunction, therapeutic strategies, and directions for future research.

2. Changes in Left Ventricular Function after Myocardial Infarction

2.1 Pathophysiological Process of Ventricular Remodeling

2.1.1 Injury and Repair of Infarcted Myocardium

After myocardial infarction, the cardiac injury repair process is a complex multi-stage pathophysiological process involving inflammation, neovascularization, and myocardial regeneration [19]. In the acute phases following myocardial infarction, neutrophils rapidly infiltrate the infarct area, triggering local inflammation and releasing matrix metalloproteinases (MMPs), neutrophil elastase (NE), and other enzymes that help phagocytize and remove dead myocardial cells and matrix debris [20, 21]. Subsequently, monocytes and M1-type macrophages are recruited to the infarct area, expressing pro-inflammatory factors such as tumor necrosis factor (TNF), further intensifying the inflammatory response [22]. In the late stage of inflammation, neutrophils undergo apoptosis, promoting macrophage polarization and transformation into anti-inflammatory M2-type macrophages, which express anti-inflammatory, profibrotic, and vascular endothelial growth factor (VEGF), promoting the resolution of inflammation [23, 24]. These cytokines and growth factors collectively stimulate the proliferation of fibroblasts and endothelial cells, initiating the cardiac repair phase. This process involves the formation of new blood vessels and a temporary extracellular matrix (ECM), ultimately leading to scar tissue formation, promoting myocardial fibrosis, and mitigating myocardial rupture [25, 26]. Left ventricular remodeling and dysfunction are the primary complications following myocardial infarction, characterized by left ventricular cavity dilation, wall thinning, and contractile dysfunction [27, 28]. For example, compared with sham-operated rats, the left ventricular ejection fraction (LVEF) of rats after myocardial infarction decreased by an average of 61%. Overexpression of peroxiredoxin-3 (Prx-3) has been shown to inhibit left ventricular remodeling and heart failure by reducing myocardial cell hypertrophy, interstitial fibrosis, and apoptosis [29]. The inflammatory response triggered by myocardial infarction aims to clear necrotic debris, followed by an anti-inflammatory repair phase [30]. An imbalance in inflammation regulation may exacerbate the infarct area, promote myocardial cell death and impair contractile function [31]. Elevated levels of C-reactive protein are associated with poor prognosis in patients with acute myocardial infarction (AMI) and heart failure (HF) [25, 28]. The process of injury and repair of the myocardium in the infarct area is shown in Fig. 1.

Reperfusion of surviving myocardium can improve cardiac function and alleviate symptoms of heart failure. Pharmacological treatment targeting the renin-angiotensin-aldosterone system and \beta-adrenergic receptors can reduce myocardial fibrosis, hypertrophy, and adverse left ventricular remodeling [32]. Anti-inflammatory treatments, such as interleukin-1 \beta (IL-1\beta) monoclonal antibody and low-dose colchicine, have shown efficacy in reducing adverse cardiovascular events after myocardial infarction [33]. Mitochondrial dysfunction is a key factor in ischemic injury and heart failure [34]. After myocardial infarction, a reduction in mitochondrial DNA copy number and enzyme leads to cell death and impaired cardiac function. Interventions targeting mitochondrial oxidative stress, such as Prx-3 overexpression, can ameliorate these effects [35, 36]. Cardiac remodeling and heart failure are the main drivers of chronic heart failure after myocardial infarction, caused by sustained ischemic injury, leading to myocardial damage, oxidative stress, inflammation, and mitochondrial dysfunction [37, 38]. These factors collectively promote adverse left ventricular remodeling, increase wall stress, and impair cardiac function.

2.1.2 Adaptive Changes in Non-Infarcted Myocardium

Adaptive changes in non-infarcted myocardium following myocardial infarction significantly impact cardiac function and remodeling processes. These changes include myocardial cell hypertrophy, apoptosis, and diffuse fibrosis, which collectively act to maintain the overall function of the heart. Initially, myocardial cell hypertrophy is a key feature of ventricular remodeling, involving an increase in the volume of non-infarcted myocardial cells to compensate for the lost contractility in the infarcted area [39, 40]. This hypertrophy, while initially helpful in maintaining cardiac pumping function, ultimately leads to myocardial cell dysfunction and further deterioration of cardiac function [41, 42]. Enlarged myocardial cells experience disruptions in energy metabolism, leading to a decline in contractile function. This process resembles the gene regulation observed in fetal and early neonatal cells, which grow in a more elongated shape. However, these embryonic isoforms are prone to fatigue, accelerating myocardial cell dysfunction and reducing their life span [43]. Secondly, fibrosis in non-infarcted myocardium is also an important feature of ventricular remodeling. The increased fibrotic tissue leads to increased heart stiffness, affecting the heart’s diastolic and systolic functions [44]. After myocardial infarction, collagenase activation in the infarct area, collagen fiber degradation, and insufficient collagen matrix contributes to progressive thinning of the infarct area, and ventricular dilation [45]. Conversely, increased collagen content can stiffen the ventricular wall, reduce ventricular compliance, and result in diastolic dysfunction [46].

Additionally, autophagy in non-infarcted myocardium plays a crucial role in ventricular remodeling. By removing damaged organelles and proteins, autophagy helps maintain cellular homeostasis and is closely linked to processes such as growth, development, differentiation, and aging. However, its dysregulation can contribute to myocardial cell death and various diseases [47, 48]. In ventricular remodeling, left ventricular dilation, increased wall stress, and changes in cardiac geometry are also important pathophysiological changes [49]. These changes cause the heart to shift from an elliptical to a spherical shape leading to increased myocardial wall mass and left ventricular enlargement. Additionally, dysfunction in non-infarcted myocardium may arise due to variations in local wall stress distribution, which can trigger fundamental biochemical and cellular alterations, such as myocardial hypertrophy and apoptosis [50].

2.2 Specific Changes in Left Ventricular Function

2.2.1 Changes in Systolic Function

Myocardial infarction significantly affects the systolic function of the left ventricle, leading to a decrease in LVEF. This decrease directly reflects a weakening of myocardial contractility. LVEF is an important indicator for assessing left ventricular systolic function, and its decrease means reduced cardiac pumping capacity and cardiac output [51]. Myocardial cell necrosis and stunning contribute to left ventricular systolic dysfunction, and local wall motion abnormalities are also prevalent, which may suggest potential coronary heart disease, Takotsubo syndrome, or myocarditis [52]. Echocardiography is the preferred method for assessing cardiac structure and systolic function, providing information about left ventricular hypertrophy and local wall motion abnormalities [53]. Study has shown that guided exercise rehabilitation can significantly improve left ventricular systolic function in patients with AMI, with a significant decrease in N-terminal pro-brain natriuretic peptide (NT-proBNP) levels in the exercise group and a stable left ventricular diastolic diameter (LVDd). In contrast, the control group showed an increase in LVDd [54]. Moreover, early cardiac rehabilitation and timely revascularization, including percutaneous coronary intervention (PCI), can reduce myocardial scar and improve LVEF by preventing myocardial cell apoptosis and promoting the repair of ischemic myocardium [55]. Stent implantation significantly reduces left ventricular volume in AMI patients and improves systolic and diastolic functions over time [56]. PCI performed within 12 hours of the onset of AMI can significantly reduce brain natriuretic peptide (BNP) levels and improve left ventricular function. When compared to conservative treatment, selective PCI demonstrates greater efficacy in enhancing LVEF while reducing left ventricular end-systolic volume (LVESV) and end-diastolic volume (LVEDV) [57]. Additionally, a history of angina, particularly pre-infarction angina, is associated with better collateral circulation in the coronary arteries and higher LVEF after AMI, thereby offering protective effects for cardiac function [58]. Myocardial remodeling after AMI involves an increase in myocardial cell proliferation and actin expression, helping hypertrophy and functional maintenance in non-infarcted areas [59]. Quantitative tissue velocity imaging (QTVI) effectively assesses left ventricular systolic dysfunction and in AMI patients, with significant differences in end-diastolic volume (EDV), end-systolic volume (ESV), and ejection fraction (EF) compared to healthy individuals [60]. Thrombolytic therapy helps reperfusion of the infarct-related artery, reduces infarct size, limits left ventricular remodeling, and maintains cardiac function [61]. Basic mitral regurgitation (MR) and its development after AMI are related to left ventricular size, shape, and function, affecting cardiovascular outcomes [62]. An increase in VEGF and granulocyte colony-stimulating factor (G-CSF) levels after PCI is related to the improvement of LVEF, indicating their role in myocardial repair and neovascularization [63]. AMI patients with ventricular arrhythmias show reduced heart rate variability and reduced LVEF, with an increased incidence of early repolarization and fragmented QRS waves [64]. Autologous bone marrow stem cell transplantation enhances segmental myocardial function and LVEF following AMI, as assessed by tissue tracking and myocardial perfusion imaging [65]. Additionally, rescue PCI after failed thrombolysis significantly improves cardiac function compared to delayed PCI, with benefits sustained for at least six months [66].

2.2.2 Impact on Diastolic Function

Diastolic dysfunction after myocardial infarction is a complex process involving changes in cardiac structure and function. This injury is often manifested as increased left ventricular filling pressure, affecting cardiac filling and diastolic end-pressure [67]. Diastolic dysfunction is closely related to the severity and prognosis of heart failure and is an indispensable part of heart failure treatment. Cardiac magnetic resonance (CMR) imaging and echocardiography play important roles in assessing left ventricular diastolic function [68]. Strain analysis of CMR can detect early systolic and diastolic strain injuries, providing a new perspective on the assessment of diastolic function [69]. Echocardiographic indicators for assessing left ventricular diastolic function are divided into primary and secondary indicators, including mitral valve diastolic flow velocity (E peak, A peak) and mitral valve E peak deceleration time (DT) [70]. These indicators help determine filling types and further judge filling pressure related to prognosis.

Echocardiography, as a non-invasive and simple means, can effectively reflect cardiac function. However, there are certain defects in the commonly used ultrasound indicators during ventricular remodeling after myocardial infarction. Cardiac remodeling is a global phenomenon that also involves the left atrium and the mitral apparatus. Different remodeling patterns have been identified, showing that cases with increased left ventricular end-diastolic volume index (LVEDVI) and normal left ventricular end-systolic volume index (LVESVI) have the smallest infarct size and better hemodynamics compared to cases with increased LVESVI and normal LVEDVI. The current patterns of cardiac remodeling are not clearly defined after myocardial infarction, which limits the application of echocardiographic imaging in assessing the severity of remodeling [71]. The Tei index, as a new evaluation index, can comprehensively evaluate the systolic and diastolic functions of the ventricles and is not affected by cardiac geometry, heart rate, blood pressure, etc [72].

2.2.3 Cardiac Remodeling and Functional Failure

Cardiac remodeling after myocardial infarction is a complex process involving changes in the size, shape, structure, and function of the heart, including left ventricular enlargement, reduced LVEF, and local wall motion abnormalities [73, 74]. Cardiac remodeling not only affects the redistribution of myocardial cells, interstitial cells, and blood vessels but also leads to increased heart stiffness and decreased contractility [75, 76]. The latest research indicates that in the process of cardiac remodeling, myocardial cell hypertrophy, apoptosis, fibrosis remodeling, vascular remodeling, and electrical signal remodeling all play a role [77, 78]. Cardiac remodeling is the main factor determining the incidence and long-term prognosis of cardiac events after myocardial infarction and is an independent predictor of heart failure [79, 80]. Loss and dysfunction of cardiomyocytes due to oxygen deprivation or lack of blood flow can initiate a series of events leading to cardiac remodeling. This process is marked by the pathological enlargement of cardiomyocytes, regulated by pathways like calcium-dependent excitation-transcription coupling [78]. Additionally, cardiac fibrosis, characterized by the abnormal accumulation of extracellular matrix, is a key part of remodeling, mainly driven by cardiac fibroblasts [72, 78]. Inflammation also plays a significant role, with white blood cells contributing to remodeling through the release of cytokines and chemokines [78]. The molecular mechanisms of cardiac remodeling are shown in Fig. 2.

Prevention and treatment strategies for cardiac remodeling include pharmacological treatment, interventional treatment, and lifestyle adjustments, aiming to improve cardiac structure and function, prevent or reverse cardiac remodeling, and reduce the occurrence and development of heart failure [79]. Recent research indicates that the novel aminopeptidase A inhibitor Firibastat is not superior to ramipril in preventing left ventricular dysfunction after acute myocardial infarction. However, it has a comparable safety profile, effectively inhibits angiotensin II, and may contribute to improved myocardial remodeling [80]. In addition, the molecular mechanisms of cardiac remodeling involve various pathophysiological stimuli, including myocardial cell loss, cardiac hypertrophy, changes in extracellular matrix homeostasis, fibrosis, autophagy deficiency, metabolic abnormalities, and mitochondrial dysfunction [81]. These processes may initially serve as protective compensatory mechanisms for the heart, but if prolonged, they can lead to the progression of heart failure.

3. The Role of Autophagy in Ventricular Remodeling

3.1 Definition and Physiological Functions of Autophagy

Autophagy is an intracellular process responsible for the degradation and recycling of damaged or excess organelles, serving as a vital component of the cell’s internal cleaning and recycling system. This process plays a crucial role in maintaining cellular homeostasis, promoting cell survival under nutrient deficiency, and responding to cytotoxic stimuli [82, 83]. This degradation and recycling of unnecessary or dysfunctional cellular components occurs through the formation of autophagosomes, which then fuse with lysosomes to achieve the degradation of its contents.

The physiological functions of autophagy mainly include maintaining cellular survival and homeostasis, cardiac protection, regulating cell death, participating in immune responses, and metabolic regulation [82]. In terms of cardiac protection, autophagy plays a protective role during MI by degrading and recycling cellular components, reducing cell death, and improving cardiac function [84]. Autophagy is also involved in regulating various cell death mechanisms, including apoptosis and necrosis, affecting the balance of cell survival and death. Additionally, it also plays a significant role in immune responses, including the regulation of inflammation and the function of immune cells such as macrophages [85]. In terms of metabolic regulation, autophagy affects processes such as oxidative phosphorylation and glycolysis, which are crucial for energy production and cellular function.

Autophagy also plays an important role in cardiac remodeling [86]. After myocardial infarction, autophagy helps maintain cardiac function by promoting the clearance of damaged cells and reducing scar size [86, 87, 88]. Autophagy interacts with other cell death mechanisms such as apoptosis and necrosis, and its regulation can affect the overall outcome of cardiac remodeling and function [87]. In terms of molecular mechanisms, autophagy involves the formation and removal of autophagosomes [86]. If this process is impaired, it may lead to the accumulation of autophagosomes and cellular dysfunction. Autophagy is also regulated by various signaling pathways, including mechanistic target of rapamycin (mTOR) and adenosine 5’-monophosphate-activated protein kinase (AMPK), which affect cellular metabolism and stress responses [87].

Mitophagy, as a selective form of autophagy, specifically targets damaged mitochondria and is particularly important for maintaining cardiovascular homeostasis due to the high energy demands of the cardiovascular system [88]. As the myocardium is a metabolically active tissue with high oxidative demands, mitochondria play a central role in maintaining optimal cardiac function. The accumulation of dysfunctional mitochondria is involved in the pathophysiology of cardiovascular diseases, including myocardial infarction, cardiomyopathy, and heart failure [88]. After myocardial infarction, the increase in mitophagy and mitochondrial biogenesis indicates that mitochondria play a key role in cardiac remodeling, and enhanced mitophagy repairs mitochondrial homeostasis by clearing abnormal mitochondria [89]. Mitophagy plays a significant role in diseases such as myocardial infarction, heart failure, and atherosclerosis, and its main regulatory pathways have been widely studied, revealing the close connection between mitophagy and cardiovascular diseases [89]. Additionally, autophagy in the tumor microenvironment, under metabolic stress, allows tumor cells to primarily use glycolysis as a source of energy metabolism [90]. Autophagy supplies energy by recycling metabolites to increase their survival rate. The study further emphasizes the importance of autophagy in maintaining cellular homeostasis and responding to different physiological and pathological states [91]. As research on autophagy mechanisms continues to deepen, the regulation of autophagy provides new perspectives and potential therapeutic strategies for the treatment of cardiovascular diseases [92].

3.2 The Role of Autophagy in Ventricular Remodeling After Myocardial Infarction

3.2.1 Autophagy and Myocardial Cell Survival and Death

After myocardial infarction, myocardial cells face the severe challenges of ischemia and energy deficiency, and autophagy plays a complex and crucial role in this process. Autophagy is an intracellular degradation and recycling mechanism that maintains intracellular homeostasis by clearing damaged organelles and misfolded proteins [93]. In the context of myocardial infarction, activation of autophagy helps protect myocardial cells by clearing harmful substances that induce myocardial cell death, thus maintaining cell survival and function [94, 95]. However, excessive activation of autophagy can result in uncontrolled degradation of cellular materials, leading to cellular dysfunction and death. This form of cell death, known as Type II programmed cell death, occurs when excessive autophagy exacerbates myocardial injury, further compromising cardiac function [96]. In myocardial infarction models, excessive autophagy activation is associated with decreased myocardial cell survival rates and impaired heart function.

The beneficial effects of autophagy on left ventricular function have also been studied. Research indicates that the activation of autophagy can improve left ventricular function after myocardial infarction. For example, overexpression of miR-99a promotes autophagy, leading to significant improvements in ejection fraction and fractional shortening in mice [97]. Similarly, the upregulation of cathepsin D (CTSD) (a lysosomal protease) enhances autophagic flux, combating cardiac remodeling and dysfunction. In terms of therapeutic intervention, strategies such as adenovirus-mediated hepatocyte growth factor (Ad-HGF) have been found to improve cardiac remodeling and protect cardiac function by promoting autophagy and necroptosis while inhibiting apoptosis [98]. Additionally, delivery of miR-24 after infarction reduces infarct size and improves cardiac function by downregulating pro-apoptotic proteins [99].

The beneficial effects of autophagy on left ventricular function are mediated through various molecular pathways, including the mTOR/P70/S6K (P70/S6K, p70 ribosomal protein S6 kinase) signaling pathway, and involve the regulation of subcellular organelles crucial for myocardial cell function [100]. Clinically, inhibiting myocardial cell apoptosis and promoting autophagy is crucial for reducing cardiac remodeling and improving heart function, highlighting the potential of autophagy-targeted therapeutic strategies in managing heart failure after myocardial infarction [101]. The latest research also indicates that mitophagy, as a selective form of autophagy, plays a key role in clearing damaged mitochondria and maintaining mitochondrial number and function [102]. After myocardial infarction, myocardial cells undergo ischemia and reperfusion injury, accompanied by abnormal mitochondrial function and increased numbers, leading to the formation of myocardial fibrosis. The activation of mitophagy has potential therapeutic value for improving myocardial injury and fibrosis.

3.2.2 Autophagy’s Role in Cardiac Remodeling

Autophagy plays a significant role in the process of cardiac remodeling, protecting myocardial cells by clearing damaged organelles and misfolded proteins [99, 101]. The mechanism of autophagy in myocardial remodeling involves the p-PI3K/Akt (p-PI3K, phosphorylated phosphatidylinositol 3-Kinase; Akt, protein kinase B) signaling pathway and the phosphorylation status of p-mTOR, which together regulate the process of autophagy and affect the survival and apoptosis of cardiomyocytes [99]. When the p-PI3K/Akt pathway is activated in cardiomyocytes, it can promote the formation of autophagosomes by inhibiting mTOR, thereby promoting cell survival. The formation of autophagosomes is a key step in the process of autophagy, which relies on the precise regulation of a series of autophagy-related genes (ATGs) [99]. After myocardial infarction, moderate autophagy clears damaged proteins and organelles, enhances metabolic adaptability, protects cardiomyocytes, and reduces cardiac remodeling. p-mTOR plays a central role in regulating autophagy with its phosphorylation status determining autophagy activation [99, 100]. The mechanism of autophagy in myocardial remodeling is shown in Fig. 3, highlighting its dual effects. While moderate autophagy activation supports myocardial cell survival and cardiac function, excessive autophagy may lead to cellular dysfunction and death [102, 103]. This protective effect of autophagy is especially significant in cardiac function post-myocardial infarction. For instance, overexpression of miR-99a promotes autophagy, improving survival rates and cardiac function in mice after myocardial infarction, possibly through the mTOR/P70/S6K signaling pathway [104]. Additionally, Ad-HGF treatment improves cardiac remodeling, helps maintain cardiac function, reduces scar size, and decreases aggregates in cardiac tissue by promoting autophagy and necroptosis while inhibiting apoptosis [105, 106].

4. Discussion and Outlook

After myocardial infarction, the process of autophagy, mitophagy, and mitochondrial function are intricately interconnected and play pivotal roles in ventricular remodeling. It is evident that these processes are not merely passive responses to cardiac injury but actively contribute to the pathogenesis and the development of potential therapeutic interventions. Autophagy and mitophagy, in particular, emerge as double-edged swords, with their moderate activation being cardioprotective and their dysregulation contributing to maladaptive remodeling.

Future research should focus on elucidating the precise molecular mechanisms that govern the balance between the protective and detrimental effects of autophagy and mitophagy. Additionally, there is a pressing need for clinical trials to validate the safety and efficacy of novel therapeutics aimed at modulating these pathways in patients post-myocardial infarction. The advent of precision medicine offers a promising avenue for personalized treatment strategies, where the baseline autophagy and mitophagy profiles of individual patients could inform tailored interventions. Moreover, the intersection of mitochondrial biology with emerging technologies such as gene editing and stem cell therapy opens up new frontiers in regenerative cardiology.

Current therapies for cardiac remodeling have shown moderate results. Identifying new factors, such as autophagy, that regulate inflammation and repair responses may provide new therapeutic targets to prevent adverse remodeling and heart failure [107]. The latest research indicates that exercise can regulate autophagy levels or autophagic flux, improving cardiac function and having a certain therapeutic and guiding effect on cardiovascular diseases [108]. Exercise upregulates mitochondrial autophagy through the FNDC5/Irisin-PINK1/Parkin-LC3II/L-P62 (FNDC5, fibronectin type III domain containing 5; PINK1, PTEN-induced kinase 1; LC3II, microtubule-associated protein 1 light chain 3-II; L-P62, lipidated p62) signaling pathway, enhances antioxidant capacity, inhibits oxidative stress, and improves cardiac function [109]. These findings provide a new perspective for the treatment of cardiac remodeling, emphasizing the importance of autophagy in cardiac remodeling and offering new targets for future therapeutic strategies.

5. Conclusion

Left ventricular dysfunction, frequently resulting from post-myocardial infarction remodeling, is a significant risk factor for cardiovascular health, potentially leading to heart failure. Effective management of this condition, incorporating pharmacological, treatments, interventional therapies, and lifestyle changes, is crucial to prevent further remodeling and heart failure. Autophagy and mitochondrial function are crucial in this process. Autophagy when balanced, plays a protective role, but excessive activation can lead to detrimental effects. Given the central role of mitochondria in cardiac remodeling, regulating these processes offers promising strategies for treatment. The content summary of this article is presented in Table 1 (Ref. [11, 12, 13, 14, 19, 20, 21, 22, 25, 26, 27, 28, 31, 32, 33, 34, 35, 36, 37, 38]).

References

[1] He J, Lu Y, Song X, Gong X, Li Y. Inhibition of microRNA-146a attenuated heart failure in myocardial infarction rats. Bioscience Reports. 2019; 39: BSR20191732. https://doi.org/10.1042/BSR20191732.

[2] Stujanna EN, Murakoshi N, Tajiri K, Xu D, Kimura T, Qin R, et al. Rev-erb agonist improves adverse cardiac remodeling and survival in myocardial infarction through an anti-inflammatory mechanism. PloS One. 2017; 12: e0189330. https://doi.org/10.1371/journal.pone.0189330.

[3] Heusch G. Coronary blood flow in heart failure: cause, consequence and bystander. Basic Research in Cardiology. 2022; 117: 1. https://doi.org/10.1007/s00395-022-00909-8.

[4] Arriagada C, Lin E, Schonning M, Astrof S. Mesodermal fibronectin controls cell shape, polarity, and mechanotransduction in the second heart field during cardiac outflow tract development. Developmental Cell. 2025; 60: 62–84.e7. https://doi.org/10.1016/j.devcel.2024.09.017.

[5] Anker MS, Rashid AM, Butler J, Khan MS. Cardiac wasting in patients with cancer. Basic Research in Cardiology. 2025; 120: 25–34. https://doi.org/10.1007/s00395-024-01079-5.

[6] Zhang CH, Li TT. ST-Segment Elevation Myocardial Infarction Mimic: Unearthing the Hidden Truth. JAMA Internal Medicine. 2021; 181: 1509–1510. https://doi.org/10.1001/jamainternmed.2021.4427.

[7] Liu S, Chen X, Bao L, Liu T, Yuan P, Yang X, et al. Treatment of infarcted heart tissue via the capture and local delivery of circulating exosomes through antibody-conjugated magnetic nanoparticles. Nature Biomedical Engineering. 2020; 4: 1063–1075. https://doi.org/10.1038/s41551-020-00637-1.

[8] Chang Q, Pan D, Liu R. Unusual Electrocardiographic Findings in a Patient With a Postmyocardial Infarction. JAMA Internal Medicine. 2020; 180: 1680–1681. https://doi.org/10.1001/jamainternmed.2020.1890.

[9] Thavapalachandran S, Grieve SM, Hume RD, Le TYL, Raguram K, Hudson JE, et al. Platelet-derived growth factor-AB improves scar mechanics and vascularity after myocardial infarction. Science Translational Medicine. 2020; 12: eaay2140. https://doi.org/10.1126/scitranslmed.aay2140.

[10] Lin X, Liu Y, Bai A, Cai H, Bai Y, Jiang W, et al. A viscoelastic adhesive epicardial patch for treating myocardial infarction. Nature Biomedical Engineering. 2019; 3: 632–643. https://doi.org/10.1038/s41551-019-0380-9.

[11] Ke J, Pan J, Lin H, Huang S, Zhang J, Wang C, et al. Targeting Rab7-Rilp mediated microlipophagy alleviates lipid toxicity in diabetic cardiomyopathy. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2024; 11: e2401676. https://doi.org/10.1002/advs.202401676.

[12] Wang Y, Song Y, Xu L, Zhou W, Wang W, Jin Q, et al. A membrane-targeting aggregation-induced emission probe for monitoring lipid droplet dynamics in ischemia/reperfusion-induced cardiomyocyte ferroptosis. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2024; 11: e2309907. https://doi.org/10.1002/advs.202309907.

[13] Barcena ML, Aslam M, Norman K, Ott C, Ladilov Y. Role of AMPK and sirtuins in aging heart: basic and translational aspects. Aging and Disease. 2024. https://doi.org/10.14336/AD.2024.1216. (online ahead of print)

[14] Liu J, Wu Y, Meng S, Xu P, Li S, Li Y, et al. Selective autophagy in cancer: mechanisms, therapeutic implications, and future perspectives. Molecular Cancer. 2024; 23: 22. https://doi.org/10.1186/s12943-024-01934-y.

[15] Helal AM, Yossef MM, Seif IK, Abd El-Salam M, El Demellawy MA, Abdulmalek SA, et al. Nanostructured biloalbuminosomes loaded with berberine and berberrubine for Alleviating heavy Metal-Induced male infertility in rats. International Journal of Pharmaceutics. 2024; 667: 124892. https://doi.org/10.1016/j.ijpharm.2024.124892.

[16] Patel RB. Mechanistic Insights of SGLT2 Inhibition in heart failure through proteomics: appreciating the cardiovascular-kidney connection. Journal of the American College of Cardiology. 2024; 84: 1995–1998. https://doi.org/10.1016/j.jacc.2024.07.030.

[17] Packer M, Ferreira JP, Butler J, Filippatos G, Januzzi JL, Jr, González Maldonado S, et al. Reaffirmation of mechanistic proteomic signatures accompanying SGLT2 inhibition in patients with heart failure: a validation cohort of the EMPEROR program. Journal of the American College of Cardiology. 2024; 84: 1979–1994. https://doi.org/10.1016/j.jacc.2024.07.013.

[18] Zhang Q, Yaoita N, Tabuchi A, Liu S, Chen SH, Li Q, et al. Endothelial heterogeneity in the response to autophagy drives small vessel muscularization in pulmonary hypertension. Circulation. 2024; 150: 466–487. https://doi.org/10.1161/CIRCULATIONAHA.124.068726.

[19] Benkhoff M, Polzin A. Lipoprotection in cardiovascular diseases. Pharmacology & Therapeutics. 2024; 264: 108747. https://doi.org/10.1016/j.pharmthera.2024.108747.

[20] Liu Q, Huang J, Ding H, Tao Y, Nan J, Xiao C, et al. Flavin-containing monooxygenase 2 confers cardioprotection in ischemia models through its disulfide bond catalytic activity. The Journal of Clinical Investigation. 2024; 134: e177077. https://doi.org/10.1172/JCI177077.

[21] Li J, Yao Y, Zhou J, Yang Z, Qiu C, Lu Y, et al. Epicardial transplantation of antioxidant polyurethane scaffold based human amniotic epithelial stem cell patch for myocardial infarction treatment. Nature Communications. 2024; 15: 9105. https://doi.org/10.1038/s41467-024-53531-8.

[22] Wang K, Sun Y, Zhu K, Liu Y, Zheng X, Yang Z, et al. Anti-pyroptosis biomimetic nanoplatform loading puerarin for myocardial infarction repair: From drug discovery to drug delivery. Biomaterials. 2025; 314: 122890. https://doi.org/10.1016/j.biomaterials.2024.122890.

[23] Melot A, Groussin P, Martins RP. Ventricular septal rupture after ST-segment elevation myocardial infarction. JAMA Cardiology. 2024; 9: 1169. https://doi.org/10.1001/jamacardio.2024.3308.

[24] Biscaglia S, Erriquez A, Campo G. Frailty in an elderly cohort with myocardial infarction and high bleeding risk-reply. JAMA Cardiology. 2024; 9: 1170–1171. https://doi.org/10.1001/jamacardio.2024.3020.

[25] Kim C, Kim H, Sim WS, Jung M, Hong J, Moon S, et al. Spatiotemporal control of neutrophil fate to tune inflammation and repair for myocardial infarction therapy. Nature Communications. 2024; 15: 8481. https://doi.org/10.1038/s41467-024-52812-6.

[26] Cui X, Guo J, Yuan P, Dai Y, Du P, Yu F, et al. Bioderived nanoparticles for cardiac repair. ACS Nano. 2024; 18: 24622–24649. https://doi.org/10.1021/acsnano.3c07878.

[27] Silvain J, Cayla G, Ferrari E, Range G, Puymirat E, Delarche N, et al. Beta-blocker interruption or continuation after myocardial infarction. The New England Journal of Medicine. 2024; 391: 1277–1286. https://doi.org/10.1056/NEJMoa2404204.

[28] King G, Hamilton GW. Left ventricular thrombus after anterior myocardial infarction. The New England Journal of Medicine. 2024; 390: e50. https://doi.org/10.1056/NEJMicm2308972.

[29] Rouleau J. Decreasing the risk of heart failure in a changing post-myocardial infarction environment. The New England Journal of Medicine. 2024; 390: 1524–1526. https://doi.org/10.1056/NEJMe2402719.

[30] Pfeffer MA, Claggett B, Lewis EF, Granger CB, Køber L, Maggioni AP, et al. Angiotensin receptor-neprilysin inhibition in acute myocardial infarction. The New England Journal of Medicine. 2021; 385: 1845–1855. https://doi.org/10.1056/NEJMoa2104508.

[31] Jabbar A, Ingoe L, Junejo S, Carey P, Addison C, Thomas H, et al. Effect of levothyroxine on left ventricular ejection fraction in patients with subclinical hypothyroidism and acute myocardial infarction: a randomized clinical trial. JAMA. 2020; 324: 249–258. https://doi.org/10.1001/jama.2020.9389.

[32] Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT. Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. The Cochrane Database of Systematic Reviews. 2018; 6: CD012721. https://doi.org/10.1002/14651858.CD012721.pub3.

[33] Widjaja AA, Lim WW, Viswanathan S, Chothani S, Corden B, Dasan CM, et al. Inhibition of IL-11 signalling extends mammalian healthspan and lifespan. Nature. 2024; 632: 157–165. https://doi.org/10.1038/s41586-024-07701-9.

[34] West EE, Woodruff T, Fremeaux-Bacchi V, Kemper C. Complement in human disease: approved and up-and-coming therapeutics. Lancet (London, England). 2024; 403: 392–405. https://doi.org/10.1016/S0140-6736(23)01524-6.

[35] Bapat SP, Whitty C, Mowery CT, Liang Y, Yoo A, Jiang Z, et al. Obesity alters pathology and treatment response in inflammatory disease. Nature. 2022; 604: 337–342. https://doi.org/10.1038/s41586-022-04536-0.

[36] Ridker PM, Devalaraja M, Baeres FMM, Engelmann MDM, Hovingh GK, Ivkovic M, et al. IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial. Lancet (London, England). 2021; 397: 2060–2069. https://doi.org/10.1016/S0140-6736(21)00520-1.

[37] Yusuf S, Joseph P, Pais P. Polypill in persons without cardiovascular disease. Reply. The New England Journal of Medicine. 2021; 384: 1676–1677. https://doi.org/10.1056/NEJMc2102972.

[38] Thomsen M, Ingebrigtsen TS, Marott JL, Dahl M, Lange P, Vestbo J, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013; 309: 2353–2361. https://doi.org/10.1001/jama.2013.5732.

[39] Zafeiropoulos S, Ahmed U, Bekiaridou A, Jayaprakash N, Mughrabi IT, Saleknezhad N, et al. Ultrasound neuromodulation of an anti-inflammatory pathway at the spleen improves experimental pulmonary hypertension. Circulation Research. 2024; 135: 41–56. https://doi.org/10.1161/CIRCRESAHA.123.323679.

[40] Xu GE, Yu P, Hu Y, Wan W, Shen K, Cui X, et al. Exercise training decreases lactylation and prevents myocardial ischemia-reperfusion injury by inhibiting YTHDF2. Basic Research in Cardiology. 2024; 119: 651–671. https://doi.org/10.1007/s00395-024-01044-2.

[41] Packer M. Qiliqiangxin: A multifaceted holistic treatment for heart failure or a pharmacological probe for the identification of cardioprotective mechanisms? European Journal of Heart Failure. 2023; 25: 2130–2143. https://doi.org/10.1002/ejhf.3068.

[42] Chen G, An N, Shen J, Chen H, Chen Y, Sun J, et al. Fibroblast growth factor 18 alleviates stress-induced pathological cardiac hypertrophy in male mice. Nature Communications. 2023; 14: 1235. https://doi.org/10.1038/s41467-023-36895-1.

[43] Cuthbertson I, Morrell NW, Caruso P. BMPR2 mutation and metabolic reprogramming in pulmonary arterial hypertension. Circulation Research. 2023; 132: 109–126. https://doi.org/10.1161/CIRCRESAHA.122.321554.

[44] Wang L, Wang J, Yu P, Feng J, Xu GE, Zhao X, et al. METTL14 is required for exercise-induced cardiac hypertrophy and protects against myocardial ischemia-reperfusion injury. Nature Communications. 2022; 13: 6762. https://doi.org/10.1038/s41467-022-34434-y.

[45] Zhao M, Wei H, Li C, Zhan R, Liu C, Gao J, et al. Gut microbiota production of trimethyl-5-aminovaleric acid reduces fatty acid oxidation and accelerates cardiac hypertrophy. Nature Communications. 2022; 13: 1757. https://doi.org/10.1038/s41467-022-29060-7.

[46] Yokota T, Li J, Huang J, Xiong Z, Zhang Q, Chan T, et al. p38 Mitogen-activated protein kinase regulates chamber-specific perinatal growth in heart. The Journal of Clinical Investigation. 2020; 130: 5287–5301. https://doi.org/10.1172/JCI135859.

[47] Yerra VG, Batchu SN, Kaur H, Kabir MDG, Liu Y, Advani SL, et al. Pressure overload induces ISG15 to facilitate adverse ventricular remodeling and promote heart failure. The Journal of Clinical Investigation. 2023; 133: e161453. https://doi.org/10.1172/JCI161453.

[48] Rose BA, Yokota T, Chintalgattu V, Ren S, Iruela-Arispe L, Khakoo AY, et al. Cardiac myocyte p38α kinase regulates angiogenesis via myocyte-endothelial cell cross-talk during stress-induced remodeling in the heart. The Journal of Biological Chemistry. 2017; 292: 12787–12800. https://doi.org/10.1074/jbc.M117.784553.

[49] Zhang H, Gao Y, Zhang M, Yuan Z, Chen Y, Wang A, et al. Schaftoside improves HFpEF through regulation the autophagy-lysosome pathway by allosterically targeting CaMKII-δ. Redox Biology. 2024; 78: 103424. https://doi.org/10.1016/j.redox.2024.103424.

[50] Han X, Zhang YL, Lin QY, Li HH, Guo SB. ATGL deficiency aggravates pressure overload-triggered myocardial hypertrophic remodeling associated with the proteasome-PTEN-mTOR-autophagy pathway. Cell Biology and Toxicology. 2023; 39: 2113–2131. https://doi.org/10.1007/s10565-022-09699-0.

[51] Pei Z, Xiong Y, Jiang S, Guo R, Jin W, Tao J, et al. Heavy metal scavenger metallothionein rescues against cold stress-evoked myocardial contractile anomalies through regulation of mitophagy. Cardiovascular Toxicology. 2024; 24: 85–101. https://doi.org/10.1007/s12012-023-09823-4.

[52] Zhang YJ, Yang SH, Li MH, Iqbal J, Bourantas CV, Mi QY, et al. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy. Clinical and Experimental Pharmacology & Physiology. 2014; 41: 995–1002. https://doi.org/10.1111/1440-1681.12309.

[53] Yang N, Sun H, Xi L, Zhang L, Lu Y, Wang Q, et al. Oroxin B resembles bisoprolol in attenuating Beta1-adrenergic receptor autoantibody-induced atrial remodelling via the PTEN/AKT/mTOR signalling pathway. Clinical and Experimental Pharmacology & Physiology. 2025; 52: e70011. https://doi.org/10.1111/1440-1681.70011.

[54] Izumida T, Imamura T, Onoda H, Tanaka S, Ushijima R, Ueno H, et al. Effect of optimal heart rate on left ventricular remodeling in patients with systolic heart failure following acute coronary syndrome. International Heart Journal. 2024; 65: 833–840. https://doi.org/10.1536/ihj.24-027.

[55] Zhao WS, Xu L, Wang LF, Zhang L, Zhang ZY, Liu Y, et al. A 60-s postconditioning protocol by percutaneous coronary intervention inhibits myocardial apoptosis in patients with acute myocardial infarction. Apoptosis. 2009; 14: 1204–1211. https://doi.org/10.1007/s10495-009-0387-x.

[56] Aziz F, Tripolt NJ, Pferschy PN, Scharnagl H, Abdellatif M, Oulhaj A, et al. Ketone body levels and its associations with cardiac markers following an acute myocardial infarction: a post hoc analysis of the EMMY trial. Cardiovascular Diabetology. 2024; 23: 145. https://doi.org/10.1186/s12933-024-02221-2.

[57] Zhang X, Dong S, Jia Q, Zhang A, Li Y, Zhu Y, et al. The microRNA in ventricular remodeling: the miR-30 family. Bioscience Reports. 2019; 39: BSR20190788. https://doi.org/10.1042/BSR20190788.

[58] Nishida K, Otsu K. Autophagy during cardiac remodeling. Journal of Molecular and Cellular Cardiology. 2016; 95: 11–18. https://doi.org/10.1016/j.yjmcc.2015.12.003.

[59] Marenzi G, Cosentino N, Genovese S, Campodonico J, De Metrio M, Rondinelli M, et al. Reduced cardio-renal function accounts for most of the in-hospital morbidity and mortality risk among patients with type 2 diabetes undergoing primary percutaneous coronary intervention for st-segment elevation myocardial infarction. Diabetes Care. 2019; 42: 1305–1311. https://doi.org/10.2337/dc19-0047.

[60] Garzillo CL, Hueb W, Gersh B, Rezende PC, Lima EG, Favarato D, et al. Association between stress testing-induced myocardial ischemia and clinical events in patients with multivessel coronary artery disease. JAMA Internal Medicine. 2019; 179: 1345–1351. https://doi.org/10.1001/jamainternmed.2019.2227.

[61] Lin X, Mao Y, Li P, Bai Y, Chen T, Wu K, et al. Ultra-conformable ionic skin with multi-modal sensing, broad-spectrum antimicrobial and regenerative capabilities for smart and expedited wound care. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2021; 8: 2004627. https://doi.org/10.1002/advs.202004627.

[62] Nguyen PD, de Bakker DEM, Bakkers J. Cardiac regenerative capacity: an evolutionary afterthought? Cellular and Molecular Life Sciences: CMLS. 2021; 78: 5107–5122. https://doi.org/10.1007/s00018-021-03831-9.

[63] Gao L, Wang L, Wei Y, Krishnamurthy P, Walcott GP, Menasché P, et al. Exosomes secreted by hiPSC-derived cardiac cells improve recovery from myocardial infarction in swine. Science Translational Medicine. 2020; 12: eaay1318. https://doi.org/10.1126/scitranslmed.aay1318.

[64] Liu S, Li K, Wagner Florencio L, Tang L, Heallen TR, Leach JP, et al. Gene therapy knockdown of Hippo signaling induces cardiomyocyte renewal in pigs after myocardial infarction. Science Translational Medicine. 2021; 13: eabd6892. https://doi.org/10.1126/scitranslmed.abd6892.

[65] Zheng X, Liu L, Liu J, Zhang C, Zhang J, Qi Y, et al. Fibulin7 Mediated pathological cardiac remodeling through egfr binding and egfr-dependent fak/akt signaling activation. Advanced Science (Weinheim, Baden-Wurttemberg, Germany). 2023; 10: e2207631. https://doi.org/10.1002/advs.202207631.

[66] Brown OI, Drozd M, McGowan H, Giannoudi M, Conning-Rowland M, Gierula J, et al. Relationship among diabetes, obesity, and cardiovascular disease phenotypes: a uk biobank cohort study. Diabetes Care. 2023; 46: 1531–1540. https://doi.org/10.2337/dc23-0294.

[67] Winiarczyk M, Dziewięcka E, Wiśniowska-Śmiałek S, Stępień A, Graczyk K, Leśniak-Sobelga A, et al. Left ventricular diastolic dysfunction worsens prognosis in patients with heart failure due to dilated cardiomyopathy. ESC Heart Failure. 2024; 10.1002/ehf2.15119. https://doi.org/10.1002/ehf2.15119.

[68] Wang L, Weber J, Craft J, Passick M, Khalique OK, Ali ZA, et al. Improving the assessment of left ventricular diastolic dysfunction by including left atrial strain in the algorithm. Journal of Cardiac Failure. 2024. https://doi.org/10.1016/j.cardfail.2024.08.064. (online ahead of print)

[69] Li B, Chen M, Huang X. Left atrial function in uraemic patients: Four-dimensional automatic left atrial quantitative technology study. ESC Heart Failure. 2024. https://doi.org/10.1002/ehf2.15146. (online ahead of print)

[70] Carrizales-Sepúlveda EF, Ordaz-Farías A, Vera-Pineda R, Rodríguez-Gutierrez R, Flores-Ramírez R. Comprehensive echocardiographic and biomarker assessment of patients with diabetic ketoacidosis. Cardiovascular Diabetology. 2024; 23: 385. https://doi.org/10.1186/s12933-024-02471-0.

[71] Guan X, Feng P, Lu L, Chang Q. Transesophageal ultrasound study on left ventricular diastolic function and its correlation with thrombus formation in patients with atrial fibrillation. Asian Journal of Surgery. 2024. https://doi.org/10.1016/j.asjsur.2024.10.182. (online ahead of print)

[72] Tam CHT, Lim CKP, Luk AOY, Ng ACW, Lee HM, Jiang G, et al. Development of genome-wide polygenic risk scores for lipid traits and clinical applications for dyslipidemia, subclinical atherosclerosis, and diabetes cardiovascular complications among East Asians. Genome Medicine. 2021; 13: 29. https://doi.org/10.1186/s13073-021-00831-z.

[73] Bashir Z, Shu L, Guo Y, Chen EW, Wang S, Goldstein ED, et al. Left Ventricular diastolic dysfunction with elevated filling pressures is associated with embolic stroke of undetermined source and atrial fibrillation. Tomography (Ann Arbor, Mich.). 2024; 10: 1694–1705. https://doi.org/10.3390/tomography10100124.

[74] Klementsson V, Bhat M, Steding-Ehrenborg K, Hedström E, Liuba P, Sjöberg P. Non-invasive pressure-volume loops show high arterial elastance in children with repaired tetralogy of Fallot. Scandinavian Cardiovascular Journal: SCJ. 2024; 58: 2418085. https://doi.org/10.1080/14017431.2024.2418085.

[75] Furukawa N, Matsui H, Sunaga H, Nagata K, Hirayama M, Obinata H, et al. Sacubitril/valsartan improves diastolic left ventricular stiffness with increased titin phosphorylation via cGMP-PKG activation in diabetic mice. Scientific Reports. 2024; 14: 25081. https://doi.org/10.1038/s41598-024-75757-8.

[76] Bonanni F, Caciolli S, Berteotti M, Grasso Granchietti A, Tozzetti V, Cenni N, et al. Left Ventricular diastolic dysfunction predicts global longitudinal strain recovery after surgical aortic valve replacement. Diagnostics (Basel, Switzerland). 2024; 14: 2176. https://doi.org/10.3390/diagnostics14192176.

[77] Braha A, Timar B, Ivan V, Balica MM, Dăniluc L, Timar R. Novel biomarkers of grade i left ventricular diastolic dysfunction in type 2 diabetes patients with metabolic-dysfunction-associated steatotic liver disease. Journal of Clinical Medicine. 2024; 13: 5901. https://doi.org/10.3390/jcm13195901.

[78] Alexanian M, Padmanabhan A, Nishino T, Travers JG, Ye L, Pelonero A, et al. Chromatin remodelling drives immune cell-fibroblast communication in heart failure. Nature. 2024; 635: 434–443. https://doi.org/10.1038/s41586-024-08085-6.

[79] Delorey TM, Ziegler CGK, Heimberg G, Normand R, Yang Y, Segerstolpe Å et al. COVID-19 tissue atlases reveal SARS-CoV-2 pathology and cellular targets. Nature. 2021; 595: 107–113. https://doi.org/10.1038/s41586-021-03570-8.

[80] Januzzi JL, Jr, Prescott MF, Butler J, Felker GM, Maisel AS, McCague K, et al. Association of change in n-terminal pro-B-type natriuretic peptide following initiation of sacubitril-valsartan treatment with cardiac structure and function in patients with heart failure with reduced ejection fraction. JAMA. 2019; 322: 1085–1095. https://doi.org/10.1001/jama.2019.12821.

[81] Inohara T, Manandhar P, Kosinski AS, Matsouaka RA, Kohsaka S, Mentz RJ, et al. Association of renin-angiotensin inhibitor treatment with mortality and heart failure readmission in patients with transcatheter aortic valve replacement. JAMA. 2018; 320: 2231–2241. https://doi.org/10.1001/jama.2018.18077.

[82] Yoshii A, McMillen TS, Wang Y, Zhou B, Chen H, Banerjee D, et al. Blunted cardiac mitophagy in response to metabolic stress contributes to HFpEF. Circulation Research. 2024; 135: 1004–1017. https://doi.org/10.1161/CIRCRESAHA.123.324103.

[83] Zhu Q, Combs ME, Liu J, Bai X, Wang WB, Herring LE, et al. GRAF1 integrates PINK1-Parkin signaling and actin dynamics to mediate cardiac mitochondrial homeostasis. Nature Communications. 2023; 14: 8187. https://doi.org/10.1038/s41467-023-43889-6.

[84] Dahmane S, Kerviel A, Morado DR, Shankar K, Ahlman B, Lazarou M, et al. Membrane-assisted assembly and selective secretory autophagy of enteroviruses. Nature Communications. 2022; 13: 5986. https://doi.org/10.1038/s41467-022-33483-7.

[85] Kargapolova Y, Rehimi R, Kayserili H, Brühl J, Sofiadis K, Zirkel A, et al. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology. Nature Communications. 2021; 12: 3014. https://doi.org/10.1038/s41467-021-23327-1.

[86] Lerchenmüller C, Rabolli CP, Yeri A, Kitchen R, Salvador AM, Liu LX, et al. CITED4 protects against adverse remodeling in response to physiological and pathological stress. Circulation Research. 2020; 127: 631–646. https://doi.org/10.1161/CIRCRESAHA.119.315881.

[87] Sciarretta S, Forte M, Frati G, Sadoshima J. New Insights Into the Role of mTOR Signaling in the Cardiovascular System. Circulation Research. 2018; 122: 489–505. https://doi.org/10.1161/CIRCRESAHA.117.311147.

[88] Su M, Wang J, Wang C, Wang X, Dong W, Qiu W, et al. MicroRNA-221 inhibits autophagy and promotes heart failure by modulating the p27/CDK2/mTOR axis. Cell Death and Differentiation. 2015; 22: 986–999. https://doi.org/10.1038/cdd.2014.187.

[89] Ruozi G, Bortolotti F, Mura A, Tomczyk M, Falcione A, Martinelli V, et al. Cardioprotective factors against myocardial infarction selected in vivo from an AAV secretome library. Science Translational Medicine. 2022; 14: eabo0699. https://doi.org/10.1126/scitranslmed.abo0699.

[90] Wang L, Ma H, Huang P, Xie Y, Near D, Wang H, et al. Down-regulation of Beclin1 promotes direct cardiac reprogramming. Science Translational Medicine. 2020; 12: eaay7856. https://doi.org/10.1126/scitranslmed.aay7856.

[91] Santulli G. Cardioprotective effects of autophagy: Eat your heart out, heart failure!. Science Translational Medicine. 2018; 10: eaau0462. https://doi.org/10.1126/scitranslmed.aau0462.

[92] Wyant GA, Jiang Q, Singh M, Qayyum S, Levrero C, Maron BA, et al. Induction of DEPP1 by HIF mediates multiple hallmarks of ischemic cardiomyopathy. Circulation. 2024; 150: 770–786. https://doi.org/10.1161/CIRCULATIONAHA.123.066628.

[93] Gao L, Liu W. Knockdown of SDCBP induces autophagy to promote cardiomyocyte growth and angiogenesis in hypoxia/reoxygenation model. Mutation Research. 2024; 829: 111885. https://doi.org/10.1016/j.mrfmmm.2024.111885.

[94] Tao P, Zhang HF, Zhou P, Wang YL, Tan YZ, Wang HJ. Growth differentiation factor 11 alleviates oxidative stress-induced senescence of endothelial progenitor cells via activating autophagy. Stem Cell Research & Therapy. 2024; 15: 370. https://doi.org/10.1186/s13287-024-03975-y.

[95] Yuan Y, Huang H, Hu T, Zou C, Qiao Y, Fang M, et al. Curcumin pretreatment attenuates myocardial ischemia/reperfusion injury by inhibiting ferroptosis, autophagy and apoptosis via HES1. International Journal of Molecular Medicine. 2024; 54: 110. https://doi.org/10.3892/ijmm.2024.5434.

[96] Qi P, Zhang W, Gao Y, Chen S, Jiang M, He R, et al. N6-methyladenosine demethyltransferase FTO alleviates sepsis by upregulating BNIP3 to induce mitophagy. Journal of Cellular Physiology. 2024; 239: e31448. https://doi.org/10.1002/jcp.31448.

[97] Pang Y, Li Q, Wang J, Wang S, Sharma A, Xu Y, et al. An ultrasound-activated supramolecular modulator enhancing autophagy to prevent ventricular arrhythmias post-myocardial infarction. Angewandte Chemie (International Ed. in English). 2024; e202415802. https://doi.org/10.1002/anie.202415802.

[98] Liu S, Liu FZ, Yan JY, Fang X, Xu ZP, Cai HL, et al. The Elabela-APJ axis attenuates sepsis-induced myocardial dysfunction by reducing pyroptosis by balancing the formation and degradation of autophagosomes. Free Radical Biology & Medicine. 2024; 224: 405–417. https://doi.org/10.1016/j.freeradbiomed.2024.09.003.

[99] Peng H, Zhang J, Zhang Z, Turdi S, Han X, Liu Q, et al. Cardiac-specific overexpression of catalase attenuates lipopolysaccharide-induced cardiac anomalies through reconciliation of autophagy and ferroptosis. Life Sciences. 2023; 328: 121821. https://doi.org/10.1016/j.lfs.2023.121821.

[100] Zhang S, Wei X, Zhang H, Wu Y, Jing J, Huang R, et al. Doxorubicin downregulates autophagy to promote apoptosis-induced dilated cardiomyopathy via regulating the AMPK/mTOR pathway. Biomedicine & Pharmacotherapy. 2023; 162: 114691. https://doi.org/10.1016/j.biopha.2023.114691.

[101] Yu X, Yang Y, Chen T, Wang Y, Guo T, Liu Y, et al. Cell death regulation in myocardial toxicity induced by antineoplastic drugs. Frontiers in Cell and Developmental Biology. 2023; 11: 1075917. https://doi.org/10.3389/fcell.2023.1075917.

[102] Li D, Zhang G, Wang Z, Guo J, Liu Y, Lu Y, et al. Idebenone attenuates ferroptosis by inhibiting excessive autophagy via the ROS-AMPK-mTOR pathway to preserve cardiac function after myocardial infarction. European Journal of Pharmacology. 2023; 943: 175569. https://doi.org/10.1016/j.ejphar.2023.175569.

[103] Feng J, Guo J, Yan J, Zhang X, Qu H, Yang T, et al. Luhong Formula and Hydroxysafflor yellow A protect cardiomyocytes by inhibiting autophagy. Phytomedicine: International Journal of Phytotherapy and Phytopharmacology. 2023; 110: 154636. https://doi.org/10.1016/j.phymed.2022.154636.

[104] Xu Y, Dong Z, Zhang R, Wang Z, Shi Y, Liu M, et al. Sonodynamic therapy reduces cardiomyocyte apoptosis through autophagy activated by reactive oxygen species in myocardial infarction. Free Radical Biology & Medicine. 2023; 195: 36–46. https://doi.org/10.1016/j.freeradbiomed.2022.12.080.

[105] Kandula N, Kumar S, Mandlem VKK, Siddabathuni A, Singh S, Kosuru R. Role of AMPK in myocardial ischemia-reperfusion injury-induced cell death in the presence and absence of diabetes. Oxidative Medicine and Cellular Longevity. 2022; 2022: 7346699. https://doi.org/10.1155/2022/7346699.

[106] Nah J, Zablocki D, Sadoshima J. The role of autophagic cell death in cardiac disease. Journal of Molecular and Cellular Cardiology. 2022; 173: 16–24. https://doi.org/10.1016/j.yjmcc.2022.08.362.

[107] Deng R, Jiang K, Chen F, Miao Y, Lu Y, Su F, et al. Novel cardioprotective mechanism for Empagliflozin in nondiabetic myocardial infarction with acute hyperglycemia. Biomedicine & Pharmacotherapy. 2022; 154: 113606. https://doi.org/10.1016/j.biopha.2022.113606.

[108] Sasset L, Manzo OL, Zhang Y, Marino A, Rubinelli L, Riemma MA, et al. Nogo-A reduces ceramide de novo biosynthesis to protect from heart failure. Cardiovascular Research. 2023; 119: 506–519. https://doi.org/10.1093/cvr/cvac108.

[109] Wu W, Chen X, Hu Q, Wang X, Zhu J, Li Q. Improvement of myocardial cell injury by mir-199a-3p/mtor axis through regulating cell apoptosis and autophagy. Journal of Immunology Research. 2022; 2022: 1642301. https://doi.org/10.1155/2022/1642301.

Funding

Sichuan Provincial Department of Science and Technology(2022YFS0578)