To function properly, the heart must remain a one-way system, pumping out oxygenated blood into the aorta – the largest artery in the body – so it can be distributed across the organism. The aortic valve, which sits at the entrance of the aorta, is a key component of this system. Its three flaps (or ‘cusps’) are pushed open when the blood exits the heart, and they shut tightly so it does not flow back in the incorrect direction.

Nearly 1.4% of people around the world are born with ‘bicuspid’ aortic valves that only have two flaps. These valves may harden or become leaky, forcing the heart to work harder. This defect is also associated with bulges on the aorta which progressively weaken the artery, sometimes causing it to rupture.

Open-heart surgery is currently the only way to treat these bulges (or ‘aneurysms’), as no drug exists that could slow down disease progression. This is partly because the biological processes involved in the aneurysms worsening and bursting open is unclear.

Recent studies have highlighted that many individuals with bicuspid aortic valves also have lower levels of a protein known as NOTCH1, which plays a key signalling role for cells. Problems in the mitochondria – the structures that power up a cell – are also observed. However, it is not known how these findings are connected or linked with the aneurysms developing.

To answer this question, Abudupataer et al. analyzed the proteins present in diseased and healthy aortic muscle cells, confirming a lower production of NOTCH1 and impaired mitochondria in diseased tissues. They also created an ‘aorta-on-a-chip’ model where aortic muscle cells were grown in the laboratory under conditions resembling those found in the body – including the rhythmic strain that the aorta is under because of the heart beating. Abudupataer et al. then reduced NOTCH1 levels in healthy samples, which made the muscle tissue less able to contract and reduced the activity of the mitochondria. Applying drugs that tweak mitochondrial activity helped tissues from patients with bicuspid aortic valves to work better.

These compounds could potentially benefit individuals with deficient aortic valves, but experiments in animals and clinical trials would be needed first to confirm the results and assess safety. The aorta-on-a-chip model developed by Abudupataer et al. also provides a platform to screen for drugs and examine the molecular mechanisms at play in aortic diseases.

Bicuspid aortic valve (BAV) disease is the most common congenital cardiovascular abnormality and is found in nearly 1.4% of the general population (Garg et al., 2005; Michelena et al., 2011; Verma and Siu, 2014). BAV arises from incomplete separation or fusion of the aortic valve cusps and is associated with an approximately 40% risk of developing thoracic aortic aneurysm (TAA), namely, bicuspid aortopathy (Verma and Siu, 2014). BAV-TAA poses a severe health threat to a large population because progressive aneurysmal dilation can potentially develop into lethal dissection or rupture (Goldfinger et al., 2014; Olsson et al., 2006). The current clinical management mainly relies on prophylactic surgical repair of the notably dilated aorta (Coady et al., 2010). At present, the understanding of pathophysiological mechanisms of BAV-TAA is incomplete, which leads to the absence of effective pharmaceutical therapy to alleviate aortopathy progression (Lindeman and Matsumura, 2019). Multiple factors, such as genetics and hemodynamics, are involved in the etiologies of BAV-TAA. In particular, genetic factors are considered to play a pivotal role in the disease progression (Isselbacher et al., 2016; Prakash et al., 2014). NOTCH1 insufficiency has been observed in the population with BAV (Balistreri et al., 2018; Harrison et al., 2019; Malashicheva et al., 2020; Sciacca et al., 2013). However, the underlying mechanism through which insufficient NOTCH1 induces aortopathy remains to be explored.

Mitochondrial dysfunction has been closely linked to a variety of cardiovascular disorders, such as heart failure and atherosclerosis. Recent studies found that mitochondrial dysfunction was also related to the development of arterial aneurysm formation (Cooper et al., 2021; van der Pluijm et al., 2018; Oller et al., 2021). A single-cell transcriptome analysis on aneurysmal human aortic tissue suggested that mitochondrial dysfunction and increased chromatin oxidative phosphorylation (OXPHOS) were found in TAA tissues and insufficient ATP production might not be sufficient for the contractile activities of human aortic smooth muscle cells (HAoSMCs) (Li et al., 2020). Particularly, mitochondrial fission and fusion are dynamically balanced to maintain mitochondrial homeostasis and functions; and a shift toward fission event is one of the main causes of mitochondrial dysfunction. In a mice model of abdominal aortic aneurysm (AAA), impaired mitochondrial dynamics was found to play salient roles in disease development, and could be attenuated by the mitochondrial fission inhibitor Mdivi1 (Cooper et al., 2021). However, these studies focused on the analysis of abdominal aortic aneurysms and genetic TAA with FBN1 or Fubulin-4 mutation. It has been reported that there was close interaction between NOTCH1 signaling and homeostatic mitochondrial dynamics in the differentiation of cardiomyocytes (Kasahara et al., 2013) and the survival of breast cancer cells (Chen et al., 2018). Therefore, the relationship between NOTCH1 signaling pathway and mitochondrial dynamics in BAV-TAA needs to be clarified.

The traditional TAA animal models are frequently applied for the pathogenesis research and pharmaceutical therapy, however, not suitable for studying BAV-TAA. Although Koenig et al. generated NOTCH1-haploinsufficient mice in a preliminary 129S6 background that exhibited aortic root dilation, these mice did not show BAV characteristics (Koenig et al., 2017). Therefore, these models may not provide sufficient information of pathogenesis and drug response of BAV-TAA. Owing to the bioengineering advance, microfluidic-based organ-on-chip models have been widely developed to replicates human tissue microenvironment for toxicity analysis, drug screening and disease modeling and thus promotes pharmaceutical translation from preclinical studies to clinical trials (Zhang et al., 2018; Ingber, 2016; Park et al., 2019; Thacker et al., 2020; Hofemeier et al., 2021). It provides an opportunity to use a novel platform to study BAV-TAA on a susceptible human genetic background and may fill the gap between animal and human medicine. Here, we engineered an in vitro aorta smooth muscle-on-a-chip model of primary HAoSMCs that emulates the biomechanics of the human aortic wall. We characterized the association between mitochondrial dynamics and NOTCH1 deficiency in BAV-TAA on this platform. Our study provides the first demonstration previously undocumented role of impairment of mitochondrial fusion in bicuspid aortopathy, which may serve as a potential pharmacological target for preventing disease progression.

In this study, protein analyses of human aortic aneurysm tissues suggested the insufficient expression of NOTCH1 in BAV-TAA was associated with the impaired mitochondrial dynamics and OXPHOS. To verify it, we established a microfluidic model of aorta smooth muscle-on-a-chip, inspired by previous organ-on-chips models (Ribas et al., 2017; Yasotharan et al., 2015; Huh et al., 2010), enabling us to reproducibly generate the rhythmic tensile strain of the native human aortic wall. We showed that this model could apply a biomimetic rhythmic tensile strain with a confined amplitude/magnitude and rhythm to HAoSMCs. We also confirmed that impaired mitochondrial fusion contributed to the attenuated contractile phenotype observed in NOTCH1-KD HAoSMCs. We further identified that MFN1/2 agonists and DRP1 inhibitors were able to reverse the imbalance in mitochondrial dynamics and partly rescue the contractile phenotype in NOTCH1-insufficient HAoSMCs.

The majority of studies on the molecular mechanism and pharmacotherapy for TAA have been conducted using conventional cell culture models and animal models. The pathophysiological features of human aortic aneurysm can be induced in animal models by elastase, calcium chloride, angiotensin II or transgenesis, which partially enable investigation of the etiology, pathogenesis, and therapeutic targets of TAA at an early stage (Eckhouse et al., 2013; Ikonomidis et al., 2003; Mao et al., 2015). However, all these animal models cannot replicate the native characteristics of BAV-TAA. Moreover, the apparent species gap between preclinical animal experiments and clinical studies might also impede pharmaceutical discovery (Lindeman and Matsumura, 2019). In contrast, the shortcoming of the conventional cell culture model of aortic disease lies in its inability to recapitulate in vivo biomechanical stimuli. Advances in microfabrication and microfluidics have provided novel techniques for building organ-on-a-chip models that integrate rhythmic tensile strains into in vitro cell culture. Differently from conventional two dimensional (2D) and three dimensional (3D) cell culture methods, which are widely used in biological research, organ-on-a-chip models can replicate multicellular architectures, tissue-tissue interfaces, and biomechanical forces that exist in vivo, and precisely pattern cells and manipulate various mechanical and chemical parameters, such as flow rate, stretch, pressure, oxygen, and pH, providing controllable culture conditions not possible with conventional cultures (Ahadian et al., 2018). In the case of cardiovascular research, the functionally important cardiomyocytes, endothelial cells and smooth muscle, are constantly subjected to hemodynamic factors in vivo, including blood flow shear stress, rhythmic strain and fluid pressure, which cannot be simulated and given to the cells by conventional cell culture techniques. Organ-on-a-chip models can be broadly defined as any form of microfabricated cell culture device that models organ-specific biochemical and physical microenvironments (Zhao et al., 2019; Park et al., 2019) and represent an in vitro platform that is complementary to animal models.

The present aorta smooth muscle-on-a-chip model was designed based on the inspiration and reference of pioneering researchers' works, such as progeria-on-a-chip (Ribas et al., 2017), artery-on-a-chip (Yasotharan et al., 2015), and so on. Previous reported 'artery-on-a-chip' platforms are mainly focused on peripheral vessel, cerebral artery, or other arterial diseases. Yasotharan et al. reported an artery-on-a-chip platform that mimicked in vivo transmural pressure of an outer diameter of 120 μm olfactory artery segment, in which vascular tone and calcium dynamics were simultaneously assessed (Poussin et al., 2020). Poussin et al. have established a model of microvessels-on-a-chip under flow using primary human coronary arterial endothelial cells, to measure the adhesion of monocytes to the lumen of perfused microvessels (Poussin et al., 2020). Arterioles with a diameter of 15 μm, branches of the large artery, are mainly affected by fluid shear but receive little tensile tension. In contrast, aorta diameter is about 25–35 mm with thick three layers, in which smooth muscle cells are the main component in tunica media and experience high tensile strain. Aortopathies are the degenerative changes in the aortic wall inducing thinning or even rupture of the aorta. Thus, HAoSMCs in tunica media and the tensile strain they receive are essential components for the success of aorta smooth muscle-on-a-chip model.

By anatomizing the complexity of the biomechanical microenvironment, this study focused on the physiological rhythmic strain on HAoSMCs in the aortic tunica media, which plays a central role in the pathogenesis of aneurysms. In particular, the strain of the ascending aorta, which was defined as the maximal change in the ascending aorta diameter over a cardiac cycle, can vary diversely from a low value of 7.0 ± 2.5% to a high value of 21.5 ± 12.4% depending on age, sex and disease severity (Akazawa et al., 2016; Bell et al., 2014; Morrison et al., 2009). Under rhythmic strain, healthy HAoSMCs maintain a contractile phenotype, which allows regulation of the vascular tone. While, diseased HAoSMCs dedifferentiate into a synthetic phenotype under pathological conditions, and this dedifferentiation represents the initial step toward an aneurysm pathology (Petsophonsakul et al., 2019). The aorta smooth muscle-on-a-chip model developed in this study featured the controlled magnitude and rhythm of mechanical stimuli relevant to the human pathophysiological parameters of aorta biomechanics. In this study, HAoSMCs exhibited longer shapes in morphology, align unidirectionally, and present contractile phenotype on the on-chip model. In static conventional condition, HAoSMCs present more synthetic phenotype, which is oppositely different from the phenotype exist in native normal aortic wall. Most importantly, the on-chip model recapitulated the imbalanced mitochondrial dynamics which was accordant with analyses on tissues from human BAV-TAA and in vivo mouse model of abdominal aortic aneurysm (Cooper et al., 2021). In short, organ-on-a-chip models can mimic the biomechanical parameters, which are essential for aortopathy disease development and more fully explore the pathophysiological changes of the cells and their real responsiveness to drugs, in a complementary manner with conventional cell culture and in vivo models. However, both of extracellular matrix and vascular cells, including epithelial cells, VSMCs, fibroblasts, macrophages, contribute to the pathological process of the aortic diseases. The present reductionist on-chip model merely represented HAoSMCs activities and did not recapitulated the entire aortic wall. Future works are expected to incorporate more components, especially the aortic extracellular matrix, into the on-chip model and explore ECM degradation and interactive molecular mechanisms involved in human aortopathies.

NOTCH1 has an important role in the maintenance of normal mitochondrial dynamics. Previous studies have reported that the expression of NOTCH1 signaling was attenuated in the aortic tissues of patients with BAVs (Sciacca et al., 2013). Additionally, Balistreri et al. found decreased mRNA levels of NOTCH1-4 in aortic aneurysm tissues and decreased protein levels of soluble NOTCH1 in plasma (Balistreri et al., 2018). Using clinical samples, our protein analysis also indicated that patients with BAV-TAA presented lower expression of NOTCH1 protein in ascending aortic aneurysms; and the NOTCH1 insufficiency was accompanied with attenuated mitochondrial fusion. This was consistent with the previous studies that reported NOTCH1 regulates mitochondria dynamics in cardiovascular cell differentiation and survival. Kasahara et al. found that mitochondrial fusion regulates the differentiation of myocardial cells through NOTCH1 signaling pathway (Kasahara et al., 2013). Here, we found that NOTCH1 insufficiency induced mitochondrial dysfunction in HAoSMCs by reducing mitochondrial fusion, along with loss of mitochondrial membrane potential, increasing ROS production and generating insufficient ATP under rhythmic strain. These results indicated that the relationship between impaired mitochondrial fusion and NOTCH1 deficiency in BAV-TAA. Consistently, we found decreased contractile phenotype in NOTCH1-deficient HAoSMCs under rhythmic tensile strain and in BAV-TAA aortic tissues, accompanied by lower NOTCH1 expression and impaired mitochondrial fusion.

NOTCH1 signaling is also involved in the regulation of HAoSMCs differentiation and the expression of contractile proteins. HAoSMCs are highly plastic cells and undergo reversible changes in phenotype in response to environmental stimuli (Vásquez-Trincado et al., 2016). In the aorta, HAoSMCs are considered to have the functional roles of both maintaining aortic tone in response to hemodynamic stimuli, and synthesizing and modeling the ECM (Michel et al., 2018). Most healthy HAoSMCs in the vascular wall in vivo exhibit a contractile phenotype, which allows them to maintain vascular tone (Milewicz et al., 2008). HAoSMCs contractile units associated proteins, such as SM22, CNN1, MYH11, and α-SMA, distribute the force on the aortic wall through regulation of extracellular matrix. Decreases in α-SMA, MYH11, SM22, and CNN1 attenuate HAoSMCs contractility unit formation and further disrupt force generation, promoting the development of aortic aneurysm or dissections (Gillis et al., 2013). Differentiated HAoSMCs have a contractile phenotype with little proliferation and little secretion of extracellular matrix. HAoSMCs transform from a contractile into a synthetic phenotype and induce loose of vascular tone, which is one of the major pathological process in TAA. Thus, the enhancement of HAoSMCs contractility is indicative of the effectiveness of pharmacotherapy for controlling aortic aneurysm (Oller et al., 2021). In this study, we found that NOTCH1 insufficiency in HAoSMCs downregulated the contractile phenotype proteins SM22 and CNN1 under rhythmic strain. Also, the expressions of SM22 and CNN1 were decreased in BAV-TAA aortic tissues compared to non-diseased aortic tissues. Noseda et al. reported that NOTCH1 activation was needed for expression of the contractile phenotype protein αSMA in VSMCs via the NOTCH/CSL axis (Noseda et al., 2006). High et al. reported that NOTCH1 promotes the differentiation of the cardiac neural crest into differentiated VSMCs and the expression of αSMA (High et al., 2007). However, the specific mechanism by which NOTCH1 leads to a reduced contractile phenotype has not been fully investigated. Based on results obtained from the aorta smooth muscle-on-a-chip model, it comes to the assumption that NOTCH1-insufficiency reduced the contractile phenotype through decreasing mitochondrial fusion.

Mitochondrial dynamics itself has been recognized as one of the critical factors that regulate the phenotype switching of vascular smooth muscle cells (VSMCs). Salabei and Hill reported that PDGF-BB induces the dedifferentiation of VSMCs into the synthetic phenotype through overactivation of mitochondrial fission (Salabei and Hill, 2013). Chen et al. found that the expression of MFN2 is markedly reduced in hyperproliferative VSMCs from spontaneously hypertensive rat arteries (Chen et al., 2004). Using the aorta smooth muscle-on-a-chip model, we demonstrated the decreased mitochondrial fusion in NOTCH1-insufficient HAoSMCs, accompanied with decreased contractile phenotypes. Thus, mitochondrial dynamics regulated by NOTCH1 may have a role in maintains of contractile phenotype. In addition, we also found the contractile phenotype was upregulated in NOTCH1-insufficient HAoSMCs after treatment with mitochondrial fusion activators and mitochondrial fission inhibitors, which further verified the hypothesis that contractile phenotype of HAoSMCs was regulated by NOTCH1-mitochondrial fusion axis. In clinical samples, our protein analysis indicated that aortic tissues from patients with BAV-TAA presented the reduced expressions of mitochondrial fusion proteins and contractile phenotype proteins, compared with non-diseased aortic tissues. Further, the mass spectrometry-based proteomic analysis of aortic tissue samples indicated that mitochondrial dysfunction and OXPHOS pathways were significantly altered in BAV-TAA aortic tissues. Consistent with the previous single-cell transcriptome analysis, TAA aortic tissues showed decreased mitochondrial function; and this finding suggests that OXPHOS ATP production might be insufficient for VSMC contractile activities (Li et al., 2020). Therefore, maintaining normal mitochondrial dynamics via NOTCH1 could be one of the mechanisms through which NOTCH1 regulates HAoSMCs’s contractility and maintains vascular wall tension.

The mitochondria morphology, that is fragmentation or elongation, which is controlled by precisely regulated mitochondrial fusion and fission, has been related to cardiovascular disorders, such as atherosclerosis and myocardial infarction (Murphy et al., 2016). Excessive mitochondrial fission induced a reduction in mitochondrial membrane potential and contractile phenotype of vascular VSMCs, and an increase in oxygen species production (Lim et al., 2015). These effects induced by mitochondrial fission were prevented by Mdivi-1, which is an inhibitor of mitochondrial fission related protein DRP1. Cooper et al. found that the upregulated DRP1 and mitochondrial fission in mouse abdominal aortic aneurysm, associated with impaired mitochondrial function and decreased contractility of mouse VSMCs (Cooper et al., 2021). The induction of the contractile to synthetic phenotype switch of VSMCs by platelet-derived growth factor, was also found to be associated with mitochondrial fragmentation/fission and attenuated MFN2 protein levels (Salabei and Hill, 2013). In this study, the excessive mitochondrial fragmentation of HAoSMCs implied diseased phenotype, while the restoration of mitochondrial homeostasis, i.e. the balance of fragmentation/fission and elongation/fusion, implied the rescue of HAoSMC contractility abnormality. However, the specific mechanism by which reduced mitochondrial fusion causes a reduction in the contractile phenotype requires further investigation. In addition, our proteomic analysis of tissue samples showed that several mitochondrial dysfunction-related pathways, namely, EIF2 signaling and the sirtuin signaling pathway, were also altered in BAV-TAA aortic tissue, which may provide research directions to investigate further mechanisms.

Lastly, we demonstrated that MFN1/2 agonists and DRP1 inhibitors reversed the imbalanced mitochondrial dynamics in BAV-TAA p-HAoSMCs with intrinsic NOTCH1 insufficiency or in NOTCH1-KD HAoSMCs on the aorta smooth muscle-on-a-chip model, which provides a prototype for an in vitro drug testing platform. Two FDA-approved drugs, leflunomide or teriflunomide, rescued the contractile phenotype of BAV-TAA p-HAoSMCs and showed their potential to ameliorate disease progression. Zorzano’s group first found that dihydroorotate dehydrogenase inhibitors (leflunomide, teriflunomide, or brequinar sodium) could promote mitochondrial elongation through induction of the mitochondrial proteins MFN1 and MFN2 in HeLa cells (Miret-Casals et al., 2018). The experimental data obtained in this study encourage further studies on the application of leflunomide and teriflunomide in BAV-TAA.

This study has several limitations. Although the phenotypic reversal has observed after treatments of mitochondrial fission inhibitor and fusion agonists based on aorta smooth muscle-on-chip model, in vivo genetically modified mouse experiments are still needed to further confirm the therapeutic effects, that is whether these drugs can halt the progression of the disease. Also, genetically modified mouse aortic aneurysm model is required to further elucidate the genetic mechanism of NOTCH1—mitofusin axis in ascending aortic aneurysm. At the current stage, aorta smooth muscle-on-chip is still insufficient to alone predict clinical success, but it may be complementary with animal models in the sense that, together they are able to provide more comprehensive basis for preclinical assays with greater predictive power. Therefore, more verification tests, including in vitro on-chip tests and in vivo animal validations, are needed before translating the finding into prospective clinical tail.

In conclusion, we constructed an aorta smooth muscle-on-a-chip model, which could serve as a complementary tool to the current cell culture system and animal models. Using the aorta smooth muscle-on-a-chip model, we found that NOTCH1 insufficiency in HAoSMCs induced phenotypic switching from a contractile to a synthetic phenotype accompanied by an impairment of mitochondrial fusion, implying its potential role as a therapeutic target for BAV-TAA. At the current stage, in vitro microphysiological models and animal models are complementary to each other in the sense that they are able to provide more comprehensive basis for preclinical assays with greater predictive power.

The mass spectrometry proteomics data, including raw data from the mass spectrometry runs, have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD026303. The analysis of the proteomics datasetare included in Figure 1. All other data supporting the findings of this study are included in the paper or supplementary files.

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Author details

1. Mieradilijiang Abudupataer

   Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5421-9820

2. Shichao Zhu

   Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

   Contribution

   Validation, Investigation

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5057-9434

3. Shiqiang Yan

   Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

   Contribution

   Software, Formal analysis, Visualization, Methodology

   Competing interests

   No competing interests declared

4. Kehua Xu

   Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

   Contribution

   Software, Formal analysis, Methodology

   Competing interests

   No competing interests declared

5. Jingjing Zhang

   Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

   Contribution

   Formal analysis, Validation, Investigation

   Competing interests

   No competing interests declared

6. Shaman Luo

   1. Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
   2. The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

7. Wenrui Ma

   Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

   Contribution

   Resources, Formal analysis, Investigation

   Competing interests

   No competing interests declared

8. Md Fazle Alam

   1. Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
   2. The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China

   Contribution

   Writing - review and editing

   Competing interests

   No competing interests declared

9. Yuyi Tang

   Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

10. Hui Huang

    Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

    Contribution

    Formal analysis, Investigation

    Competing interests

    No competing interests declared

11. Nan Chen

    Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Contribution

    Resources

    Competing interests

    No competing interests declared

12. Li Wang

    Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

    Contribution

    Validation, Writing - review and editing

    Competing interests

    No competing interests declared

13. Guoquan Yan

    Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

    Contribution

    Software, Formal analysis

    Competing interests

    No competing interests declared

14. Jun Li

    1. Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
    2. Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China

    Contribution

    Resources

    Competing interests

    No competing interests declared

15. Hao Lai

    Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Contribution

    Resources

    Competing interests

    No competing interests declared

16. Chunsheng Wang

    Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Contribution

    Conceptualization, Resources, Writing - review and editing

    For correspondence

    wangchunsheng@fudan.edu.cn

    Competing interests

    No competing interests declared

17. Kai Zhu

    Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China

    Contribution

    Conceptualization, Funding acquisition, Visualization, Writing - review and editing

    For correspondence

    zhu.kai1@zs-hospital.sh.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0002-2391-4193

18. Weijia Zhang

    1. Department of Cardiac Surgery and Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China
    2. Institutes of Biomedical Sciences and the Shanghai Key Laboratory of Medical Epigenetics, Shanghai Medical College, Fudan University, Shanghai, China
    3. The State Key Laboratory of Molecular Engineering of Polymers, Fudan University, Shanghai, China

    Contribution

    Conceptualization, Supervision, Funding acquisition, Visualization, Writing - original draft, Writing - review and editing

    For correspondence

    weijiazhang@fudan.edu.cn

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-6928-0416

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