Scott Hummel, MD
Associate Professor of Internal Medicine
[email protected]

Daniel Beard, PhD, MD
Carl J Wiggers Collegiate Professor of Cardiovascular Physiology
Professor of Molecular and Integrative Physiology
Professor of Biomedical Engineering
University of Michigan Medical School
[email protected]

Yida Tang, MD, PhD
Professor and Chief, Department of Cardiology and Institute of Vascular Medicine
Peking University Third Hospital

JI Program: Cardiovascular Medicine

Project Status: Active/Ongoing

Heart failure (HF) with preserved ejection fraction (HFpEF) is common, increasing in prevalence, and associated with poor quality of life and outcomes. There are currently few effective therapies for HFpEF due to phenotypic heterogeneity. This proposed collaborative research project aims to develop, extend, and apply state-of-the-art computational approaches for precision phenotyping of HFpEF. The overarching goal is to use patient-specific computer modeling and simulation, combined with data-driving machine learning approaches, to classify patients into phenogroups that represent distinct categories of underlying cardiovascular dysfunction. In a retrospective study we will extend and refine analytic technology developed in preliminary studies in an application to several hundred patients drawn from clinical records at UMich and PKU. In addition, in a proposed prospective study we will further extend and refine our technology to assess cardiovascular function data obtained during cardiopulmonary exercise testing, to deepen our understanding of the mechanisms governing exercise intolerance in HFpEF patients, and to determine if and how these mechanisms can be identified from analysis of baseline-state data alone. Finally, using the results from these retrospective and prospective studies, we will design and test an optimal patient classifier that uses solely noninvasively obtained data. With a multi-disciplinary collaborative team that brings a unique combination of clinical expertise and data, experimental tools, computational technology, and novel technology to this leading edge problem, we are uniquely positioned to fundamentally improve the ways in which HFpEF is diagnosed and ultimately treated.

Jifeng Zhang, PhD
Research Associate Professor, Internal Medicine
University of Michigan Medical School
[email protected]

Lemin Zheng, PhD
Vice Chair & Professor, Institute of Cardiovascular Science
Peking University Health Science Center

Wei Li, MD
Professor and Vice Director of Vascular Surgery
Peking University People's Hospital

JI Program: Cardiovascular Medicine

Project Status: Active/Ongoing

Aortic aneurysm and dissection (AAD) is a high-risk cardiovascular disease with no approved drug currently available for treatment. Once ruptured, the mortality rate is as high as 65%-85%. It creates an urgent need to identify novel targets for developing drug-based therapeutic strategies. Using the untargeted metabolomic analysis from 20 AAD patients and 20 control samples, we found that succinate was the most upregulated metabolite in AAD patients, which was confirmed in the validation cohort (1,665 patients) by targeted metabolomic assay. In addition, we showed that succinate administration exacerbated Angiotensin II-induced AAD in the mouse model. We propose to identify novel metabolic markers and pathways in AAD development through screening more patient samples with multi-omics approaches and data mining. Combining our unique clinical resources, data mining strategies, and well established murine AAD models, this project aims to determine the key metabolites and molecular markers by multiomics approaches and data mining and to demonstrate that succinate supplementation aggravates AAD in the more clinically relevant BAPN/Ang II-induced AAD murine models. This work will provide a premier resource that will be shared with the research community and set the foundation for developing novel diagnoses and therapies for AAD and other related cardiovascular diseases.

Zhong Wang, PhD(link is external)
Associate Professor of Cardiac Surgery
University of Michigan Medical School
[email protected]

Ming Cui, MD, PhD
崔鸣教授
Professor of Cardiovascular Medicine, Heart Center
Peking University Third Hospital

JI Program: Cardiovascular Medicine

Project Status: Active/Ongoing

Myocardial infarction (MI) is the leading cause of death worldwide with severe loss of cardiomyocytes (CMs). Existing treatments for MI do not address directly the fundamental problem of CM loss. Cell transplantation represents a promising therapeutic strategy to restore the damaged myocardial tissue, but is challenged by the low engraftment and integration of the transplanted cells to host heart. MI leads to deprivation of nutrient, oxygen and subsequent histone acetylation decrease in heart. Therefore, we hypothesize that simultaneous restoration of the energy metabolism and histone acetylation would be an effective strategy to protect either endogenous or transplanted cells. Indeed, our studies have identified that energy metabolite octanoate (8C) (UM) as well as nuclear factor erythroid 2-related factor 2 (NRF2) (PUHSC) preserves cardiac function after MI by mediating both histone acetylation and energy metabolism. Moreover, we have developed a novel biodegradable nanofibrous temperature responsive gelling microspheres (NF-GMS), which dramatically improve (10-fold) engraftment of transplanted cells in infarcted hearts (UM). In parallel, we have been able to robustly derive cardiac progenitor cells from human iPSCs (hiPSC-CPCs), which can differentiate further into almost all cardiac lineages (PUHSC).

Bertram Pitt, MD
Professor Emeritus of Internal Medicine
University of Michigan Medical School
[email protected]

Porama Thanaporn, MD
Assistant Professor of Medicine
University of Michigan Medical School

Wei Gao, MD
高炜教授
Director, Department of Internal Medicine
Peking University Third Hospital

JI Program: Cardiovascular

Status: Active/ Ongoing

An estimated 700 million people in East Asia carry a single nucleotide mutation ALDH2*2 (rs671) that impairs aldehyde dehydrogenase type 2 activity in all carriers. These patients have an increased risk of hypertension, heart failure, chronic kidney disease, coronary artery disease, and myocardial infarction. Both the heterozygous and homozygous mutation lead to impaired ALDH2 enzyme activity and increased ROS, which in turn leads to increased reactive aldehyde production. In a small animal model, we have shown that ALDH2 deficiency benefits from treatment with Alda-1, an ALDH2 activator, by decreasing CaMKII activation by both phosphorylation and oxidation. Adoption of mineralocorticoid receptor antagonists would reduce production of reactive oxygen species and ameliorate aldehyde dehydrogenase deficiency by decreasing aldehydic burden particularly in patients with ALDH2 deficiency. Our study will assess clinical response to spironolactone in patients with HFmrEF stratified by ALDH2 deficiency as determined by genotype. If these patients who are at increased risk of ROS and cardiovascular events can be shown to respond more favorably than those without ALDH2*2 mutations, this would allow a “precision medicine” approach in these patients and would justify an intensive clinical approach in these patients to allow for monitoring for hyperkalemia.

Marschall S. Runge, MD, PhD
Dean, University of Michigan Medical School
Executive Vice President for Medical Affairs
CEO, Michigan Medicine

Youyi Zhang, MD, PhD
张幼怡教授
Associate Director
Department of Cardiology and Institute of Vascular Medicine
Peking University Third Hospital
[email protected]

JI Program: Cardiovascular

Status: Active/ Ongoing

Cardiovascular disease (CVD) is the leading cause of death worldwide, representing 31% of all deaths. Emerging evidence suggests that stress in adulthood acts as a disease trigger in individuals with high atherosclerotic burden and is a determinant of prognosis and clinical outcomes. Increases in cardiovascular events were reported immediately after traumatic events such as natural disasters, war, and terrorist attacks of 9-11. Although the link between various stressors and disease end points is obvious, much less is known about the pathophysiological mechanisms through which stress responses transform into changes that initiate the development and progression of CVD. Another challenge is addressing the stressors by intervention, because such events are stochastic and therefore difficult to predict. We propose to elucidate the molecular signaling pathways which regulate the transformation of stress responses into cardiovascular events in people with atherosclerotic burden using mouse models of oxidative stress available in the Runge laboratory. Our proposal has three innovative aspects. First, our team has complementary strengths required for investigating the effect of sympathetic adrenergic activation on the onset of cardiovascular events in the backdrop of high atherosclerotic burden. Second, we generated atherosclerosis data using novel Apoe-/-/mNox4TG (mitochondria-targeted NADPH oxidase 4 transgenic) mice and Apoe-/-/Nox4-/- mice. Third, we plan to evaluate the effect of metformin and GKT137831 on β-AR activation associated cardiac dysfunction in mNox4TG mice and atherosclerotic burden and plaque stability in Apoe-/-/mNox4TG mice. Our research strategy includes the following two specific aims: (1) determine the molecular mechanism of sympathetic activation induced cardiac inflammatory injuries in mice deficient in and with mitochondrial-targeted overexpression of Nox4; (2) investigate the mechanisms of β-AR induced atherosclerotic burden/ plaque instability in Apoe-/- mice deficient in and with mitochondrial-targeted overexpression of Nox4. Together, these studies will establish the role of NOX4 NADPH oxidase in cardiovascular events in the backdrop of high atherosclerotic burden and potentially identify strategies that work in concert with standard of care treatment for the prevention of cardiovascular events under stress conditions.

Bertram Pitt, MD
Professor Emeritus of Internal Medicine
University of Michigan Medical School
[email protected]

Guisong Wang, MD
王贵松教授
Department of Cardiology
Peking University Third Hospital

JI Program: Cardiovascular

Status: Active/ Ongoing

Thiazide diuretics have been widely used for the management of essential hypertension, especially in patients with salt-sensitive hypertension. Most recent guidelines continue to recommend thiazide diuretics as first-line agents for all patients with hypertension in spite of the potential metabolic side effects such as hypokalemia, hypertriglyceridemia, impaired glucose tolerance and increases in serum cholesterol and uric acid. However, mineralocorticoid receptor antagonists (MRAs), such as spironolactone or eplerenone, are mainly recommended to be used in patients with resistant hypertension or heart failure because they have never been evaluated for efficacy in reducing cardiovascular events in uncomplicated patients with hypertension. In the proposed study, we planned to randomize 400 patients with essential hypertension and increased waist circumference to receive spironolactone or indapamide in combination with amlodipine for 12 months. The effects of the two diuretics on target organ damage detected by changes in left atrial volume index(LAVI) by echocadiography reflecting left ventricular diastolic dysfunction or changes in carotid-femoral pulse wave velocity(PWV) reflecting arterial stiffness and oscillatory compliance(C2) reflecting small artery elasticity will be compared. If it proves that spironolactone as first-line antihypertensive medication is more effective than indapamide in target organ protection, we would propose a large scale cardiovascular outcome trial to evaluate cardiovascular events in patients with essential hypertension and visceral obesity.

Daniel Eitzman, MD, PhD
Professor of Internal Medicine - Cardiology
University of Michigan Medical School
[email protected]

Haoming Zhang, PhD
Research Associate Professor
Department of Pharmacology
University of Michigan Medical School
[email protected]

Jianping Li, MD, PhD
李建平教授
Professor
Executive Deputy Director
Department of Cardiology
Peking University First Hospital
Peking University Health Science Center
[email protected]

JI Program: Cardiovascular

Status: Active/ Ongoing

Summary

Dual antiplatelet therapy (DAPT) with a combination of aspirin and P2Y12 inhibitors is the cornerstone of treatment for patients with acute coronary syndrome (ACS). The current ACC/AHA guidelines recommend aspirin with clopidogrel, prasugrel, or ticagrelor for all patients receiving percutaneous coronary intervention (PCI). Clinical studies have demonstrated the effectiveness of extended DAPT (>12 months) in preventing thrombotic events in ACS and peripheral artery diseases (PAD), but at the expense of increased risks of bleeding. Despite the availability of three P2Y12 inhibitors, the efficacy and bleeding risks of DAPT significantly differ between Caucasian and East Asian patients. Heterogeneity of platelet response profiles is also apparent in patients with obesity and diabetes. Although clinical studies have associated diabetes with poor responsiveness to P2Y12 inhibitors, the underlying mechanism for this impairment is unclear. This proposal would represent the first systematic analysis of the PK/PD of P2Y12 inhibitors in a mouse model of obesity and diabetes. We expect to establish whether the PK/PD of P2Y12 inhibitors are altered in a diet-induced obesity mouse model and whether elimination of CYP-mediated metabolism overcomes impaired platelet responsiveness without increasing bleeding risk. Results from this pilot study will provide a better understanding of the variability in response to P2Y12 inhibitors and accelerate development of new antiplatelet drugs to overcome interpatient variability in response to DAPT.

Outcome

We have developed an obese, insulin resistant murine model in which the effects of clopidogrel and DT-678 can be tested towards clinically relevant endpoints of both platelet aggregation and arterial thrombosis. This finding is clinically important considering millions of obese patients are treated with clopidogrel.

Cristen Willer, PhD
Frank Norman Wilson Professor of Cardiovascular Medicine
Associate Professor of Internal Medicine
Associate Professor of Human Genetics
Associate Professor of Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Zhe Zhang, MD
张喆教授
Professor of Cardiac Surgery
Vice Director, Department of Cardiac Surgery
Peking University Third Hospital

JI Program: Cardiovascular

Status: Active/ Ongoing

Summary

Aortic aneurysm and dissection (AAD) is a devastating disease with a high mortality rate affecting ~4% of Americans above age 65. Although smoking, hypertension and hyperlipidemia are risk factors for AAD, genetics also plays a very strong role in risk. Approximately 35% of AAD patients have a family member with aortic aneurysm. In some cases, mutations in genes related to the TGF-beta signal cascade appear to greatly increase risk of AAD (TGFBR1, TGFBR2, ACTA2, FBN1), but most cases do not carry mutations in these genes. We aim to identify the underlying genetic causes of AAD in multi-ethnic cohorts using exome sequencing and genome-wide association approaches. This study has the potential to provide paradigm-shifting discoveries of translational importance for this devastating cardiovascular disease.

Publications

1. Wolford BN, Hornsby WE, Guo D, Zhou W, Lin M, Farhat L, McNamara J, Driscoll A, Wu X, Schmidt EM, Norton EL, Mathis MR, Ganesh SK, Douville NJ, Brummett CM, Kitzman J, Chen YE, Kim K, Deeb GM, Patel H, Eagle KA, Milewicz DM, J Willer C, Yang B. "Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection". Circulation: Genomic and Precision Medidcine. 2019 Jun;12(6):e002476. doi: 10.1161/CIRCGEN.118.002476. Epub 2019 Jun 18. https://www.ncbi.nlm.nih.gov/pubmed/31211624

Santhi Ganesh, MD
Associate Professor of Internal Medicine
Division of Cardiovascular Medicine
University of Michigan Medical School
[email protected]

Yan Zhang, MD
张岩教授
Associate Professor of Cardiovascular Medicine
Department of Cardiology
Peking University First Hospital

JI program: Cardiovascular

Status: Active/ Ongoing

Summary

Cardiovascular disease (CVD) is the leading cause of death globally. Elevated blood pressure (BP), or hypertension (HTN), is a major and heritable risk factor for CVD. Genetic associations with BP/HTN found to date explain little of the variance of BP in the general population, and the mechanisms are largely unknown. This project will investigate the impact of hematologic traits on BP and HTN. The team hypothesizes that genetic variants underlying the joint associations between hematologic and BP traits can be identified using an unbiased genetic association study, and that these findings extend to CVD outcomes.

Publications

1. Yuan W, Liu Z, Lei W, Sun L,... Li JZ, Yang K ( June 27, 2017). Mutation landscape and intra-tumor heterogeneity of two MANECs of the esophagus revealed by multi-region sequencing. Oncotarget
2. Li J, Yan S, Liu Z, … Ke Y. Multiregional sequencing reveal genomic alterations and clonal dynamics in primary malignant melanoma of the esophagus. Cancer Research. 2018;78(2):338-347

Zhong Wang, PhD
Associate Professor of Cardiac Surgery
University of Michigan Medical School
[email protected]

Hongkui Deng, MD
邓宏魁教授
Professor of Cellular Biology
Peking University Health Science Center
[email protected]

JI Program: Cardiovascular

Status: Completed

Summary

Cardiovascular disease (CVD) is the leading cause of death in the world today, and the death rate has remained virtually unchanged in the last twenty years. The severity and prevalence of this disease underscores a critical need for developing novel therapeutic strategies for effective treatment. Cell-based therapy represents an extremely promising approach to treat heart diseases but requires strict safety and efficacy tests before clinical trials. In principle, somatic cells obtained from a heart patient can be reprogrammed to generate his/her own human induced pluripotent stem cells (hiPSCs). These iPSCs can then be differentiated into heart cells or tissues for transplantation. While this strategy should avoid any undesired immune response from patients, two major issues exist: the potential oncogenic property of the hiPSCs due to the use of viral vectors and the oncogenic transgenes, and the uncertainty of appropriate differentiated cell types for successful heart transplantation therapies. The study’s objectives are: 1) to optimize a chemical approach as a much safer strategy to generate patient specific iPSCs, and 2) to efficiently differentiate the chemically induced iPSCs into cardiac progenitor cells as an ideal cell source for heart regeneration. The PKUHSC and Michigan Medicine team offers unparalleled expertise and resources for the success of the pioneer work proposed here – addressing these two critical issues in heart disease therapy. The team hopes to achieve the long-term goal of developing stem cell-based heart therapies to effectively prolong and improve the life of patients with CVD.

Outcomes

• Mastered the technique for chemical induced mouse iPSCs and characterized the mouse iPSCs into cardiac lineages.
• Derived embryonic stem cell lines or induced pluripotent stem cell lines that are able to contribute both embryonic and extra-embryonic lineages.
• Transplanted ESC/iPSC derived cardiac progenitor cells and cardiomyocytes into infarcted animal hearts.
• Exploring the regulatory pathway with the FDA to repurpose a currently approved drug to treat acute heart attack.

Publications

1. Liu Q, Tian S, Zhao C, Wang Z*, Ma PX* (2015) Porous nanofibrous poly(l-lactic acid) scaffolds supporting cardiovascular progenitor cells for cardiac tissue engineering. Acta Biomaterialia. 2015;26:105-114.
2. Tian S, Liu Q, Gnatovskiy L, …Wang Z (2015) Heart regeneration with embryonic cardiac progenitor cells and cardiac tissue engineering. J Stem Cell and Transplantation Biology. 2015; 1(1):104
3. Liu L, Lei I, Wang Z (2016) Improving cardiac reprogramming for heart regeneration. Curr Opin Organ Transplant 2016; 21(6): 588-594.
4. Liu L, Lei I, … Shaomeng Wang, Wang Z (2016) Targeting Mll1 H3K4 methyltransferase activity to guide cardiac lineage specific reprogramming of fibroblasts. Cell Discovery 2016;2:16036.
5. Li Y, Tian S, Lei I, … Wang Z (2017) Transplantation of multipotent Isl1+ cardiac progenitor cells preserves infarcted heart function in mice. Am J Transl Res.2017;9(3): 1530-1542
6. Yang Y, Liu B, Xu J, Wang J, Wu J, Shi C, Xu Y, Dong J, Wang C, Lai W, Zhu J, Xiong L, Zhu D, Li X, Yang W, Yamauchi T, Sugawara A, Li Z, Sun F, Li X, Li C, He A, Du Y, Wang T, Zhao C, Li H, ChiX, Zhang H, Liu Y, Li C, Duo S, Yin M, Shen H, Belmonte JC, Deng H (2017) Derivation of Pluripotent Stem Cells with In Vivo Embryonic and Extraembryonic Potency. Cell 169: 243-257
7. Wang L, Meier E, Tian S, Lei I, Liu L, Xian S, Lam MT, & Wang Z : Transplantation of Isl1+ cardiac progenitor cells in small intestinal submucosa improves infarcted heart function Stem Cell Res Ther 8: 230, 2017. PMC5644064.
8. Shuo Tian; Ienglam Lei; Wenbin Gao; Liu Liu, Yijing Guo; Shaoxiang Xian; Peter X. Ma; Y. Eugene Chen; Yongqing Li; Hasan B. Alam; and Zhong Wang*. HDAC inhibitor valproic acid protects heart function through Foxm1 pathway after acute myocardial infarction. EBioMedicine 39 (2019) 83-94.

Bo Yang, MD
杨波教授
Assistant Professor of Cardiac Surgery
University of Michigan Medical School
[email protected]

Zhe Zhang, MD
张喆教授
Professor of Cardiac Surgery
Vice Director, Department of Cardiac Surgery
Peking University Third Hospital

JI Program: Cardiovascular

Status: Completed

Summary

Acute aortic dissection (AAD) is a lethal disease and early diagnosis significantly improves an AAD patient’s chances of survival. Yet, there are no ideal biomarkers or the early diagnosis of AAD. AAD occurs when the media of the aortic wall becomes dissected by the blood stream through a primary intimal tear. There is extensive smooth muscle cells (SMC) injury during AAD and – by identifying SMC proteins in the serum of AAD, coronary artery syndrome, and healthy donor patients – we hypothesize that SMC-specific proteins will be elevated only in the AAD group. The most sensitive and specific protein will then be considered a candidate biomarker for use in early diagnosis of AAD. Both institutional partners have access to a large population of AAD patients, as well as the research infrastructure and capability to perform all proposed experiments. Both institutions also have the proteomics core facilities and laboratory support necessary to measure SMC-specific proteins in the serum.

Outcomes

• 104 patients have been enrolled to identify elevated proteins in the serum in patients of AAD using proteomics.
• Three target proteins were identified as biomarkers of AAD with proteomics.

Guohua Xi, MD
Associate Director of Crosby Neurosurgical Laboratories
Richard C. Schneider Research Professor, Neurosurgery
University of Michigan Medical School
[email protected]

Yining Huang, MD
黄一宁教授
Professor of Neurology
Director, Department of Neurology
Peking University First Hospital

JI Program: Cardiovascular

Status: Completed

Project Summary

Spontaneous intracerebral hemorrhage (ICH) is a common and often fatal stroke subtype. If the patient survives the ictus, the resulting hematoma within brain parenchyma triggers a series of events leading to secondary insults and severe neurological deficits, which are usually permanent and disabling. Clinical data suggest that iron overload plays a role in brain injury and atrophy following ICH. High levels of serum ferritin, an iron-binding protein, have been associated with poor outcome and severe brain edema in ICH patients; however, deferoxamine, an iron chelator has been found to reduce brain edema, neuronal death, brain atrophy and neurological deficits in rats and pigs. Brain iron overload is an attractive therapeutic target as it occurs over weeks and may be amenable to delayed treatment, yet, the natural history of brain iron overload in ICH has not been well studied clinically or in large animal models. This project aims to validate the utility of T2* magnetic resonance imaging (MRI) in quantifying brain iron after ICH using a porcine model and to use this imaging technique to examine the natural history of brain iron accumulation after ICH and the effects of deferoxamine treatment on that accumulation in pigs and patients. As a biomarker, T2* MRI may provide a method of examining and optimizing iron chelation therapy and establishing a novel endpoint for ICH clinical trials.

Outcomes

• 30 ICH patients were enrolled for MRI imaging analysis to define the relationship between early hemolysis and perihematomal edema.
• 1 PKUHSC faculty received extensive training at Michigan Medicine’s Crosby Neurosurgical Laboratories from February 2016 to January 2017.
• Received $2.785 million dollars of extramural funding from the National Institute of Health.

Publications

1. Pandey AS and Xi G. Intracerebral hemorrhage: a multimodality approach to improving outcome. Transl Stroke Res. 2014; 5: 313-315.
2. Chaudhary N, Pandey AS, Gemmete JJ,…Yining Huang….Xi G. (2015) Diffusion tensor imaging in hemorrhagic stroke. Experimental Neurology. 2015; 272: 88-96.
3. Liu R, Cao S, Hua Y, Keep RF, Huang Y, Xi G. (2017) CD163 expression in neurons after experimental intracerebral hemorrhage. Stroke. 2017;48(5), pp.1369-1375.
4. Liu R, Li H, Hua Y, Keep RF, Xiao J, Xi G, Huang Y. Early Hemolysis Within Human Intracerebraln Hematomas: an MRI Study. Transl Stroke Res. 2018 May 15. doi: 10.1007/s12975-018-0630-2. [Epub ahead of print]
5. Cao S, Hua Y, Keep RF, Chaudhary N, Xi G. Minocycline effects on intracerebral hemorrhage-induced iron overload in aged rats: brain iron quantification with MRI. Stroke, 2018;49:995-1002. PMCID:PMC5871578.
6. Tong X, Lv P, Mathew AV, …Pennathur S,…Huang Y. (2014) The compensatory enrichment of sphingosine -1-phosphate harbored on glycated high-density lipoprotein restores endothelial protective function in type 2 diabetes mellitus. Cardiovasc Diabetol. 2014; 13: 82.

Jianping Li, MD, PhD
李建平教授
Professor
Executive Deputy Director
Department of Cardiology
Peking University First Hospital
Peking University Health Science Center
[email protected]

JI Program: Cardiovascular

Status: Completed

Summary

Fine particulate matter air pollution (PM2.5) is the 9th leading risk factor for morbidity and mortality worldwide. Whist contributing to lung diseases, the largest cause of PM2.5-related morbidity and mortality is actually due to cardiovascular (CV) events. This study will be the first investigation in humans regarding the impact of PM2.5 on high-density lipoprotein (HDL) function, and should provide novel insights into a potentially critically-important mechanism by which air pollution, a ubiquitous CV risk factor of tremendous global public health importance, causes CV diseases.

Numerous adverse biological responses have been shown to occur in response to PM2.5 exposures; however, the underlying pathway whereby PM2.5 triggers CV changes remote from the site of inhalation in the lungs is not yet understood. This partnership aims to determine if HDL particles within the pulmonary circulation/ tissue are adversely affected by inhaled PM2.5 and if the resulting genesis of circulating dysfunctional HDL is thereafter an important pathway whereby diverse systemic CV perturbations can be investigated. By investigating the impact of sub-acute PM2.5 exposures across the global spectrum of ambient-concentrations on 4 measurable HDL function assays in obsess and lean adults without CV diseases, the team will evaluate the associations between ambient PM2.5 exposures and HDL function and determine the role of PM2.5-mediated HDL dysfunction on adversely affecting other CV endpoints at each site and pooled together.

Outcomes

• Initial results demonstrate adverse effects of air pollutants on several cardiovascular parameters in Beijing, particularly among overweight participants.

Publications

1. Brook, R. D., & Rajagopalan, S. (2017). “Stressed” About Air Pollution: Time for Personal Action. Circulation. 2017;136:628–631. DOI: 10.1161
2. Ejike C, Wang L, Liu M, … Brook RD. (2017). Personal-level exposure to environmental temperature is a superior predictor of endothelial-dependent vasodilatation than outdoor-ambient level. J Am Soc Hypertens. 2017 Nov;11(11):746-753.e1. doi: 10.1016/j.jash.2017.09.006.
3. Brook RD, Newby DE, Rajagopalan S. (2017). Air Pollution and Cardiometabolic Disease: An Update and Call for Clinical Trials. Am J Hypertens. 2017 Dec 8;31(1):1-10. doi: 10.1093/ajh/hpx109.
4. Huang W, Wang L, Li J, …Brook RD. Short-Term Blood Pressure Responses to Ambient Fine Particulate Matter Exposures at the Extremes of Global Air Pollution Concentrations. (2018). Am J Hypertens. 2018 Feb 2. doi: 10.1093/ajh/hpx216
5. Brook RD. (2018). Effect of Ambient Fine Particulate Matter Air Pollution and Colder Outdoor Temperatures on High-Density Lipoprotein Function. American Journal of Cardiology.

Jose Jalife, MD, PhD
Professor, Molecular & Integrative Physiology (Emeritus)
University of Michigan Medical School
[email protected]

Xuebin Li, MD
李学斌教授
Professor and Associate Director
Department of EP Lab
Peking University Second Hospital

JI Program: Cardiovascular

Status: Completed

Summary

This translational research project addresses the roles played by specific pathways of the renin-angiotensin-aldosterone system (RAAS) in the molecular mechanisms that lead to the transition from paroxysmal to persistent atrial fibrillation (AF). We will use clinically relevant in-vivo models of pacing-induced long-term persistent AF in sheet and Chinese mini swine to investigate the specific roles played by transforming growth factor-β1 (TGF-β1) and platelet derived growth factor (PDGF), two of the RAAS signaling molecules, in regulating such a transition. Temporal changes in plasma and cardiac specific levels of TGF-β1, PDGF and serum fibrosis markers will be correlated with changes in the atrial fibrillatory rate during the progression from paroxysmal to persistent AF. In addition, the effects of eplerenone and/or traditional Chinese medicines in preventing the paroxysmal-to-persistent AF transition will be compared. Two cohorts of patients with paroxysmal AF will be established – one at each institution – to test the hypothesis that systemic plasma and cardiac specific levels of serum fibrosis markers correlate with the progression from paroxysmal to persistent AF. The translation from bench-to-bedside research has major clinical relevance in the U.S. and in China, and the results from this work may lead to the development of novel diagnostic targets and pharmacologic tools aimed at the prevention of persistent AF in patients.

Outcomes

• More than 55 patients with either paroxysmal or persistent AF were recruited and being followed up according to the protocol.
• Dr. Yoshio Takemoto, was awarded the 2016 Young Author Achievement Award by the American College of Cardiology for this JI publication.
• One resident from Michigan Medicine completed a one-month clinical rotation mentored by Dr. Li.
• Two PKUHSC PhD graduates were supported by this project.
• One grant from the Chinese National Natural Science Foundation as approved based on part of the research done through this JI collaboration.

Publications

1. Takemoto Y, Ramirez RJ, Yokokawa, M, …Jalife J. (2016) Galectin-3 Regulates Atrial Fibrillation Remodeling and Predicts Catheter Ablation Outcomes. JACC Basic Transl Sci. 1(3): 143–154.
2. Takemoto Y, Slough DP, Meinke G, Katnik C, Graziano ZA, Chidipi B, Reiser M, Alhadidy MM, Ramirez R, Salvador-Montañés O, Ennis S, Guerrero-Serna G, Haburcak M, Diehl C, Cuevas J, Jalife J, Bohm A, Lin YS, Noujaim SF. Structural basis for the antiarrhythmic blockade of a potassium channel with a small molecule. FASEB J. 2018 Apr;32(4):1778-1793.
3. Takemoto Y, Ramirez RJ, Kaur K, Salvador-Montañés O, Ponce-Balbuena D,Ramos-Mondragón R, Ennis SR, Guerrero-Serna G, Berenfeld O, Jalife J. Eplerenone Reduces Atrial Fibrillation Burden Without Preventing Atrial Electrical Remodeling. J Am Coll Cardiol. 2017, Dec 12;70(23):2893-2905.
4. Pandit SV, Anumonwo J, Jalife J. Atrial Fibrillation Susceptibility in Obesity: An Excess Adiposity and Fibrosis Complicity? Circ Res. 2016 May 13;118(10):1468-1471.

Santhi Ganesh, MD
Associate Professor of Internal Medicine
Division of Cardiovascular Medicine
University of Michigan Medical School
[email protected]

Yan Zhang, MD
张岩教授
Associate Professor of Cardiovascular Medicine
Department of Cardiology
Peking University First Hospital

JI Program: Cardiovascular

Status: Completed

Summary

Blood pressure is a heritable and major determinant of cardiovascular disease risk and a leading cause of morbidity and mortality in China. The incidence of hypertension is increasing at an alarming rate. Of the trends known to be relevant to cardiovascular diseases, the blood pressure trend is expected to lead to the highest predicted increase in stroke and combined cardiovascular disease in Chinese individuals. This project aims to study the association of common and rare genetic variants with blood pressure and hypertension in a cohort of patients at the Peking University First and Third Hospitals. The relationship of genetic determinants for blood pressure with cardiovascular outcomes and other factors known to predict cardiovascular disease will also be explored. The study teams have collaborated in a consortium-based genetic analysis of longitudinal blood pressure measures identifying three novel genes influencing BP in the population.

Outcomes

• A mouse null for the CCDC93 gene using CRISPR/Cas 9 methods was generated.
• 3 PKUHSC faculty members received extensive training at Michigan Medicine mentored by Dr. Santhi Ganesh.

Publications

1. Ganesh SK, Chasman DI, Larson MG….Zhang Y,... et al. (2014) Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. Am J Hum Genet. 2014; 95(1): 49-65.

Eugene Chen, MD
陈育庆教授
Frederick G L Huetwell Professor of Cardiovascular Medicine
Professor of Internal Medicine
Professor, Pharmacology
Professor of Molecular and Integrative Physiology
University of Michigan Medical School
[email protected]

Guisong Wang, MD
王贵松教授
Department of Cardiology
Peking University Third Hospital

JI Program: Cardiovascular

Status: Completed

Project Summary

Even with substantial improvements in cardiovascular disease (CVD) treatments, CVD continues to be the leading cause of death in China. Epidemiologic studies and large-scale clinical trials have conclusively established a strong inverse relationship between high-density lipoprotein (HDL) cholesterol levels and cardiovascular risk. Insight into the dynamic differences in HDL biology and function in complication prone individual will identify new diagnostic markers and therapeutic targets in subjects with CVD. To gain this insight, we propose to develop state-of-the-art mass spectrometry based platform to identify and validate novel HDL protein markers that would predict risk of endothelial dysfunction in CVD patients. The proposed study will examine the roles and myeloperoxidase (MPO)-oxidized HDL and HDL proteome in vascular dysfunction in Chinese patients, comparing this data to data collected at UMHS.

Outcomes

Numerous training opportunities were derived from the collaboration, including:

• 3 PKUHSC junior faculty members received extensive training at Michigan Medicine mentored by Dr. Eugene Chen and Dr. Sub Pennathur.
• 3 Michigan Medicine residents completed one-month clinical rotation at PKUHSC mentored by Dr. Wei Gao and Dr. Guisong Wang.

Publications

1. Wang G, Mathew AV, Yu H, Li L, He L, Gao W, Liu X, Guo Y, Byun J, Zhang J, Chen YE, Pennathur S. Myeloperoxidase Mediated HDL Oxidation and HDL Proteome Changes Do Not Contribute to Dysfunctional HDL in Chinese Subjects with Coronary Artery Disease. PLoS One. 2018,13 (3) :e0193782.
2. Liu D, Ji L, Tong X, Pan B, Han JY, Huang Y, Chen YE, Pennathur S, Zhang Y, Zheng L. (2011). Human apolipoprotein A-I induces cyclooxygenase-2 expression and prostaglandin I-2 release in endothelial cells through ATP-binding cassette transporter A1. American Journal of Cell Physiology. 2011;301(3): C739- 48.
3. Pan B, Ma Y, Ren H, He Y, Wang Y, Lv X, Liu D, Ji L, Yu B, Wang Y, Chen YE, Pennathur S, Smith JD, Liu G, Zheng L. (2012) Diabetic HDL is dysfunctional in stimulating endothelial cell migration and proliferation due to down regulation of SR-BI expression. PLoS One. 2012; 7(11): e48530.
4. Guo Y, Fan Y, Zhang J, Lomberk GA, Zhou Z, Sun L, Mathison AJ, Garcia-Barrio MT, Zhang J, Zeng L, Li L, Pennathur S, Willer CJ, Rader DJ, Urrutia R, Chen YE. (2015) Perhexiline Activates KLF14 and Reduces Atherosclerosis by Modulating ApoA-I Production.  Journal of Clinical Investigation. 2015;125(10):3819-3830. doi:10.1172/JCI7904.
5. Pan B, Yu B, Ren H, Willard B, Pan L, Zu L, Shen X, Ma Y, Li X, Niu C, Kong J, Kang S, Eugene Chen Y, Pennathur S, Zheng L. (2013) High-density lipoprotein nitration and chlorination catalyzed by myeloperoxidase impair its effect of promoting endothelial repair. Free Radical Biology Medicine. 2013; 60: 272-81.

Extramural Funding

NIH R01-HL134569 (Chen)
3/1/2017-2/28/2021
Title: KLF14 and Atherosclerosis
Total Funding: $2,821,885

Cristen Willer, PhD
Frank Norman Wilson Professor of Cardiovascular Medicine
Associate Professor of Internal Medicine
Associate Professor of Human Genetics
Associate Professor of Computational Medicine and Bioinformatics
University of Michigan Medical School
[email protected]

Ming Xu, PhD
徐明教授
Professor of Cardiology
Peking University Third Hospital
[email protected]

JI Program: Cardiovascular

Status: Completed

Summary

Myocardial infarction (MI) is the leading cause of death in the United States and the 2nd leading cause of death in China, responsible for 22.5% of deaths in the Chinese population. Despite nearly 2,300 Americans and 25,800 Chinese patients dying of cardiovascular diseases every day, little is known about the etiology of MI. Genome-wide association studies (GWAS) have been proven successful at mapping genomic loci that influence human disease and traits (www.genome.gov/gwastudies), including MI, cardiovascular diseases, and lipid levels. However, for MI, the vast majority of the heritability remains unexplained, due to the lack of complete understanding of the causal variants and genes at known loci. In addition, many additional disease genes were likely not found by the GWAS approach. This study hypothesizes that studying Chinese individuals with MI will test whether the same variants and genes identified in Europeans will also be associated in Asian individuals. Evidence for selection at lipid genes will also be investigated.

Outcomes

• 8,621 samples from 4 hospitals were collected for genotyping.
• 3 novel lipid variants present in Asians were identified.
• New genes involved in blood cholesterol levels were discovered; one of which has already shown to increase risk of fatty liver diseases.

Publications

1. Tang CS, Zhang H, Cheung CY,…Willer CJ, Gao W. (2015) Exome-wide association analysis reveals novel coding sequence variants associated with lipid traits in Chinese. Nat Commun. 2015;22(6):10206. doi: 10.1038/ ncomms10206.
2. Lu X, Peloso G, Liu D,…Willer CJ. (2017) Exome chip meta-analysis identifies novel loci and East Asian–specific coding variants contributing to lipid levels and coronary artery disease. Nat. Genet. Dec;49(12):1722-1730. doi: 10.1038/ng.3978. Epub 2017 Oct 30.
3. Ganesh SK, Chasman DI, Larson MG, Guo X, Verwoert G, Bis JC, Gu X, Smith AV, Yang ML, Zhang Y, Ehret G, Rose LM, Hwang SJ, Papanicolau GJ, Sijbrands EJ, Rice K, Eiriksdottir G, Pihur V, Ridker PM, Vasan RS, Newton-Cheh C; Global Blood Pressure Genetics Consortium, Raffel LJ, Amin N, Rotter JI, Liu K, Launer LJ, Xu M, Caulfield M, Morrison AC, Johnson AD, Vaidya D, Dehghan A, Li G, Bouchard C, Harris TB, Zhang H, Boerwinkle E, Siscovick DS, Gao W, Uitterlinden AG, Rivadeneira F, Hofman A, Willer CJ, Franco OH, Huo Y, Witteman JC, Munroe PB, Gudnason V, Palmas W, van Duijn C, Fornage M, Levy D, Psaty BM, Chakravarti A. Effects of Long-Term Averaging of Quantitative Blood Pressure Traits on the Detection of Genetic Associations. The American Journal of Human Genetics.2014; 95(1),49–65