McKay Miles Saladin Mullen

All Publications

• Disparities in cardio-oncology: Implication of angiogenesis, inflammation, and chemotherapy. Life sciences Vera, C. D., Lopez, A. R., Ewaneewane, A. S., Lewis, K., Parmisano, S., Mondejar-Parreno, G., Upadhyaya, C., Mullen, M. 2023; 332: 122106

  Abstract

  Cancers and cardiovascular diseases are the top two causes of death in the United States. Over the past decades, novel therapies have slowed the cancer mortality rate, yet cardiac failures have risen due to the toxicity of cancer treatments. The mechanisms behind this relationship are poorly understood and it is crucial that we properly treat patients at risk of developing cardiac failure in response to cancer treatments. Currently, we rely on early-stage biomarkers of inflammation and angiogenesis to detect cardiotoxicity before it becomes irreversible. Identification of such biomarkers allows healthcare professionals to decrease the adverse effects of cancer therapies. Angiogenesis and inflammation have a systemic influence on the heart and vasculature following cancer therapy. In the field of cardio-oncology, there has been a recent emphasis on gender and racial disparities in cardiotoxicity and the impact of these disparities on disease outcomes, but there is a scarcity of data on how cardiotoxicity varies across diverse populations. Here, we will discuss how current markers of angiogenesis and inflammation induced by cancer therapy are related to disparities in cardiovascular health.

  View details for DOI 10.1016/j.lfs.2023.122106

  View details for PubMedID 37730108

• Cardiovascular Impact of Androgen Deprivation Therapy: from Basic Biology to Clinical Practice. Current oncology reports Kim, J., Freeman, K., Ayala, A., Mullen, M., Sun, Z., Rhee, J. 2023

  Abstract

  PURPOSE OF THE REVIEW: There have been increasing reports of cardiovascular complications of androgen deprivation therapy (ADT) leading to worse outcomes among patients with prostate cancer. While this may result from the direct effects of androgen suppression in the cardiovascular systems, there are ADT-type-specific distinct cardiovascular complications suggestive of mechanisms beyond androgen-mediated. Thus, it is critical to understand the biological and clinical impact of ADT on the cardiovascular system.RECENT FINDINGS: Gonadotropin-releasing hormone (GnRH) agonists cause increased cardiovascular events compared to GnRH antagonists. Androgen receptor antagonists are linked to an increased risk of long QT syndrome, torsades de pointes, and sudden cardiac death. Androgen synthesis inhibitors are associated with increased rates of hypertension, atrial tachyarrhythmia, and, in rare incidences, heart failure. ADT increases the risk of cardiovascular disease. The risk among ADT drugs differs and must be evaluated to develop a medically optimal plan for prostate cancer patients.

  View details for DOI 10.1007/s11912-023-01424-2

  View details for PubMedID 37273124

• Modeling Susceptibility to Cardiotoxicity in Cancer Therapy Using Human iPSC-Derived Cardiac Cells and Systems Biology. Heart failure clinics Mullen, M., Wen Tan, W. L., Rhee, J., Wu, J. C. 2022; 18 (3): 335-347

  Abstract

  The development of human-induced pluripotent stem cell-derived cardiac cell types has created a new paradigm in assessing drug-induced cardiotoxicity. Advances in genomics and epigenomics have also implicated several genomic loci and biological pathways that may contribute to susceptibility to cancer therapies. In this review, we first provide a brief overview of the cardiotoxicity associated with chemotherapy. We then provide a detailed summary of systems biology approaches being applied to elucidate potential molecular mechanisms involved in cardiotoxicity. Finally, we discuss combining systems biology approaches with iPSC technology to help discover molecular mechanisms associated with cardiotoxicity.

  View details for DOI 10.1016/j.hfc.2022.02.009

  View details for PubMedID 35718410

• Intersectionality and genetic ancestry: New methods to solve old problems. EBioMedicine Vera, C. D., Mullen, M., Minhas, N., Wu, J. C. 2022; 80: 104049

  View details for DOI 10.1016/j.ebiom.2022.104049

  View details for PubMedID 35561454

• Sex-Specific Cardiovascular Risks of Cancer and Its Therapies. Circulation research Wilcox, N. S., Rotz, S. J., Mullen, M., Song, E. J., Ky Hamilton, B., Moslehi, J., Armenian, S. H., Wu, J. C., Rhee, J., Ky, B. 2022; 130 (4): 632-651

  Abstract

  In both cardiovascular disease and cancer, there are established sex-based differences in prevalence and outcomes. Males and females may also differ in terms of risk of cardiotoxicity following cancer therapy, including heart failure, cardiomyopathy, atherosclerosis, thromboembolism, arrhythmias, and myocarditis. Here, we describe sex-based differences in the epidemiology and pathophysiology of cardiotoxicity associated with anthracyclines, hematopoietic stem cell transplant (HCT), hormone therapy and immune therapy. Relative to males, the risk of anthracycline-induced cardiotoxicity is higher in prepubertal females, lower in premenopausal females, and similar in postmenopausal females. For autologous hematopoietic cell transplant, several studies suggest an increased risk of late heart failure in female lymphoma patients, but sex-based differences have not been shown for allogeneic hematopoietic cell transplant. Hormone therapies including GnRH (gonadotropin-releasing hormone) modulators, androgen receptor antagonists, selective estrogen receptor modulators, and aromatase inhibitors are associated with cardiotoxicity, including arrhythmia and venous thromboembolism. However, sex-based differences have not yet been elucidated. Evaluation of sex differences in cardiotoxicity related to immune therapy is limited, in part, due to low participation of females in relevant clinical trials. However, some studies suggest that females are at increased risk of immune checkpoint inhibitor myocarditis, although this has not been consistently demonstrated. For each of the aforementioned cancer therapies, we consider sex-based differences according to cardiotoxicity management. We identify knowledge gaps to guide future mechanistic and prospective clinical studies. Furthering our understanding of sex-based differences in cancer therapy cardiotoxicity can advance the development of targeted preventive and therapeutic cardioprotective strategies.

  View details for DOI 10.1161/CIRCRESAHA.121.319901

  View details for PubMedID 35175846

• Utilization of induced pluripotent stem cells to model the molecular network regulating congenital heart disease. Cardiovascular research Mullen, M. M., Wu, J. C. 1800

  View details for DOI 10.1093/cvr/cvab373

  View details for PubMedID 34971365

• Race and Genetics in Congenital Heart Disease: Application of iPSCs, Omics, and Machine Learning Technologies. Frontiers in cardiovascular medicine Mullen, M. n., Zhang, A. n., Lui, G. K., Romfh, A. W., Rhee, J. W., Wu, J. C. 2021; 8: 635280

  Abstract

  Congenital heart disease (CHD) is a multifaceted cardiovascular anomaly that occurs when there are structural abnormalities in the heart before birth. Although various risk factors are known to influence the development of this disease, a full comprehension of the etiology and treatment for different patient populations remains elusive. For instance, racial minorities are disproportionally affected by this disease and typically have worse prognosis, possibly due to environmental and genetic disparities. Although research into CHD has highlighted a wide range of causal factors, the reasons for these differences seen in different patient populations are not fully known. Cardiovascular disease modeling using induced pluripotent stem cells (iPSCs) is a novel approach for investigating possible genetic variants in CHD that may be race specific, making it a valuable tool to help solve the mystery of higher incidence and mortality rates among minorities. Herein, we first review the prevalence, risk factors, and genetics of CHD and then discuss the use of iPSCs, omics, and machine learning technologies to investigate the etiology of CHD and its connection to racial disparities. We also explore the translational potential of iPSC-based disease modeling combined with genome editing and high throughput drug screening platforms.

  View details for DOI 10.3389/fcvm.2021.635280

  View details for PubMedID 33681306

  View details for PubMedCentralID PMC7925393

• Leptin-Induced JAK/STAT Signaling and Cancer Growth. Vaccines Mullen, M., Gonzalez-Perez, R. R. 2016; 4 (3)

  Abstract

  Growth factor and cytokine signaling can influence the development of several cancer types. One of the key players in the development of cancer is the Janus kinas (JAK) signal transducer of activators of transcription (STAT) signaling pathway. The majority of growth factors and cytokine interactions with their membrane-bound receptors trigger JAK-STAT activation. The influential relationship between obesity and cancer is a fact. However, there is a complex sequence of events contributing to the regulation of this mechanism to promote tumor growth, yet to be fully elucidated. The JAK-STAT pathway is influenced by obesity-associated changes that have been shown to impact cancer growth and progression. This intricate process is highly regulated by a vast array of adipokines and cytokines that exert their pleiotropic effects on cancer cells to enhance metastasis to distant target sites. Leptin is a cytokine, or more precise, an adipokine secreted mainly by adipose tissue that requires JAK-STAT activation to exert its biological functions. Leptin is the central regulator of energy balance and appetite. Leptin binding to its receptor OB-R in turn activates JAK-STAT, which induces proliferation, angiogenesis, and anti-apoptotic events in normal cells and malignant cells expressing the receptor. Leptin also induces crosstalk with Notch and IL-1 (NILCO), which involves other angiogenic factors promoting tumor growth. Therefore, the existence of multiple novel classes of therapeutics that target the JAK/STAT pathway has significant clinical implications. Then, the identification of the signaling networks and factors that regulate the obesity-cancer link to which potential pharmacologic interventions can be implemented to inhibit tumor growth and metastasis. In this review, we will discuss the specific relationship between leptin-JAK-STAT signaling and cancer.

  View details for DOI 10.3390/vaccines4030026

  View details for PubMedID 27472371

  View details for PubMedCentralID PMC5041020