Cardiovascular Research Faculty And Primary Area Of Investigation
Neurobiology · Arrhythmias · Heart Failure
The autonomic nervous system plays an important role in the initiation and maintenance of arrhythmias. My research efforts focus on developing a detailed understanding of the basic mechanisms of cardiac arrhythmias. My lab's overall goal is to develop neuromodulation therapies to treat arrhythmias as the degree of sympatho-excitation has been related to arrhythmias and sudden death. To this end, my lab has developed expertise in large and small animal models of heart failure and post-myocardial infarction ventricular tachycardia (VT), which closely mimics human conditions. We have shown that within the sympathetic neurons of the stellate ganglia, which is physically removed from the heart but is intricately involved in efferent regulation of cardiac function, there is significant structural and functional remodeling. We have established within both the porcine model of myocardial infarction and in humans with ischemic and non-ischemic cardiomyopathy, that neurochemical properties in these neurons are changed. My lab has expertise in a variety of in vivo and ex vivo techniques such as cardiac viral injections in mouse and pigs, multi-electrode and transmural cardiac electrical mapping, cardiovascular autonomic reflexes, neural recordings, neural networks, tissue clearing for confocal and super-resolution imaging, and most recently RNA-seq and its associated bioinformatic tools.
- Yoshie K, Rajendran PS, Massoud L, Mistry J, Swid MA, Wu X, Sallam T, Zhang R, Goldhaber JI, Salavatian S, Ajijola OA. Cardiac TRPV1 afferent signaling promotes arrhythmogenic ventricular remodeling after myocardial infarction. JCI Insight. 2020 13;5(3):e124477. doi: 10.1172/jci.insight.124477.
- Ajijola OA, Hoover DB, Simerly TM, Brown TC, Yanagawa J, Biniwale RM, Lee JM, Sadeghi A, Khanlou N, Ardell JL, Shivkumar K. Inflammation, oxidative stress, and glial cell activation characterize stellate ganglia from humans with electrical storm. JCI Insight. 2017 21;2(18):e94715. doi: 10.1172/jci.insight.94715. eCollection 2017 Sep 21.
- Ajijola OA, Lux RL, Khahera A, Kwon O, Aliotta E, Ennis DB, Fishbein MC, Ardell JL, Shivkumar K. Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis. Am J Physiol Heart Circ Physiol. 2017 1;312(3):H608-H621. doi: 10.1152/ajpheart.00575.2016. Epub 2017 Jan 13.
Neurocardiology · Arrhythmia · Heart Failure
My primary research interest is in the field of neurocardiology. Our initial work defined the primary elements of the intrinsic cardiac nervous system (ICNS) and how they interacted together to control regional cardiac function in the normal heart. Our subsequent work demonstrated that the progression of cardiac disease reflects maladaptive interactions between the cardiac nervous system and the heart. Our recent work has demonstrated that targeting select elements within this neural network can lead to efficacious results in select cardiac disease states, including atrial arrhythmias, myocardial infarction, and congestive heart failure. With appropriate neuromodulation therapy, myocytes are rendered stress resistant, autonomic responsiveness for control of the heart is preserved, and the potential for fatal arrhythmias is reduced. My laboratory also has an interest in technology development with major efforts in evolving technologies for high density form/fit electrodes for cardiac electrophysiology and interfaces and equipment allowing for real-time detection of intra-myocardial and trans-organ neurotransmitter detection.
- Ardell JL, Nier H, Hammer M et al. Defining the neural fulcrum for chronic vagus nerve stimulation: implications for integrated cardiac control. The Journal of Physiology 2017;595:6887-6903.
- Ardell JL, Foreman RD, Armour JA, Shivkumar K. Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation. JCI Insight 2019;4.
- Hanna P, Shivkumar K, Ardell JL. Calming the Nervous Heart: Autonomic Therapies in Heart Failure. Cardiac Failure Review 2018;4:92-98.
Cardiac Neural Control · Mechanism of Arrhythmias · Visceral Neuroscience
Dr. Shivkumar is an interventional cardiac electrophysiologist focusing on the neural control of the heart and mechanisms of arrhythmias in humans. His group has advanced neuraxial modulation treatment for patients with refractory ventricular arrhythmias in whom death was imminent. He and his colleagues identified that explanted stellate ganglia in patients with cardiomyopathy showed neural remodeling. In parallel, utilizing an integrative physiology approach and infarct models, his group has characterized neural remodeling, mechanisms of arrhythmias and mechanistic basis of neuraxial modulation. Recently his group has identified the ‘neural signature’ of cardiac injury, the consequence of altered afferent cardiac neurotransmission, that ultimately activates the neuroendocrine system which underlies heart failure and arrhythmias. ‘Myocardial+neural’ electrophysiological mapping that has been developed by his group paves the way for neuroscience-based therapies for the cardiovascular system. Understanding the function of the intrinsic nervous system of the heart (‘little-brain’) has major therapeutic implications. Dr. Shivkumar has assembled a team of physicians, scientists and engineers [the UCLA Neurocardiology Research Program of Excellence] to seek new knowledge in the molecular, cellular & network levels of cardiac neurobiology to develop globally applicable cardiac therapeutics and advance neurovisceral sciences.
- Rajendran PS et al Shivkumar K . Identification of peripheral neural circuits that regulate heart rate using optogenetic and viral vector strategies. Nat Commun. 2019;10(1):1944. doi: 10.1038/s41467-019-097701.
- Ardell JL., Shivkumar K. Cardiac sympathectomy and spinal cord stimulation attenuate reflex-mediated norepinephrine release during ischemia preventing ventricular fibrillation. JCI Insight. 2019;4(23). doi: 10.1172/jci.insight.131648.
- Rajendran PS….Shivkumar K. Myocardial infarction induces structural and functional remodelling of the intrinsic cardiac nervous system. J. Physiol. 2016;594(2):321-41. doi: 10.1113/JP271165.
Cardiac Neurobiology · Autonomic Ganglia · Electrophysiology
I have a long-standing interest in the autonomic regulation of the cardiovascular system. As a cellular neurophysiologist, my main focus is on the cellular membrane properties of peripheral neurons which control the heart and vasculature. I routinely make intracellular and patch-clamp recordings from both intact and dissociated peripheral autonomic neurons. As a graduate student, I worked to identify the role of a sensory neuropeptide, substance P, at sympathetic ganglia in the increased sympathetic nerve activity of the spontaneously hypertensive rat. As a post-doc, I investigated the localization and role of the neuropeptide PACAP (pituitary adenylate cyclase-activating polypeptide) in the regulation of membrane excitability at intrinsic cardiac neurons—cells residing on the surface of the heart which control every heartbeat. Currently, I am focused on identifying the specialized morphology, electrophysiology, and connectivity of sympathetic and parasympathetic neurons which control the heart—including neurons of the stellate and intrinsic cardiac ganglia. We use a combination of approaches including, electrophysiology, immunohistochemistry, confocal and functional imaging, as well as electron microscopy to identify unique subpopulations of these autonomic neurons. In addition to mapping out the basic structure and function of these peripheral neural circuits, we also aim to develop molecular approaches to target these cells for treatment of cardiac dysautonomias.
Cardiac Arrhythmias · Autonomic Nervous System · Neuromodulation
The autonomic nervous system plays an essential role in the initiation and maintenance of arrhythmias. My lab has a keen interest in understanding fundamental mechanisms behind cardiac autonomic dysfunction in cardiovascular disease and developing novel neuromodulatory therapies. We have demonstrated important changes throughout the peripheral sympathetic and parasympathetic nervous system that result from cardiac injury and contribute to arrhythmias and worsening heart failure in patients with ischemic and non-ischemic cardiomyopathy. To better evaluate mechanisms behind this neural remodeling that leads to sympathoexcitation and parasympathetic dysfunction, my lab has developed and has a decade of experience using a porcine model of myocardial infarction and ventricular tachycardia, an experimental model with electrical and neural changes akin to humans, and utilizing genetic mouse models of heart failure and cardiomyopathy. We use detailed multi-electrode high resolution electrophysiological recordings, neural recordings and network analysis, tissue clearing and confocal/super-resolution imaging, viral tracer techniques, and genetic analysis/RNA-seq to improve our understanding of the substrate of arrhythmias. In addition, as the Director of Clinical and Translational Research at the UCLA Cardiac Arrhythmia Center, I oversee several human mechanistic and multicenter clinical studies, a role that fosters a bench-to-bedside and back approach, with a focus on discovering novel therapeutic pathways that can be directly translated to patients.Publications
- Hoang JD, Salavatian SS, Yamaguchi N, Swid MA, Hamon D, Vaseghi M. Cardiac sympathetic activation circumvents high-dose beta blocker therapy in part through the release of neuropeptide Y. JCI Insight 2020; doi 10.1172/jciinsight.135519.
- Vaseghi M, Salavatian SS, Rajendran PS, Yagishita P, Woodward WR, Hamon D, Yamakawa K, Irie T, Habecker BA, Shivkumar K. Prasympathetic dysfunction and antiarrhythmic effect of vagal nerve stimulation following myocardial infarction. JCI Insight 2017;2(16).
- Irie T, Yamakawa K, Hamon D, Nakamura K, Shivkumar K, Vaseghi M. Cardiac sympathetic innervation via the middle cervical ganglia and anti-arrhythmic mechanism of bilateral stellectomy. Am J Phys Heart Circ Phys 2017;312:H392-405.
Lipoprotein Metabolism · Intravascular Lipolysis · Triglyceride Metabolism
In collaboration with Drs. Stephen Young and Loren Fong at UCLA, we showed that GPIHBP1 is crucial for the lipolytic processing of triglyceride-rich lipoproteins. GPIHBP1 is a cell-surface protein of microvascular endothelial cells that binds lipoprotein lipase (LPL) in the subendothelial spaces and transports it to its site of action in the capillary lumen.
A major focus of my laboratory has been to define structure–function relationships of GPIHBP1 and LPL. GPIHBP1 has two domains, an acidic domain and a cysteine-rich domain (LU domain). The LU domain binds with high affinity to the carboxyl-terminus domain of LPL. We showed that hypertriglyceridemia can result from GPIHBP1 missense mutations in the LU domain that abolish GPIHBP1’s ability to bind and transport LPL. In collaboration with Dr. Katsuyuki Nakajima (Japan), we discovered that some cases of acquired chylomicronemia are due to autoantibodies against GPIHBP1’s LU domain.
In collaboration with Dr. Michael Ploug (Denmark), we showed that GPIHBP1’s acidic domain prevents the unfolding of the amino-terminus domain of LPL, thereby stabilizing LPL.
Recently, we upended the long-lived assumption that LPL is only active as a dimer. We showed that freshly secreted LPL is monomeric, and that LPL monomers bind to GPIHBP1 and are active.
- Beigneux AP et al. 2007, Glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 plays a critical role in the lipolytic processing of chylomicrons. Cell Metab. 5:279–291 [PMC1913910]
- Pillai I, Beigneux AP et al. 2017, Autoantibodies against GPIHBP1 as a cause of hypertriglyceridemia. N. Engl. J. Med. 376:1647–1658 [PMC5555413]
- Beigneux AP et al. 2019, Lipoprotein lipase is active as a monomer. Proc. Natl. Acad. Sci. USA 116:6319–6328 [PMC6442593]
Congenital Heart Disease · Cardio-Obstetrics · Placentation
The Afshar Lab is a translational laboratory integrating cutting-edge prenatal maternal-fetal imaging, underlying genetic predispositions, and environmental clues to understand congenital heart disease and the placenta-cardiac axis. The laboratory seeks to understand the upstream and downstream signaling alterations in congenital heart disease and the placenta to define what we have termed the prenatal vascular phenotype.
- Afshar Y, Dong J, Zhao P, Li L, Wang S, Zhang RY, Zhang C, Yin O, Han CS, Einerson BD, Gonzalez TL, Zhang H, Zhou A, Yang Z, Chou SJ, Sun N, Cheng J, Zhu H, Wang J, Zhang TX, Lee YT, Wang JJ, Teng PC, Yang P, Qi D, Zhao M, Sim MS, Zhe R, Goldstein JD, Williams J 3rd, Wang X, Zhang Q, Platt LD, Zou C, Pisarska MD, Tseng HR, Zhu Y. Circulating trophoblast cell clusters for early detection of placenta accreta spectrum disorders. Nat Commun. 2021 Aug 3;12(1):4408. doi: 10.1038/s41467-021-24627-2. PMID: 34344888; PMCID: PMC8333096.
- Afshar Y, Hogan WJ, Conturie C, Sunderji S, Duffy JY, Peyvandi S, Boe NM, Melber D, Fajardo VM, Tandel MD, Holliman K, Kwan L, Satou G, Moon-Grady AJ. Multi-Institutional Practice-Patterns in Fetal Congenital Heart Disease Following Implementation of a Standardized Clinical Assessment and Management Plan. J Am Heart Assoc. 2021 Aug 3;10(15):e021598. doi: 10.1161/JAHA.121.021598. Epub 2021 Jul 28. PMID: 34315235.
- Imany-Shakibai H, Yin O, Russell MR, Sklansky M, Satou G, Afshar Y. Discordant congenital heart defects in monochorionic twins: Risk factors and proposed pathophysiology. PLoS One. 2021 May 6;16(5):e0251160. doi: 10.1371/journal.pone.0251160. PMID: 33956871; PMCID: PMC8101911.
Cardiovascular Development · Stem Cells · Metabolism
My research is focused on understanding how the heart is formed during mammalian development and how the congenital heart disease develops. We use mouse models and human ES/iPS cells to tackle several key questions.
- Cardio-hemo-vascular lineage analysis: We are among the first groups who uncovered the multipotency of cardiovascular progenitors (Cell, 2006), which is currently a widely accepted concept in the field. This lead to the discovery of ‘hemogenic endocardium’ (Nat Comm, 2013). We further extended this project and discovered an ‘endocardially-derived subset of cardiac tissue macrophages’ (JMCC, 2015, Dev Cell, 2019). This work suggests that aberrant macrophage function underlies congenital valvular heart disease.
- Non-genetic factors: Metabolic environment is a critical regulator of cardiogenesis. Maternal hyperglycemia is the most common medical condition that is associated with congenital heart disease. We discovered that high glucose impairs cardiomyocyte maturation by overflowing the pentose phosphate pathway (eLife, 2017). This knowledge is being applied to the intervention to the congenital heart disease and heart regeneration. Another key non-genetic cue for cardiogenesis is the biophysical environment. We study how biophysical cues are sensed by atrial and ventricular cardiomyocytes (STAM, 2013, Circ Res, 2014).
- Haemogenic endocardium contributes to transient definitive haematopoiesis. (2013) Nat Commun, 4, 1564. PubMed PMID: 23463007.
- Glucose inhibits cardiac muscle maturation through nucleotide biosynthesis. (2017). Elife 6. PubMed PMID: 29231167; PMCID: PMC5726851.
- Endocardially derived macrophages are essential for valvular remodeling. (2019). Dev Cell 48, 617-630 e613. PubMed PMID: 30799229; PMCID: PMC6440481. *equal contribution
Congenital Heart Defects · Neonatal Heart Maturation · Developmental Genomics
Dr. Touma is a physician-scientist specialized in Neonatal-Perinatal Medicine and Developmental Genomics in the context of neonatal/congenital heart defects. She is the lead investigator of the UCLA Congenital Heart Defects (CHD) Research Program and the founder and principal investigator of the Neonatal/Congenital Heart Laboratory and the BioCore for Congenital Heart Defects at UCLA, which serves as a hub for basic science discoveries and translational applications in collaboration with the UCLA Institute of Precision Health and the Cardiovascular Theme.
Dr. Touma performed the first genome-wide analysis of chamber-specific transcriptome in neonatal murine heart. She discovered numerous novel regulatory long non-coding RNAs (lncRNA), and identified their orthologs in human CHD hearts. She and her team, which include medical students and research trainees, have elucidated the mechanisms by which a novel lncRNA-PPP1R1B regulates myogenic differentiation of cardiac and skeletal myocytes using human iPSCs derived cardiomyocytes. They have also discovered a novel gene-environment regulatory circuit, involving Wnt11 signaling and hypoxia, which dictates neonatal heart chamber maturation. A recent discovery by the team is the identification of a causal gene related to ciliopathy in a rare form of congenital cardiomyopathy.
- A Path to Implement Precision Child Health Cardiovascular Medicine. Touma M*, Reemtsen B, Halnon N, Alejos J, Finn JP, Nelson SF, Wang Y. Front Cardiovasc Med. 2017 Jun 1;4:36.
- Gene-Environment Regulatory Circuits of Right Ventricular Pathology in Tetralogy of Fallot. Zhao Y, Kang X, Gao F, Guzman A, Lau RP, Biniwale R, Wadehra M, Reemtsen B, Garg M, Halnon N, Quintero-Rivera F, Van Arsdell G, Coppola G, Nelson SF, Touma M*; UCLA Congenital Heart Defects BioCore Faculty. J Mol Med (Berl). 2019 Dec;97(12):1711-1722.
- Ppp1r1b-lncRNA Inhibits PRC2 at Myogenic Regulatory Genes to Promote Cardiac and Skeletal Muscle Development in Mouse and Human. Kang X, Zhao Y, Van Arsdell G, Nelson SF, Touma M*. RNA. 2020 Apr;26(4):481- 491.
Cardiac development · Cardiac repair · Vascular biology
The epicardium is composed of a single cell layer that encapsulates the heart during embryogenesis. The epicardium also serves as a rich source of mesenchymal cells and growth factors that support coronary vasculature development. Although the function of the epicardium is invariably linked to the growth of the primitive coronary plexus, the cellular and molecular mechanisms that regulate the function of the epicardium remain unclear. To facilitate the identification of the epicardium’s role in embryonic angiogenesis, our lab utilizes transgenic mouse models and single-cell transcriptomic sequencing to discover novel epicardium-directed guidance cues required for arterio-venous specification and maturation of endothelial cells. As compared to the fetal heart, the adult myocardium is unable to undergo angiogenesis in response to ischemic injury, which ultimately leads to cardiac functional decline. By using information acquired from our studies during development, we are investigating the effects of pro-angiogenic factors from the epicardium to promote angiogenesis and repair after ischemic injury in the adult heart.
- Pearl Quijada, Trembley MA, Small EM. (2020) The Role of Epicardium During Heart Development and Repair. Circ Res. Jan 31;126(3):377-394. PMID: 31999538 ; PMCID: PMC7000171
- Pearl Quijada, Misra A, Velasquez LS, Burke RM, Lighthouse JK, Mickelsen DM, Dirkx RA Jr, Small EM. (2019) Pre-existing fibroblasts of epicardial origin are the primary source of pathological fibrosis in cardiac ischemia and aging. J Mol Cell Cardiol. 129:92-104. PMID: 30771308 ; PMCID: PMC6585455
- Pearl Quijada, Salunga HT, Hariharan N, Cubillo J, El-Sayed Farid, Moshref M, Bala KM, Emathinger J, De La Torre A, Ormachea L, Alvarez R, Gude NA, Sussman MA. (2015) Cardiac stem cell hybrids enhance myocardial repair. Circ Res. 117(8):695-706. PMID: 26228030 ; PMCID: PMC4583815
Cardiovascular imaging · MRI
Professor Hu is interested in translational magnetic resonance imaging (MRI) research with a special focus on cardiovascular imaging applications. He is a co-Director of the UCLA Cardiovascular MRI (CMR) research program. The CMR program is a multi-disciplinary research program that consists of several other key investigators from Radiology and Cardiology at UCLA. The CMR program develops MRI pulse sequences, image reconstruction and processing techniques for diagnosis, monitoring and treatment of various diseases of the heart and blood vessels. Several MRI techniques developed in the UCLA CMR program have been adopted at regional, national and international levels. Our research is supported by grants from the American Heart Association, National Institutes of Health, the Veterans Health Administration and several industry sponsors.
Cardiovascular imaging · Ischemic heart disease · Heart failure
Our lab is interested in the development and translation of multiscale imaging technology for cardiovascular applications. We apply radiomics to phenotype myocardial disease processes. Our current grant-funded work focuses on the development of USPIO-enhanced MRI for ischemic epicardial and microvascular coronary disease and on applications of MR technology in a spectrum of heart failure indications. Using percutaneous rapid prototyping technology, we have developed a swine model of hypoperfusion and ischemia for diagnostic steady-state myocardial blood volume mapping. In collaboration with radiology colleagues, we have demonstrated safety and efficacy for the diagnostic use of ferumoxytol in a wide array of cardiovascular applications and currently lead an international multicenter MRI registry (FeraSafe) for diagnostic use of ferumoxytol. We apply advanced MRI, MR spectroscopy, and cardiac ultrasound techniques to study diastolic dysfunction and heart failure mechanisms. We collaborate with data scientists to advance precision medicine by contributing quantitative imaging tools for phenotypic characterization of cardiovascular disease. Our research is supported by grants from the American Heart Association, National Institutes of Health, and the Veterans Health Administration.
Physiological Assessments & Screening · Heart Failure · Translational Physiology
Dr. Roos directs the UCLA Mouse Physiology Core Lab. The lab and his research focus upon the physiological assessment of basic and translational cardiac function in rodent models. The core lab utilizes a wide range of invasive and non-invasive tools to assess animal models in a manner parallel to human assessments. These include echocardiography, ECG, EEG, pressure & vital sign monitoring, telemetric screening, HRV analyses, surgical manipulations, safety toxicology assessment, metabolic and exercise testing. Major research emphases have been on the evaluation of rodent models of heart failure and cardiac disease, circadian rhythm disturbances, ionic homeostasis, blood pressure regulation and regenerative treatments post MI. The current focus is primarily on the effects of electronic and conventional cigarette vapor exposure on cardiovascular function and pathology in mice. Since the lab’s inception, Dr. Roos has made contributions to a wide variety of studies at UCLA and elsewhere to better understand basic cardiac physiology as well as to better understand potential treatment strategies using various mouse models and investigative tools.
- Jordan, M.C., S.A. Henderson, T. Han, M.C. Fishbein, K.D. Philipson, K.P. Roos. 2010. Myocardial function with reduced expression of the sodium-calcium exchanger. J. Cardiac Failure, 16:786-796. PMID: 20797603. PMCID:PMC2929393.
- Viola, H.M., M.C. Jordan, K.P. Roos, L.C. Hool. 2014. Decreased myocardial injury and improved contractility after administration of a peptide derived against the alpha-interacting domain of the L-type calcium channel. J. Am. Heart Assoc. 3(3):e000961. PMID:24958783.
- Espinoza-Derout, J., Hasan, M.K., Shao, X.M., Jordan, M.C., Sims, C., Lee, D.L., Sinha, S., Simmons, Z., Mtume, N., Liu, Y., Roos, K.P., Sinha-Hikim, A.P., Friedman, T.C. 2019. Chronic Intermittent Electronic Cigarette Exposure Induces Cardiac Dysfunction and Atherosclerosis in Apolipoprotein E (ApoE) Knockout Mice. Am. J. Physiol. Heart & Circ. Physiol. 317(2):H445-H459. doi: 10.1152/ajpheart.00738.2018. Epub 2019 Jun 7. PMID: 31172811.
Cardiovascular Systems of Care · Heart Failure · Preventative Cardiology
The research interests of this investigator center on acute and chronic heart failure, preventative cardiology, cardiovascular quality of care and outcomes, and implementing treatment systems to improve clinical outcome. published over 1400 research studies and clinical trials in heart failure, disease management, preventative cardiology, and outcomes research. New therapies and management strategies for advanced heart failure and research into the pathophysiology of this disease are conducted at UCLA under his direction. He has also developed and successfully implemented a comprehensive atherosclerosis treatment program at the UCLA Medical Center (Cardiovascular Hospitalization Atherosclerosis Management Program: CHAMP), which served as the model for the American Heart Association’s Get With The Guidelines Program. Dr Fonarow serves as PI for ADHERE, OPTIMIZE-HF, IMPROVE-HF, and CHAMP-HF performance improvement registries. He is on the steering committee or serves on the data safety monitoring committee for a number of ongoing randomized clinical trials in heart failure. Dr Fonarow is immediate past chair of the ACC/AHA Task Force for Performance Measures.
- Fonarow GC, Zhao X, Smith EE, Saver JL, Reeves MJ, Bhatt DL, Xian Y, Hernandez AF, Peterson ED, Schwamm LH. Door-to-Needle Times for Tissue Plasminogen Activator Administration and Clinical Outcomes in Acute Ischemic Stroke Before and After a Quality Improvement Initiative. JAMA 2014;311(16):1632-40.
- Fonarow GC, Albert NM, Curtis AB, Stough WG, Gheorghiade M, Heywood JT, McBride ML, Inge PJ, Mehra MR, O'Connor CM, Reynolds D, Walsh MN, Yancy CW. Improving evidence-based care for heart failure in outpatient cardiology practices: primary results of the Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting (IMPROVE HF). Circulation. 2010;122(6):585-96.
- Lewis WR, Peterson ED, Cannon CP, Super DM, LaBresh KA, Quealy K, Liang L, Fonarow An organized approach to improvement in guideline adherence for acute myocardial infarction: results with the Get With The Guidelines quality improvement program. Arch Intern Med. 2008;168(16):1813-9.
Heart Transplantation · Cardiac Allograft Vasculopathy · Endothelin-1
Dr. Parikh’s primary research focus is on the mechanisms of cardiac allograft vasculopathy, a complex immune and inflammatory-mediated disease of the graft coronary arteries that occurs following heart transplantation. His current Career Development Award from the American Heart Association aims to use contemporary invasive tools to prospectively evaluate the role of endothelin-1 in the development of cardiac allograft vasculopathy in heart transplant recipients through a comprehensive assessment of coronary anatomy, physiology, and vasomotor function. In addition, he has recently received industry-sponsored grants that will involve the use of emerging invasive imaging modalities including optical coherence tomography (Abbott Vascular) and near-infrared spectroscopy (NIRS) to further investigate plaque composition/development early after transplant and its impact on coronary physiology and outcomes. Previously, Dr. Parikh has examined the association of asymmetric dimethylarginine, a marker of nitric oxide-mediated endothelial dysfunction, with cardiac allograft vasculopathy.
Dr. Parikh’s other clinical research interests include fractional flow reserve and HIV-associated cardiovascular disease. He is also the Co-Assistant Director of the Interventional Cardiology Research Program and serves as a co-investigator on a number of clinical trials at UCLA.
- Parikh RV, Khush K, Pargaonkar V, Luikart H, Grimm D, Yu M, Valantine H, Yeung A, Fearon WF. Association of Endothelin-1 with Accelerated Cardiac Allograft Vasculopathy and Late Mortality Following Heart Transplantation. Journal of Cardiac Failure. 2018 Dec; pii: S1071-9164(18)30947-3.
- Parikh RV, Khush K, Luikart H, Sakarovitch C, Lee J, Desai M, Valantine H, Yeung A, Fearon WF. Usefulness of Asymmetric Dimethylarginine to Predict Outcomes After Heart Transplantation. American Journal of Cardiology. 2018 Aug 21; pii: S0002-9149(18)31640-0.
- Parikh RV, Khush K, Luikart H, Pargaonkar V, Kobayashi Y, Lee J, Sinha S, Cohen G, Valantine H, Yeung A, Fearon WF. Impact of Asymmetric Dimethylarginine on Coronary Physiology Early After Heart Transplantation. American Journal of Cardiology. 120(6): 1020-1025. Sept 2017.
UCLA Cardio-Oncology Program · Cardio-Oncology · Cancer Treatment Associated Cardiotoxicity
In 2016, the UCLA Cardio-oncology Program officially made its debut, actively managing patients undergoing cancer treatments, providing risk stratification, evaluating for and treating cardiotoxicity, as well as providing long term cardiotoxicity surveillance for cancer survivors.
This is a multidisciplinary collaboration across multiple specialties within the Divisions of Cardiovascular Disease and Hematolog/Oncology at UCLA in promoting awareness, research projects in looking at the effects of malignancies and cardiotoxic treatments on both the adult and pediatric populations. I have been the primary cardiology consultant for the UCLA-LIVESTRONG Survivorship Center of Excellence since 2012 and also conducting research projects in looking at the application of multimodality imaging such as echocardiography, cardiac magnetic resonance and cardiac computed tomography in evaluating for short and long-term clinical and subclinical evidence of cardiotoxicity from cancer treatments; this includes, but is not limited to chemotherapy, novel targeted therapies, and radiotherapy.
- Vascular Toxicities of Cancer Therapies: The Old and The New—An Evolving Avenue. Joerg Herrmann, Eric H Yang, Cezar Iliescu, Cindy Grines, Mehmet Cilingiroglu, Kostantinos Charitakis, Abdul Hakeem, Konstantinos Toutouzas, Massoud A Lessar, Konstantinos Marmagkiolis. Circulation 2016;133(13): 1272-89. doi:10.1161/CIRCULATIONAHA.115.018347.
- Preparing the Cardiovascular Workforce to Care for Oncology Patients: JACC Review Topic of the Week. Salim S Hayek, Sarju Ganatra, Carrie Lenneman, Marielle Scherrer-Crosbie, Monika Leja, Daniel J Lenihan, Eric Yang, Thomas D Ryan, Jennifer Liu, Joseph Carver, Negareh Mousavi, Rupal O’Quinn, Anita Arnold, Jose Banchs, Ana Barac, Bonnie Ky. J Am Coll Cardiol 2019;73(17):2226-35.
- Chimeric Antigen Receptor T-Cell Therapy for Cancer and Heart: JACC Council Perspectives. Sarju Ganatra, Joseph R Carver, Salim S Hayek, Monika J Leja, Daniel J Lenihan, Carrie Lennenman, Negaresh Mousavi, Jae H Park, Miguel A Perales, Thomas D Ryan, Marielle Scherrer-Crosbie, Richard M Steingart, Eric H Yang, Vlad Zaha, Ana Barac, Jennifer E Liu. J Am Coll Cardiol 2019;74:3153-63.
- Olujimi Ajijola, MD, PhD
- Gentian Lluri, MD, PhD
- Megan Kamath, MD
- Gabriel Vorobiof, MD
- Melkon Hacobian, MD
- Megha Agarwal, MD
- Boris Arbit, MD
- Nidhi Thareja, MD
Health Equity · Preventative Cardiology · Cardiovascular Epidemiology
Dr. Ziaeian is an Assistant Professor of Medicine, general cardiologist, and interested in evaluating and improving the receipt of evidence-based therapies for the primary and secondary prevention of cardiovascular events and mortality. He is currently funded by the American Heart Association and National Institutes of Health. His projects are focused on understanding how access to care and geospatial distance influence the quality of heart failure care received. He has also led a novel implementation of Bayesian epidemiologic modeling to understand the national burden of ischemic strokes and the quality of hospital care delivered. He serves as a member of the Writing Committee on the American Heart Association and American College of Cardiology guideline committees for Performance Measurement and the Primary Prevention of Cardiovascular Disease. He is a Core Investigator at the VA Greater Los Angeles Center for the Study of Healthcare, Innovation, Implementation & Policy (CSHIIP). He also serves as the Director of Telecardiology at the VA Greater Los Angeles Healthcare System.
Ongoing Registries: American Heart Association – Get With the Guidelines Programs (Heart Failure, Stroke)
- Boback Ziaeian, Yan Zhang, Nancy M. Albert, Anne B. Curtis, Mihai Gheorghiade, J. Thomas Heywood, Mandeep R. Mehra, Christopher M. O’Connor, Dwight Reynolds, Mary N. Walsh, Clyde W. Yancy, Gregg C. Fonarow. Clinical Effectiveness of CRT and ICD Therapy in Heart Failure Patients by Racial/Ethnic Classification: Insights from the IMPROVE HF Registry. Journal of the American College of Cardiology. 2014 August 26;64(8):797-807.
- Boback Ziaeian, Gregg C. Fonarow. Epidemiology and aetiology of heart failure. Nature Reviews Cardiology. 2016 Jun;13(6):368-78.
- Boback Ziaeian, Adrian F. Hernandez, Adam D. DeVore, Jingjing Wu, Haolin Xu, Paul A. Heidenreich, Roland A. Matsouaka, Deepak L. Bhatt MD, Clyde W. Yancy, Gregg C. Fonarow. Long-Term Outcomes for Heart Failure Patients with and without Diabetes: From the Get With The Guidelines-Heart Failure Registry. American Heart Journal. 2019 Jan 27;211:1-10
Heart Failure · Autonomic · Neuroimaging
Kumar lab is interested to examine neural control processes regulating autonomic and cognitive functions. The lab uses various magnetic resonance imaging and spectroscopy procedures, including structural, functional, metabolic, hemodynamic, and vascular permeability methods. Several patient population, including heart failure and congenital heart disease patients are used to examine such regulatory processes.
- Park, B. Roy, M.A. Woo, J.A. Palomares, G.C. Fonarow, R.M. Harper, R. Kumar. Lateralized resting-state functional brain network organization changes in heart failure. PLoS One 11(5):e0155894, 2016, PMCID:PMC4874547.
- A. Woo, R. Kumar, P.M. Macey, G.C. Fonarow, R.M. Harper. Brain injury in autonomic, emotion, and cognitive regulatory areas in patients with heart failure. J. Card. Fail. 15:214-223, 2009, PMCID: PMC2730774.
- A. Woo, J.A. Ogren, C.M. Abouzeid, P.M. Macey, P.S. Saharan, P.M. Thompson, G.C. Fonarow, M.A. Hamilton, R.M. Harper, R. Kumar. Regional hippocampal damage in heart failure. Eur. J.Heart Fail. 17(5):494-500, 2015, PMCID:PMC4651448.
Cardio-oncology · Cardiac Repair · Atherosclerosis Characterization
Our group integrates molecular and cellular techniques with novel bioengineering and multiscale imaging approaches to address biological pathways of cardiovascular disease. Our research efforts are to (i) dissect novel mechanisms of chemotherapy-induced cardiotoxicity, (ii) explore cardiac repair pathways, and (iii) characterize high-risk atherosclerotic lesions.
- Chen J., Ding Y., Chen M., Gau J., Jen N., Nahal C., Tu S., Chen C., Zhou S., Chang C.-C., Lyu J., Xu X., Hsiai T.K., Packard R.R.S. Displacement analysis of myocardial mechanical deformation (DIAMOND) reveals segmental susceptibility to doxorubicin-induced injury and regeneration, Journal of Clinical Investigation (JCI) Insight 2019 Apr 18; 4(8): 125362.
- Packard R.R.S., Luo Y., Abiri P., Jen N., Aksoy O., Suh W.M., Tai Y.-C., Hsiai T.K. 3-D electrochemical impedance spectroscopy mapping of arteries to detect metabolically active but angiographically invisible atherosclerotic lesions, Theranostics 2017 June 22; 7(9): 2431-2442.
- Packard R.R.S., Huang S.-C., Dahlbom M., Czernin J., Maddahi J. Absolute quantitation of myocardial blood flow in human subjects with or without myocardial ischemia using dynamic Flurpiridaz F18 positron emission tomography, The Journal of Nuclear Medicine 2014 Sep; 55(9): 1438-1444.
Heart failure · Epigenetics · Cardioprotection
Research in the Vondriska Laboratory is focused on understanding the epigenomic basis of heart failure. In the basic science realm, one of the most important questions in biology is how the same genome encodes the function of the hundreds of cells in a human being. We are trying to answer this question by studying the structure and regulation of chromatin. In recent years, we have carried out the first chromatin conformation capture experiments in the heart, determining the endogenous organization of the genome in cardiac myocytes. With this blueprint, we are now answering the following questions: How do transcription neighborhoods form? What is the role of inter-chromosomal interactions and other nuclear features in genomic architecture? How do features of local accessibility relate to local and global architecture?
In the translational realm, we are examining the role of chromatin structural reorganization in heart failure. To this end, we are determining the structural features required for disease-associated gene expression and investigating how global chromatin accessibility is altered during cardiovascular disease. These studies are targeted to identify diagnostic features of the epigenome that indicate the progression or reversion of disease and to develop strategies to remodel chromatin therapeutically.
- Karbassi E, Rosa-Garrido M, Chapski DJ, Wu Y, Ren S, Wang Y, Stefani E, Vondriska TM. Direct visualization of cardiac transcription factories reveals regulatory principles of nuclear architecture during pathological remodeling. J Mol Cell Cardiol. 2019. 128:198-211. PMID: 30742811.
- Chapski DJ, Rosa-Garrido M, Hua N, Alber F, Vondriska TM. Spatial principles of chromatin architecture associated with organ-specific gene regulation. Frontiers in Cardiovascular Medicine. 2019. 5:186. PMID: 30697540.
- Rosa-Garrido M, Chapski DJ, Schmitt AD, Kimball TH, Karbassi E, Monte E, Balderas E, Pellegrini A, Shih T-T, Soehalim E, Liem D, Ping P, Galjart NJ, Ren S, Wang Y, Ren B, Vondriska TM. High resolution mapping of chromatin conformation in cardiac myocytes reveals structural remodeling of the epigenome in heart failure. Circulation. 2017. 136:1613-1625 PMID:28802249.
Skeletal muscle · Channelopathy · Periodic paralysis
We study how ion channels regulate the electrical excitability of cells and how defects in these channels lead to human disease. In the past three decades, mutations of ion channel genes have been found to be the primary cause for over 100 human diseases. The focus of our laboratory has been to understand the mechanistic basis for a group of inherited disorders of skeletal muscle caused by mutations of voltage-gated ion channels (Na, Ca, K, or Cl). The derangements in electrical excitability of affected muscle may cause involuntary after-contractions (myotonia) or transient episodes of severe weakness (periodic paralysis). Our lab studies the consequences of mutations identified in patients with myotonia or periodic paralysis on channel function, uses computational models of muscle excitability to explore the impact of altered channel behavior, and developed genetically-engineered mouse models to gain insights on the pathomechanisms of these disorders and to test pre-clinical strategies for therapeutics and disease modification.
- Elia, N., Nault, T., McMillan, H. J., Graham, G. E., Huang, L., Cannon, S. C. (2020). "Myotonic Myopathy With Secondary Joint and Skeletal Anomalies From the c.2386C>G, p.L769V Mutation in SCN4A." Front Neurol 11: 77.
- Elia, N, Palmio, J., Sampedro Castaneda, M., Shieh, P.B., Quinonez, M., Souminen, T., Hanna, M., Mannikko, R., Udd, B., Cannon, S.C. (2019) Myasthenic congenital myopathy from recessive mutations at a single residue in NaV1.4. Neurology 92:e1405-e1415.
- DiFranco, M., Quinonez, M., Dziedzic, R.M., Spokoyny, A.M., Cannon, S.C. (2019). A highly-selective chloride microelectrode based on a mercuracarborand anion carrier. Sci Rep 9(1): 18860.
- Mi, W., Wu, F., Quinonez, M., DiFranco, M., Cannon, S.C. (2019) Recovery from acidosis is a robust trigger for loss of force in murine hypokalemic periodic paralysis. Gen. Physiol. 151:555-566.
- Wu, F., Quinonez, M., DiFranco, M., Cannon, S.C. (2018). "Stac3 enhances expression of human CaV1.1 in Xenopus oocytes and reveals gating pore currents in HypoPP mutant channels." J Gen Physiol. 150:475-489.
- Wu, F.F, Mi, W., Struyk A.S., Cannon, S.C. (2016) Mice with an NaV1.4 sodium channel null allele have latent myasthenia, without susceptibility to periodic paralysis. Brain 39:1688-1699.
Ion Channels · Cardiac Arrhythmia · Early Afterdepolarizations (EAD)
Ion channels and their role in cellular excitability are central themes of the research programs developed in the laboratory of Dr. Riccardo Olcese at UCLA, which integrates molecular-level biophysical studies with organ-wide phenomena of clinical significance, such as cardiac arrhythmia. The quantitative tools of biophysics are used in a translational context to understand the role of ion channels in health and disease.
Every year in the United States, >300,000 people suffer a sudden cardiac death due to ventricular arrhythmias. We are investigating the arrhythmogenic properties of anomalies of the repolarization phase of the cardiac action potential known as Early Afterdepolarizations (EAD). We are searching for novel interventions to prevent EADs and their arrhythmogenic consequences by modulating the activity of cardiac L-type calcium channels without adverse effects on contractility (excitation-contraction coupling). The laboratory also explores the fundamental mechanisms of ion channel function. Ion channels are exquisitely complex membrane proteins that control specific ionic fluxes across the cell membrane controlling cell excitability.
We learn about the molecular and structural basis of ion channel function and regulation in the heart, muscle, and nerves. We are particularly interested in voltage-activated channels, which respond to changes in the membrane potential with a rearrangement of their voltage-sensing structures. We study how their voltage-sensing structures operate driving the channel into ion-conducting (open) and closed conformations. We use state-of-the-art techniques in electrophysiology, biochemistry, molecular biology, and computational modeling. By combining optical methods with electrophysiology, we track in real time the structural changes of ion channel associated with their operation (Voltage-Clamp Fluorometry).
Other independent laboratories associated with ion channel research include Dr. Cannon, Dr. Qu, Dr. Garfinkel and Dr. Scott John (see individual lab profiles).
- Madhvani, R. V., Angelini, M., Xie, Y., Pantazis, A., Suriany, S., Borgstrom, N. P., Garfinkel, A., Qu, Z., Weiss, J. N., & Olcese, R. (2015). Targeting the late component of the cardiac L-type Ca2+ current to suppress early afterdepolarizations.The Journal of general physiology,145(5), 395–404. https://doi.org/10.1085/jgp.201411288
- Antonios Pantazis, Karin Westerberg, Thorsten Althoff, Jeff Abramson, Riccardo Olcese (2018)Harnessing photoinduced electron transfer to optically determine protein sub-nanoscale atomic distances. Nature Communications https://dx.doi.org/10.1038/s41467-018-07218-6
- Pantazis A, Savalli N, Sigg D, Neely A, Olcese R. (2014) Functional heterogeneity of the four voltage sensors of a human L-type calcium channel. Proc Natl Acad Sci U S Ahttps://doi.org/10.1073/pnas.1411127112
Cardiac muscle · Transporters · Excitation-Contraction Coupling
Disturbed intracellular calcium homeostasis is the hallmark of numerous cardiovascular diseases. The primary area of interest of the Ottolia Laboratory is to understand how cytosolic calcium is regulated in cardiac cells. We focus on the role of the plasma membrane sodium-calcium exchanger (NCX) which constitutes the main calcium extrusion mechanism in the heart and alterations in its activity have been associated with ischemia reperfusion injury, arrhythmia, and heart failure.
The implications of normal and aberrant NCX activity on cardiac function are investigated using a variety of approaches spanning from protein biophysics and single cell electrophysiology to organ and whole animal studies in genetically modified mouse lines.
The long-term objective of these studies is to understand the critical mechanisms and functional implications of calcium extrusion in cardiac cells, and to leverage our investigations of NCX and its modulation to control and suppress cardiac arrhythmias.
- Molecular determinants of pH regulation in the cardiac Na+-Ca2+ exchanger. John S, Kim B, Olcese R, Goldhaber JI, Ottolia M. J Gen Physiol. 2018 Feb 5; 150 (2):245-257.
- The cardiac Na+-Ca2+ exchanger has two cytoplasmic ion permeation pathways. John SA, Liao J, Jiang Y, Ottolia M. Proc Natl Acad Sci U S A. 2013 Apr 30; 110 (18):7500-5.
- Ca2+-dependent structural rearrangements within Na+-Ca2+ exchanger dimers. John SA, Ribalet B, Weiss JN, Philipson KD, Ottolia M. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1699-704.
Biophysics · Arrhythmias · Computer modeling
My group uses computer modeling and simulations to investigate the mechanisms of cardiac arrhythmias and other physiological and pathophysiological phenomena. In modeling of cardiac arrhythmias, we use models of stochastic Markovian transitions of ion channels, and ordinary and partial differential equations to simulate subcellular, cellular, tissue and whole-heart calcium and voltage dynamics that are associated with arrhythmias. We collaborate with experimentalists to test our theories and to reveal the underlying mechanisms of experimental observations. Our general goal is to use multi-scale computer modeling and simulations combined with theories of nonlinear dynamics and complex systems to understand the mechanisms and identify therapeutic targets for treating human diseases.
- Qu, A. Garfinkel, P.-S. Chen, and J. N. Weiss. Mechanisms of discordant alternans and induction of reentry in a simulated cardiac tissue. Circulation 102, 1664-1670 (2000).
- Yang, R. MacLellan, Z. Han, J. N. Weiss, and Z. Qu. Multi-site phosphorylation and network dynamics of cyclin-dependent kinase signaling in the eukaryotic cell cycle. Biophys. J. 86, 3432-3443 (2004).
- Sato, L.-H. Xie, A. Sovari, D. X. Tran, N. Morita, F. Xie, H. Karagueuzian, A. Garfinkel, J. N. Weiss, and Z. Qu. Synchronization of chaotic early afterdepolarizations in the genesis of cardiac arrhythmias. PNAS 106, 2983-2988 (2009).
- Nivala, C. Y. Ko, M. Nivala, J. N. Weiss, Z. Qu. Criticality in intracellular calcium signaling in cardiac myocytes. Biophys. J. 102, 2433-2442 (2012).
- Song, M. B. Liu, Z. Qu. Transverse tubular network structures in the genesis of intracellular calcium alternans and triggered activity in cardiac cells. J. Mol. Cell Cardiol. 114, 288-299 (2018).
- B. Liu, N. Vandersickel, A. V. Panfilov, Z. Qu. “R-from-T” as a common mechanism of arrhythmia initiation in long QT syndromes. Circ Arrhythm Electrophysiol 12, e007571 (2019).
Pulmonary Hypertension · Right Ventricular Failure · Perioperative Cardiopulmonary Protection
The Umar Laboratory’s research is focused on investigating the molecular mechanisms and pathophysiology of primary and secondary forms of pulmonary hypertension and associated right ventricular dysfunction. Our long-term goal is to devise novel regenerative therapies for these cardiopulmonary disorders. We are also interested in investigating novel strategies for perioperative cardiopulmonary organ protection. Pulmonary hypertension is a chronic pulmonary vascular disease without a definitive cure. We are using state-of-the-art in vivo mouse and rat models, in vitro cell culture systems, and human blood and tissue samples to investigate the molecular mechanisms of the development of primary and secondary pulmonary hypertension. We are also investigating adverse structural and electrical remodeling of the right ventricle secondary to pressure overload that often leads to arrhythmias and sudden cardiac death.
- Vaillancourt M, Chia P, Medzikovic L, Cao N, Ruffenach G, Younessi D, Umar S. Experimental Pulmonary Hypertension Is Associated With Neuroinflammation in the Spinal Cord. Front Physiol. 2019;10:1186.
- Park JF, Banerjee S, Umar S. In the eye of the storm: the right ventricle in COVID-19. Pulm Circ. 2020 Jul-Sep;10(3): 2045894020936660.
- Razee A, Umar S. Pulmonary Artery Denervation for Pulmonary Hypertension: Recent Updates and Future Perspectives. Trends Cardiovasc Med. 2020 May 17.
Cardiac repair · Extracellular matrix · Ectopic Calcification
The Deb lab is an interdisciplinary laboratory focused on the biology of cardiac wound healing. The lab uses a variety of genetic lineage tracing, and genetic and pharmacologic loss and gain of function approaches to understand how the heart heals following a heart attack. The lab studies the role of the extracellular matrix and cell-matrix cross talk in regulating wound healing. Another interest of the lab is to model genetic diseases in the dish using human pluripotent stem cells. Candidates interested in rotating or joining the lab would get wide exposure to animal physiology, human stem cell biology and disease in a dish modeling, extracellular matrix biology and understanding the role of metabolism in wound healing.
- Yokota T, McCourt J, Ma F, Ren S, Li S, Kim TH, Kurmangaliyev Y, Ahadian S, Nasiri R, Nguyen T, Haw M, Zhou Y, Wu R, Rodriguez A, Cohn W, Wang Y, Julian Whitelegge, Ryazantsev S, Khademhosseini A, Teitell MA, Chiou PY, Rowat AC, Crosbie RH, Pellegrini M, Seldin M, Lusis AJ, Deb A. Type V collagen in scar tissue regulates the size of scar after heart injury. Cell.2020Aug 6;182(3):545-562.e23. doi: 10.1016/j.cell.2020.06.030. Epub 2020 Jul 3. PubMed PMID: 32621799; PubMed Central PMCID: PMC7415659.
- Pillai I, Li S, Romay M, Lam L, Lu Y, Jie Huang, Dillard N, Zemanova M, Rubbi L, Wang Y, Lee J, Xia M, Liang O, Xie Y, Pellegrini M, Lusis A, Deb A. Cardiac fibroblasts adopt osteogenic cell fates and contribute to pathologic heart calcification. Cell Stem Cell, 2017 20(2):218-232 PMID: .
- Ubil E, Duan J, Pillai I, Rosa-Garrido M, Wu Y, Bargiacchi F, Lu Y, Stanbouly S, Huang J, Rojas M, Vondrinska T, Stefani E & Deb A. Mesenchymal-endothelial transition contributes to cardiac neovascularization. Nature. 2014; 514: 585-590 [PMID 25317562].
Vascular biology · Vascular & Valvular calcification · Inflammation
Demer-Tintut Cardiovascular Biomineralization Laboratory
Our laboratory is addressing the problems of coronary calcification and aortic stenosis, with a focus on the mechanism by which calcium mineral forms inside cardiovascular tissues and atherosclerotic plaque. This field began with our discovery that the process is regulated at the molecular level and that multipotent vascular stem cells produce calcium mineral by the same processes driving embryonic skeletal osteogenesis. We are characterizing these cells with respect to multilineage capacity, transdifferentiation to osteoblastic cells, and hydroxyapatite nanocrystal formation. One particularly interesting finding is that, in culture, these cells self-organize into intricate patterns that we can predict and control using computational analysis and reaction-diffusion principles. Another, relevant to tissue engineering, is left-right chirality, a preference for rightward orientation and alignment when they migrate across micromachined matrix interfaces. Our robust in vitro and mouse models of vascular calcification are assayed by several quantitative techniques including live, fused PET-CT imaging, computer-controlled biomechanical testing, and atomic force and second-harmonic generation microscopy. We are also testing effects of hyperlipidemia, exercise, and lipid-lowering agents on vascular and valvular calcification. These findings have major clinical implications given the widespread recommendations for use of vitamin D, calcium, exercise, bone-anabolic agents, and cholesterol-lowering drugs.
- Hsu JJ, Fong F, Patel R, et al. Changes in microarchitecture of atherosclerotic calcification assessed by 18F-NaF PET and CT after a progressive exercise regimen in hyperlipidemic mice [published online ahead of print, 2020 Jan 2]. J Nucl Cardiol. 2020;10.
- Demer LL, Hsu JJ, Tintut Y. Steroid Hormone Vitamin D: Implications for Cardiovascular Disease. Circ Res. 2018;122(11):1576-1585.
- Chen TH, Hsu JJ, Zhao X, et al. Left-right symmetry breaking in tissue morphogenesis via cytoskeletal mechanics. Circ Res. 2012;110(4):551-559.
Vascular Mechanotransduction · Advanced Imaging · Bio-sensors
Dr. Hsiai is the Maud Cady Guthman Endowed Term Chair in Cardiology and Professor of Medicine and Bioengineering. His research team focuses on advanced sensors and laser light-sheet to study cardiovascular development, injury and repair. Following his STAR Fellowship (BioMEMS in Mechanical & Aerospace Engineering), he was recruited to the University of Southern California Schools of Engineering and Medicine with an Early Career Endowed Chair. In 2014, he was recruited back to UCLA to promote team science, which led to the LA PRISMS Center connecting UCLA Bioinformatics with USC’s Environmental Engineering. Dr. Hsiai directs the NIH T32 UCLA/Caltech training program, which has established a track record of converging engineering with medicine through the NIH-funded team science projects with Caltech, Cornell, Stanford, and USC.
- Hsiai, Li, Gao et al., A laser-enable flexible lab on the skin for metabolic and nutritional management. Nature Biotechnology. 2020 Feb;38(2):217-224. PMID: 31768044
- Fei, Ho, Zhu, Hsiai et al., Sub-voxel light-sheet microscopy for high-resolution, high-throughput volumetric imaging of large biomedical specimens. Advanced Photonics. 1(1), 016002 (2019) (cover page). PMCID N/A
- Lee, Fei, Hsiai et al., 4-D Light-Sheets to Elucidate Shear Stress Modulation of Cardiac Trabeculation. Journal of Clinical Investigation. 2016 126(5):1679-90. PMCID: PMC4855946
Vascular Biology · Endothelial Cell Signaling · Mechanotransduction
The Mack Lab studies mechanisms of endothelial cell mechanotransduction in the context of cardiovascular health and disease. We investigate how mechanical forces influence blood vessel function, both at the single cell and tissue level. We are interested in the role of blood flow forces in controlling individual endothelial cell response within a monolayer of cells. To visualize the heterogeneity of response, we utilize high resolution live cell imaging and atomic force microscopy to measure plasma membrane fluidity, quantify the dynamics of Ca2+ signaling and immune cell binding, and determine the localization of proteins at the subcellular level. In addition, we utilize mouse models to understand the role of blood flow and dyslipidemia in the development of vascular inflammation and atherosclerosis.
- Mack J.J., Mosqueiro T.S., Archer B.J., Jones W.M., Sunshine H., Faas G.C., Briot A., Arago´n R.L., Su T., Romay M.C., McDonald A.I., Kuo C-H., Lizama C.O., Lane T.F., Zovein A.C., Fang Y., Tarling E.J., de Aguiar Vallim T.Q., Navab M., Fogelman A.M., Bouchard L.S., Iruela-Arispe M.L., NOTCH1 is a Mechanosensor in Adult Arteries. Nature Communications 8, 1620 (2017).
- Mack J.J. and Iruela-Arispe M.L., NOTCH Regulation of the Endothelial Cell Phenotype. Current Opinion in Hematology 25, 212 (2018).
- Mack J.J., Youssef K., Noel O.D., Lake M.P., Wu A., Iruela-Arispe M.L., Bouchard L.S., Real-time Maps of Fluid Flow Fields in Porous Biomaterials. Biomaterials 34, 1980 (2013).
Arteriovenous malformations · Vascular calcification · Vascular-related diseases
Our research focuses on several aspects of cardiovascular disease, such as cerebral and pulmonary arteriovenous malformations (AVMs) and the prevention of vascular calcification. We are also broadly interested in the vascular-related diseases, such as corticosteroid-associated osteoporosis and pulmonary fibrosis.
We have discovered that ill-fated cell transitions occurring in endothelial cells (ECs) play an essential role vascular disease and cause the ECs to become a source of pathological cells. To prevent or reverse this, we are creating novel approaches to shift the ill-fated ECs back to normal differentiation and re-gain functional capacities, which reverse the course of these disease processes.
We are combining several cutting-edge techniques to achieve the goals. We use molecular tools to examine human specimens and animal models to reveal pathological progression. By examining gene expression profile at single-cell resolution, we uncover the ill-fated differential trajectories in the cells and identify relevant target genes or genetic perturbations. With high throughput system, we screen small chemical compounds to target specific genes or signaling pathways. By using high-resolution imaging together with molecular biology approaches, we validate the effects of the compounds in cellular and animal models.
By using these approaches for disease targeting, our studies have successfully identified several compounds with effects on vascular calcification and AVMs. These compounds may be starting points for new therapeutic strategies and clinical translation.
- Yao J, Guihard P, Blazquez Medela AM, Boström KI, Yao Y. Vascular endothelium plays a key role in directing pulmonary epithelial cell differentiation. Journal of Cell Biology. 216:3369-3385, 2017.
- Yao J, Guihard P, Blazquez Medela AM, Yao J, Moon JH, Jumubay M, Boström KI, Yao Y. Serine protease activation essential for endothelial-mesenchymal transition in vascular calcification. Circulation Research. 2015; 117(9):758-769
- Yao Y, Jumabay M, Ly A, Radparvar M, Cubberly MR, Boström KI. A role for the endothelium in vascular calcification. Circculation Research. 2013; 113(5): 495-504.
- Yao Y, Yao J, Radparvar M, Blazquez-Medela AM, Guihard PJ, Jumabay M, Boström KI. Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency. Proc Natl Acad Sci U S A. 2013; 110(47):19071-19076.
- Yao Y, Jumabay M, Ly A, Radparvar M, Wang AH, Abdmaulen R, Boström KI. Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium. Blood. 2012, 119(21): 5037-47.
- Yao Y, Jumabay M, Wang A, Boström KI. Matrix Gla protein deficiency causes arteriovenous malformations in mice. Journal of Clinical Investigation. 2011;121(8): 2993-3004. Yao J, Wu X, Zhang D, Wang L, Zhang L, Reynolds EX, Hernandez C, Boström KI, and Yao Y. Elevated Endothelial Sox2 Causes Lumen Disruption and Cerebral AVMs. Journal of Clinical Investigation. 129: 3121-3133, 2019.