Bio

Bio


Dr. Kawana joined Advanced Heart Failure and Transplant Cardiology group in 2018 as an Instructor in the Division of Cardiovascular Medicine. He completed his internal medicine, cardiovascular medicine and heart failure training at Stanford. He also completed postdoctoral research fellowship under Dr. James Spudich in Department of Biochemistry. He sees advanced heart failure patients in clinic, and attends on inpatient service taking care of post-heart transplant patients and patients on MCS support. His research interests is in the fundamental mechanism of inherited cardiomyopathies, and he studies the effect of gene mutation on the cardiac sarcomere function using cutting-edge biochemical and biophysical approach, which would lead to development of novel pharmacotherapy that directly modulates cardiac muscle protein.

Clinical Focus


  • Cardiovascular Disease
  • Heart Failure
  • Heart Transplantation
  • Mechanical Circulatory Support
  • Left Ventricular Assist Device
  • Inherited Cardiomyopathy
  • Hypertrophic Cardiomyopathy
  • Dilated Cardiomyopathy

Academic Appointments


Professional Education


  • Fellowship:Stanford University Advanced Heart Failure and Transplant Fellowship (2018) CA
  • Residency:Stanford University Internal Medicine Residency Training (2012) CA
  • Board Certification: Cardiovascular Disease, American Board of Internal Medicine (2017)
  • Board Certification: Adult Comprehensive Echocardiography, National Board of Echocardiography (2017)
  • Fellowship:Stanford University Cardiovascular Medicine Fellowship (2017) CA
  • Board Certification: Internal Medicine, American Board of Internal Medicine (2012)
  • Medical Education:Warren Alpert Medical School Brown University (2009) RI
  • Fellow, Stanford University Medical Center, Advanced Heart Failure and Transplant Cardiology (2018)
  • Fellow, Stanford University Medical Center, Cardiovascular Medicine (2017)
  • Postdoctoral Fellow, Stanford University School of Medicine, Biochemistry (2015)
  • Resident, Stanford University Medical Center, Internal Medicine (2012)
  • MD, Brown University, Medicine (2009)

Publications

All Publications


  • Dilated cardiomyopathy myosin mutants have reduced force-generating capacity JOURNAL OF BIOLOGICAL CHEMISTRY Ujfalusi, Z., Vera, C. D., Mijailovich, S. M., Svicevic, M., Yu, E., Kawana, M., Ruppel, K. M., Spudich, J. A., Geeves, M. A., Leinwand, L. A. 2018; 293 (23): 9017–29

    Abstract

    Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) can cause arrhythmias, heart failure, and cardiac death. Here, we functionally characterized the motor domains of five DCM-causing mutations in human β-cardiac myosin. Kinetic analyses of the individual events in the ATPase cycle revealed that each mutation alters different steps in this cycle. For example, different mutations gave enhanced or reduced rate constants of ATP binding, ATP hydrolysis, or ADP release or exhibited altered ATP, ADP, or actin affinity. Local effects dominated, no common pattern accounted for the similar mutant phenotype, and there was no distinct set of changes that distinguished DCM mutations from previously analyzed HCM myosin mutations. That said, using our data to model the complete ATPase contraction cycle revealed additional critical insights. Four of the DCM mutations lowered the duty ratio (the ATPase cycle portion when myosin strongly binds actin) because of reduced occupancy of the force-holding A·M·D complex in the steady state. Under load, the A·M·D state is predicted to increase owing to a reduced rate constant for ADP release, and this effect was blunted for all five DCM mutations. We observed the opposite effects for two HCM mutations, namely R403Q and R453C. Moreover, the analysis predicted more economical use of ATP by the DCM mutants than by WT and the HCM mutants. Our findings indicate that DCM mutants have a deficit in force generation and force-holding capacity due to the reduced occupancy of the force-holding state.

    View details for DOI 10.1074/jbc.RA118.001938

    View details for Web of Science ID 000434941900024

    View details for PubMedID 29666183

    View details for PubMedCentralID PMC5995530

  • Controlling load-dependent kinetics of beta-cardiac myosin at the single-molecule level. Nature structural & molecular biology Liu, C., Kawana, M., Song, D., Ruppel, K. M., Spudich, J. A. 2018; 25 (6): 505–14

    Abstract

    Concepts in molecular tension sensing in biology are growing and have their origins in studies of muscle contraction. In the heart muscle, a key parameter of contractility is the detachment rate of myosin from actin, which determines the time that myosin is bound to actin in a force-producing state and, importantly, depends on the load (force) against which myosin works. Here we measure the detachment rate of single molecules of human beta-cardiac myosin and its load dependence. We find that both can be modulated by both small-molecule compounds and cardiomyopathy-causing mutations. Furthermore, effects of mutations can be reversed by introducing appropriate compounds. Our results suggest that activating versus inhibitory perturbations of cardiac myosin are discriminated by the aggregate result on duty ratio, average force, and ultimately average power output and suggest that cardiac contractility can be controlled by tuning the load-dependent kinetics of single myosin molecules.

    View details for DOI 10.1038/s41594-018-0069-x

    View details for PubMedID 29867217

  • Controlling Cardiac Contractility at the Single Molecule Level Liu, C., Song, D. L., Kawana, M., Ruppel, K. M., Spudich, J. A. CELL PRESS. 2018: 37A
  • Biophysical properties of human ß-cardiac myosin with converter mutations that cause hypertrophic cardiomyopathy. Science advances Kawana, M., Sarkar, S. S., Sutton, S., Ruppel, K. M., Spudich, J. A. 2017; 3 (2)

    Abstract

    Hypertrophic cardiomyopathy (HCM) affects 1 in 500 individuals and is an important cause of arrhythmias and heart failure. Clinically, HCM is characterized as causing hypercontractility, and therapies are aimed toward controlling the hyperactive physiology. Mutations in the β-cardiac myosin comprise ~40% of genetic mutations associated with HCM, and the converter domain of myosin is a hotspot for HCM-causing mutations; however, the underlying primary effects of these mutations on myosin's biomechanical function remain elusive. We hypothesize that these mutations affect the biomechanical properties of myosin, such as increasing its intrinsic force and/or its duty ratio and therefore the ensemble force of the sarcomere. Using recombinant human β-cardiac myosin, we characterize the molecular effects of three severe HCM-causing converter domain mutations: R719W, R723G, and G741R. Contrary to our hypothesis, the intrinsic forces of R719W and R723G mutant myosins are decreased compared to wild type and unchanged for G741R. Actin and regulated thin filament gliding velocities are ~15% faster for R719W and R723G myosins, whereas there is no change in velocity for G741R. Adenosine triphosphatase activities and the load-dependent velocity change profiles of all three mutant proteins are very similar to those of wild type. These results indicate that the net biomechanical properties of human β-cardiac myosin carrying these converter domain mutations are very similar to those of wild type or are even slightly hypocontractile, leading us to consider an alternative mechanism for the clinically observed hypercontractility. Future work includes how these mutations affect protein interactions within the sarcomere that increase the availability of myosin heads participating in force production.

    View details for DOI 10.1126/sciadv.1601959

    View details for PubMedID 28246639

    View details for PubMedCentralID PMC5302870

  • Acute Right Ventricular Failure After Successful Opening of Chronic Total Occlusion in Right Coronary Artery Caused by a Large Intramural Hematoma. Circulation. Cardiovascular interventions Kawana, M., Lee, A. M., Liang, D. H., Yeung, A. C. 2017; 10 (2)
  • Effects of hypertrophic and dilated cardiomyopathy mutations on power output by human beta-cardiac myosin JOURNAL OF EXPERIMENTAL BIOLOGY Spudich, J. A., Aksel, T., Bartholomew, S. R., Nag, S., Kawana, M., Yu, E. C., Sarkar, S. S., Sung, J., Sommese, R. F., Sutton, S., Cho, C., Adhikari, A. S., Taylor, R., Liu, C., Trivedi, D., Ruppel, K. M. 2016; 219 (2): 161-167

    Abstract

    Hypertrophic cardiomyopathy is the most frequently occurring inherited cardiovascular disease, with a prevalence of more than one in 500 individuals worldwide. Genetically acquired dilated cardiomyopathy is a related disease that is less prevalent. Both are caused by mutations in the genes encoding the fundamental force-generating protein machinery of the cardiac muscle sarcomere, including human β-cardiac myosin, the motor protein that powers ventricular contraction. Despite numerous studies, most performed with non-human or non-cardiac myosin, there is no clear consensus about the mechanism of action of these mutations on the function of human β-cardiac myosin. We are using a recombinantly expressed human β-cardiac myosin motor domain along with conventional and new methodologies to characterize the forces and velocities of the mutant myosins compared with wild type. Our studies are extending beyond myosin interactions with pure actin filaments to include the interaction of myosin with regulated actin filaments containing tropomyosin and troponin, the roles of regulatory light chain phosphorylation on the functions of the system, and the possible roles of myosin binding protein-C and titin, important regulatory components of both cardiac and skeletal muscles.

    View details for DOI 10.1242/jeb.125930

    View details for Web of Science ID 000368546300006

  • Understanding the Effects of Cardiomyopathy Causing Mutations on Human Beta Cardiac Myosin Biomechanical Function Nag, S., Sommese, R., Sung, J., Choe, E., Kawana, M., Cho, C., Taylor, R., Liu, C., Sutton, S., Ruppel, K., Spudich, J. CELL PRESS. 2014: 156A
  • Improved Loaded In Vitro Motility Assay and Actin Filament Tracking Software Delineates the Effect of Hypertrophic and Dilated Cardiomyopathy Mutations on the Power Output of Cardiac Myosin Aksel, T., Kawana, M., Adhikari, A., Sutton, S., Ruppel, K., Spudich, J. CELL PRESS. 2014: 562A
  • Quantification of gene transcripts with deep sequencing analysis of gene expression (DSAGE) using 1 to 2 µg total RNA. Current protocols in molecular biology Christodoulou, D. C., Gorham, J. M., Kawana, M., DePalma, S. R., Herman, D. S., Wakimoto, H. 2011; Chapter 25: Unit25B 9-?

    Abstract

    Deep sequencing analysis of gene expression (DSAGE) measures global gene transcript levels from only 1 to 2 µg total RNA by massively parallel sequencing of cDNA tags. This unit describes the construction of 21-bp cDNA tag libraries appropriate for massively parallel sequencing and analysis of the resulting sequence data. The adapter oligonucleotides used are optimized for sequencing with current Illumina massively parallel sequencers, and a step-by-step implementation of the analysis protocol is described. The expression profiles obtained are highly reproducible, enabling sensitive detection of differences between experimental conditions as well as assessment of the relative transcript abundance of different genes.

    View details for DOI 10.1002/0471142727.mb25b09s93

    View details for PubMedID 21225638

    View details for PubMedCentralID PMC4139004

  • Heterogeneous myocyte enhancer factor-2 (Mef2) activation in myocytes predicts focal scarring in hypertrophic cardiomyopathy PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Konno, T., Chen, D., Wang, L., Wakimoto, H., Teekakirikul, P., Nayor, M., Kawana, M., Eminaga, S., Gorham, J. M., Pandya, K., Smithies, O., Naya, F. J., Olson, E. N., Seidman, J. G., Seidman, C. E. 2010; 107 (42): 18097–102

    Abstract

    Unknown molecular responses to sarcomere protein gene mutations account for pathologic remodeling in hypertrophic cardiomyopathy (HCM), producing myocyte growth and increased cardiac fibrosis. To determine if hypertrophic signals activated myocyte enhancer factor-2 (Mef2), we studied mice carrying the HCM mutation, myosin heavy-chain Arg403Gln, (MHC(403/+)) and an Mef2-dependent β-galactosidase reporter transgene. In young, prehypertrophic MHC(403/+) mice the reporter was not activated. In hypertrophic hearts, activation of the Mef2-dependent reporter was remarkably heterogeneous and was observed consistently in myocytes that bordered fibrotic foci with necrotic cells, MHC(403/+) myocytes with Mef2-dependent reporter activation reexpressed the fetal myosin isoform (βMHC), a molecular marker of hypertrophy, although MHC(403/+) myocytes with or without βMHC expression were comparably enlarged over WT myocytes. To consider Mef2 roles in severe HCM, we studied homozygous MHC(403/403) mice, which have accelerated remodeling, widespread myocyte necrosis, and neonatal lethality. Levels of phosphorylated class II histone deacetylases that activate Mef2 were substantially increased in MHC(403/403) hearts, but Mef2-dependent reporter activation was patchy. Sequential analyses showed myocytes increased Mef2-dependent reporter activity before death. Our data dissociate myocyte hypertrophy, a consistent response in HCM, from heterogeneous Mef2 activation and reexpression of a fetal gene program. The temporal and spatial relationship of Mef2-dependent gene activation with myocyte necrosis and fibrosis in MHC(403/+) and MHC(403/403) hearts defines Mef2 activation as a molecular signature of stressed HCM myocytes that are poised to die.

    View details for DOI 10.1073/pnas.1012826107

    View details for Web of Science ID 000283184800047

    View details for PubMedID 20923879

    View details for PubMedCentralID PMC2964244

  • Endogenous regulation of cardiovascular function by apelin-APJ AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY Charo, D. N., Ho, M., Fajardo, G., Kawana, M., Kundu, R. K., Sheikh, A. Y., Finsterbach, T. P., Leeper, N. J., Ernst, K. V., Chen, M. M., Ho, Y. D., Chun, H. J., Bernstein, D., Ashley, E. A., Quertermous, T. 2009; 297 (5): H1904-H1913

    Abstract

    Studies have shown significant cardiovascular effects of exogenous apelin administration, including the potent activation of cardiac contraction. However, the role of the endogenous apelin-APJ pathway is less clear. To study the loss of endogenous apelin-APJ signaling, we generated mice lacking either the ligand (apelin) or the receptor (APJ). Apelin-deficient mice were viable, fertile, and showed normal development. In contrast, APJ-deficient mice were not born in the expected Mendelian ratio, and many showed cardiovascular developmental defects. Under basal conditions, both apelin and APJ null mice that survived to adulthood manifested modest decrements in contractile function. However, with exercise stress both mutant lines demonstrated consistent and striking decreases in exercise capacity. To explain these findings, we explored the role of autocrine signaling in vitro using field stimulation of isolated left ventricular cardiomyocytes lacking either apelin or APJ. Both groups manifested less sarcomeric shortening and impaired velocity of contraction and relaxation with no difference in calcium transient. Taken together, these results demonstrate that endogenous apelin-APJ signaling plays a modest role in maintaining basal cardiac function in adult mice with a more substantive role during conditions of stress. In addition, an autocrine pathway seems to exist in myocardial cells, the ablation of which reduces cellular contraction without change in calcium transient. Finally, differences in the developmental phenotype between apelin and APJ null mice suggest the possibility of undiscovered APJ ligands or ligand-independent effects of APJ.

    View details for DOI 10.1152/ajpheart.00686.2009

    View details for Web of Science ID 000271143400045

    View details for PubMedID 19767528

    View details for PubMedCentralID PMC2781363

  • PTC124 targets genetic disorders caused by nonsense mutations NATURE Welch, E. M., Barton, E. R., Zhuo, J., Tomizawa, Y., Friesen, W. J., Trifillis, P., Paushkin, S., Patel, M., Trotta, C. R., Hwang, S., Wilde, R. G., Karp, G., Takasugi, J., Chen, G., Jones, S., Ren, H., Moon, Y., Corson, D., Turpoff, A. A., Campbell, J. A., Conn, M., Khan, A., Almstead, N. G., Hedrick, J., Mollin, A., Risher, N., Weetall, M., Yeh, S., Branstrom, A. A., Colacino, J. M., Babiak, J., Ju, W. D., Hirawat, S., Northcutt, V. J., Miller, L. L., Spatrick, P., He, F., Kawana, M., Feng, H., Jacobson, A., Peltz, S. W., Sweeney, H. 2007; 447 (7140): 87–U6

    Abstract

    Nonsense mutations promote premature translational termination and cause anywhere from 5-70% of the individual cases of most inherited diseases. Studies on nonsense-mediated cystic fibrosis have indicated that boosting specific protein synthesis from <1% to as little as 5% of normal levels may greatly reduce the severity or eliminate the principal manifestations of disease. To address the need for a drug capable of suppressing premature termination, we identified PTC124-a new chemical entity that selectively induces ribosomal readthrough of premature but not normal termination codons. PTC124 activity, optimized using nonsense-containing reporters, promoted dystrophin production in primary muscle cells from humans and mdx mice expressing dystrophin nonsense alleles, and rescued striated muscle function in mdx mice within 2-8 weeks of drug exposure. PTC124 was well tolerated in animals at plasma exposures substantially in excess of those required for nonsense suppression. The selectivity of PTC124 for premature termination codons, its well characterized activity profile, oral bioavailability and pharmacological properties indicate that this drug may have broad clinical potential for the treatment of a large group of genetic disorders with limited or no therapeutic options.

    View details for DOI 10.1038/nature05756

    View details for Web of Science ID 000246149300049

    View details for PubMedID 17450125

  • Systemic administration of L-arginine benefits mdx skeletal muscle function MUSCLE & NERVE Barton, E. R., Morris, L., Kawana, M., Bish, L. T., Toursel, T. 2005; 32 (6): 751–60

    Abstract

    A major consequence of muscular dystrophy is that increased membrane fragility leads to high calcium influx and results in muscle degeneration and myonecrosis. Prior reports have demonstrated that increased nitric oxide production via L-arginine treatment of normal and mdx mice resulted in increased expression of utrophin and increased activation of muscle satellite cells, which could ameliorate the dystrophic pathology. We delivered L-arginine to normal and mdx mice, and examined muscles for any functional changes associated with its administration. Treated mdx muscles were less susceptible to contraction-induced damage and exhibited a rightward shift of the force-frequency relationship. Immunoblotting revealed increases in utrophin and gamma-sarcoglycan in the treated muscles. There was also a decrease in Evans blue dye uptake, indicating a reduction in myonecrosis. However, there was no decrease in serum creatine kinase or the proportion of central nuclei, nor any improvement in specific force. Together, these results show that L-arginine treatment can be beneficial to mdx muscle function, perhaps through a combination of enhanced calcium handling and increased utrophin, thereby decreasing muscle degeneration.

    View details for DOI 10.1002/mus.20425

    View details for Web of Science ID 000233734100007

    View details for PubMedID 16116642

  • gamma-sarcoglycan deficiency increases cell contractility, apoptosis and MAPK pathway activation but does not affect adhesion JOURNAL OF CELL SCIENCE Griffin, M. A., Feng, H. S., Tewari, M., Acosta, P., Kawana, M., Sweeney, H. L., Discher, D. E. 2005; 118 (7): 1405–16

    Abstract

    The functions of gamma-sarcoglycan (gammaSG) in normal myotubes are largely unknown, however gammaSG is known to assemble into a key membrane complex with dystroglycan and its deficiency is one known cause of limb-girdle muscular dystrophy. Previous findings of apoptosis from gammaSG-deficient mice are extended here to cell culture where apoptosis is seen to increase more than tenfold in gammaSG-deficient myotubes compared with normal cells. The deficient myotubes also exhibit an increased contractile prestress that results in greater shortening and widening when the cells are either lightly detached or self-detached. However, micropipette-forced peeling of single myotubes revealed no significant difference in cell adhesion. Consistent with a more contractile phenotype, acto-myosin striations were more prominent in gammaSG-deficient myotubes than in normal cells. An initial phosphoscreen of more than 12 signaling proteins revealed a number of differences between normal and gammaSG(-/-) muscle, both before and after stretching. MAPK-pathway proteins displayed the largest changes in activation, although significant phosphorylation also appeared for other proteins linked to hypertension. We conclude that gammaSG normally moderates contractile prestress in skeletal muscle, and we propose a role for gammaSG in membrane-based signaling of the effects of prestress and sarcomerogenesis.

    View details for DOI 10.1242/jcs.01717

    View details for Web of Science ID 000228631000011

    View details for PubMedID 15769854