Associate Professor of Medicine (Cardiovascular Medicine) at the Stanford University Medical Center


  • Exosomes From Induced Pluripotent Stem Cell-Derived Cardiomyocytes Promote Autophagy for Myocardial Repair. Journal of the American Heart Association Santoso, M. R., Ikeda, G., Tada, Y., Jung, J., Vaskova, E., Sierra, R. G., Gati, C., Goldstone, A. B., von Bornstaedt, D., Shukla, P., Wu, J. C., Wakatsuki, S., Woo, Y. J., Yang, P. C. 2020; 9 (6): e014345


    Background Induced pluripotent stem cells and their differentiated cardiomyocytes (iCMs) have tremendous potential as patient-specific therapy for ischemic cardiomyopathy following myocardial infarctions, but difficulties in viable transplantation limit clinical translation. Exosomes secreted from iCMs (iCM-Ex) can be robustly collected in vitro and injected in lieu of live iCMs as a cell-free therapy for myocardial infarction. Methods and Results iCM-Ex were precipitated from iCM supernatant and characterized by protein marker expression, nanoparticle tracking analysis, and functionalized nanogold transmission electron microscopy. iCM-Ex were then used in in vitro and in vivo models of ischemic injuries. Cardiac function in vivo was evaluated by left ventricular ejection fraction and myocardial viability measurements by magnetic resonance imaging. Cardioprotective mechanisms were studied by JC-1 (tetraethylbenzimidazolylcarbocyanine iodide) assay, immunohistochemistry, quantitative real-time polymerase chain reaction, transmission electron microscopy, and immunoblotting. iCM-Ex measured 140nm and expressed CD63 and CD9. iCM and iCM-Ex microRNA profiles had significant overlap, indicating that exosomal content was reflective of the parent cell. Mice treated with iCM-Ex demonstrated significant cardiac improvement post-myocardial infarction, with significantly reduced apoptosis and fibrosis. In vitro iCM apoptosis was significantly reduced by hypoxia and exosome biogenesis inhibition and restored by treatment with iCM-Ex or rapamycin. Autophagosome production and autophagy flux was upregulated in iCM-Ex groups in vivo and in vitro. Conclusions iCM-Ex improve post-myocardial infarction cardiac function by regulating autophagy in hypoxic cardiomyoytes, enabling a cell-free, patient-specific therapy for ischemic cardiomyopathy.

    View details for DOI 10.1161/JAHA.119.014345

    View details for PubMedID 32131688

  • Manganese-enhanced T1 mapping to quantify myocardial viability: validation with 18F-fluorodeoxyglucose positron emission tomography. Scientific reports Spath, N., Tavares, A., Gray, G. A., Baker, A. H., Lennen, R. J., Alcaide-Corral, C. J., Dweck, M. R., Newby, D. E., Yang, P. C., Jansen, M. A., Semple, S. I. 2020; 10 (1): 2018


    Gadolinium chelates are widely used in cardiovascular magnetic resonance imaging (MRI) as passive intravascular and extracellular space markers. Manganese, a biologically active paramagnetic calcium analogue, provides novel intracellular myocardial tissue characterisation. We previously showed manganese-enhanced MRI (MEMRI) more accurately quantifies myocardial infarction than gadolinium delayed-enhancement MRI (DEMRI). Here, we evaluated the potential of MEMRI to assess myocardial viability compared to gold-standard 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) viability. Coronary artery ligation surgery was performed in male Sprague-Dawley rats (n = 13) followed by dual MEMRI and 18F-FDG PET imaging at 10-12 weeks. MEMRI was achieved with unchelated (EVP1001-1) or chelated (mangafodipir) manganese. T1 mapping MRI was followed by 18F-FDG micro-PET, with tissue taken for histological correlation. MEMRI and PET demonstrated good agreement with histology but native T1 underestimated infarct size. Quantification of viability by MEMRI, PET and MTC were similar, irrespective of manganese agent. MEMRI showed superior agreement with PET than native T1. MEMRI showed excellent agreement with PET and MTC viability. Myocardial MEMRI T1 correlated with 18F-FDG standard uptake values and influx constant but not native T1. Our findings indicate that MEMRI identifies and quantifies myocardial viability and has major potential for clinical application in myocardial disease and regenerative therapies.

    View details for DOI 10.1038/s41598-020-58716-x

    View details for PubMedID 32029765

  • Sacubitril/Valsartan Improves Cardiac Function and Decreases Myocardial Fibrosis Via Downregulation of Exosomal miR-181a in a Rodent Chronic Myocardial Infarction Model. Journal of the American Heart Association Vaskova, E., Ikeda, G., Tada, Y., Wahlquist, C., Mercola, M., Yang, P. C. 2020: e015640


    Background Exosomes are small extracellular vesicles that function as intercellular messengers and effectors. Exosomal cargo contains regulatory small molecules, including miRNAs, mRNAs, lncRNAs, and small peptides that can be modulated by different pathological stimuli to the cells. One of the main mechanisms of action of drug therapy may be the altered production and/or content of the exosomes. Methods and Results We studied the effects on exosome production and content by neprilysin inhibitor/angiotensin receptor blockers, sacubitril/valsartan and valsartan alone, using human-induced pluripotent stem cell-derived cardiomyocytes under normoxic and hypoxic injury model in vitro, and assessed for physiologic correlation using an ischemic myocardial injury rodent model in vivo. We demonstrated that the treatment with sacubitril/valsartan and valsartan alone resulted in the increased production of exosomes by induced pluripotent stem cell-derived cardiomyocytes in vitro in both conditions as well as in the rat plasma in vivo. Next-generation sequencing of these exosomes exhibited downregulation of the expression of rno-miR-181a in the sacubitril/valsartan treatment group. In vivo studies employing chronic rodent myocardial injury model demonstrated that miR-181a antagomir has a beneficial effect on cardiac function. Subsequently, immunohistochemical and molecular studies suggested that the downregulation of miR-181a resulted in the attenuation of myocardial fibrosis and hypertrophy, restoring the injured rodent heart after myocardial infarction. Conclusions We demonstrate that an additional mechanism of action of the pleiotropic effects of sacubitril/valsartan may be mediated by the modulation of the miRNA expression level in the exosome payload.

    View details for DOI 10.1161/JAHA.119.015640

    View details for PubMedID 32538237

  • Ferumoxytol-enhanced cardiovascular magnetic resonance detection of early stage acute myocarditis. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance Tada, Y., Tachibana, A., Heidary, S., Yang, P. C., McConnell, M. V., Dash, R. 2019; 21 (1): 77


    BACKGROUND: The diagnostic utility of cardiovascular magnetic resonance (CMR) is limited during the early stages of myocarditis. This study examined whether ferumoxytol-enhanced CMR (FE-CMR) could detect an earlier stage of acute myocarditis compared to gadolinium-enhanced CMR.METHODS: Lewis rats were induced to develop autoimmune myocarditis. CMR (3T, GE Signa) was performed at the early- (day 14, n=7) and the peak-phase (day 21, n=8) of myocardial inflammation. FE-CMR was evaluated as % myocardial dephasing signal loss on gradient echo images at 6 and 24h (6h- & 24h-FE-CMR) following the administration of ferumoxytol (300mumolFe/kg). Pre- and post-contrast T2* mapping was also performed. Early (EGE) and late (LGE) gadolinium enhancement was obtained after the administration of gadolinium-DTPA (0.5mmol/kg) on day 14 and 21. Healthy rats were used as control (n=6).RESULTS: Left ventricular ejection fraction (LVEF) was preserved at day 14 with inflammatory cells but no fibrosis seen on histology. EGE and LGE at day 14 both showed limited myocardial enhancement (EGE: 11.7±15.5%; LGE: 8.7±8.7%; both p=ns vs. controls). In contrast, 6h-FE-CMR detected extensive myocardial signal loss (33.2±15.0%, p=0.02 vs. EGE and p<0.01 vs. LGE). At day 21, LVEF became significantly decreased (47.4±16.4% vs control: 66.2±6.1%, p<0.01) with now extensive myocardial involvement detected on EGE, LGE, and 6h-FE-CMR (41.6±18.2% of LV). T2* mapping also detected myocardial uptake of ferumoxytol both at day 14 (6h R2*=299±112s-1vs control: 125±26s-1, p<0.01) and day 21 (564±562s-1, p<0.01 vs control). Notably, the myocardium at peak-phase myocarditis also showed significantly higher pre-contrast T2* (27±5ms vs control: 16±1ms, p<0.001), and the extent of myocardial necrosis had a strong positive correlation with T2* (r=0.86, p<0.001).CONCLUSIONS: FE-CMR acquired at 6h enhance detection of early stages of myocarditis before development of necrosis or fibrosis, which could potentially enable appropriate therapeutic intervention.

    View details for DOI 10.1186/s12968-019-0587-7

    View details for PubMedID 31842900

  • Iron Oxide Labeling and Tracking of Extracellular Vesicles MAGNETOCHEMISTRY Tada, Y., Yang, P. C. 2019; 5 (4)
  • Meta-analysis of short- and long-term efficacy of mononuclear cell transplantation in patients with myocardial infarction. American heart journal Yang, D., O'Brien, C. G., Ikeda, G., Traverse, J. H., Taylor, D. A., Henry, T. D., Bolli, R., Yang, P. C. 2019; 220: 155–75


    BACKGROUND: Mononuclear cells (MNCs) have been tested in clinical trials across multiple cardiovascular pathologies with mixed results. Major adverse cardiac events (MACE) and markers of cardiovascular capacity have been particularly challenging to interpret because of small size. This meta-analysis is aimed to assess the efficacy of MNC therapy in randomized clinical trials to identify the markers of efficiency that could influence future trial design.METHODS: PubMed, Embase, Cochrane library, and were searched from inception through November 8, 2018. Changes in left ventricular ejection fraction (LVEF) and infarct size from baseline to follow-up were selected as primary outcomes. Changes in the left ventricular end-systolic volume, left ventricular end-diastolic volume, brain natriuretic peptide/N-terminal pro-B-type natriuretic peptide, 6-minute walk test, New York Heart Association class, and MACE incidences were considered secondary outcomes.RESULTS: In short-term follow-up, patients treated with MNCs demonstrated a significant increase in absolute LVEF of 2.21% (95% CI 1.59-2.83; P < .001; I2 = 32%) and 6.01% (95% CI 4.45-7.57; P < .001; I2 = 0%) in acute myocardial infarction (AMI) and ischemic cardiomyopathy studies, respectively. This effect was sustained in long-term follow-up. MNC therapy significantly reduced left ventricular end-systolic volume; however, infarct size, 6-minute walk test, New York Heart Association class, and MACE rates were comparable.CONCLUSIONS: MNC therapy may convey a modest but sustained increase in LVEF in ischemic cardiomyopathy patients, supporting further investigation. AMI trials, however, demonstrated minimal improvement in LVEF of unclear clinical significance, suggesting a limited role for MNC therapy in AMI.

    View details for DOI 10.1016/j.ahj.2019.09.005

    View details for PubMedID 31821904

  • Combined T2 -preparation and multidimensional outer volume suppression for coronary artery imaging with 3D cones trajectories. Magnetic resonance in medicine Zeng, D. Y., Baron, C. A., Malave, M. O., Kerr, A. B., Yang, P. C., Hu, B. S., Nishimura, D. G. 2019


    PURPOSE: To develop a modular magnetization preparation sequence for combined T2 -preparation and multidimensional outer volume suppression (OVS) for coronary artery imaging.METHODS: A combined T2 -prepared 1D OVS sequence with fat saturation was defined to contain a 90°-60 180°60 composite nonselective tip-down pulse, two 180°Y hard pulses for refocusing, and a -90° spectral-spatial sinc tip-up pulse. For 2D OVS, 2 modules were concatenated, selective in X and then Y. Bloch simulations predicted robustness of the sequence to B0 and B1 inhomogeneities. The proposed sequence was compared with a T2 -prepared 2D OVS sequence proposed by Luo et al, which uses a spatially selective 2D spiral tip-up. The 2 sequences were compared in phantom studies and in vivo coronary artery imaging studies with a 3D cones trajectory.RESULTS: Phantom results demonstrated superior OVS for the proposed sequence compared with the Luo sequence. In studies on 15 healthy volunteers, the proposed sequence had superior image edge profile acutance values compared with the Luo sequence for the right (P < .05) and left (P < .05) coronary arteries, suggesting superior vessel sharpness. The proposed sequence also had superior signal-to-noise ratio (P < .05) and passband-to-stopband ratio (P < .05). Reader scores and reader preference indicated superior coronary image quality of the proposed sequence for both the right (P < .05) and left (P < .05) coronary arteries.CONCLUSION: The proposed sequence with concatenated 1D spatially selective tip-ups and integrated fat saturation has superior image quality and suppression compared with the Luo sequence with 2D spatially selective tip-up.

    View details for DOI 10.1002/mrm.28057

    View details for PubMedID 31691350

  • Broad Genetic Testing in a Clinical Setting Uncovers a High Prevalence of Titin Loss-of-Function Variants in Very Early-Onset Atrial Fibrillation. Circulation. Genomic and precision medicine Goodyer, W. R., Dunn, K., Caleshu, C., Jackson, M., Wylie, J., Moscarello, T., Platt, J., Reuter, C., Smith, A., Trela, A., Ceresnak, S. R., Motonaga, K. S., Ashley, E., Yang, P., Dubin, A. M., Perez, M. 2019


    Atrial fibrillation (AF) is the most common sustained arrhythmia, affecting approximately 34 million worldwide. The pathophysiology of AF remains incompletely understood but is clearly complex with multiple underlying genetic, physiologic and environmental factors. Very early-onset AF (vEAF) (defined here as onset <45 years and without significant comorbidities), while rare (only ~0.5-3% of AF cases), is highly heritable, with a greater prevalence of rare variants in genes previously associated with AF. Patients with vEAF, therefore, represent an ideal population for discovering novel genes involved in the underlying genetic basis of AF. Notably, the Framingham study showed that patients with AF without comorbidities have a three-fold higher risk for heart failure. Conversely, several forms of inherited cardiomyopathy have been strongly associated with AF suggestive of a shared etiology.

    View details for DOI 10.1161/CIRCGEN.119.002713

    View details for PubMedID 31638414

  • Stem Cell-Derived Exosomes Protect Astrocyte Cultures From in vitro Ischemia and Decrease Injury as Post-stroke Intravenous Therapy FRONTIERS IN CELLULAR NEUROSCIENCE Sun, X., Jung, J., Arvola, O., Santoso, M. R., Giffard, R. G., Yang, P. C., Stary, C. M. 2019; 13
  • Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction INTERNATIONAL JOURNAL OF CARDIOLOGY Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019; 281: 8–14
  • Whole-heart coronary MR angiography using a 3D cones phyllotaxis trajectory MAGNETIC RESONANCE IN MEDICINE Malave, M. O., Baron, C. A., Addy, N., Cheng, J. Y., Yang, P. C., Hu, B. S., Nishimura, D. G. 2019; 81 (2): 1092–1103

    View details for DOI 10.1002/mrm.27475

    View details for Web of Science ID 000462086300030

  • Myocardial viability of the peri-infarct region measured by T1 mapping post manganese-enhanced MRI correlates with LV dysfunction. International journal of cardiology Tada, Y., Heidary, S., Tachibana, A., Zaman, J., Neofytou, E., Dash, R., Wu, J. C., Yang, P. C. 2019


    BACKGROUND: Manganese-enhanced MRI (MEMRI) detects viable cardiomyocytes based on the intracellular manganese uptake via L-type calcium-channels. This study aimed to quantify myocardial viability based on manganese uptake by viable myocardium in the infarct core (IC), peri-infarct region (PIR) and remote myocardium (RM) using T1 mapping before and after MEMRI and assess their association with cardiac function and arrhythmogenesis.METHODS: Fifteen female swine had a 60-minute balloon ischemia-reperfusion injury in the LAD. MRI (Signa 3T, GE Healthcare) and electrophysiological study (EPS) were performed 4 weeks later. MEMRI and delayed gadolinium-enhanced MRI (DEMRI) were acquired on LV short axis. The DEMRI positive total infarct area was subdivided into the regions of MEMRI-negative non-viable IC and MEMRI-positive viable PIR. T1 mapping was performed to evaluate native T1, post-MEMRI T1, and delta R1 (R1post-R1pre, where R1 equals 1/T1) of each territory. Their correlation with LV function and EPS data was assessed.RESULTS: PIR was characterized by intermediate native T1 (1530.5 ± 75.2 ms) compared to IC (1634.7 ± 88.4 ms, p = 0.001) and RM (1406.4 ± 37.9 ms, p < 0.0001). Lower post-MEMRI T1 of PIR (1136.3 ± 99.6 ms) than IC (1262.6 ± 126.8 ms, p = 0.005) and higher delta R1 (0.23 ± 0.08 s-1) of PIR than IC (0.18 ± 0.09 s-1, p = 0.04) indicated higher myocardial manganese uptake of PIR compared to IC. Post-MEMRI T1 (r = -0.57, p = 0.02) and delta R1 (r = 0.51, p = 0.04) of PIR correlated significantly with LVEF.CONCLUSIONS: PIR is characterized by higher manganese uptake compared to the infarct core. In the subacute phase post-IR, PIR viability measured by post-MEMRI T1 correlates with cardiac function.

    View details for PubMedID 30739802