My long-term goal as a physician-scientist is to develop therapeutic strategies for right heart failure by elucidating its pathophysiology.
I graduated from Kyushu University, School of Medicine in Fukuoka, Japan in 2008. Following a residency program at Aso Iizuka Hospital, I finished fellowship in Emergency Medicine (1 year) and Cardiovascular Medicine (2 years). My clinical expertise is general cardiology, cardiac catheterization, echocardiography, and cardiac critical care.
After my clinical training, I started my research career working towards a Ph.D. under the mentorship of Dr. Kensuke Egashira. During my Ph.D., I published two papers focusing on the development of novel therapeutics for acute myocardial infarction and pulmonary arterial hypertension. Through this research experience, I developed skills in modeling and assessing cardiovascular disease in both small (rodents) and large animals (pigs)
In 2017, I was appointed as an Assistant Professor and attending physician in the Department of Emergency and Critical Care Medicine at Kyushu University Hospital. During this period, I learned that right heart failure was one of the most devastating conditions with no treatment options in patients with pulmonary hypertension, congenital heart disease, and patients on long-term mechanical ventricular assist devices. I also continued my research with a research grant funded by the Japanese Society for the Promotion of Science.
In 2019, I decided to further expand my research field into right heart failure and joined Dr. Edda Spiekerkoetter’s lab at Stanford University as a postdoctoral fellow. I am currently focusing on the role of BMPR2 in the cardiomyocytes, the structural changes in the right ventricle under pressure overload, and the development of right ventricle-targeting therapy in pulmonary hypertension.
Honors & Awards
Young Investigator Award, Clinical Research, Japanese Association of Cardiovascular Intervention and Therapeutics (July 2017)
Young Researcher Award, ESC, Working Group on Pulmonary Circulation and Right Ventricular Function (Aug. 2016)
Young Investigator Award, Basic Science, European Society of Cardiology (Aug. 2016)
Young Investigator Award, Clinical Research, Japanese Association of Cardiovascular Intervention and Therapeutics (Aug. 2016)
Top Score Poster AwardTop Score Poster Award, European Society of Cardiology (Aug. 2014)
Boards, Advisory Committees, Professional Organizations
Fellow, Japanese Society of Internal Medicine (2018 - Present)
Board Certification, Japanese Association of Acute Medicine, Emergency Medicine (2020)
Board Certification, Japanese Society of Intensive Care Medicine, Intensive Care Medicine (2020)
Doctor of Philosophy, Kyushu University (2018)
Board Certification, Japanese Society of Echocardiography, Echocardiography for Structural Heart Disease (2018)
Board Certification, Japanese Circulation Society, Cardiology (2017)
Board Certification, Japanese Society of Cardiovascular Anesthesiologists, Perioperative Transesophageal Echocardiography (2016)
Clinical Fellow, Aso Iizuka Hospital, Cardiovascular Medicine (2013)
Board Certification, Japanese Society of Internal Medicine, Internal Medicine (2012)
Clinical Fellow, Aso Iizuka Hospital, Emergency Medicine (2011)
Residency, Aso Iizuka Hospital (2010)
Doctor of Medicine, Kyushu University (2008)
Pulmonary arterial banding in mice may be a suitable model for studies on ventricular mechanics in pediatric pulmonary arterial hypertension.
Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance
2021; 23 (1): 66
BACKGROUND: The role of interventricular mechanics in pediatric pulmonary arterial hypertension (PAH) and its relation to right ventricular (RV) dysfunction has been largely overlooked. Here, we characterize the impact of maintained pressure overload in the RV-pulmonary artery (PA) axis on myocardial strain and left ventricular (LV) mechanics in pediatric PAH patients in comparison to a preclinical PA-banding (PAB) mouse model. We hypothesize that the PAB mouse model mimics important aspects of interventricular mechanics of pediatric PAH and may be beneficial as a surrogate model for some longitudinal and interventional studies not possible in children.METHODS: Balanced steady-state free precession (bSSFP) cardiovascular magnetic resonance (CMR) images of 18 PAH and 17 healthy (control) pediatric subjects were retrospectively analyzed using CMR feature-tracking (FT) software to compute measurements of myocardial strain. Furthermore, myocardial tagged-CMR images were also analyzed for each subject using harmonic phase flow analysis to derive LV torsion rate. Within 48h of CMR, PAH patients underwent right heart catheterization (RHC) for measurement of PA/RV pressures, and to compute RV end-systolic elastance (RV_Ees, a measure of load-independent contractility). Surgical PAB was performed on mice to induce RV pressure overload and myocardial remodeling. bSSFP-CMR, tagged CMR, and intra-cardiac catheterization were performed on 12 PAB and 9 control mice (Sham) 7 weeks after surgery with identical post-processing as in the aforementioned patient studies. RV_Ees was assessed via the single beat method.RESULTS: LV torsion rate was significantly reduced under hypertensive conditions in both PAB mice (p=0.004) and pediatric PAH patients (p<0.001). This decrease in LV torsion rate correlated significantly with a decrease in RV_Ees in PAB (r=0.91, p=0.05) and PAH subjects (r=0.51, p=0.04). In order to compare combined metrics of LV torsion rate and strain parameters principal component analysis (PCA) was used. PCA revealed grouping of PAH patients with PAB mice and control subjects with Sham mice. Similar to LV torsion rate, LV global peak circumferential, radial, and longitudinal strain were significantly (p<0.05) reduced under hypertensive conditions in both PAB mice and children with PAH.CONCLUSIONS: The PAB mouse model resembles PAH-associated myocardial mechanics and may provide a potential model to study mechanisms of RV/LV interdependency.
View details for DOI 10.1186/s12968-021-00759-8
View details for PubMedID 34078382
Improving Right Ventricular Function by Increasing BMP Signaling with FK506.
American journal of respiratory cell and molecular biology
Right Ventricular (RV) function is the predominant determinant of survival in patients suffering from pulmonary arterial hypertension (PAH). In pre-clinical models, pharmacological activation of bone morphogenetic protein (BMP) signaling with FK506 (Tacrolimus) improved RV function by decreasing RV afterload. FK506 therapy further stabilized three end-stage PAH patients. Whether FK506 has direct effects on the pressure overloaded RV is yet unknown. We hypothesized that increasing cardiac BMP signaling with FK506 improves RV structure and function in a model of fixed RV afterload after pulmonary artery banding (PAB). Direct cardiac effects of FK506 on the microvasculature and RV fibrosis were studied after surgical PAB in wildtype and heterozygous Bmpr2 mutant mice. Right ventricular function and strain were assessed longitudinally via cardiac magnetic resonance (CMR) imaging during continuous FK506 infusion. Genetic lineage tracing of endothelial cells (ECs) was performed to assess the contribution of ECs to fibrosis. Molecular mechanistic studies were performed in human cardiac fibroblasts (hCFs) and endothelial cells. In mice, low BMP signaling in the RV exaggerated PAB-induced RV fibrosis. FK506 therapy restored cardiac BMP signaling, reduced RV fibrosis in a BMP-dependent manner independent from its immunosuppressive effect, preserved RV capillarization and improved RV function and strain over the time-course of disease. Endothelial mesenchymal transition was a rare event and did not significantly contribute to cardiac fibrosis after PAB. Mechanistically, FK506 required ALK1 in hCFs as BMPR2 co-receptor to reduce TGFbeta1-induced proliferation and collagen production. Our study demonstrates that increasing cardiac BMP signaling with FK506 improves RV structure and function independent from its previously described beneficial effects on pulmonary vascular remodeling.
View details for DOI 10.1165/rcmb.2020-0528OC
View details for PubMedID 33938785
Promising therapeutic approaches in pulmonary arterial hypertension.
Current opinion in pharmacology
2021; 59: 127-139
Pulmonary arterial hypertension (PAH) is a debilitating multifactorial disease characterized by progressive pulmonary vascular remodeling, elevated pulmonary arterial pressure, and pulmonary vascular resistance, resulting in right ventricular failure and subsequent death. Current available therapies do not reverse the disease, resulting in a persistent high morbidity and mortality. Thus, there is an urgent unmet medical need for novel effective therapies to better treat patients with PAH. Over the past few years, enthusiastic attempts have been made to identify novel effective therapies that address the essential roots of PAH with targeting key signaling pathways in both preclinical models and patients with PAH. This review aims to discuss the most emerging and promising therapeutic interventions in PAH pathogenesis.
View details for DOI 10.1016/j.coph.2021.05.003
View details for PubMedID 34217109
Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of PA de-banding.
AIMS: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload are unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodeling events.METHODS AND RESULTS: Surgical pulmonary artery banding (PAB) around a 26G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic and vascular myocardial remodeling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB) - after RV dysfunction and structural remodeling were established - initiated recovery of RV function (cardiac output, exercise capacity) along with rapid normalization in RV hypertrophy (RV/LV+S, cardiomyocyte area) and RV pressures (RVSP). RV fibrotic (collagen, elastic fibers, vimentin+ fibroblasts) and vascular (capillary density) remodeling were equally reversible, however reversal occurred at a later time-point after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators and apoptosis mediators as major cellular components underlying functional RV recovery.CONCLUSIONS: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodeling events.TRANSLATIONAL PERSPECTIVE: The right ventricle (RV) in pulmonary arterial hypertension possesses a remarkable ability to recover after lung transplantation. Yet, some transplant centers prefer a heart-lung instead of lung transplantation when the RV function is severely impaired because knowledge is lacking whether fibrotic and vascular myocardial remodeling are completely reversible once the increased afterload burden is relieved. We have developed a mouse model to study gradual unloading of the RV and identified key molecular components and the timing of RV reverse-remodeling events with the ultimate goal to understand the RV recovery process and identify ways how to support the RV during recovery.
View details for DOI 10.1093/cvr/cvz310
View details for PubMedID 31738411
Nanoparticle-Mediated Targeting of Pitavastatin to Small Pulmonary Arteries and Leukocytes by Intravenous Administration Attenuates the Progression of Monocrotaline-Induced Established Pulmonary Arterial Hypertension in Rats.
International heart journal
2018; 59 (6): 1432–44
Statins are known to improve pulmonary arterial hypertension (PAH) by their anti-inflammatory and anti-proliferative effects in animal models. However, recent clinical studies have reported that clinically approved statin doses failed to improve clinical outcomes in patients with PAH. We therefore hypothesized that nanoparticle (NP) -mediated targeting of pitavastatin could attenuate the progression of established PAH.We induced PAH by subcutaneously injecting monocrotaline (MCT) in Sprague-Dawley rats. On day 14 after the MCT injection, animals that displayed established PAH on echocardiography were included. On day 17, they were randomly assigned to the following 5 groups: daily intravenous administration of (1) vehicle, (2) fluorescein-isothiocyanate-NP, (3) pitavastatin, (4) pitavastatin-NP, or (5) oral sildenafil. Intravenous NP was selectively delivered to small pulmonary arteries and circulating CD11b-positive leukocytes. On day 21, pitavastatin-NP attenuated the progression of PAH at lower doses than pitavastatin alone. This was associated with the inhibition of monocyte-mediated inflammation, proliferation, and remodeling of the pulmonary arteries. Interestingly, sildenafil attenuated the development of PAH, but had no effects on inflammation or remodeling of the pulmonary arteries. In separate experiments, only treatment with pitavastatin-NP reduced the mortality rate at day 35.NP-mediated targeting of pitavastatin to small pulmonary arteries and leukocytes attenuated the progression of established MCT-induced PAH and improved survival. Therapeutically, pitavastatin-NP was associated with anti-inflammatory and anti-proliferative effects on small pulmonary arteries, which was completely distinct from the vasodilatory effect of sildenafil. Pitavastatin-NP can be a novel therapeutic modality for PAH.
View details for DOI 10.1536/ihj.17-683
View details for PubMedID 30369578
A Translational Study of a New Therapeutic Approach for Acute Myocardial Infarction: Nanoparticle-Mediated Delivery of Pitavastatin into Reperfused Myocardium Reduces Ischemia-Reperfusion Injury in a Preclinical Porcine Model.
2016; 11 (9): e0162425
There is an unmet need to develop an innovative cardioprotective modality for acute myocardial infarction, for which interventional reperfusion therapy is hampered by ischemia-reperfusion (IR) injury. We recently reported that bioabsorbable poly(lactic acid/glycolic acid) (PLGA) nanoparticle-mediated treatment with pitavastatin (pitavastatin-NP) exerts a cardioprotective effect in a rat IR injury model by activating the PI3K-Akt pathway and inhibiting inflammation. To obtain preclinical proof-of-concept evidence, in this study, we examined the effect of pitavastatin-NP on myocardial IR injury in conscious and anesthetized pig models.Eighty-four Bama mini-pigs were surgically implanted with a pneumatic cuff occluder at the left circumflex coronary artery (LCx) and telemetry transmitters to continuously monitor electrocardiogram as well as to monitor arterial blood pressure and heart rate. The LCx was occluded for 60 minutes, followed by 24 hours of reperfusion under conscious conditions. Intravenous administration of pitavastatin-NP containing ≥ 8 mg/body of pitavastatin 5 minutes before reperfusion significantly reduced infarct size; by contrast, pitavastatin alone (8 mg/body) showed no therapeutic effects. Pitavastatin-NP produced anti-apoptotic effects on cultured cardiomyocytes in vitro. Cardiac magnetic resonance imaging performed 4 weeks after IR injury revealed that pitavastatin-NP reduced the extent of left ventricle remodeling. Importantly, pitavastatin-NP exerted no significant effects on blood pressure, heart rate, or serum biochemistry. Exploratory examinations in anesthetized pigs showed pharmacokinetic analysis and the effects of pitavastatin-NP on no-reflow phenomenon.NP-mediated delivery of pitavastatin to IR-injured myocardium exerts cardioprotective effects on IR injury without apparent adverse side effects in a preclinical conscious pig model. Thus, pitavastatin-NP represents a novel therapeutic modality for IR injury in acute myocardial infarction.
View details for DOI 10.1371/journal.pone.0162425
View details for PubMedID 27603665
View details for PubMedCentralID PMC5014419