Bio


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


  • Cournand & Comroe Early Career Investigator Prize, Finalist, American Heart Association, Council on 3CPR (Nov. 2022)
  • Poster Award at the Stanford-Cornell Cardiovascular Research Symposium, Stanford Cardiovascular Institute (Nov. 2022)
  • American Thoracic Society Abstract Scholarship, ATS Assembly on Pulmonary Circulation (May 2022)
  • Postdoctoral Fellowship, American Heart Association (Jan. 2022 - Dec. 2024)
  • CVI Travel Award, Stanford Cardiovascular Institute (Sept. 2021)
  • Grant-in-Aid for Young Scientists, Japan Society for the Promotion of Science (Apr. 2018 - Mar. 2020)
  • Young Investigator Award, Clinical Research, Japanese Association of Cardiovascular Intervention and Therapeutics (July 2017)
  • Research Grant, Kowa Life Science Foundation (Jan. 2017 - Dec. 2017)
  • 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)
  • Young Researcher Award, ESC, Working Group on Pulmonary Circulation and Right Ventricular Function (Aug. 2016)
  • Top Score Poster Award, European Society of Cardiology (Aug. 2014)

Boards, Advisory Committees, Professional Organizations


  • Fellow, Japanese Society of Internal Medicine (2018 - Present)

Professional Education


  • Doctor of Philosophy, Kyushu University (2018)
  • Doctor of Medicine, Kyushu University (2008)
  • Board Certification, Japanese Association of Acute Medicine, Emergency Medicine (2020)
  • Board Certification, Japanese Society of Intensive Care Medicine, Intensive Care Medicine (2020)
  • 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)

Lab Affiliations


All Publications


  • Cardiorenal Syndrome in Right Heart Failure Due to Pulmonary Arterial Hypertension-The Right Ventricle as a Therapeutic Target to Improve Renal Function. Cardiovascular drugs and therapy Ichimura, K., Gross, A., Mathew, R. O., Salman, L., Reddy, S., Spiekerkoetter, E., Sidhu, M. S. 2024

    Abstract

    Cardiorenal syndrome (CRS) due to right ventricular (RV) failure is a disease entity emerging as a key indicator of morbidity and mortality. The multifactorial aspects of CRS and the left-right ventricular interdependence complicate the link between RV failure and renal function. RV failure has a direct pathophysiological link to renal dysfunction by leading to systemic venous congestion in certain circumstances and low cardiac output in other situations, both leading to impaired renal perfusion. Indeed, renal dysfunction is known to be an independent predictor of mortality in patients with pulmonary arterial hypertension (PAH) and RV failure. Thus, it is important to further understand the interaction between the RV and renal function. RV adaptation is critical to long-term survival in patients with PAH. The RV is also known for its remarkable capacity to recover once the aggravating factor is addressed or mitigated. However, less is known about the renal potential for recovery following the resolution of chronic RV failure. In this review, we provide an overview of the intricate relationship between RV dysfunction and the subsequent development of CRS, with a particular emphasis on PAH. Additionally, we summarize potential RV-targeted therapies and their potential beneficial impact on renal function.

    View details for DOI 10.1007/s10557-024-07588-8

    View details for PubMedID 38847906

  • 3D Imaging Reveals Complex Microvascular Remodeling in the Right Ventricle in Pulmonary Hypertension. Circulation research Ichimura, K., Boehm, M., Andruska, A. M., Zhang, F., Schimmel, K., Bonham, S., Kabiri, A., Kheyfets, V. O., Ichimura, S., Reddy, S., Mao, Y., Zhang, T., Wang, G., Santana, E. J., Tian, X., Essafri, I., Vinh, R., Tian, W., Nicolls, M. R., Yajima, S., Shudo, Y., MacArthur, J. W., Woo, Y. J., Metzger, R. J., Spiekerkoetter, E. 2024

    Abstract

    Pathogenic concepts of right ventricular (RV) failure in pulmonary arterial hypertension focus on a critical loss of microvasculature. However, the methods underpinning prior studies did not take into account the 3-dimensional (3D) aspects of cardiac tissue, making accurate quantification difficult. We applied deep-tissue imaging to the pressure-overloaded RV to uncover the 3D properties of the microvascular network and determine whether deficient microvascular adaptation contributes to RV failure.Heart sections measuring 250-µm-thick were obtained from mice after pulmonary artery banding (PAB) or debanding PAB surgery and properties of the RV microvascular network were assessed using 3D imaging and quantification. Human heart tissues harvested at the time of transplantation from pulmonary arterial hypertension cases were compared with tissues from control cases with normal RV function.Longitudinal 3D assessment of PAB mouse hearts uncovered complex microvascular remodeling characterized by tortuous, shorter, thicker, highly branched vessels, and overall preserved microvascular density. This remodeling process was reversible in debanding PAB mice in which the RV function recovers over time. The remodeled microvasculature tightly wrapped around the hypertrophied cardiomyocytes to maintain a stable contact surface to cardiomyocytes as an adaptation to RV pressure overload, even in end-stage RV failure. However, microvasculature-cardiomyocyte contact was impaired in areas with interstitial fibrosis where cardiomyocytes displayed signs of hypoxia. Similar to PAB animals, microvascular density in the RV was preserved in patients with end-stage pulmonary arterial hypertension, and microvascular architectural changes appeared to vary by etiology, with patients with pulmonary veno-occlusive disease displaying a lack of microvascular complexity with uniformly short segments.3D deep tissue imaging of the failing RV in PAB mice, pulmonary hypertension rats, and patients with pulmonary arterial hypertension reveals complex microvascular changes to preserve the microvascular density and maintain a stable microvascular-cardiomyocyte contact. Our studies provide a novel framework to understand microvascular adaptation in the pressure-overloaded RV that focuses on cell-cell interaction and goes beyond the concept of capillary rarefaction.

    View details for DOI 10.1161/CIRCRESAHA.123.323546

    View details for PubMedID 38770652

  • Identifying consistent echocardiographic thresholds for risk stratification in pulmonary arterial hypertension. Pulmonary circulation Celestin, B. E., Bagherzadeh, S. P., Ichimura, K., Santana, E. J., Sanchez, P. A., Tobore, T., Hemnes, A. R., Noordegraaf, A. V., Salerno, M., Zamanian, R. T., Sweatt, A. J., Haddad, F. 2024; 14 (2): e12361

    Abstract

    Several indices of right heart remodeling and function have been associated with survival in pulmonary arterial hypertension (PAH). Outcome analysis and physiological relationships between variables may help develop a consistent grading system. Patients with Group 1 PAH followed at Stanford Hospital who underwent right heart catheterization and echocardiography within 2 weeks were considered for inclusion. Echocardiographic variables included tricuspid annular plane systolic excursion (TAPSE), right ventricular (RV) fractional area change (RVFAC), free wall strain (RVFWS), RV dimensions, and right atrial volumes. The main outcome consisted of death or lung transplantation at 5 years. Mathematical relationships between variables were determined using weighted linear regression and severity thresholds for were calibrated to a 20% 1-year mortality risk. PAH patients (n=223) had mean (SD) age of 48.1 (14.1) years, most were female (78%), with a mean pulmonary arterial pressure of 51.6 (13.8) mmHg and pulmonary vascular resistance index of 22.5(6.3) WU/m2. Measures of right heart size and function were strongly related to each other particularly RVFWS and RVFAC (R 2=0.82, p<0.001), whereas the relationship between TAPSE and RVFWS was weaker (R 2=0.28, p<0.001). Death or lung transplantation at 5 years occurred in 78 patients (35%). Guided by outcome analysis, we ascertained a uniform set of parameter thresholds for grading the severity of right heart adaptation in PAH. Using these quantitative thresholds, we, then, validated the recently reported REVEAL-echo score (AUC 0.68, p<0.001). This study proposes a consistent echocardiographic grading system for right heart adaptation in PAH guided by outcome analysis.

    View details for DOI 10.1002/pul2.12361

    View details for PubMedID 38800494

  • Characterizing the Spatiotemporal Transcriptomic Response of the Right Ventricle to Acute Pressure Overload. International journal of molecular sciences Kheyfets, V. O., Kumar, S., Heerdt, P. M., Ichimura, K., Brown, R. D., Lucero, M., Essafri, I., Williams, S., Stenmark, K. R., Spiekerkoetter, E. 2023; 24 (11)

    Abstract

    This study analyzed microarray data of right ventricular (RV) tissue from rats exposed to pulmonary embolism to understand the initial dynamic transcriptional response to mechanical stress and compare it with experimental pulmonary hypertension (PH) models. The dataset included samples harvested from 55 rats at 11 different time points or RV locations. We performed principal component analysis (PCA) to explore clusters based on spatiotemporal gene expression. Relevant pathways were identified from fast gene set enrichment analysis using PCA coefficients. The RV transcriptomic signature was measured over several time points, ranging from hours to weeks after an acute increase in mechanical stress, and was found to be highly dependent on the severity of the initial insult. Pathways enriched in the RV outflow tracts of rats at 6 weeks after severe PE share many commonalities with experimental PH models, but the transcriptomic signature at the RV apex resembles control tissue. The severity of the initial pressure overload determines the trajectory of the transcriptomic response independent of the final afterload, but this depends on the location where the tissue is biopsied. Chronic RV pressure overload due to PH appears to progress toward similar transcriptomic endpoints.

    View details for DOI 10.3390/ijms24119746

    View details for PubMedID 37298696

  • Novel left ventricular mechanical index in pulmonary arterial hypertension. Pulmonary circulation Ichimura, K., Santana, E. J., Kuznetsova, T., Cauwenberghs, N., Sabovčik, F., Chun, L., Francisco, N. L., Kheyfets, V. O., Salerno, M., Zamanian, R. T., Spiekerkoetter, E., Haddad, F. 2023; 13 (2): e12216

    Abstract

    Ventricular interdependence plays an important role in pulmonary arterial hypertension (PAH). It can decrease left ventricular (LV) longitudinal strain (LVLS) and lead to a leftward displacement ("transverse shortening") of the interventricular septum (sTS). For this study, we hypothesized the ratio of LVLS/sTS would be a sensitive marker of systolic ventricular interactions in PAH. In a cross-sectional cohort of patients with PAH (n = 57) and matched controls (n = 57), we quantified LVLS and septal TS in the amplitude and time domain. We then characterized LV phenotypes using upset plots, ventricular interactions using network analysis, and longitudinal analysis in a representative cohort of 45 patients. We also measured LV metrics in mice subjected to pulmonary arterial banding (PAB) using a 7 T magnetic resonance imaging at baseline, Week 1, and Week 7 post-PAB (N = 9). Patients with PAH had significantly reduced absolute LVLS (15.4 ± 3.4 vs. 20.1 ± 2.3%, p < 0.0001), higher sTS (53.0 ± 12.2 vs. 28.0 ± 6.2%, p < 0.0001) and lower LVLS/sTS (0.30 ± 0.09 vs. 0.75 ± 0.16, p < 0.0001) compared to controls. Reduced LVLS/sTS was observed in 89.5% of patients, while diastolic dysfunction, impaired LVLS (<16%), and LV atrophy were observed in 73.7%, 52.6%, and 15.8%, respectively. In the longitudinal cohort, changes in LVLS/sTS were closely associated with changes in N-terminal pro B-type natriuretic peptide (r = 0.73, p < 0.0001) as well as survival. Mice subjected to PAB showed significant RV systolic dysfunction and decreased LVLS/sTS compared to sham animals. We conclude that in PAH, LVLV/sTS is a simple ratio that can reflect ventricular systolic interactions.

    View details for DOI 10.1002/pul2.12216

    View details for PubMedID 37063750

    View details for PubMedCentralID PMC10103585

  • Intrinsic Atrial Myopathy Precedes Left Ventricular Dysfunction and Predicts Atrial Fibrillation in Lamin A/C Cardiomyopathy. Circulation. Genomic and precision medicine Tremblay-Gravel, M., Ichimura, K., Picard, K., Kawano, Y., Dries, A. M., Haddad, F., Lakdawala, N. K., Wheeler, M. T., Parikh, V. N. 2022: e003480

    Abstract

    BACKGROUND: In Lamin A/C (LMNA) cardiomyopathy, atrial fibrillation (AF) commonly occurs before dilated cardiomyopathy, and the ability to predict its incidence is limited. We hypothesized that left atrial (LA) echocardiographic phenotyping can identify atrial myopathy and harbingers of AF.METHODS: Echocardiograms from patients with pathogenic or likely pathogenic variants in LMNA (n=77) with and without reduced left ventricular ejection fraction (LVEF, <50%) were compared to healthy individuals (n=70) and patients with Titin truncating variant cardiomyopathy (n=35) with similar LVEF, sex, and age distributions. Echocardiographic analysis, blinded to genotype, included strain and volumetric measures of left ventricular and atrial function. The primary outcome was incident AF.RESULTS: At baseline, 43% of the patients with pathogenic or likely pathogenic LMNA variants had a history of AF, including 26% of those with LVEF ≥50%. Compared with healthy subjects, the patients with pathogenic or likely pathogenic LMNA variants and LVEF ≥50% had reduced LA contractile strain (LMNA, 11.8±6.1% versus control, 15.0±4.2%; P=0.003). Compared to LVEF-matched Titin truncating variant cardiomyopathy patients, the patients with pathogenic or likely pathogenic LMNA variants and LVEF <50% displayed no difference in LA size, but a worse LA contractile dysfunction (6.4±4.7% versus 12.6±9.6%; P=0.02). Over a median follow-up of 2.8 (1.2-5.7) years, LA contractile strain was the only significant predictor of AF in multivariable Cox regression (hazard ratio, 4.0 [95% CI, 1.04-15.2]).CONCLUSIONS: LMNA cardiomyopathy is associated with early intrinsic atrial myopathy reflected by high AF prevalence and reduced LA contractile strain, even in the absence of LV dysfunction and LA dilation. Whether LA strain can be used as a monitoring strategy to detect and mitigate AF complications requires validation.

    View details for DOI 10.1161/CIRCGEN.121.003480

    View details for PubMedID 36548481

  • Clinical picture of the duration of venoarterial extracorporeal membrane oxygenation: analysis from JROAD-DPC HEART AND VESSELS Sakamoto, K., Matoba, T., Nakai, M., Tahara, Y., Nakashima, T., Hosoda, H., Miyamoto, Y., Nishimura, K., Sumita, Y., Yagi, T., Ichimura, K., Yonemoto, N., Tachibana, E., Nagao, K., Ikeda, T., Sato, N., Tsutsui, H. 2022

    Abstract

    Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has been widely used for critically ill patients all over the world; however, comprehensive survey regarding the relationship between VA-ECMO duration and prognosis is limited. We conducted a survey of VA-ECMO patients in the Japanese Registry of All Cardiac and Vascular Diseases-Diagnosis Procedure Combination (JROAD-DPC), which was a health insurance claim database study among cardiovascular centers associated with the Japan Circulation Society, between April 2012 and March 2016. Out of 13,542 VA-ECMO patients, we analyzed 5766 cardiovascular patients treated with VA-ECMO. 68% patients used VA-ECMO only for 1 day and 93% had VA-ECMO terminated within 1 week. In multivariate analysis, the hazard ratio of 1-day support was significantly high at 1.72 (95% confidence intervals; 95% CI 1.53-1.95) (p < 0.001), while that of 2-day [0.60 (95% CI 0.49-0.73)], 3-day [0.75 (95% CI 0.60-0.94)], 4-day [0.43 (95% CI 0.31-0.60)] and 5-day support [0.62 (95% CI 0.44-0.86)] was significantly low. Comprehensive database analysis of JROAD-DPC revealed that cardiovascular patients who were supported with VA-ECMO for 2-5 days showed lower mortality. The optimal VA-ECMO support window should be investigated in further studies.

    View details for DOI 10.1007/s00380-022-02158-0

    View details for Web of Science ID 000863127000001

    View details for PubMedID 36173448

    View details for PubMedCentralID 5735424

  • Hyperoxemia is Associated With Poor Neurological Outcomes in Patients With Out-of-Hospital Cardiac Arrest Rescued by Extracorporeal Cardiopulmonary Resuscitation: Insight From the Nationwide Multicenter Observational JAAM-OHCA (Japan Association for Acute Medicine) Registry. The Journal of emergency medicine Nishihara, M., Hiasa, K. I., Enzan, N., Ichimura, K., Iyonaga, T., Shono, Y., Kashiura, M., Moriya, T., Kitazono, T., Tsutsui, H. 2022

    Abstract

    Previous studies have shown an association between hyperoxemia and mortality in patients with out-of-hospital cardiac arrest (OHCA) after cardiopulmonary resuscitation (CPR); however, evidence is lacking in the extracorporeal CPR (ECPR) setting.The aim of this study was to test the hypothesis that hyperoxemia is associated with poor neurological outcomes in patients treated by ECPR.The Japanese Association for Acute Medicine OHCA Registry is a multicenter, prospective, observational registry of patients from 2014 to 2017. Adult (18 years or older) patients who had undergone ECPR after OHCA were included. Eligible patients were divided into two groups based on the partial pressure of oxygen in arterial blood (PaO2) levels at 24 h after ECPR: the high-PaO2 group (n = 242) defined as PaO2 ≥ 157 mm Hg (median) and the low-PaO2 group (n = 211) defined as PaO2 60 to < 157 mm Hg. The primary outcome was the favorable neurological outcome, defined as a Cerebral Performance Categories Scale score of 1 to 2 at 30 days after OHCA.Of 34,754 patients with OHCA, 453 patients were included. The neurological outcome was significantly lower in the high-PaO2 group than in the low-PaO2 group (15.9 vs. 33.5%; p < 0.001). After adjusting for potential confounders, high PaO2 was negatively associated with favorable neurological outcomes (adjusted odds ratio [aOR] 0.48; 95% confidence interval [CI] 0.24-0.97; p = 0.040). In a multivariate analysis with multiple imputation, high PaO2 was also negatively associated with favorable neurological outcomes (aOR 0.63; 95% CI 0.49-0.81; p < 0.001).Hyperoxemia was associated with worse neurological outcomes in OHCA patients with ECPR.

    View details for DOI 10.1016/j.jemermed.2022.05.018

    View details for PubMedID 36038433

  • Flexible method for generating needle-shaped beams and its application in optical coherence tomography. Optica Zhao, J., Winetraub, Y., DU, L., VAN Vleck, A., Ichimura, K., Huang, C., AAsI, S. Z., Sarin, K. Y., DE LA Zerda, A. 2022; 9 (8): 859-867

    Abstract

    Needle-shaped beams (NBs) featuring a long depth-of-focus (DOF) can drastically improve the resolution of microscopy systems. However, thus far, the implementation of a specific NB has been onerous due to the lack of a common, flexible generation method. Here we develop a spatially multiplexed phase pattern that creates many axially closely spaced foci as a universal platform for customizing various NBs, allowing flexible manipulations of beam length and diameter, uniform axial intensity, and sub-diffraction-limit beams. NBs designed via this method successfully extended the DOF of our optical coherence tomography (OCT) system. It revealed clear individual epidermal cells of the entire human epidermis, fine structures of human dermal-epidermal junction in a large depth range, and a high-resolution dynamic heartbeat of alive Drosophila larvae.

    View details for DOI 10.1364/optica.456894

    View details for PubMedID 37283722

    View details for PubMedCentralID PMC10243785

  • Cardiac Fibrosis in the Pressure Overloaded Left and Right Ventricle as a Therapeutic Target. Frontiers in cardiovascular medicine Schimmel, K., Ichimura, K., Reddy, S., Haddad, F., Spiekerkoetter, E. 2022; 9: 886553

    Abstract

    Myocardial fibrosis is a remodeling process of the extracellular matrix (ECM) following cardiac stress. "Replacement fibrosis" is a term used to describe wound healing in the acute phase of an injury, such as myocardial infarction. In striking contrast, ECM remodeling following chronic pressure overload insidiously develops over time as "reactive fibrosis" leading to diffuse interstitial and perivascular collagen deposition that continuously perturbs the function of the left (L) or the right ventricle (RV). Examples for pressure-overload conditions resulting in reactive fibrosis in the LV are systemic hypertension or aortic stenosis, whereas pulmonary arterial hypertension (PAH) or congenital heart disease with right sided obstructive lesions such as pulmonary stenosis result in RV reactive fibrosis. In-depth phenotyping of cardiac fibrosis has made it increasingly clear that both forms, replacement and reactive fibrosis co-exist in various etiologies of heart failure. While the role of fibrosis in the pathogenesis of RV heart failure needs further assessment, reactive fibrosis in the LV is a pathological hallmark of adverse cardiac remodeling that is correlated with or potentially might even drive both development and progression of heart failure (HF). Further, LV reactive fibrosis predicts adverse outcome in various myocardial diseases and contributes to arrhythmias. The ability to effectively block pathological ECM remodeling of the LV is therefore an important medical need. At a cellular level, the cardiac fibroblast takes center stage in reactive fibrotic remodeling of the heart. Activation and proliferation of endogenous fibroblast populations are the major source of synthesis, secretion, and deposition of collagens in response to a variety of stimuli. Enzymes residing in the ECM are responsible for collagen maturation and cross-linking. Highly cross-linked type I collagen stiffens the ventricles and predominates over more elastic type III collagen in pressure-overloaded conditions. Research has attempted to identify pro-fibrotic drivers causing fibrotic remodeling. Single key factors such as Transforming Growth Factor β (TGFβ) have been described and subsequently targeted to test their usefulness in inhibiting fibrosis in cultured fibroblasts of the ventricles, and in animal models of cardiac fibrosis. More recently, modulation of phenotypic behaviors like inhibition of proliferating fibroblasts has emerged as a strategy to reduce pathogenic cardiac fibroblast numbers in the heart. Some studies targeting LV reactive fibrosis as outlined above have successfully led to improvements of cardiac structure and function in relevant animal models. For the RV, fibrosis research is needed to better understand the evolution and roles of fibrosis in RV failure. RV fibrosis is seen as an integral part of RV remodeling and presents at varying degrees in patients with PAH and animal models replicating the disease of RV afterload. The extent to which ECM remodeling impacts RV function and thus patient survival is less clear. In this review, we describe differences as well as common characteristics and key players in ECM remodeling of the LV vs. the RV in response to pressure overload. We review pre-clinical studies assessing the effect of anti-fibrotic drug candidates on LV and RV function and their premise for clinical testing. Finally, we discuss the mode of action, safety and efficacy of anti-fibrotic drugs currently tested for the treatment of left HF in clinical trials, which might guide development of new approaches to target right heart failure. We touch upon important considerations and knowledge gaps to be addressed for future clinical testing of anti-fibrotic cardiac therapies.

    View details for DOI 10.3389/fcvm.2022.886553

    View details for PubMedID 35600469

    View details for PubMedCentralID PMC9120363

  • Shunt-type plexiform lesions identified in the Sugen5416/Hypoxia rat model of pulmonary arterial hypertension using SPCT. The European respiratory journal van der Have, O., Westoo, C., Ahrne, F., Tian, X., Ichimura, K., Dreier, T., Norvik, C., Kumar, M. E., Spiekerkoetter, E., Tran-Lundmark, K. 2022

    View details for DOI 10.1183/13993003.02802-2021

    View details for PubMedID 35332070

  • Delayed administration of epinephrine is associated with worse neurological outcomes in patients with out-of-hospital cardiac arrest and initial pulseless electrical activity: insight from the nationwide multicentre observational JAAM-OHCA (Japan Association for Acute Medicine) registry. European heart journal. Acute cardiovascular care Enzan, N., Hiasa, K., Ichimura, K., Nishihara, M., Iyonaga, T., Shono, Y., Tohyama, T., Funakoshi, K., Kitazono, T., Tsutsui, H. 2022

    Abstract

    AIMS: The delayed administration of epinephrine has been proven to worsen the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) and shockable rhythm or asystole. We aimed to investigate whether the delayed administration of epinephrine might also worsen the neurological outcomes of patients with witnessed OHCA and initial pulseless electrical activity (PEA).METHODS AND RESULTS: The JAAM-OHCA Registry is a multicentre registry including OHCA patients between 2014 and 2017. Patients with emergency medical services (EMS)-treated OHCA and initial PEA rhythm were included. The primary exposure was the time from the EMS call to the administration of epinephrine. The secondary exposure was the time to epinephrine dichotomized as early (≤15 min) or delayed (>15 min). The primary outcome was the achievement of a favourable neurological outcome, defined as Cerebral Performance Categories Scale 1-2 at 30 days after OHCA. Out of 34 754 patients with OHCA, 3050 patients were included in the present study. After adjusting for potential confounders, the delayed administration of the epinephrine was associated with a lower likelihood of achieving a favourable neurological outcome [adjusted odds ratio (OR) 0.96; 95% confidence interval (CI) 0.93-0.99; P = 0.016]. The percentage of patients who achieved a favourable neurological outcome in the delayed epinephrine group was lower than that in the early epinephrine group (1.3% vs. 4.7%; adjusted OR 0.33; 95% CI 0.15-0.72; P = 0.005). A restricted cubic spline analysis demonstrated that delayed epinephrine administration could decrease the likelihood of achieving a favourable neurological outcome; this was significant within the first 10 min.CONCLUSIONS: The delayed administration of epinephrine was associated with worse neurological outcomes in patients with witnessed OHCA patients with initial PEA.

    View details for DOI 10.1093/ehjacc/zuac026

    View details for PubMedID 35238895

  • Flexible method for generating needle-shaped beams and its application in optical coherence tomography Optica Zhao, J., Winetraub, Y., Du, L., Vleck, A. V., Ichimura, K., Huang, C., Aasi, S. Z., Sarin, K. Y., de la Zerda, A. 2022; 9 (8): 859-867

    View details for DOI 10.1364/optica.456894

  • Institutional Characteristics and Prognosis of Acute Myocardial Infarction With Cardiogenic Shock in Japan - Analysis From the JROAD/JROAD-DPC Database - CIRCULATION JOURNAL Matoba, T., Sakamoto, K., Nakai, M., Ichimura, K., Mohri, M., Tsujita, Y., Yamasaki, M., Ueki, Y., Tanaka, N., Hokama, Y., Fukutomi, M., Hashiba, K., Fukuhara, R., Suwa, S., Matsuura, H., Hosoda, H., Nakashima, T., Tahara, Y., Sumita, Y., Nishimura, K., Miyamoto, Y., Yonemoto, N., Yagi, T., Tachibana, E., Nagao, K., Ikeda, T., Sato, N., Tsutsui, H. 2021; 85 (10): 1797-1805

    Abstract

    The high mortality of acute myocardial infarction (AMI) with cardiogenic shock (i.e., Killip class IV AMI) remains a challenge in emergency cardiovascular care. This study aimed to examine institutional factors, including the number of JCS board-certified members, that are independently associated with the prognosis of Killip class IV AMI patients.Methods and Results:In the Japanese registry of all cardiac and vascular diseases-diagnosis procedure combination (JROAD-DPC) database (years 2012-2016), the 30-day mortality of Killip class IV AMI patients (n=21,823) was 42.3%. Multivariate analysis identified age, female sex, admission by ambulance, deep coma, and cardiac arrest as patient factors that were independently associated with higher 30-day mortality, and the numbers of JCS board-certified members and of intra-aortic balloon pumping (IABP) cases per year as institutional factors that were independently associated with lower mortality in Killip class IV patients, although IABP was associated with higher mortality in Killip classes I-III patients. Among hospitals with the highest quartile (≥9 JCS board-certified members), the 30-day mortality of Killip class IV patients was 37.4%.A higher numbers of JCS board-certified members was associated with better survival of Killip class IV AMI patients. This finding may provide a clue to optimizing local emergency medical services for better management of AMI patients in Japan.

    View details for DOI 10.1253/circj.CJ-20-0655

    View details for Web of Science ID 000699756600017

    View details for PubMedID 33658442

  • 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 Dufva, M. J., Boehm, M., Ichimura, K., Truong, U., Qin, X., Tabakh, J., Hunter, K. S., Ivy, D., Spiekerkoetter, E., Kheyfets, V. O. 2021; 23 (1): 66

    Abstract

    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 Boehm, M., Tian, X., Ali, M. K., Mao, Y., Ichimura, K., Zhao, M., Kuramoto, K., Dannewitz Prosseda, S., Fajardo, G., Dufva, M. J., Qin, X., Kheyfets, V. O., Bernstein, D., Reddy, S., Metzger, R. J., Zamanian, R. T., Haddad, F., Spiekerkoetter, E. 2021

    Abstract

    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 Ali, M. K., Ichimura, K., Spiekerkoetter, E. 2021; 59: 127-139

    Abstract

    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. Cardiovascular research Boehm, M., Tian, X., Mao, Y., Ichimura, K., Dufva, M. J., Ali, K., Prosseda, S. D., Shi, Y., Kuramoto, K., Reddy, S., Kheyfets, V. O., Metzger, R. J., Spiekerkoetter, E. 2019

    Abstract

    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 Ichimura, K., Matoba, T., Koga, J. I., Nakano, K., Funamoto, D., Tsutsui, H., Egashira, K. 2018; 59 (6): 1432-1444

    Abstract

    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. PloS one Ichimura, K., Matoba, T., Nakano, K., Tokutome, M., Honda, K., Koga, J., Egashira, K. 2016; 11 (9): e0162425

    Abstract

    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