Doctor of Philosophy, University Of Tokyo (2014)
Doctor of Medicine, University Of Tokyo (2005)
Although ischemic heart disease is the leading cause of death worldwide, mainstay treatments ultimately fail because they do not adequately address disease pathophysiology. Restoring the microvascular perfusion deficit remains a significant unmet need and may be addressed via delivery of pro-angiogenic cytokines. The therapeutic effect of cytokines can be enhanced by encapsulation within hydrogels, but current hydrogels do not offer sufficient clinical translatability due to unfavorable viscoelastic mechanical behavior which directly impacts the ability for minimally-invasive catheter delivery. In this report, we examine the therapeutic implications of dual-stage cytokine release from a novel, highly shear-thinning biocompatible catheter-deliverable hydrogel. We chose to encapsulate two protein-engineered cytokines, namely dimeric fragment of hepatocyte growth factor (HGFdf) and engineered stromal cell-derived factor 1? (ESA), which target distinct disease pathways. The controlled release of HGFdf and ESA from separate phases of the hyaluronic acid-based hydrogel allows extended and pronounced beneficial effects due to the precise timing of release. We evaluated the therapeutic efficacy of this treatment strategy in a small animal model of myocardial ischemia and observed a significant benefit in biological and functional parameters. Given the encouraging results from the small animal experiment, we translated this treatment to a large animal preclinical model and observed a reduction in scar size, indicating this strategy could serve as a potential adjunct therapy for the millions of people suffering from ischemic heart disease.
View details for DOI 10.1016/j.cyto.2019.154974
View details for PubMedID 31978642
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
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
Post-operative adhesions form as a result of normal wound healing processes following any type of surgery. In cardiac surgery, pericardial adhesions are particularly problematic during reoperations, as surgeons must release the adhesions from the surface of the heart before the intended procedure can begin, thereby substantially lengthening operation times and introducing risks of haemorrhage and injury to the heart and lungs during sternal re-entry and cardiac dissection. Here we show that a dynamically crosslinked supramolecular polymer-nanoparticle hydrogel, with viscoelastic and flow properties that enable spraying onto tissue as well as robust tissue adherence and local retention in vivo for two weeks, reduces the formation of pericardial adhesions. In a rat model of severe pericardial adhesions, the hydrogel markedly reduced the severity of the adhesions, whereas commercial adhesion barriers (including Seprafilm and Interceed) did not. The hydrogels also reduced the severity of cardiac adhesions (relative to untreated animals) in a clinically relevant cardiopulmonary-bypass model in sheep. This viscoelastic supramolecular polymeric hydrogel represents a promising clinical solution for the prevention of post-operative pericardial adhesions.
View details for DOI 10.1038/s41551-019-0442-z
View details for PubMedID 31391596
Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging has demonstrated the capability of stratifying hypertrophic cardiomyopathy (HCM). Stress perfusion test of CMR can quantify myocardial perfusion reserve (MPR), but its clinical role is not determined. The purpose of this study was to investigate the relationship between MPR and LGE in patients with HCM. A total of 61 consecutive cases underwent complete evaluation with electrocardiography and CMR [cine imaging, coronary MR angiography (MRA), and stress perfusion testing with LGE]. HCM cases were diagnosed by the Japanese conventional guideline prior to this CMR study. Mild LVH was defined as more than 13 mm in maximum LV wall thickness at end diastole on the cine imaging of the CMR. MPR was calculated as the ratio of stress/rest myocardial blood flow using an intensity curve on the stress perfusion test. Cases with ischemic heart disease were excluded from the study based on clinical history and coronary MRA. There were 37 HCM and 24 mild LVH cases (average age: 60.5 ± 10.9 vs. 64.8 ± 10.8; male: 62.2 vs. 75.0%, respectively, non-significant). MPR in HCM was lower than in LVH (1.5 ± 0.5 vs. 2.2 ± 0.9, p < 0.001) and normal subjects (2.4 ± 0.9, p < 0.001). MPR in HCM with LGE (N = 34) was lower than in HCM without LGE (N = 3) (1.4 ± 0.5 vs. 2.1 ± 0.2, p = 0.014). Multiple regression analysis verified that LGE was the strongest predictor of MPR among multiple clinical parameters, including LVH, LV dysfunction (ejection fraction < 50%), and the presence of negative T wave (p < 0.001). MPR was impaired in HCM with LGE compared with HCM without LGE. The clinical role of MPR on CMR needs to be clarified by further research.
View details for PubMedID 29168014
View details for PubMedID 28775009
Inflammation plays a significant role in a wide range of cardiovascular diseases (CVDs). The numerous implications of inflammation in all steps of CVDs, including initiation, progression and complications, have prompted the emergence of noninvasive imaging modalities as diagnostic, prognostic and monitoring tools. In this review, we first synthesize the existing evidence on the role of inflammation in vascular and cardiac diseases, in order to identify the main targets used in noninvasive imaging. We chose to focus on positron emission tomographic (PET) and magnetic resonance imaging (MRI) studies, which offer the greatest potential of translation and clinical application. We detail the main preclinical and clinical studies in the following CVDs: coronary and vascular atherosclerosis, abdominal aortic aneurysms, myocardial infarction, myocarditis, and acute heart transplant rejection. We highlight the potential complementary roles of these imaging modalities, which are currently being studied in the emerging technology of PET/MRI. Finally, we provide a perspective on innovations and future applications of noninvasive imaging of cardiovascular inflammation. (Circ J 2016; 80: 1269-1277).
View details for DOI 10.1253/circj.CJ-16-0224
View details for PubMedID 27151335