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Abstract Aims Myocardial fibrosis of the left ventricle (LV) is a prognostic factor in dilated cardiomyopathy (DCM). This study aims to evaluate whether fibrosis of right ventricular (RV) endomyocardial biopsy (EMB) can predict the degree of LV fibrosis beforehand in DCM. Methods and results Fibrosis extent in 70 RV‐EMB specimens of DCM diagnosis was compared with that in the whole cross‐sectional LV of excised hearts in the same patients (52 explanted hearts for transplant and 18 autopsied hearts). The median interval between biopsy and excision was 4.1 (0.13–19.3) years. The fibrosis area ratio of the EMBs and excised hearts were evaluated via image analysis. The distribution of cardiovascular magnetic resonance–late gadolinium enhancement (LGE) in the intraventricular septum was classified into four quartile categories. The fibrosis area ratio in RV‐EMB correlated significantly with that in the short‐axis cut of the LV of excised hearts (r = 0.82, P

The link between the structural properties and the rupturing of chordae tendineae in the mitral valve complex is still unclear. Synchrotron-radiation-based X-ray phase computed tomography (SR-XPCT) imaging is an innovative way to quantitatively analyze three-dimensional morphology. XPCT has been employed in this study to evaluate the chordae tendineae from patients with mitral regurgitation and to analyze structural changes in the ruptured chordae tendineae in patients with this condition. Six ruptured mitral chordae tendineae were obtained during surgical repairs for mitral regurgitation and were fixed with formalin. In addition, 12 healthy chordae tendineae were obtained from autopsies. Employing XPCT (effective pixel size, 3.5 µm; density resolution, 1 mg cm−3), the density of the chordae tendineae in each sample was measured. The specimens were subsequently analyzed pathologically. The mean age was 70.2 ± 3.0 in the rupture group and 67.2 ± 14.1 years old in the control group (p = 0.4927). All scans of chorda tendineae with SR-XPCT were performed successfully. The mean densities were 1.029 ± 0.004 in the rupture group and 1.085 ± 0.015 g cm−3 in the control group (p < 0.0001). Density based on SR-XPCT in the ruptured mitral chordae tendineae was significantly lower compared with the healthy chorda tendinea. Histological examination revealed a change in the components of the connective tissues in ruptured chorda tendinea, in accordance with the low density measured by SR-XPCT. SR-XPCT made it possible to measure tissue density in mitral chordae tendineae. Low density in mitral chordae tendineae is associated with a greater fragility in ruptured mitral chordae tendineae.

Abstract Background Effective diagnostic biomarkers for aortic aneurysm (AA) that are detectable in blood tests are required because early detection and rupture risk assessment of AA can provide insights into medical therapy and preventive treatments. However, known biomarkers for AA lack specificity and reliability for clinical diagnosis. Methods We performed proteome analysis of serum samples from patients with atherosclerotic thoracic AA (TAA) and healthy control (HC) subjects to identify diagnostic biomarkers for AA. Serum samples were separated into low-density lipoprotein, high-density lipoprotein, and protein fractions, and the major proteins were depleted. From the proteins identified in the three fractions, we narrowed down biomarker candidates to proteins uniformly altered in all fractions between patients with TAA and HC subjects and evaluated their capability to discriminate patients with TAA and those with abdominal AA (AAA) from HC subjects using receiver operating characteristic (ROC) analysis. For the clinical validation, serum concentrations of biomarker candidates were measured in patients with TAA and AAA registered in the biobank of the same institute, and their capability for the diagnosis was evaluated. Results Profilin 1 (PFN1) and complement factor D (CFD) showed the most contrasting profiles in all three fractions between patients with TAA and HC subjects and were selected as biomarker candidates. The PFN1 concentration decreased, whereas the CFD concentration increased in the sera of patients with TAA and AAA when compared with those of HC subjects. The ROC analysis showed that these proteins could discriminate patients with TAA and AAA from HC subjects. In the validation study, these candidates showed significant concentration differences between patients with TAA or AAA and controls. PFN1 and CFD showed sufficient area under the curve (AUC) in the ROC analysis, and their combination further increased the AUC. The serum concentrations of PFN1 and CFD also showed significant differences between patients with aortic dissection and controls in the validation study. Conclusion PFN1 and CFD are potential diagnostic biomarkers for TAA and AAA and measurable in blood samples; their diagnostic performance can be augmented by their combination. These biomarkers may facilitate the development of diagnostic systems to identify patients with AA.

Purpose: Achromatopsia (ACHM) is an early-onset cone dysfunction caused by 5 genes with cone-specific functions (CNGA3, CNGB3, GNAT2, PDE6C, and PDE6H) and by ATF6, a transcription factor with ubiquitous expression. To improve the relatively low variant detection ratio in these genes in a cohort of exome-sequenced Japanese patients with inherited retinal diseases (IRD), we performed genome sequencing to detect structural variants and intronic variants in patients with ACHM. Methods: Genome sequencing of 10 ACHM pedigrees was performed after exome sequencing. Structural, non-coding, and coding variants were filtered based on segregation between the affected and unaffected in each pedigree. Variant frequency and predicted damage scores were considered in identifying pathogenic variants. Results: A homozygous deletion involving exon 18 of RPGRIP1 was detected in 5 of 10 ACHM probands, and variant inheritance from each parent was confirmed. This deletion was relatively frequent (minor allele frequency = 0.0023) in the Japanese population but was only homozygous in patients with ACHM among the 199 Japanese IRD probands analyzed by the same genome sequencing pipeline. Conclusion: The deletion involving exon 18 of RPGRIP1 is a prevalent cause of ACHM in Japanese patients and contributes to the wide spectrum of RPGRIP1-associated IRD phenotypes, from Leber congenital amaurosis to ACHM.

The Japanese archipelago is a terminal location for human migration, and the contemporary Japanese people represent a unique population whose genomic diversity has been shaped by multiple migrations from Eurasia. We analyzed the genomic characteristics that define the genetic makeup of the modern Japanese population from a population genetics perspective from the genomic data of 9,287 samples obtained by high-coverage whole-genome sequencing (WGS) by the National Center Biobank Network. The dataset comprised populations from the Ryukyu Islands and other parts of the Japanese archipelago (Hondo). The Hondo population underwent two episodes of population decline during the Jomon period, corresponding to the Late Neolithic, and the Edo period, corresponding to the Early Modern era, while the Ryukyu population experienced a population decline during the shell midden period of the Late Neolithic in this region. Haplotype analysis suggested increased allele frequencies for genes related to alcohol and fatty acid metabolism, which were reported as loci that had experienced positive natural selection. Two genes related to alcohol metabolism were found to be 12,500 years out of phase with the time when they began to increase in the allele frequency; this finding indicates that the genomic diversity of Japanese people has been shaped by events closely related to agriculture and food production.

Abstract We present a diagnostically challenging case of intimal sarcoma of the pulmonary artery (PA) due to the histologic finding of a sclerosing appearance with no appreciable spindle/pleomorphic cell proliferation. Initial endarterectomy specimens were composed of sclerosing extracellular matrix with a few bland cells, some recanalization, and fibrin thrombi, impeding the confirmation of intimal sarcoma as these findings were also consistent with chronic thromboembolic pulmonary hypertension. However, the patient experienced recurrence 5 years later, and the second endarterectomy specimens revealed more firm and solid mass and the proliferation of atypical spindle/pleomorphic cells within a myxomatous matrix in the distal PA, leading to the definitive diagnosis of undifferentiated intimal sarcoma of the PA. The archival specimens from the endarterectomy confirmed intense MDM2 expression by immunohistochemistry, suggesting its role as a potential diagnostic marker for intimal sarcoma. This case highlights that prominent sclerosing extracellular matrix with very few atypical cells should raise the possibility of intimal sarcoma of the PA and that high index of suspicion, generous sampling, and ancillary tests are critical for accurate diagnosis. In this case, the tumor was incidentally removed by endarterectomy, resulting in 5 years of survival.

Abstract Background The flow capacity of the in situ internal thoracic artery (ITA) is not necessarily sufficient and can be a cause of hypoperfusion syndrome. We present a catastrophic case of in situ ITA grafting for an isolated left main trunk obstruction 13 years after the modified Bentall operation. Case presentation A 33-years-old woman had undergone the modified Bentall operation. Coronary angiography showed a critical stenosis in the left coronary artery. The patient underwent emergency off-pump coronary artery bypass graft with the left ITA to the left anterior descending artery (LAD). On the 7th day, the patient had severe dyspnoea and hypotension. Catheter angiography showed that the ITA was patent; however, blood flow from the in situ ITA was delayed, and reversal flow from the apex to the proximal LAD was found. The patient underwent implantation of a left ventricular assist device. Conclusions Concomitant aortocoronary bypass to the circumflex branch will minimise the risk of hypoperfusion, especially for young patients without atherosclerotic disease.

Abstract Background Thyroid storm (TS) is a rare but potentially life-threatening sequelae of untreated or undertreated hyperthyroidism. While TS frequently causes high-output heart failure, low-output heart failure related to dilated cardiomyopathy (DCM) is extremely rare. Tachycardia is a common clinical presentation of TS, and β1-selective blockers are the first-line agents for treating TS-associated tachycardia. However, given that β-blockers have negative chronotropic and negative inotropic effects, amiodarone may be safe and effective for the treatment of TS-induced tachyarrhythmia in patients with moderate to severe heart failure. While long-term amiodarone administration causes hypothyroidism, or less frequently, hyperthyroidism, little is known about the effects of short-term amiodarone administration on thyroid function. Case presentation A 31-year-old healthy woman presented with worsening dyspnoea. She was tachycardic with multifocal atrial tachycardia (MAT) of 184 beats/min, confirmed by electrocardiogram. Echocardiographic findings were consistent with DCM, with an ejection fraction of 20%. Thus, she was initially diagnosed with acute heart failure due to DCM with coexistent MAT. Tachycardia persisted despite cardioversion attempts and treatment with multiple anti-arrhythmic drugs. Consequently, she rapidly progressed to cardiogenic shock and respiratory decompensation, which required intubation and an intra-aortic balloon pump support. Moreover, the undiagnosed Graves' disease, lack of suspicion, and postponed analysis of thyroid function tests led to a delayed diagnosis of TS. Amiodarone, which was initiated for MAT, unexpectedly ameliorated thyrotoxicosis, resulting in a euthyroid state and the patient’s significantly improved condition and cardiac function. She was discharged on day 40. Finally, she underwent total thyroidectomy; thyroid pathology was consisting with Graves' disease. Her postoperative course was uneventful. Conclusions Herein, we describe a case of delayed diagnosis of dilated thyrotoxic cardiomyopathy with coexistent MAT. The patient required intensive care due to the catastrophic sequelae and was successfully treated with amiodarone. This is the first case report of TS-associated MAT and highlights the clinical importance of high suspicion of TS in de novo heart failure with any tachyarrhythmia or DCM of unknown etiology and the potential effects of short-term amiodarone administration in the treatment of TS.

Immunoglobulin G4 (IgG4)–related pericarditis, an immune-mediated fibro-inflammatory condition, is a rare yet life-threatening disease presenting with constrictive pericarditis. We describe a case of IgG4-related pericarditis presenting with epicardial nodules successfully treated with corticosteroids. This case highlights the clinical significance of assessing IgG4-related pericarditis in the diagnostic workup of pericardial masses. (Level of Difficulty: Advanced.)

Coronary artery aneurysm (CAA) is potentially life-threatening. We describe a case of multiple giant CAAs and a single left gastric artery aneurysm caused by immunoglobulin G4-related disease (IgG4-RD). Our case highlights the significance of assessing IgG4-RD in the diagnosis of CAA and screening for other concurrent cardiovascular involvements. (Level of Difficulty: Intermediate.)

Abstract Pulmonary tumor thrombotic microangiopathy (PTTM) is a rapidly progressive subtype of pulmonary hypertension (PH) associated with impaired right ventricular adaptation and very poor prognosis in cancer, and its rapid progression makes antemortem diagnosis and treatment extremely difficult. We describe the case of a 35‐year‐old woman who developed severe PH with subsequent circulatory collapse. The patient was clinically diagnosed with PTTM induced by lung adenocarcinoma harboring the c‐ros oncogene 1 (ROS1) rearrangement within 1–2 weeks, while hemodynamics were stabilized by rescue venoarterial extracorporeal membrane oxygenation support. Crizotinib, an oral tyrosine kinase inhibitor targeting anaplastic lymphoma kinase, MET, and ROS1 kinase domains dramatically resolved PH, resulting in more than 3 years of survival. Targeted gene‐tailored therapy with mechanical support can improve survival in PTTM.

BackgroundRight ventricular function is an important prognostic marker for pulmonary arterial hypertension. Native T1 mapping using cardiovascular magnetic resonance imaging can characterize the myocardium, but accumulating evidence indicates that T1 values of the septum or ventricular insertion points do not have predictive potential in pulmonary arterial hypertension. We aimed to elucidate whether native T1 values of the right ventricular free wall (RVT1) can predict poor outcomes in patients with pulmonary arterial hypertension.MethodsThis retrospective study included 30 patients with pulmonary arterial hypertension (median age, 45 years; mean pulmonary artery pressure, 41±13 mmHg) and 16 healthy controls (median age, 43 years) who underwent native T1 mapping. RVT1 was obtained from the inferior right ventricular free wall during end systole.ResultsPatients with pulmonary arterial hypertension had significantly higher native RVT1 than did controls (1384±74 vs. 1217±57 ms, pConclusionsRVT1 was predictive of right ventricular performance and outcomes in patients with pulmonary arterial hypertension. Thus, native T1 mapping in the right ventricular free wall may be an effective prognostic method for pulmonary arterial hypertension.

Cerebral amyloid angiopathy (CAA) is characterised by the progressive accumulation of β-amyloid (Aβ) in the walls of cerebral capillaries and arteries representing a major cause of haemorrhagic stroke including lobar intracerebral haemorrhage (ICH) and convexity subarachnoid haemorrhage (SAH). Haemorrhaging from CAA predominantly involves smaller arteries rather than arterial aneurysm. Restricted bleeding into the subarachnoid space in CAA results in asymptomatic or mild symptomatic SAH. Herein, we present an autopsied case of massive SAH related to CAA. An 89-year-old male with a history of mild Alzheimer’s disease (AD) and advanced pancreatic cancer with liver metastasis developed sudden onset of coma. Head CT illustrated ICH located in the right frontal lobe and right insula, as well as SAH bilaterally spreading from the basal cistern to the Sylvian fissure, with hydrocephalus and brain herniation. He died about 24 h after onset and the post-mortem examination showed no evidence of arterial aneurysm. The substantial accumulation of Aβ in the vessels around the haemorrhagic lesions led to the diagnosis of ICH related to CAA and secondary SAH, which may have been aggravated by old age and malignancy. This case suggests that CAA can cause severe SAH resembling aneurysmal origin and thus may be overlooked when complicated by atypical cerebral haemorrhage.

A 49-year-old woman was admitted with suspicion of acute myocarditis. On the next day after admission, her serum troponin I level continued to rise, indicating progression of myocardial damage. Moreover, her symptoms persisted, and left ventricular ejection fraction did not improve. Because of a predominant infiltration of lymphocytes in the myocardial specimens, lymphocytic myocarditis was diagnosed. However, a close observation of the specimens revealed eosinophil degranulation. Based on this finding, intravenous steroid therapy was initiated. High-dose methylprednisolone led to rapid and appreciable improvements in symptoms and left ventricular function within 12 hours after the first administration, which was followed by normalization of serum troponin I level. Steroid therapy was switched to oral administration and tapered carefully. There was no recurrence of left ventricular dysfunction or elevation of serum troponin I level. In eosinophilic myocarditis, eosinophil degranulation has been recognized as an important finding associated with progression of inflammation and myocardial damage. However, no attention has been paid to the presence and clinical implications of eosinophil degranulation in lymphocytic myocarditis. This case indicates that eosinophil degranulation in lymphocytic myocarditis may be an important finding associated with a high therapeutic response to steroid therapy.

Abstract We present two cases of biopsy‐proven hypertrophic cardiomyopathy (HCM). Both cases showed abnormal electrocardiographic (ECG) findings more than 8 years before diagnosis. A 16‐year‐old healthy male experienced a rescued cardiac arrest. Another male adolescent showed abnormal Q wave and thickened ventricular wall at 15 years old. Retrospective analyses of ECGs performed at 6 years old indicated abnormal ECG findings. However, the diagnosis was normal because no ventricular wall thickening was present in echocardiography. For early diagnosis of HCM to prevent sudden cardiac arrest or death, it is essential to establish ECG and echocardiographic criteria to screen HCM in the young.

Abstract Background A retrospective analysis was performed to determine the impact of genetically diagnosed connective tissue disease (CTD) on the early and late outcomes of surgical treatment for aortic dissection in patients having aortic pathology associated with cystic medial necrosis (CMN). Methods Between 2003 and 2013, a total of 43 patients (37 ± 12.8 years old, 23 men, 20 women) who had undergone surgery for aortic dissection associated with CMN in the aortic wall underwent genetic examinations. Subsequently, there were 30 patients with CTD (CTD group) and 13 without CTD (non-CTD group). Results There were no early or late deaths (the follow-up rate was 100% for 57.1 ± 43.0 months). The median age was significantly lower in the CTD group (p = 0.030). The rate of elastic fiber loss was significantly higher in the CTD group (p = 0.014). In the long-term follow-up, there were no significant differences in the incidences of re-dissection (p = 0.332). However, re-operations were required more frequently in the CTD group (p = 0.037). Conclusions In patients with CTD as well as CMN, the onset of aortic dissection tends to be earlier, which would result in higher rates of re-operation, compared with the non-CTD group. Closer and stricter follow-up with medication and adequate surgical treatments with appropriate timing are mandatory for such high-risk patients.

Reperfusion pulmonary edema (RPE) is a common complication after pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, the precise mechanisms underlying the development of RPE remain unclear. To evaluate the effects of pulmonary vasculopathy on RPE, the severity of the pulmonary arteriopathies and venopathies of lung tissues biopsied during PEA were pathologically quantified in 33 CTEPH patients. The severity of RPE was classified from grade 0 (no RPE) to 4 (death due to RPE) based on the arterial oxygen tension/inspiratory oxygen fraction (P/F ratio) and necessity of respiratory management. Among the 33 patients (27 women; mean age = 63.3 years), 17 (51.5%) patients developed RPE. The severity of pulmonary arteriopathy (obstruction ratio) correlated with the grade of RPE (r = 0.576, P = 0.0005). The obstruction ratio also correlated with the P/F ratio (r = −0.543, P = 0.001) and the perioperative mean pulmonary arterial pressure (r = 0.445, P = 0.009). Multivariate logistic regression analysis revealed that the obstruction ratio was a significant independent determinant for the development of RPE (odds ratio = 15.7; 95% confidence interval = 2.29–108.00, P = 0.005). In conclusion, pulmonary arteriopathy could be a determinant of the development and severity of RPE after PEA.

Background We aimed to improve the assessment quality of plaque vulnerability with combined use of magnetic resonance imaging and contrast‐enhanced ultrasound (CEUS). Methods and Results We prospectively enrolled 71 patients with internal carotid artery stenosis who underwent carotid endarterectomy and performed preoperative CEUS and magnetic resonance plaque imaging. We distinguished high–signal‐intensity plaques (HIPs) and non‐HIPs based on magnetization‐prepared rapid acquisition with gradient echo images. We graded them according to the CEUS contrast effect and compared the CEUS images with the carotid endarterectomy specimens. Among the 70 plaques, except 1 carotid endarterectomy tissue sample failure, 59 were classified as HIPs (43 symptomatic) and 11 were classified as non‐HIPs (5 symptomatic). Although the magnetization‐prepared rapid acquisition with gradient echo findings alone had no significant correlation with symptoms (P=0.07), concomitant use of magnetization‐prepared rapid acquisition with gradient echo and CEUS findings did show a significant correlation (P

Pulmonary intimal sarcoma (PIS) constitutes a rare sarcoma originating from the intimal cells of pulmonary arteries. The pathogenesis of PIS remains to be elucidated and specific treatments have not been established; therefore, prognosis is generally poor. The purpose of our study was to isolate and characterize PIS cells from a specimen resected from a patient with PIS. The surgical specimen was minced and incubated, and spindle-shaped and small cells were successfully isolated and designated as PIS-1. PIS-1 cells at passages 8-9 were used for all in vitro and in vivo experiments. Immunocytochemistry showed that PIS-1 cells were positive for vimentin, murine double minute 2, and CD44 and negative for α-smooth muscle actin, CD31, von Willebrand factor, and desmin. PIS-1 cells exhibited the hallmarks of malignant cells including the potential for autonomous proliferation, anchorage-independent growth, invasion, genetic instability, and tumorigenicity in severe combined immunodeficiency mice. The PIS-1 cells highly expressed tyrosine kinase receptors such as platelet-derived growth factor receptor, and vascular endothelial growth factor receptor 2. Pazopanib, a multi-targeted tyrosine kinase inhibitor, suppressed the proliferation of PIS-1 cells in vitro and the growth of tumors formed from xenografted PIS-1 cells. A PIS cell line was thus successfully established. The PIS-1 cells highly expressed tyrosine kinase receptors, which may be a target for treatment of PIS.

Background The diagnosis of cardiac sarcoidosis (CS) is challenging because endomyocardial biopsy has only a 20% to 30% sensitivity rate for diagnosis and it presents with similar clinical features of idiopathic dilated cardiomyopathy (DCM). Lymphatic vessel proliferation in pulmonary sarcoidosis has been previously demonstrated. In this study, we compared endomyocardial biopsy samples obtained from patients with CS and DCM to determine whether lymph vessel counts using D2‐40 immunostaining can be utilized as a complementary tool to distinguish CS from DCM. Methods and Results Endomyocardial biopsy tissues were obtained from 62 patients with CS (30 patients with a diagnosis made histologically, 32 patients with a diagnosis made clinically), and hematoxylin/eosin, Masson trichrome, and D2‐40 immunostaining were performed. Their results were compared with those from 53 patients with DCM. The histological CS group showed significantly increased lymphatic vessels (12.0 [4.0–40.0] versus 2.6 [1.9–3.4], P

Tumor necrosis factor–stimulated gene-6 (TSG-6), an anti-inflammatory protein, was shown to be localized in the neointima of injury-induced rat arteries. However, the modulatory effect of TSG-6 on atherogenesis has not yet been reported. We aimed to evaluate the atheroprotective effects of TSG-6 on human endothelial cells (HECs), human monocyte-derived macrophages (HMDMs), human aortic smooth muscle cells (HASMCs) in vitro, and aortic lesions in apolipoprotein E–deficient mice, along with expression levels of TSG-6 in coronary lesions and plasma from patients with coronary artery disease (CAD). TSG-6 was abundantly expressed in HECs, HMDMs, and HASMCs in vitro. TSG-6 significantly suppressed cell proliferation and lipopolysaccharide-induced up-regulation of monocyte chemotactic protein-1, intercellular adhesion molecule-1, and vascular adhesion molecule-1 in HECs. TSG-6 significantly suppressed inflammatory M1 phenotype and suppressed oxidized low-density lipoprotein–induced foam cell formation associated with down-regulation of CD36 and acyl-CoA:cholesterol acyltransferase-1 in HMDMs. In HASMCs, TSG-6 significantly suppressed migration and proliferation, but increased collagen-1 and -3 expressions. Four-week infusion of TSG-6 into apolipoprotein E–deficient mice significantly retarded the development of aortic atherosclerotic lesions with decreased vascular inflammation, monocyte/macrophage, and SMC contents and increased collagen fibers. In addition, it decreased peritoneal M1 macrophages with down-regulation of inflammatory molecules and lowered plasma total cholesterol levels. In patients with CAD, plasma TSG-6 levels were significantly increased, and TSG-6 was highly expressed in the fibrous cap within coronary atherosclerotic plaques. These results suggest that TSG-6 contributes to the prevention and stability of atherosclerotic plaques. Thus, TSG-6 may serve as a novel therapeutic target for CAD.

BackgroundNeopterin, a metabolite of GTP, is produced by activated macrophages and is abundantly expressed within atherosclerotic lesions in human aorta and carotid and coronary arteries. We aimed to clarify the influence of neopterin on both vascular inflammation and atherosclerosis, as neither effect had been fully assessed. Methods and ResultsWe investigated neopterin expression in coronary artery lesions and plasma from patients with coronary artery disease. We assessed the atheroprotective effects of neopterin in vitro using human aortic endothelial cells, human monocyte‐derived macrophages, and human aortic smooth muscle cells. In vivo experiments included a study of aortic lesions in apolipoprotein E–deficient mice. Neopterin expression in coronary artery lesions and plasma was markedly increased in patients with versus without coronary artery disease. In human aortic endothelial cells, neopterin reduced proliferation and TNF‐α (tumor necrosis factor α)–induced upregulation of MCP‐1 (monocyte chemotactic protein 1), ICAM‐1 (intercellular adhesion molecule 1), and VCAM‐1 (vascular cell adhesion molecule 1). Neopterin attenuated TNF‐α–induced monocyte adhesion to human aortic endothelial cells and the inflammatory macrophage phenotype via NF‐κB (nuclear factor‐κB) downregulation. Neopterin suppressed oxidized low‐density lipoprotein–induced foam cell formation associated with CD36 downregulation and upregulation of ATP‐binding cassette transporters A1 and G1 in human monocyte‐derived macrophages. In human aortic smooth muscle cells, neopterin suppressed angiotensin II–induced migration and proliferation via c‐Src/Raf‐1/ERK1/2 downregulation without inducing apoptosis. Exogenous neopterin administration and endogenous neopterin attenuation with its neutralizing antibody for 4 weeks retarded and promoted, respectively, the development of aortic atherosclerotic lesions in apolipoprotein E–deficient mice. ConclusionsOur results indicate that neopterin prevents both vascular inflammation and atherosclerosis and may be induced to counteract the progression of atherosclerotic lesions. Consequently, neopterin could be of use as a novel therapeutic target for atherosclerotic cardiovascular diseases.

AIMS:Left atrial (LA) structural remodelling develops in rheumatic heart disease (RHD) according to the disease severity of the mitral valve and the presence of atrial fibrillation. Sustained active inflammation has been previously reported in the LA of patients with RHD, suggesting a direct role of cell-mediated immunity in the pathogenesis of LA remodelling. Dendritic cells (DCs) have a major antigen-presenting role, and are known as crucial modulators of innate and adaptive immunity. We investigated whether DCs are involved in the pathogenesis of LA remodelling in RHD. METHODS AND RESULTS:Immunohistochemical analyses were performed using antibodies to CD11c, CD209 and CD80 as markers of myeloid DCs, migratory-active DCs, mature DCs and infiltrated inflammatory cells including T lymphocytes (CD3) and M1 (CD68; pro-inflammatory profile) and M2 (CD163; pro-resolution profile) macrophages. Furthermore, tenascin-C, an extracellular matrix (ECM) protein that appears during ECM remodelling and inflammatory response, was examined. Infiltrated myeloid DCs, migratory-active DCs, mature DCs and other inflammatory infiltrates including T lymphocytes and M1 and M2 macrophages, were significantly higher in the RHD group than the non-RHD group. The positive area fraction for tenascin-C was significantly higher in the RHD group than in the non-RHD group. CONCLUSION:Our histological findings suggest that inflammation may persist long after a bout of rheumatic fever, ultimately leading to ECM remodelling. We identified and quantitatively assessed several subsets of DCs and other immunocompetent cells, and our results indicated that activation of DCs has some role in persistence of LA inflammation in patients with chronic RHD.

BackgroundKisspeptin‐10 (KP‐10), a potent vasoconstrictor and inhibitor of angiogenesis, and its receptor, GPR54, have currently received much attention in relation to pre‐eclampsia. However, it still remains unknown whether KP‐10 could affect atherogenesis. Methods and ResultsWe evaluated the effects of KP‐10 on human umbilical vein endothelial cells, human monocyte‐derived macrophages, human aortic smooth muscle cells in vitro, and atherosclerotic lesions in apolipoprotein E–deficient (ApoE−/−) mice in vivo. KP‐10 significantly increased the adhesion of human monocytes to human umbilical vein endothelial cells, which was significantly inhibited by pretreatment with P234, a GPR54 antagonist. KP‐10 stimulated mRNA expression of tumor necrosis factor‐α, interleukin‐6, monocyte chemotactic protein‐1, intercellular adhesion molecule‐1, vascular adhesion molecule‐1, and E‐selectin in human umbilical vein endothelial cells. KP‐10 significantly enhanced oxidized low‐density lipoprotein–induced foam cell formation associated with upregulation of CD36 and acyl‐CoA:cholesterol acyltransferase‐1 in human monocyte‐derived macrophages. In human aortic smooth muscle cells, KP‐10 significantly suppressed angiotensin II–induced migration and proliferation, but enhanced apoptosis and activities of matrix metalloproteinase (MMP)‐2 and MMP‐9 by upregulation of extracellular signal‐regulated kinase 1 and 2, p38, Bcl‐2‐associated X protein, and caspase‐3. Four‐week‐infusion of KP‐10 into ApoE−/− mice significantly accelerated the development of aortic atherosclerotic lesions with increased monocyte/macrophage infiltration and vascular inflammation as well as decreased intraplaque vascular smooth muscle cells contents. Proatherosclerotic effects of endogenous and exogenous KP‐10 were completely canceled by P234 infusion in ApoE−/− mice. ConclusionsOur results suggest that KP‐10 may contribute to accelerate the progression and instability of atheromatous plaques, leading to plaque rupture. The GPR54 antagonist may be useful for prevention and treatment of atherosclerosis. Thus, the KP‐10/GPR54 system may serve as a novel therapeutic target for atherosclerotic diseases.

BACKGROUND:Although rare, cardiac sarcoidosis (CS) is potentially fatal. Early diagnosis and intervention are essential, but histopathologic diagnosis is limited. We aimed to detect Propionibacterium acnes, a commonly implicated etiologic agent of sarcoidosis, in myocardial tissues obtained from CS patients. METHODS AND RESULTS:We examined formalin-fixed paraffin-embedded myocardial tissues obtained by surgery or autopsy and endomyocardial biopsy from patients with CS (n = 26; CS-group), myocarditis (n = 15; M-group), or other cardiomyopathies (n = 39; CM-group) using immunohistochemistry (IHC) with a P. acnes-specific monoclonal antibody. We found granulomas in 16 (62%) CS-group samples. Massive (≥14 inflammatory cells) and minimal (

BackgroundThe histological diagnosis of cardiac sarcoidosis (CS) is based on the presence of myocardial granulomas; however, the sensitivity of endomyocardial biopsy is relatively low. We investigated whether immunocompetent cells including dendritic cells (DC) and macrophages in nongranuloma sections of endomyocardial biopsy samples could be histopathological surrogates for CS diagnosis. Methods and ResultsThe numbers of DC and macrophages were investigated in 95 consecutive CS patients and 50 patients with nonischemic cardiomyopathy as controls. All patients underwent endomyocardial biopsy, and immunohistochemical staining was performed on all samples. We examined these immunocompetent cells in nongranuloma sections in CS patients diagnosed by the presence of myocardial granulomas (n=26) and in CS patients without myocardial granulomas diagnosed by the Japanese Ministry of Health Welfare 2007 criteria (n=65) or the Heart Rhythm Society 2014 criteria (n=26). In CS patients with and without myocardial granulomas, CD209+ DC and CD68+ macrophages were more frequently observed (P

Congenital bicuspid aortic valve (CBAV) is the main cause of aortic stenosis (AS) in young adults. However, the histopathological features of AS in patients with CBAV have not been fully investigated.We examined specimens of aortic valve leaflets obtained from patients who had undergone aortic valve re/placement at our institution for severe AS with CBAV (n = 24, CBAV-AS group), severe AS with tricuspid aortic valve (n = 24, TAV-AS group), and severe aortic regurgitation (AR) with CBAV (n = 24, CBAV-AR group). We compared the histopathological features among the three groups. Pathological features were classified using semi-quantitative methods (graded on a scale 0 to 3) by experienced pathologists without knowledge of the patients' backgrounds. The severity of inflammation, neovascularization, and calcium and cholesterol deposition did not differ between the CBAV-AS and TAV-AS groups, and these four parameters were less marked in the CBAV-AR group than in the CBAV-AS (all p

Cerebral amyloid angiopathy (CAA) is characterized by the deposition of amyloid aggregates in the walls of the cerebral vasculature. Recently, the development of molecular imaging probes targeting CAA has been attracting much attention. We previously reported the 99mTc-hydroxamamide (99mTc-Ham) complex with a bivalent benzothiazole scaffold as a binding moiety for amyloid aggregates ([99mTc]BT2) and its utility for CAA-specific imaging. However, the simultaneous generation of two radiolabeled complexes derived from the geometric isomers was observed in the 99mTc-labeling reaction. It was recently reported that the complexation reaction of 99Tc with N-methyl-substituted Ham provided a single 99Tc-Ham complex consisting of two N-methylated Ham ligands with marked stability. In this article, we designed and synthesized a novel N-methylated bivalent 99mTc-Ham complex ([99mTc]MBT2) and evaluated its utility for CAA-specific imaging. N-Methyl substitution of [99mTc]BT2 prevented the generation of its isomer in the 99mTc-labeling reaction. Enhanced in vitro stability of [99mTc]MBT2 as compared with [99mTc]BT2 was observed. [99mTc]MBT2 showed very low brain uptake, which is favorable for CAA-specific imaging. An in vitro inhibition assay using β-amyloid aggregates and in vitro autoradiographic examination of brain sections from a Tg2576 mouse and a CAA patient showed a decline in the binding affinity for amyloid aggregates due to N-methylation of the 99mTc-Ham complex. These results suggest that the scaffold of the 99mTc-Ham complex may play important roles in the in vitro stability and the binding affinity for amyloid aggregates.

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by occlusion of pulmonary arteries by organized chronic thrombi. Persistent hypoxemia and residual pulmonary hypertension (PH) following successful pulmonary endarterectomy (PEA) are clinically important problems; however, the underlying mechanisms remain unclear. We have previously reported that residual PH is closely related to severe pulmonary vascular remodeling and hypothesize that this arteriopathy might also be involved in impaired gas exchange. The purpose of this study was to evaluate the association between hypoxemia and pulmonary arteriopathy after PEA.Between December 2011 and November 2014, 23 CTEPH patients underwent PEA and lung biopsy. The extent of pulmonary arteriopathy was quantified pathologically in lung biopsy specimens. We then analyzed the relationship between the severity of pulmonary arteriopathy and gas exchange after PEA. We observed that the severity of pulmonary arteriopathy was negatively correlated with postoperative and follow-up PaO2 (postoperative PaO2: r = -0.73, p = 0.0004; follow-up PaO2: r = -0.66, p = 0.001), but not with preoperative PaO2 (r = -0.373, p = 0.08). Multivariate analysis revealed that the obstruction ratio and patient age were determinants of PaO2 one month after PEA (R2 = 0.651, p = 0.00009). Furthermore, the obstruction ratio and improvement of pulmonary vascular resistance were determinants of PaO2 at follow-up (R2 = 0.545, p = 0.0002). Severe pulmonary arteriopathy might increase the alveolar-arterial oxygen difference and impair diffusion capacity, resulting in hypoxemia following PEA.The severity of pulmonary arteriopathy was closely associated with postoperative and follow-up hypoxemia.

Accurate prediction of both mortality and morbidity is of significant importance, but it is challenging in patients with severe heart failure. It is especially difficult to detect the optimal time for implanting mechanical circulatory support devices in such patients. We aimed to analyze the morphometric ultrastructure of nuclear chromatin in cardiomyocytes by developing an original clinical histopathological method. Using this method, we developed a biomarker to predict poor outcome in patients with dilated cardiomyopathy (DCM).As a part of their diagnostic evaluation, 171 patients underwent endomyocardial biopsy (EMB). Of these, 63 patients diagnosed with DCM were included in this study. We used electron microscopic imaging of cardiomyocyte nuclei and an automated image analysis software program to assess whether it was possible to detect discontinuity of the nuclear periphery. Twelve months after EMB, all patients with a discontinuous nuclear periphery (Group A, n = 11) died from heart failure or underwent left ventricular assist device (VAD) implantation. In contrast, in patients with a continuous nuclear periphery (Group N, n = 52) only 7 patients (13%) underwent VAD implantation and there were no deaths (p

Chronic thromboembolic pulmonary hypertension (CTEPH) is generally recognized to be caused by persistent organized thrombi that occlude the pulmonary arteries. The aim of this study was to investigate the characteristics of small vessel remodeling and its impact on the hemodynamics in CTEPH patients.Hemodynamic data were obtained from right heart catheterization in 17 CTEPH patients before pulmonary endarterectomy (PEA). Lung tissue specimens were obtained at the time of PEA. Pathological observations and evaluation of quantitative changes in pulmonary muscular arteries and veins were performed using light microscopy on 423 slides in 17 patients. The relationship between the results and the hemodynamics of CTEPH was investigated. Pulmonary arteriopathy and venopathy were recognized in most cases, although no plexiform lesions and no capillary-hemangiomatosis-like lesions were detected in any of the specimens. The severity of pulmonary arteriopathy was correlated with pulmonary vascular resistance (PVR) in the postoperative and follow-up periods. The PVR and mean pulmonary arterial pressure were significantly higher in the high-obstruction group than in the low-obstruction group. The findings in pulmonary venopathy were similar to the findings seen in pulmonary veno-occlusive disease in some cases, although severe venopathy was only observed in a portion of the pulmonary veins. There was a significant correlation between the extent of pulmonary arteriopathy and venopathy, although an effect of pulmonary venopathy to hemodynamics, including pulmonary arterial wedged pressure (PAWP), could not be identified.The vascular remodeling of the pulmonary muscular arteries was closely associated with the hemodynamics of CTEPH. Severe pulmonary arteriopathy might be related to residual pulmonary hypertension after PEA. Those altered pulmonary arteries might be a new target for the persistent PH after the operation.

[This corrects the article DOI: 10.1371/journal.pone.0133167.].

We examined the expression of ephrin-B1 and its cognate receptor EphB2, key regulators of angiogenesis and embryogenesis, in human abdominal aortic aneurysm (AAA) and analyzed their functional roles in cell migration. From 10 patients (9 males and 1 female; age, 68.5±2.4) who underwent vascular surgery for AAA, we obtained AAA and adjacent control tissues. Using real-time RT-PCR, we analyzed expression of ephrin-B1 and EphB2. We also histologically localized these molecules in AAA tissues. Finally, effects of ephrin-B1 and EphB2 on inflammatory cell chemotaxis were examined by cell migration assay. Expression levels of ephrin-B1 (0.410±0.046 versus 1.198±0.252, 𝑃=0.027) and EphB2 (0.764±0.212 versus 1.272±0.137, 𝑃=0.594) were higher in AAA than normal control. Both ephrin-B1 and EphB2 were expressed in macrophages, T lymphocytes, and endothelial cells within AAA. In chemotaxis assay, ephrin-B1 and EphB2 inhibited mononuclear-cell chemotaxis induced by stromal derived factor-1 down to 54.7±12.7% (𝑃=0.01) and 50.7±13.1% (𝑃=0.01), respectively. These data suggest that ephrin-B1 and EphB2 might be functional in human adult inflammatory cells and involved in the pathogenesis of AAA, although specific roles of these molecules should further be sought.

Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into a variety of lineages including myocytes and vascular endothelial cells. However, little information is available regarding the therapeutic potential of MSCs in patients with atrioventricular block (AVB). We investigated whether local implantation of MSCs improves AV conduction in a rat model of complete AVB. Complete AVB was achieved by injection of ethanol into the AV nodal region of Lewis rats. Five days after ethanol injection, 2 × 10 6 of MSCs (MSC group) or vehicle (Control group) were injected into the AV nodal region. Animals were monitored by electrocardiograms for 14 days, and physiological and histological examinations were performed. The 1:1 AV conduction was recovered in 5 of 15 rats (33%) in the MSC group during the follow-up period, whereas no improvement was observed in the control group. MSC transplantation significantly decreased collagen deposition in the AV node, which was associated with a marked decrease in transforming growth factor-β1 expression. In vitro experiments demonstrated that MSCs secreted a large amount of antifibrotic factors such as hepatocyte growth factor and interleukin-10, and MSC conditioned medium inhibited the growth of adult cardiac fibroblasts. In addition, local injection of MSC conditioned medium recovered AV conduction in 2 of 15 rats (13%). MSC transplantation improved AV conduction in a rat model of complete AVB, at least in part through antifibrotic paracrine effects.

In this study, vascular-like tubular tissues called biotubes, consisting of autologous tissues, were prepared using in vivo tissue engineering. Their mechanical properties were evaluated for application as a small-caliber artificial vascular prosthesis. The biotubes were prepared by embedding six kinds of polymeric rods [poly(ethylene) (PE), poly(fluoroacetate) (PFA), poly(methyl methacrylate) (PMMA), segmented poly(urethane) (PU), poly(vinyl chloride) (PVC), and silicone (Si)] as a mold in six subcutaneous pouches in the dorsal skin of New Zealand White rabbits. For rods apart from PFA, biotubes were constructed after 1 month of implantation by encapsulation around the polymeric implants. The wall thickness of the biotubes ranged from about 50 to 200 μm depending on the implant material and were in the order PFA < PVC < PMMA < PU < PE. As for PE, PMMA, and PVC, the thickness increased after 3 months of implantation and ranged from 1.5-to 2-fold. None of the biotubes were ruptured when a hydrostatic pressure was gradually applied to their lumen up to 200 mmHg. The relationship between the intraluminal pressure and the external diameter, which was highly reproducible, showed a “J”-shaped curve similar to the native artery. The tissue mostly consisted of collagen-rich extracellular matrices and fibroblasts. Generally, the tissue was relatively firm and inelastic for Si and soft for PMMA. For PMMA, PE, and PVC the stiffness parameter (β value; one of the indexes for compliance) of the biotubes obtained was similar to those of the human coronary, femoral, and carotid arteries, respectively. Biotubes, which possess the ability for wide adjustments in their matrices, mechanics, shape, and luminal surface design, can be applied for use as small-caliber blood vessels and are an ideal implant because they avoid immunological rejection.