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BACKGROUND: This study investigated the effects of age on the outcomes of coronavirus disease 2019 (COVID-19) and on cardiac biomarker profiles, especially in patients with cardiovascular diseases and/or risk factors (CVDRF).Methods and Results:A nationwide multicenter retrospective study included 1,518 patients with COVID-19. Of these patients, 693 with underlying CVDRF were analyzed; patients were divided into age groups (

A 61‐year‐old female with 50 000 ventricular premature contractions and a reduced left ventricular ejection fraction of 35% was referred to our center. Although the origin was considered to originate from the junction between the left and right coronary cusp, a single radiofrequency application above the aortic sinus cusp could eliminate it. LGE‐MRI was able to reveal the exact location of the single RF lesion.

Cardiovascular diseases (CVDs) have become a major health problem because of the associated high morbidity and mortality rates observed in affected patients. Gut microbiota has recently been implicated as a novel endocrine organ that plays critical roles in the regulation of cardiometabolic and renal functions of the host via the production of bioactive metabolites. This review investigated the evidence from several clinical and experimental studies that indicated an association between the gut microbiota-derived toxins and CVDs. We mainly focused on the pro-inflammatory gut microbiota-derived toxins, namely lipopolysaccharides, derived from Gram-negative bacteria, and trimethylamine N-oxide and described the present status of research in association with these toxins, including our previous research findings. Several clinical studies aimed at exploring the effectiveness of reducing the levels of these toxins to inhibit cardiovascular events are currently under investigation or in the planning stages. We believe that some of the methods discussed in this review to eliminate or reduce the levels of such toxins in the body could be clinically applied to prevent CVDs in the near future.

Background The impact of reduction in glycemic excursion on coronary plaques remains unknown. This study aimed to elucidate whether a dipeptidyl peptidase 4 inhibitor could reduce the glycemic excursion and stabilize the coronary plaques compared with conventional management in coronary artery disease (CAD) patients with impaired glucose tolerance (IGT). Methods This was a multicenter, randomized controlled trial including CAD patients with IGT under lipid-lowering therapy receiving either vildagliptin (50 mg once a day) or no medication (control group) regarding glycemic treatment. The primary endpoint was changes in the minimum fibrous cap thickness and lipid arc in non-significant native coronary plaques detected by optical coherence tomography at 6 months after intervention. Glycemic variability expressed as the mean amplitude of glycemic excursion (MAGE) measured with a continuous glucose monitoring system was evaluated before and 6 months after intervention. Results A total of 20 participants with 47 lesions were allocated to either the vildagliptin group (10 participants, 22 lesions) or the control group (10 participants, 25 lesions). The adjusted difference of mean changes between the groups was − 18.8 mg/dl (95% confidence interval, − 30.8 to − 6.8) (p = 0.0064) for the MAGE (vildagliptin, − 20.1 ± 18.0 mg/dl vs. control, 2.6 ± 12.7 mg/dl), − 22.8° (− 40.6° to − 5.1°) (p = 0.0012) for the mean lipid arc (vildagliptin, − 9.0° ± 25.5° vs. control, 15.8° ± 16.8°), and 42.7 μm (15.3 to 70.1 μm) (p = 0.0022) for the minimum fibrous cap thickness (vildagliptin, 35.7 ± 50.8 μm vs. control, − 15.1 ± 25.2 μm). Conclusions Vildagliptin could reduce the MAGE at 6 months and may be associated with the decreased lipid arc and increased minimum FCT of the coronary plaques in CAD patients with IGT as compared with the control group. These findings may represent its potential stabilization effect on coronary plaques, which are characteristic in this patient subset. Trial registration Registered in the UMIN clinical trial registry (UMIN000008620), Name of the registry: VOGUE trial, Date of registration: Aug 6, 2012, URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000010058

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by pathological pulmonary artery remodeling. Endothelial cells (EC) injury including DNA damage is critically involved in the vascular remodeling in PAH, and persistent injury leads to cellular senescence in ECs. Here, we show that EC senescence exacerbates pulmonary hypertension through Notch-mediated juxtacrine signaling. EC-specific progeroid mice that we recently generated showed exacerbated pulmonary hypertension after chronic hypoxia exposure, accompanied by the enhanced pulmonary arterial smooth muscle cells (PASMCs) proliferation in the distal pulmonary arteries. Mechanistically, we identified that senescent ECs highly expressed Notch ligands, and thus activated Notch signaling in PASMCs, leading to enhanced PASMCs proliferation and migration capacities. Consistently, pharmacological inhibition of Notch signaling attenuated the effects of senescent ECs on SMCs functions in vitro, and on the pulmonary hypertension in EC-specific progeroid mice in vivo. These data establish EC senescence as a crucial disease-modifying facor in PAH.

Chondroitin sulfate proteoglycans are the primary constituents of the macrophage glycosaminoglycan and extracellular microenvironment. To examine their potential role in atherogenesis, we investigated the biological importance of one of the chondroitin sulfate glycosaminoglycan biosynthesis gene, ChGn-2 (chondroitin sulfateChGn-2 alteration on macrophages conceivably influences LDL accumulation and subsequently accelerates plaque formation. These results collectively suggest that ChGn-2 is a novel therapeutic target amenable to clinical translation in the future. Graphic Abstract: A graphic abstract is available for this article.

A 61-year-old female with 50000 ventricular premature contractions and reduced left ventricular ejection fraction of 35% referred to our center. Although the origin was considered to be originated from the junction between the left and right coronary cusp, a single radiofrequency application above the aortic sinus cusp could eliminate it.

Background: Coronary artery spasms (CASs), which can cause angina attacks and sudden death, have been recently reported during catheter ablation. The aim of the present study was to report the incidence, characteristics, and prognosis of CASs related to atrial fibrillation (AF) ablation procedures. Methods and Results: The AF ablation records of 22,232 patients treated in 15 Japanese hospitals were reviewed. CASs associated with AF ablation occurred in 42 of 22,232 patients (0.19%). CASs occurred during ablation energy applications in 21 patients (50%). CASs also occurred before ablation in 9 patients (21%) and after ablation in 12 patients (29%). The initial change in the electrocardiogram was ST-segment elevation in the inferior leads in 33 patients (79%). Emergency coronary angiography revealed coronary artery stenosis and occlusions, which were relieved by nitrate administration. No air bubbles were observed. A comparison of the incidence of CASs during pulmonary vein isolation between the different ablation energy sources revealed a significantly higher incidence with cryoballoon ablation (11/3,288; 0.34%) than with radiofrequency catheter, hot balloon, or laser balloon ablation (8/18,596 [0.04%], 0/237 [0%], and 0/111 [0%], respectively; P

The initial process of atherosclerotic development has not been systematically evaluated. This study aimed to observe atherosclerotic progression from normal vessel wall (NVW) to atherosclerotic plaque and examine local factors associated with such progression using > 5-year long-term follow-up data obtained by serial optical coherence tomography (OCT). A total of 49 patients who underwent serial OCT for lesions with NVW over 5 years (average: 6.9 years) were enrolled. NVW was defined as a vessel wall with an OCT-detectable three-layer structure and intimal thickness ≤ 300 μm. Baseline and follow-up OCT images were matched, and OCT cross sections with NVW > 30° were enrolled. Cross sections were diagnosed as “progression” when the NVW in these cross sections was reduced by > 30° at > 5-year follow-up. Atherogenic progression from NVW to atherosclerotic plaque was observed in 40.8% of enrolled cross sections. The incidence of microchannels in an adjacent atherosclerotic plaque within the same cross section (6.7 vs. 3.3%; p = 0.046) and eccentric distribution of atherosclerotic plaque (25.0 vs. 12.6%; p

Background:A thorough understanding of the anatomy of the aortic valve is necessary for aortic valve-sparing surgery. Normal valvar dimensions and their relationships in the living heart, however, have yet to be fully investigated in a 3-dimensional fashion. Methods and Results: In total, 123 consecutive patients (66±12 years, Men 63%) who underwent coronary computed tomographic angiography were enrolled. Mid-diastolic morphology of the aortic roots, including height of the interleaflet triangles, geometric height, free margin length of each leaflet, effective height, and coaptation length were measured using multiplanar reconstruction images. Average height of the interleaflet triangle, geometric height, free margin length, effective height, and the coaptation length were 17.3±1.8, 14.7±1.3, 32.6±3.6, 8.6±1.4, and 3.2±0.8 mm, respectively. The right coronary aortic leaflet displayed the longest free margin length and shortest geometric height. Geometric height, free margin length, and effective height showed positive correlations with aortic root dimensions. Coaptation length, however, remained constant regardless of aortic root dimensions. Conclusions: Diversities, as well as characteristic relationships among each value involving the aortic root, were identified using living-heart datasets. The aortic leaflets demonstrated compensatory elongation along with aortic root dilatation to maintain constant coaptation length. These measurements will serve as the standard value for revealing the underlying mechanism of aortic regurgitation to plan optimal aortic valve-sparing surgery.

Culprit lesions of acute coronary syndrome (ACS) could be classified as plaque rupture (PR), erosion, or calcified nodule (CN). We aimed to determine the relationship among clinical characteristics, morphological plaque features, and long-term prognosis in ACS. Patients with ACS, who underwent pre-intervention optical coherence tomography between April 2013 and July 2018 were retrospectively enrolled, and classified into the three groups based on the culprit lesion morphology. In the 436 patients enrolled, incidences of PR, erosion, and CN in ACS culprit lesions were 46.1, 39.9, and 14.0%, respectively. Plaque erosion was more frequent in men aged

Funding Acknowledgements Type of funding sources: None. Background Type 2 diabetes mellitus (T2DM) is a well-known risk factor for heart failure (HF), even in patients without a structural heart disease or a symptom of HF. Diabetes-related cardiomyopathy is presented as an left ventricular (LV) diastolic dysfunction, which, like cardiovascular disease, is a contributor of the development of HF in both patients with reduced ejection fraction (HFrEF) and with preserved ejection fraction (HFpEF). Furthermore, comorbid factors other than T2DM also have been identified as high risk factors for of progression to HF. Dapagliflozin is a sodium glucose cotransporter type 2 (SGLT2) inhibitor, and represents a new class of anti-hyperglycemic agents for T2DM. A result from a recent large clinical trial showed that dapagliflozin reduced risk of worsening HF or death from cardiovascular causes for patients with HFrEF compared to those who received a placebo, regardless of the presence or absence of T2DM. However, the effect of SGLT2 inhibitors on LV diastolic function in T2DM patients with HF who had cardiovascular risk factors other than T2DM remains uncertain. Purpose Our purpose was to investigate the impact of dapagliflozin on LV diastolic function in T2DM patients with stable HF complicating cardiovascular risk factors. Methods We analyzed data from our previous prospective multicenter study, which investigate the effect of dapagliflozin on LV diastolic function of 53 T2DM patients with stable HF at five institutions in Japan. Patients who had been taking at least one antidiabetic drugs other than SGLT2 inhibitor started the administration of dapagliflozin. Cardiovascular risk factors other than T2DM was determined as age, gender, hypertension, dyslipidemia, history of cardiovascular events and overweight. Results E/e′ significantly decreased from 9.3 to 8.5 cm/s 6 months after administration of dapagliflozin (p = 0.020) as previously described. Multivariate logistic regression analysis showed that dyslipidemia was the only independent determinant of an improvement of E/e’ among cardiovascular risk factors. Furthermore, relative changes in E/e’ from baseline to 6 months after administration of dapagliflozin seen in HFpEF patients with dyslipidemia were significantly larger than those in HFpEF patients without dyslipidemia (-15.2% vs. 29.6%, p = 0.014), but such a difference was not observed in non-HFpEF patients. In addition, relative changes in high-density lipoprotein cholesterol (HDL-C) from baseline to 6 months after administration of dapagliflozin had significant correlation with those in E/e’ (r=-0.300, p = 0.038). However, such correlations were not observed in low-density lipoprotein cholesterol (LDL-C) and triglyceride (r = 0.05, p = 0.72 and r = 0.05, p = 0.73). Conclusion: Dapagliflozin was more beneficial effect on LV diastolic function for T2DM patients with stable HF, especially those with complicating dyslipidemia. Our findings may thus offer a new insight into the management of T2DM patients with HF. Abstract Figure.

Additional file 1: Baseline characteristics of normal patients according to the HR quartiles.

Background Pulmonary hypertension (PH) is one of the significant complications of sarcoidosis. In the clinical classification of PH proposed in the recent world symposium of PH 2018, sarcoidosis-associated PH is classified in Group 5. The mechanisms of sarcoidosis-associated PH are very heterogeneous. There is no evidence of effective treatment for this condition. Case summary We report a case of a 46-year-old female who developed severe pulmonary hypertension due to sarcoidosis. Her haemodynamics, exercise capacity, and functional class remarkably improved after the treatment with pulmonary arterial hypertension (PAH) targeted drugs including macitentan and tadalafil and secondary immunosuppressive therapy with corticosteroids. Discussion This case emphasizes the importance of considering the underlying mechanisms of sarcoidosis-associated PH in order to choose appropriate treatment.

Background Kounis syndrome (KS) is an acute coronary syndrome (ACS) induced by allergic reactions. Currently, there are three variants of KS based on the mechanism and onset of ACS. We report a rare case of KS, wherein ACS was caused by all KS variants. Case summary A 68-year-old man with a history of percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction of the left anterior descending artery 16 days ago underwent a staged PCI for the mid-left circumflex artery (LCx) stenosis under optical coherence tomography (OCT) guidance using low-molecular-weight dextran (LMWD). During OCT examination, the LMWD induced an anaphylactic reaction. The patient was immediately administered medications to manage the anaphylaxis; however, he complained of chest discomfort. Coronary angiography and subsequent intravascular ultrasound revealed a newly developed coronary thrombus in the proximal LCx. Furthermore, coronary spasm or multiple stent thromboses occurred sequentially in all coronary arteries, resulting in triple-vessel coronary artery ischaemia. Balloon angioplasty was performed under intra-aortic balloon pumping, which could rescue the patient. The patient was discharged without any complications 11 days post-KS, under a 7-day anti-histamine regimen. No further cardiovascular events had occurred by 1-year follow-up. Discussion This case documented the clinical course of KS caused by LMWD, wherein all KS variants occurred sequentially. Early recognition of KS and appropriate management with anaphylaxis medication and balloon angioplasty under mechanical circulatory support effectively prevent vascular morbidity. Interventionalists should be aware of this rare and serious complication of PCI.

Background Cardiac involvement of amyloid light-chain (AL) amyloidosis is strongly associated with poor outcome, but the early detection of cardiac involvement of AL amyloidosis can be challenging. Case summary We present a case of 49-year-old-female with heart failure with preserved ejection fraction. Echocardiography revealed normal left ventricular (LV) ejection fraction of 63% and an enlarged left atrium with a left atrial volume index (LAVI) of 54 mL/m2. Mild LV hypertrophy with an interventricular septum of 12.3 mm and posterior wall thickness of 11.0 mm was observed, and Doppler-derived LV diastolic filling showed a restrictive filling pattern. The conventional echocardiographic findings did not unequivocally indicate typical cardiac amyloidosis, but global longitudinal strain (GLS) was as low as 14.2%, and an apical sparing pattern was observed with relative apical longitudinal strain of 1.11. Finally, the patient was diagnosed as primary AL amyloidosis including histological examination of the endomyocardial specimen. After treatment with a regime of bortezomib and dexamethasone followed by high-dose melphalan followed by autologous peripheral blood stem cell transplantation (auto-PBSCT), Doppler-derived LV diastolic filling improved to normal filling pattern, and left atrial size had also decreased with an LAVI of 31 mL/m2. Moreover, GLS improved to 19.8%, and the apical sparing pattern had disappeared with relative apical longitudinal strain of 0.62. The patient has been asymptomatic during 18-month follow-up after auto-PBSCT, and recovered LV function has been maintained. Discussion An earlier diagnosis of cardiac amyloidosis by using apical sparing may therefore allow for earlier treatment intervention for AL amyloidosis.

Background: A computational model demonstrated that atrial fibrillation (AF) rotors could be distributed in patchy fibrotic tissue and play an important role in AF drivers. However, this was not validated in humans. Objective: The purpose of this study was to evaluate the fibrotic tissue properties of AF rotors in patients with persistent AF. Methods: A total of 287 segments in 15 patients with persistent AF (longstanding persistent AF in 9 patients) that underwent AF ablation were assessed. Non-passively activated areas (NPAs), where rotational activation (AF rotor) was frequently observed, were detected by the novel real-time phase mapping (ExTRa Mapping). Atrial fibrosis was detected by late-gadolinium enhancement magnetic resonance imaging (LGE-MRI), and the fibrotic heterogeneity and density were assessed by the entropy (LGE-entropy) and volume ratio of the enhancement voxel (LGE-volume ratio), respectively. Results: NPAs were found in 61 (21%) of 287 segments and were mostly found around the pulmonary vein antrum. A receiver operating characteristic curve analysis yielded an optimal cutoff value of 5.7 and 10% for the LGE-entropy and LGE-volume ratio, respectively. The incidence of NPAs was significantly higher at segments with an LGE-entropy of >5.7 and LGE-volume ratio of >10% than at the other segments (38 [30%] of 126 vs. 23 [14%] of 161 segments, p = 0.001). No NPAs were found at segments with an LGE-volume ratio of >50% regardless of the LGE-entropy. Conclusion: AF rotors are mostly distributed in relatively weak and much more heterogenous fibrotic tissue.

Background: Computer simulation model demonstrated that atrial fibrillation (AF) driver attached to the patchy fibrosis assessed by late gadolinium enhancement magnetic resonance imaging (LGE-MRI). However, it has not been well elucidated in patients with persistent AF. The aim of this study is to investigate whether radiofrequency (RF) application on the patchy LGE site (PLS) could terminate AF or convert to atrial tachycardia (AT) and improve the rhythm outcome. Methods: A total of 31consecutive persistent AF patients with PLS were enrolled (PLS ablation group, mean age: 69 ± 8 years, mean left atrial diameter: 42 ± 6 mm). AF direct termination or AT conversion during RF application on the PLS were defined as favorable response. The rhythm outcome was compared between the PLS ablation group and the propensity matched conventional ablation group. Results: Favorable response was found in 15 (48%) of 31 patients (AF termination in 7, AT conversion in 8 patients). AF recurrence at 12 months follow-up was significantly less in the PLS group as compared to the control group (4 (13%) of 31 patients vs. 11 (35%) of 31 patients, log-rank p = 0.019). In patients with favorable response, AT recurred in 1 (7%) of 15 patients but AF. Conclusions: The PLS ablation could terminate AF or convert to AT in half of the patients and improve the rhythm outcome as compared to the conventional ablation. No AF recurrence was documented in patients with a favorable response.

We report the case of a 31-year-old man with Uhl’s anomaly. Echocardiography revealed severely enlarged nonfunctioning right ventricle and unusual findings of the premature opening of the pulmonary valve along with substantial forward flow during late-diastole, indicating that pulmonary circulation was largely dependent on compensatory right atrial contraction. Moreover, right-to-left shunt through the patent foramen ovale (PFO) achieved systemic circulation at the expense of severe hypoxia. During accelerated idioventricular rhythm (AIVR) accompanied by ventriculo-atrial (VA) conduction, hypoxemia deteriorated further because of an increased right-to-left shunt through the PFO. We report the case of an adult with Uhl’s anomaly whose hemodynamics was largely dependent on the ventricularized right atrium and PFO. Although the unique hemodynamics contributed to his survival into adulthood, detrimental aspects manifested themselves during AIVR with VA conduction like a “double-edged sword.”

Background: The existence of microvasculopathy in patients with chronic thromboembolic pulmonary hypertension (CTEPH) had been suggested.Recent report suggested that dual-energy CT (DECT) can produce a sensitive iodine distribution map as blood perfusion to quantify lung perfusion, which could suggest the existence of microvasculopathy according to the presence of poor subpleural perfusion (PSP).This study aimed to examine the therapeutic effects of interventional treatment (pulmonary endarterectomy or/and balloon pulmonary angioplasty) in CTEPH with microvasculopathy. Methods: We retrospectively reviewed PSP of 70 consecutive CTEPH patients underwent DECT before and after treatment from January 2014 to January 2020.Patients were divided according to baseline PSP: microvasculopathy (MV group, n=37) or non-microvasculopathy (Non-MV group, n=33). We assessed cardiopulmonary exercise test, pulmonary function test, right heart catheterization,and DECT parameters as quantitative evaluation of pulmonary blood volume (PBV), calculated as the average of entire lung iodine density. Results: In MV group, baseline mPAP, PVR and VE/VCO2 slope were higher and PBV were lower. After treatment, mPAP, PVR, VE/VCO2 slope and PBV showed almost equivalent between the groups. %DLCO/VA did not improve after treatment in both groups. Conclusion: Hemodynamics, pulmonary perfusion, exercise capacities significantly improved after the treatments in spite of the existence or absence of microvasculopathy. However, DLCO might indicate the existence of microvasculopathy did not improve. Interventional treatments could not improve microvasculopathy because of their limit of accessibilities.

Background: It has been reported that the efficacy of balloon pulmonary angioplasty (BPA) for patients with non-operable chronic thromboembolic pulmonary hypertension (CTEPH) would be promising. However, some patients have shown poor response in oxygenation and lung function parameter even after hemodynamics improved. The aim of our study was to investigate lung function and oxygenation after BPA. Method: Consecutive 103 patients who underwent BPA from September 2011 to August 2018 were enrolled. We evaluated hemodynamics with right heart catheterization, respiratory function test, arterial blood gas examination, and exercise capacity with 6 minute-walk-distance (6MWD)at baseline and after BPA. Result: At the median 12-month follow-up after the final BPA session, pulmonary vascular resistance, and PaO2 improved significantly (782 ± 378 to 331 ± 187 dynes / sec / cm-5, p Conclusion: BPA could dramatically improve hemodynamics and exercise tolerance. However, arterial oxygenation was not normalized after BPA. Moreover, oxygen desaturation in exercise, and %DLCO were almost unchanged. These observations might suggest the remaining arteriopathy and anastomosis in arteriole or capillary level in CTEPH.

A large amount of evidence suggests that high-density lipoprotein (HDL) has anti-atherosclerotic properties. HDL-cholesterol (HDL-C) has also been widely used as a marker of cardiovascular disease. Recently, it was reported that plasma HDL-C levels are inversely correlated with cancer risk. However, the relationship between HDL and cancer pathophysiology remains unknown. Here, we sought to investigate the effect of HDL on cancer progression. First, we focused on fibronectin—an essential extracellular matrix glycoprotein—as an HDL-associated protein and found that only 7.4% of subjects in this study had fibronectin in HDL isolated from their plasma. The fibronectin-containing HDL (FN-HDL) increased the phosphorylation of focal adhesion kinase (FAK) in HeLa cells compared to HDL without fibronectin, further inducing the phosphorylation in a dose-dependent manner. Second, we found that fibronectin-treated HDL activated the phosphorylation of FAK, and its upstream effector blocked the phosphorylation induced by FN-HDL. Finally, we demonstrated that FN-HDL promoted cancer cell proliferation and adhesion compared to HDL without fibronectin. Our study showed the possible mechanism by which FN-HDL enhanced cancer cell proliferation and adhesion via the FAK signaling pathway. Further investigation of the roles of HDL components in tumorigenesis might provide novel insight into cancer pathophysiology.

To investigate the feasibility of pre-procedural morphological assessment of coronary artery calcification in severely calcified lesions with electrocardiography (ECG)-gated non-contrast computed tomography (CT). Severely calcified coronary arteries in patients who underwent ECG-gated non-contrast CT prior to optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) were studied retrospectively. CT and OCT data were co-registered by marking landmark structures such as side branches and reviewed side by side with cross-sectional images. The maximum calcium angle (MCA) and presence of nodular calcification (NC) were evaluated. A total of 496 cross-sections in 16 lesions were included in this analysis. The Pearson correlation coefficient between CT- and OCT-derived MCA was 0.92 (p 0.001). Bland-Altman plots of OCT-derived MCA in relation to CT-derived MCA showed a mean bias of 4.8 degrees with 95% limits of agreement of - 69.7 to 79.4 degrees. Sensitivity, specificity, and positive and negative predictive values of CT in identifying MCA 270 degrees were 90.3%, 79.7%, 92.1%, and 97.4%, respectively. Sensitivity, specificity, and positive and negative predictive values of CT in identifying NC were 73.3%, 97.5%, 47.8%, and 99.2%, respectively. ECG-gated non-contrast coronary CT might be helpful to obtain detailed information of severe coronary artery calcification before PCI.

Faecal lipopolysaccharides (LPS) have attracted attention as potent elements to explain a correlation between the gut microbiota and cardiovascular disease (CVD) progression. However, the underlying mechanism of how specific gut bacteria contribute to faecal LPS levels remains unclear. We retrospectively analysed the data of 92 patients and found that the abundance of the genus Bacteroides was significantly and negatively correlated with faecal LPS levels. The controls showed a higher abundance of Bacteroides than that in the patients with CVD. The endotoxin units of the Bacteroides LPS, as determined by the limulus amoebocyte lysate (LAL) tests, were drastically lower than those of the Escherichia coli LPS; similarly, the Bacteroides LPS induced relatively low levels of pro-inflammatory cytokine production and did not induce sepsis in mice. Fermenting patient faecal samples in a single-batch fermentation system with Bacteroides probiotics led to a significant increase in the Bacteroides abundance, suggesting that the human gut microbiota could be manipulated toward decreasing the faecal LPS levels. In the clinical perspective, Bacteroides decrease faecal LPS levels because of their reduced LAL activity; therefore, increasing Bacteroides abundance might serve as a novel therapeutic approach to prevent CVD via reducing faecal LPS levels and suppressing immune responses.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Aims A mineralocorticoid receptor antagonist (MRA) is effective in patients with chronic heart failure; however, the effects of the early initiation of an MRA in patients with acute heart failure (AHF) have not been elucidated. Methods and results In this multicentre, randomized, double-blind, placebo-controlled, parallel-group study, we focused on the safety and effectiveness of the treatment with eplerenone, a selective MRA in 300 patients with AHF, that is, 149 in the eplerenone group and 151 in the placebo group in 27 Japanese institutions. The key inclusion criteria were (i) patients aged 20 years or older and (ii) those with left ventricular ejection fraction of ≤40%. The primary outcome was a composite of cardiac death or first re-hospitalization due to cardiovascular disease within 6 months. The mean age of the participants was 66.8 years, 27.3% were women, and the median levels of brain natriuretic peptide were 376.0 pg/mL. The incidences of the primary outcome were 19.5% in the eplerenone group and 17.2% in the placebo group [hazard ratio (HR): 1.09, 95% confidence interval (CI): 0.642–1.855]. In prespecified secondary outcomes, HR for the composite endpoint, cardiovascular death, or first re-hospitalization due to heart failure within 6 months was 0.55 (95% CI: 0.213–1.434). The safety profile for eplerenone was as expected. Conclusion The early initiation of eplerenone in patients with AHF could safely be utilized. The reduction of the incidence of a composite of cardiovascular death or first re-hospitalization for cardiovascular diseases by eplerenone is inconclusive because of inadequate power.

Background Pulmonary vein isolation (PVI) lesions after cryoballoon ablation (CBA) are characterized as a wider and more continuous than that after conventional radiofrequency catheter ablation (RFCA) without the contact force (CF)-sensing technology. However, the impact on the lesion characteristics of ablation with a CF-sensing catheter has not been well discussed. We sought to assess the lesions using late-gadolinium enhancement magnetic resonance imaging (LGE-MRI) and to compare the differences between the two groups (CB group vs. RF group). Methods A total of 30 consecutive patients who underwent PVI were enrolled (CB group, 18; RF group, 12). The RF applications were delivered with a target lesion size index (LSI) of 5. The PVI lesions were assessed by LGE-MRI 3 months after the PVI. The region around the PV was divided into eight segments: roof, anterior-superior, anterior carina, anterior inferior, bottom, posterior inferior, posterior carina, and posterior superior segment. The lesion width and visual gap of each segment were compared between the two groups. The visual gaps were defined as no-enhancement site of >4 mm. Results The mean LSI was 4.7 ± 0.7. The lesion width was significantly wider but the visual gaps were more frequently documented at the bottom segment of right PV in the CBA group (lesion width: 8.1 ± 2.2 vs. 6.3 ± 2.2 mm; p = .032; visual gap at the bottom segment or right PV: 39% vs. 0%; p = .016). Conclusions The PVI lesion was wider after CBA, while the visual gaps were fewer after RFCA with a CF-sensing catheter.

Background: Hypertension is considered an important risk factors for cancer therapeutics-related cardiac dysfunction (CTRCD) as well as heart failure. However, the impact of hypertension and left ventricular (LV) hypertrophy (LVH), which is associated with hypertension, on LV function in patients treated with anthracycline chemotherapy for malignant lymphoma remains uncertain. Method: We studied 92 patients with malignant lymphoma and with preserved LV ejection fraction (LVEF). Echocardiography was performed before and two-month after anthracycline chemotherapy. CTRCD was defined as the presence of an absolute decrease in LVEF ≥10% to a final value 95 g/m2 for females and > 115 g/m2 for males. Results: Relative decrease in LVEF after anthracycline chemotherapy in patients with hypertension (n = 23) was significantly higher than that in patients without hypertension (n = 69) (-5.8% [-9.4, -1.3]) vs. (-1.1% [-4.1, 2.5]); P = .005). Moreover, the prevalence of CTRCD in patients with hypertension tended to be higher than in those without hypertension (17% vs. 5%, p = .09). A sequential logistic model for predicting CTRCD, based on baseline clinical variables including major clinical risk factors, was improved by the addition of the complication of hypertension (P = .049), and further improved by the addition of the presence of LVH (P = .023). Conclusions: Hypertension, especially when complicated by LVH, was found to be associated with LV dysfunction after anthracycline chemotherapy in patients with malignant lymphoma and preserved LVEF. Watchful observation or early therapeutic intervention may thus be needed for such patients by the addition of the presence of LVH.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare malignancy-related respiratory complication, showing rapid progression of respiratory dysfunction and pulmonary hypertension (PH). Accumulating evidence suggests that imatinib, a platelet-derived growth factor (PDGF) receptor-tyrosine kinase inhibitor, might be effective and improve severe PH in patients with PTTM associated with gastric cancer. However, its efficacy in PTTM with breast cancer is generally believed as very limited. We experienced a rare case of PTTM associated with metastatic breast cancer, a rare case who were treated with imatinib, exhibiting significant improvement of respiratory dysfunction and PH.

Although balloon angioplasty for femoropopliteal artery lesions has been associated with restenosis rates of up to 60% at 12 months, the mechanism of restenosis has not been fully evaluated. The aim of this study was to evaluate the relationship between the vascular features observed on optical frequency domain imaging (OFDI) before and after balloon angioplasty of femoropopliteal artery lesions, and restenosis at 6 months. This study was a prospective multicenter single arm study. OFDI was performed before and after balloon angioplasty and plaque characteristics and vascular features, along with de novo lesions, were assessed. The primary outcome was the presence or absence of restenosis 6 months after balloon angioplasty. Residual platelet reactivity was assessed according to VerifyNow platelet reactivity units (PRUs). The number of patients completing 6 months of follow-up was 47, of which 14 had developed restenosis. Maximum thickness of the dissection flap (odds ratio (OR) 2.71; 95% confidence interval [0.9-8.0]; p = 0.071) and lesion length were identified as risk factors for restenosis (OR 1.015; 95% confidence interval [0.001-0.029]; p = 0.039). The mean PRU at the time of treatment in patients with restenosis was significantly higher than in those without restenosis (286.3 ± 82.6 vs. 208.5 ± 03.6, p = 0.026). Long lesions and major dissection on OFDI after balloon angioplasty for femoropopliteal artery lesions increase restenosis at 6 months. In addition, high residual platelet reactivity at the time of EVT may also be a risk factor for restenosis.Clinical Trial Registration Number UMIN000021120.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease with poor prognosis due to limited clinical treatment options. IPF is characterized by the augmented deposition of extracellular matrix driven by myofibroblasts, and the epithelial-mesenchymal transition (EMT) has been known to play an essential role in the mechanism of pulmonary fibrosis. Previous genome-wide association study identified Fam13a as one of genes that showed genetic link with IPF and chronic obstructive pulmonary disease. Here, we analyzed the role of Fam13a in the pathogenesis of pulmonary fibrosis using Fam13a-deficient mice. We found that Fam13a was down-regulated in mouse lungs of bleomycin-induced pulmonary fibrosis model. Of note, genetic deletion of Fam13a exacerbated the lung fibrosis induced by bleomycin in association with enhanced EMT in mice. Moreover, silencing of Fam13a accelerated EMT induced by TGF-β and TNF-α in alveolar epithelial cells, accompanied by increased active β-catenin and its nuclear accumulation. Our data revealed a crucial role of Fam13a in the development of pulmonary fibrosis potentially through inhibiting EMT, and thus Fam13a has a therapeutic potential in the treatment of IPF.

Pulmonary hypertension is a progressive lung disease with poor prognosis due to the consequent right heart ventricular failure. Pulmonary artery remodeling and dysfunction are culprits for pathologically increased pulmonary arterial pressure, but their underlying molecular mechanisms remain to be elucidated. Previous genome-wide association studies revealed a significant correlation between the genetic locus of family with sequence similarity 13, member A (FAM13A) and various lung diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis; however whether FAM13A is also involved in the pathogenesis of pulmonary hypertension remained unknown. Here, we identified a significant role of FAM13A in the development of pulmonary hypertension. FAM13A expression was reduced in mouse lungs of hypoxia-induced pulmonary hypertension model. We identified that FAM13A was expressed in lung vasculatures, especially in endothelial cells. Genetic loss of FAM13A exacerbated pulmonary hypertension in mice exposed to chronic hypoxia in association with deteriorated pulmonary artery remodeling. Mechanistically, FAM13A decelerated endothelial-to-mesenchymal transition potentially by inhibiting β-catenin signaling in pulmonary artery endothelial cells. Our data revealed a protective role of FAM13A in the development of pulmonary hypertension, and therefore increasing and/or preserving FAM13A expression in pulmonary artery endothelial cells is an attractive therapeutic strategy for the treatment of pulmonary hypertension.

Recent studies reported cardioprotective effects of sodium glucose co-transporter 2 (SGLT2) inhibitors; however, the underlying mechanisms are still obscure. Here, we investigated whether empagliflozin attenuates atherogenesis and endothelial dysfunction in diabetic apolipoprotein E-deficient (ApoE-/-) mice. Male streptozotocin (STZ) - induced diabetic ApoE-/- mice were treated with empagliflozin for 12 or 8 weeks. Empagliflozin lowered blood glucose (P

Functional tricuspid regurgitation (FTR) is associated with prognosis for various heart diseases, but its association with pulmonary hypertension (PH) remains unclear. We studied 111 PH patients. Mid-term follow-up echocardiography was performed 7.1 ± 4.1 months after PH-specific therapy. The severity of FTR was graded as none or trace, mild, moderate, or severe, while more than moderate TR was defined as significant. Moreover, mid-term improvement in FTR after therapy was defined as an improvement in severity of FTR by a grade of 1 or more. Long-term follow-up to determine the primary endpoint of death or hospitalization for heart failure lasted 39 ± 14 months. Mid-term improvement in FTR after PH-specific treatment was observed in 25 patients (23%), and the primary end points occurred in 27 patients (24%) during the long-term follow-up. The Kaplan–Meier curve indicated that the non-FTR group showed more favorable long-term outcomes than the FTR group (log-rank P = 0.008). It further indicated that patients with mid-term improvement in FTR also had more favorable long-term outcomes than those without such improvement (log-rank P = 0.03). When divided into four sub-groups based on combined assessment of baseline FTR and mid-term improvement in FTR, long-term outcomes for patients without mid-term improvement in their baseline FTR were worse than for the other sub-groups (log-rank P = 0.02). Multiple regression analysis showed that a relative change in tricuspid annular diameter at the mid-term follow-up after PH-specific therapy was the only independent determinant parameters for mid-term improvement in FTR. FTR appears to be a valuable factor for predicting long-term outcomes for PH patients, and combined assessment of baseline FTR and mid-term improvement in FTR after PH-specific therapy may have clinical implications for better management of such patients.

Background: It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus Bacteroides is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis. Methods: We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis. Results: Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of Bacteroides vulgatus and Bacteroides dorei in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live B. vulgatus and B. dorei attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of B. vulgatus and B. dorei . Conclusions: Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live B. vulgatus and B. dorei may help prevent CAD. Clinical Trial Registration: URL: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051 . Unique identifier: UMIN000015703.

Background Recent studies suggested protruding thrombus and atheroma after stent placement could be a substrate for subsequent adverse ischemic events. Although protruded atherothrombotic burden can be assessed as intra-stent tissue (IST) by optical coherence tomography (OCT), the effects of potent antiplatelet therapy on the acute phase resolution of IST in patients with acute coronary syndrome (ACS) was unknown. Methods Ninety-six consecutive ACS patients with multi-vessel disease were enrolled in this prospective registry. In combination with aspirin, either clopidogrel or prasugrel was selected according to the date of enrolment. OCT examination was done immediately after percutaneous coronary intervention (post-PCI) and 10 days after index PCI (follow-up acute phase) to calculate averaged IST score as semi-quantitative measures of IST. High residual platelet reactivity (HRPR) was defined as platelet reactivity units (PRU) ≥ 240 by VerifyNow P2Y12 assay (Accumetrics Inc., San Diego, CA, USA). Results Thirty two patients (38 stents) were enrolled in the prasugrel group and sixty four patients (72 stents) in the clopidogrel group. Averaged IST scores post-PCI were similar between the two groups (0.68 ± 0.41 vs. 0.68 ± 0.40, p = 0.99), which decreased in all of the prasugrel group and in 87.5% of the clopidogrel group (p = 0.02). Consequently, changes in averaged IST score (delta averaged IST score) were significantly greater in the prasugrel group compared to those in the clopidogrel group (−0.411 ± 0.288 vs. −0.299 ± 0.270, p = 0.045). The frequency of HRPR was significantly lower in the prasugrel group (10.0% vs 32.4%, p = 0.028). Conclusions Prasugrel plus aspirin achieved greater acute phase reduction of IST than clopidogrel plus aspirin, which might underlie the clinical benefit of potent antiplatelet therapy in ACS. (UMIN000018751)

Focal thinning of the basal muscular ventricular septum is a characteristic morphological finding in cases of cardiac sarcoidosis, usually detected on the parasternal long-axis image during echocardiography. Surprisingly, however, its circumferential extent has rarely been demonstrated and discussed. We present a case showing typical thinning of the basal ventricular septum. The extent of circumferential wall thinning was evaluated using both echocardiography and cardiac computed tomography. The present case highlights the importance of detailed multiplanar and three-dimensional evaluation of this characteristic abnormality, more so because its mechanism as well as the precise impact on conduction has not yet been elucidated.

Obesity often causes systemic metabolic disorders in close association with adipose tissue dysfunction. Adipose tissue contains well-developed vasculatures, and obesity mediates vascular rarefaction that causes hypoxia and triggers inflammation in adipose tissue. Adipose tissue-derived neuregulin-4 (Nrg4) is an immerging factor that is critically involved in metabolic homeostasis. We recently identified that Nrg4 is an angiogenic adipokine that plays an important role in maintaining adipose tissue vasculature. Here, we further validated its beneficial role in metabolic health primarily by enhancing adipose tissue angiogenesis. Targeted activation of Nrg4 in adipocytes improved metabolic health in mice under both normal and high fat dietary condition without changes in body weight. Activation of Nrg4 increased blood vessels in white adipose tissue, and ameliorated adipose tissue hypoxia under obese condition. Of note, inhibition of angiogenesis by sugen-treatment abolished the beneficial effects of Nrg4 on systemic metabolic health. Furthermore, targeted inhibition of Nrg4-ErbB signaling in adipose tissue vasculature using prohibitin binding peptide-conjugated nanocarrier abrogated the enhanced adipose tissue angiogenesis, and canceled the improved metabolic health induced by Nrg4 activation. These data further support a crucial role of Nrg4 in maintaining systemic metabolic homeostasis at least partially through enhancing adipose tissue angiogenesis.

High-density lipoprotein cholesterol (HDL-C) has been identified as a powerful independent negative predictor of cardiovascular disease. The beneficial effect of HDL is largely attributable to its key role in reverse cholesterol transport, whereby excess cholesterol in the peripheral tissues is transported to the liver, reducing the atherosclerotic burden. However, mounting evidence indicates that HDL also has pleiotropic properties, such as anti-inflammatory, anti-oxidative, and vasodilatory properties, which may contribute in reducing the incidence of heart failure. Actually, previous data from clinical and experimental studies have suggested that HDL exerts cardioprotective effects irrespective of the presence/absence of coronary artery disease. This review summarizes the currently available evidence regarding beneficial effects of HDL on the heart beyond its anti-atherogenic property. Understanding the mechanisms of cardiac protection by HDL will provide new insight into the underlying mechanism and therapeutic strategy for heart failure.

Background Our aim was to investigate the baseline clinical and echocardiographic parameters for predicting left ventricular (LV) dysfunction after anthracycline chemotherapy and heart failure (HF) hospitalization in a single cancer disease. Methods and Results: We studied 73 patients with malignant lymphoma and preserved LV ejection fraction (LVEF). Echocardiography was performed before and after anthracycline chemotherapy. Global longitudinal strain (GLS) was determined from 3 standard apical views. LV dysfunction after anthracycline chemotherapy was defined according to the current definition of cancer therapeutics-related cardiac dysfunction. Long-term (50-month) unfavorable outcome was prespecified as hospitalization for HF. A total of 10 patients had LV dysfunction after anthracycline chemotherapy. Multivariate logistic regression analysis showed that baseline GLS was the only independent predictor of this dysfunction. Receiver-operating characteristic curve analysis identified the optimal GLS cutoff for predicting LV dysfunction after anthracycline chemotherapy as ≤19% (P=0.008). Furthermore, the Kaplan-Meier curve indicated that fewer patients with GLS >19% were hospitalized for HF than among those with GLS ≤19% (log-rank P=0.02). For sequential logistic models, a model based on baseline clinical variables (χ2=2.9) was improved by the addition of baseline LVEF (χ2=9.0; P=0.01), and further improved by the addition of baseline GLS (χ2=13.1, P=0.04). Conclusions Watchful observation or early therapeutic intervention with established cardioprotective medications may be necessary for patients with malignant lymphoma and preserved LVEF but with abnormal GLS.

Bosentan, an endothelin receptor antagonist, has been widely used as a first-line drug for the treatment of pulmonary arterial hypertension (PAH). In addition, bosentan is approved for patients with digital ulcers related to systemic sclerosis. Liver dysfunction is a major adverse effect of bosentan and may lead to discontinuation of therapy. The purpose of this study was to identify genomic biomarkers to predict bosentan-induced liver injury. A total of 69 PAH patients were recruited into the study. An exploratory analysis of 1936 single-nucleotide polymorphisms (SNPs) in 231 genes involved in absorption, distribution, metabolism, and elimination of multiple medications using Affimetrix DMET™ (Drug Metabolism Enzymes and Transporters) chips was performed. We extracted 16 SNPs (P 0.05) using the Jonckheere-Terpstra trend test and multiplex logistic analysis; we identified two SNPs in two genes, CHST3 and CHST13, which are responsible for proteoglycan sulfation and were significantly associated with bosentan-induced liver injury. We constructed a predictive model for bosentan-induced liver injury (area under the curve [AUC]: 0.89, sensitivity: 82.61%, specificity: 86.05%) via receiver operating curve (ROC) analysis using 2 SNPs and 2 non-genetic factors. Two SNPs were identified as potential predictive markers for bosentan-induced liver injury in Japanese patients with pulmonary arterial hypertension. This is the first pharmacogenomics study linking proteoglycan sulfating genes to drug-induced liver dysfunction, a frequently observed clinical adverse effect of bosentan therapy. These results may provide a way to personalize PAH medicine as well as provide novel mechanistic insights to drug-induced liver dysfunction.