Exosomal miR206 Secreted From Growing Muscle Promotes Angiogenic Response in Endothelial Cells.

BACKGROUND: Resistance exercise is beneficial in patients with lower extremity arterial disease. Muscle-derived exosomes contain many types of signaling molecules, including microRNAs (miRNAs). Here, we tested the hypothesis that exosomal miRNAs secreted by growing muscles promote an angiogenic response in endothelial cells (ECs).Methods and Results: Skeletal muscle-specific conditional Akt1 transgenic (Akt1-TG) mice, in which skeletal muscle growth can be induced were used as a model of resistance training. Remarkable skeletal muscle growth was observed in mice 2 weeks after gene activation. The protein amount in exosomes secreted by growing muscles did not differ between Akt1-TG and control mice. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway frequency analysis of 4,665 target genes, identified using an miRNA array miRNAs, revealed a significant increase in Akt and its downstream signaling pathway genes. Among the upregulated miRNAs, miR1, miR133, and miR206 were significantly upregulated in the serum of Akt1-TG mice. miR206 was also increased in insulin-like growth factor (IGF)-1-stimulated hypertrophied myotubes. Exogenous supplementation of exosomal miR206 to human umbilical vein ECs promoted angiogenesis, as assessed using the spheroid assay, and increased the expression of angiogenesis-related transcripts. CONCLUSIONS: Exosomal miR206 is upregulated in the blood of Akt1-TG mice and in IGF-stimulated cultured myotubes. Exogenous supplementation of miR206 promoted an angiogenic response in ECs. Our data suggest that miR206 secreted from growing muscles acts on ECs and promotes angiogenesis.

The E/e' ratio on echocardiography as an independent predictor of the improvement of left ventricular contraction in patients with heart failure with reduced ejection fraction.

OBJECTIVE: Clinical feature of heart failure with improved ejection fraction (HFimpEF) remains to be fully elucidated. The present study investigated the association of clinical and echocardiographic parameters with the subsequent improvement of left ventricular ejection fraction (LVEF) in heart failure with reduced ejection fraction (HFrEF). METHODS: From outpatients with a history of hospitalized for heart failure, 128 subjects diagnosed as HFrEF (LVEF <40%) on heart failure hospitalization were enrolled and longitudinally surveyed. During follow-up periods more than 1 year, 58 and 42 patients were identified as HFimpEF (improved LVEF to ≥40% and its increase of ≥10 points) and persistent HFrEF, respectively. RESULTS: There was no difference in age or sex between the two groups with HFimpEF and persistent HFrEF. The rate of ischemic heart disease was lower and that of tachyarrhythmia was higher in the HFimpEF group than in the persistent HFrEF group. At baseline (i.e., on heart failure hospitalization), LVEF did not differ between the two groups, but left ventricular systolic and diastolic diameters were already smaller and the ratio of early diastolic transmitral velocity to early diastolic tissue velocity (E/e') was lower in the HFimpEF group. A multiple logistic regression analysis revealed that lower baseline E/e' was a significant determinant of HFimpEF, independently of confounding factors such as ischemic heart disease, tachyarrhythmia, and baseline left ventricular dimension. CONCLUSION: Our findings indicate that the lower ratio of E/e' in the acute phase of heart failure onset is an independent predictor of the subsequent improvement of LVEF in HFrEF patients.

Augmented O-GlcNAcylation exacerbates right ventricular dysfunction and remodeling via enhancement of hypertrophy, mitophagy, and fibrosis in mice exposed to long-term intermittent hypoxia.

Previously, we showed that augmented O-linked N-acetylglucosaminylation (O-GlcNAcylation) mitigates cardiac remodeling in O-GlcNAc transferase-transgenic (Ogt-Tg) mice exposed to acute (2-week) intermittent hypoxia (IH) by suppressing nuclear factor of activated T cells (NFAT) and nuclear factor kappa B (NF-κB) via the O-GlcNAcylation of glycogen synthase kinase 3 beta (GSK-3ß) and NF-κB p65. Because this effect is time dependent, we exposed Ogt-Tg mice to IH for 4 weeks (IH4W) in the present study. O-GlcNAcylation was significantly enhanced in Ogt-Tg mice vs. wild-type (WT) mice exposed to normoxia and IH4W. Total O-GlcNAcylation levels were significantly increased in WT and Ogt-Tg mice after IH4W vs. normoxia. After IH4W, Ogt-Tg mice displayed significantly exacerbated signs of cardiac hypertrophy and fibrosis in the right ventricles (RVs) but not the left ventricles (LVs). Echocardiography revealed IH4W-induced right ventricular dysfunction. Phosphorylated GSK-3ß levels were increased in Ogt-Tg mice vs. WT mice after IH4W, whereas phosphorylated NF-κB p65 levels were unaffected. Mitophagy, which is associated with cardiac dysfunction, was increased in the RVs of Ogt-Tg mice after IH4W. Furthermore, the levels of phosphorylated dynamin-related protein 1 (p-Drp1) were significantly increased, and the expression of mitofusin-2 (MFN2) was significantly decreased. In human embryonic kidney cells, mitochondrial uncoupler-induced mitochondrial dysfunction was accelerated in Ogt-overexpressing cells. In addition to increasing the levels of phosphorylated Smad2, IH4W promoted cardiac fibrosis in the RVs of Ogt-Tg mice. Thus, augmented O-GlcNAcylation may aggravate IH4W-induced right ventricular dysfunction and remodeling by promoting hypertrophy, mitophagy, and fibrosis via GSK-3ß inactivation, an increased p-Drp-1/MFN2 ratio, and Smad2 activation, respectively.

Development and Validation of Artificial Intelligence-based Method for Diagnosis of Mitral Regurgitation from Chest Radiographs.

Purpose: To develop an artificial intelligence-based model to detect mitral regurgitation on chest radiographs. Materials and Methods: This retrospective study included echocardiographs and associated chest radiographs consecutively collected at a single institution between July 2016 and May 2019. Associated radiographs were those obtained within 30 days of echocardiography. These radiographs were labeled as positive or negative for mitral regurgitation on the basis of the echocardiographic reports and were divided into training, validation, and test datasets. An artificial intelligence model was developed by using the training dataset and was tuned by using the validation dataset. To evaluate the model, the area under the curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value were assessed by using the test dataset. Results: This study included a total of 10 367 images from 5270 patients. The training dataset included 8240 images (4216 patients), the validation dataset included 1073 images (527 patients), and the test dataset included 1054 images (527 patients). The area under the curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value in the test dataset were 0.80 (95% CI: 0.77, 0.82), 71% (95% CI: 67, 75), 74% (95% CI: 70, 77), 73% (95% CI: 70, 75), 68% (95% CI: 64, 72), and 77% (95% CI: 73, 80), respectively. Conclusion: The developed deep learning-based artificial intelligence model may possibly differentiate patients with and without mitral regurgitation by using chest radiographs.Keywords: Computer-aided Diagnosis (CAD), Cardiac, Heart, Valves, Supervised Learning, Convolutional Neural Network (CNN), Deep Learning Algorithms, Machine Learning Algorithms Supplemental material is available for this article. © RSNA, 2022.

Vaso reactivity test using inhaled nitric oxide for pulmonary arterial hypertension accompanied by severe interstitial lung disease attributed to systemic sclerosis: A case report.

A 70-year-old man with severe interstitial pneumonia attributed to limited cutaneous systemic sclerosis was referred to our institution because of worsening dyspnea. High-resolution computed tomography did not show considerable progression compared with previous images, whereas transthoracic echocardiography showed severe right ventricular dysfunction. Oxygen saturation was decreased to 84% at room air. A blood test showed an increase in the plasma brain natriuretic peptide level (289.4 pg/mL). Right heart catheterization (RHC) showed a remarkably high mean pulmonary arterial pressure (mPAP) of 48 mmHg at room air. A vaso reactivity test using inhaled nitric oxide showed improvement of mPAP, pulmonary vascular resistance (PVR), and partial pressure of arterial oxygen. These findings suggested that the patient responded to pulmonary hypertension (PH)-targeted drugs. We then prescribed tadalafil 10 mg and inhaled iloprost 5 µg six times daily. Three weeks after initiating PH-targeted drugs, RHC indicated hemodynamic improvement similar to hemodynamic changes in the vaso reactivity test (mPAP: 28 mmHg; PVR: 4.2 W.U.). He was discharged with improved symptoms. Inhaled nitric oxide during RHC might be helpful to consider the treatment strategy when patients have PH comorbid systemic sclerosis and severe interstitial lung disease. .

Left atrial volume index predicts future improvement of B-type natriuretic peptide levels after transcatheter aortic valve replacement.

In patients with symptomatic severe aortic stenosis (AS), those who experienced readmission due to heart failure after transcatheter aortic valve replacement (TAVR) showed poor prognosis. Furthermore, poor B-type natriuretic peptide (BNP) improvement is associated with increased morbidity and mortality. However, little is known about the clinical parameters related to the change in BNP levels after TAVR procedure. This study population consisted of 127 consecutive patients of symptomatic severe AS with preserved ejection fraction (EF) who underwent transfemoral TAVR (TF-TAVR). Comprehensive transthoracic echocardiography was performed prior to the day of TF-TAVR. BNP was measured serially before and 1 year after TF-TAVR. The median BNP level was significantly decreased from 252.5 pg/ml to 146.8 pg/ml in all 127 patients 1 year after TF-TAVR (P < 0.01). However, the patients could be divided into 2 groups according to decrease (72%) or increase (28%) in plasma BNP level. Multivariate logistic regression analysis revealed that Aortic valve (AV) peak velocity, pre-procedural BNP, and larger left atrial volume index (LAVI) were found to be an independent predictor of increased BNP level 1 year after TAVR (OR 0.55, 95% CI 0.38-0.77; P < 0.01). LAVI were negatively correlated with the change in BNP level before and 1 year after TAVR (r = 0.47, P < 0.01). The ROC analysis demonstrated that 52.9 ml/m2 was the optimal cut-off value of LAVI for decreasing BNP 1 year after TAVR (area under the curve 0.69) with 64% sensitivity and 70% specificity. In addition to AV peak velocity and pre-procedural BNP, LAVI independently predicts future improvement of BNP levels 1 year after TAVR. Our findings indicate an additive predictive value of assessment of LAVI before TAVR procedure for risk stratification.

Thigh Intramuscular Fat on Prognosis of Patients With Nonischemic Cardiomyopathy.

Skeletal muscle atrophy is an independent prognostic predictor for patients with chronic heart failure, and the concept of sarcopenia is drawing attention. Furthermore, the importance of not only muscle mass but also ectopic fat has been pointed out. However, there is a lack of consensus on the implications of ectopic fat for the prognosis in patients with nonischemic cardiomyopathy. We investigated whether ectopic fat in the thigh affects the prognosis of nonischemic cardiomyopathy. This prospective study recruited 145 patients diagnosed with nonischemic cardiomyopathy between September 2017 and January 2020. Finally, 93 patients with a reduced ejection fraction were enrolled. The clinical end points were cardiovascular death or unexpected rehospitalization because of a cardiac event. Using computed tomography, the percentage of intramuscular fat (%IMF) in the thigh was measured in all patients. Patients were divided into 2 groups based on the median %IMF. The results of Spearman's correlation coefficient analysis revealed a correlation among %IMF and peak oxygen uptake (Spearman r = -0.221, p = 0.036). Kaplan-Meier analysis results showed significantly higher risk of adverse events in the high %IMF group (log-rank p = 0.013). Multivariate Cox regression analysis results revealed the %IMF as an independent factor for adverse events (hazard ratio 1.361; 95% confidence interval 1.043 to 1.745; p = 0.018). In conclusion, %IMF may have adverse consequences such as increased cardiac events in patients with nonischemic cardiomyopathy with a reduced ejection fraction.

Kinetics of atrial and brain natriuretic peptides during hemodialysis are regulated in association with different cardiac functional changes.

The blood levels of atrial and brain natriuretic peptides (ANP and BNP) are both increased markedly in hemodialysis patients, but the kinetics of the two are not always parallel. The present study investigated the association of changes in ANP and BNP levels before and after dialysis with changes in cardiac function in hemodialysis patients. A total of 57 patients (mean age 64 years, 47 males and 10 females) on maintenance hemodialysis with sinus rhythm were enrolled. Blood samples were taken at the beginning and end of dialysis, and plasma levels of ANP and BNP were measured. Changes in cardiac function during dialysis were examined by echocardiography performed just before and after dialysis. Both plasma ANP and BNP concentrations decreased significantly after hemodialysis, but the rate of decrease in BNP [mean ± SD, 555 ± 503 to 519 ± 477 pg/mL (- 6.4%), P = 0.011] was much smaller than that in ANP [233 ± 123 to 132 ± 83 pg/mL (- 43.4%), P < 0.001]. As for the relation to the changes in echocardiographic parameters before and after dialysis, the decrease in inferior vena cava diameter had a close correlation with the decrease in ANP (r = 0.528, P < 0.001), but not BNP. In contrast, the decrease in left ventricular end-diastolic volume index was correlated only with the decrease in BNP (r = 0.297, P = 0.035). The peak velocity ratio of early diastolic to atrial filling decreased with preload reduction by dialysis, and its decrease was more strongly correlated with the decrease in BNP (r = 0.407, P = 0.002) than that in ANP (r = 0.273, P = 0.040). These results demonstrated that in hemodialysis patients, the decrease in plasma ANP by a single dialysis was essentially caused by blood volume reduction, while BNP decrease was mainly induced by the reduction of left ventricular overload. Our findings indicate that the kinetics of both peptides during dialysis are regulated by different cardiac and hemodynamic factors.

Dynapenia is an independent predictor of cardio-cerebrovascular events in patients undergoing hemodialysis.

The number of patients on maintenance hemodialysis (HD) diagnosed with sarcopenia has been increasing through as individuals age. Recent focus is on the condition termed, "dynapenia," which reduces only muscle function, as opposed to sarcopenia, which reduces both muscle mass and function. However, the association between dynapenia and cardio-cerebrovascular (CV) events in patients undergoing HD is largely unknown. The purpose of this study was to evaluate whether sarcopenia and dynapenia are associated with the onset of CV events in patients undergoing HD. We retrospectively analyzed 342 patients undergoing HD between January and December 2018. Patients who underwent HD thrice per week for > 3 months were included in the analysis. We adopted the Asian Working Group on Sarcopenia criteria for the diagnosis of sarcopenia and dynapenia. In this study, 244 patients undergoing HD were enrolled. The prevalence of sarcopenia was 38.5%. Sarcopenia was determined to be an independent contributor to CV events in patients undergoing HD. To investigate the clinical relevance of dynapenia in patients with HD, patients without sarcopenia were further divided into dynapenia and non-dynapenia groups. Among 150 patients without sarcopenia, 46 were diagnosed with dynapenia. In the Kaplan-Meier analysis, the rate of CV events was significantly different among the three groups in a stratified manner, with the highest rate in the sarcopenia group and the lowest rate in the non-sarco-dynapenia group. Both patients with sarcopenia and dynapenia had significantly increased CV events compared to those with non-sarco-dynapenia (HR 8.00; 95% CI 2.73-34.1; p < 0.0001 vs. HR 4.85; 95% CI 1.28-23.0; p < 0.02). Both sarcopenia and dynapenia resulted in significantly higher CV events than non-sarco-dynapenia in patients undergoing HD. Therefore, clinicians should evaluate muscle function in addition to muscle quantity to estimate CV events in patients undergoing HD.

Achilles tendon thickness is associated with coronary lesion severity in acute coronary syndrome patients without familial hypercholesterolemia.

BACKGROUND: Thickening of Achilles tendon (≥9 mm on radiography) is one of the diagnostic criteria for familial hypercholesterolemia (FH). Since FH is associated with premature coronary artery disease (CAD) including acute coronary syndrome (ACS), measurement of Achilles tendon thickness (ATT) is important for early diagnosis of FH. However, clinical significance of mild thickening of Achilles tendon in non-FH patients with CAD is unclear. The present study investigated the association of ATT with coronary lesion severity in early-onset ACS without clinically diagnosed FH. METHODS: From outpatients who had a history of ACS under 60 years old, 76 clinically non-FH subjects (71 men and 5 women; mean age at the onset of ACS, 50.5 years) with maximum ATT of <9 mm were enrolled in this study. The severity of coronary lesions was assessed by SYNTAX score derived from coronary angiography at the onset of ACS. RESULTS: ATT levels were not significantly different among patients with ST-elevation myocardial infarction (STEMI, n=47), non-STEMI (n=12), and unstable angina (n=17). Whereas, both average and maximum ATT were significantly larger in patients with multivessel lesions (n=25) than in those with single-vessel disease (n=51). Furthermore, SYNTAX score was positively correlated with average ATT (r=0.368, p=0.0011) and maximum ATT (r=0.388, p=0.0005). As for the relation to clinical parameters, maximum ATT had positive correlations with body mass index and C-reactive protein. A multiple regression analysis revealed that average and maximum ATT were significantly associated with SYNTAX score, independently of various confounding factors. CONCLUSIONS: Our findings demonstrated that ATT, even though its level was <9 mm, was associated with coronary lesion severity in clinically non-FH patients with early-onset ACS. Apart from diagnosing FH, ATT may be a predictor of the progression of CAD.

Angioscopic Ulcerated Plaques in the Femoropopliteal Artery Associated with Impaired Infrapopliteal Runoff.

PURPOSE: To determine the correlation between upstream atherosclerosis in the femoropopliteal arteries, assessed using angioscopy, and impaired infrapopliteal runoff. MATERIALS AND METHODS: Thirty-one patients with peripheral arterial disease who underwent endovascular therapy and angioscopy were prospectively included. Yellow plaque color scores were semiquantitatively determined as 0, 1, 2, or 3. Irregular plaques with rough surfaces, similar to gastric ulcers, were defined as ulcerated plaques (UPs). Angioscopic data were correlated with angiographic runoff scores (ARS). RESULTS: UPs were detected in 74.2% of enrolled diseased legs using angioscopy. Mural thrombi were more commonly observed in the femoropopliteal artery in patients with UPs than in those without UPs (91.3% vs 37.5%, respectively; P = .006) and were frequently found on the UPs (21/23 patients with UPs). Univariate and multivariate linear regression analyses revealed that the presence of UPs was positively and independently associated with a poor ARS and that oral anticoagulant use was independently associated with a preferable ARS (standardized ß = 0.462, P = .004 and standardized ß = -0.411, P = .009, respectively, in the multivariate analysis). CONCLUSIONS: UPs, associated with mural thrombi and diagnosed by angioscopic examination, were demonstrated to be one of the factors associated with poor infrapopliteal runoff.

Kihon checklist is useful for predicting outcomes in patients undergoing transcatheter aortic valve implantation.

BACKGROUND: Frailty is a major risk factor for death and disability following transcatheter aortic valve implantation (TAVI). The Kihon checklist (KCL) is a simple self-reporting yes/no survey consisting of 25 questions and is used as a screening tool to identify frailty in the primary care setting. No clinical studies have focused on frailty calculated by the KCL in the TAVI cohort. We investigated the 3-year prognostic impact of frailty evaluated by the KCL in patients who underwent TAVI. METHODS: This single-center prospective observational study included 280 consecutive patients with symptomatic severe aortic stenosis who underwent TAVI and evaluated pre-procedural physical performance focused on frailty at our institution. We assessed all patients' frailty by the KCL before TAVI, as described previously. We set the primary endpoint as the 3-year all-cause mortality after TAVI. RESULTS: The median patient age was 84 years (interquartile range, 81-87 years), and 31.1% were men. In the receiver operating characteristics curve, there were no significant differences between the KCL and Cardiovascular Health Study frailty index [area under the curve (AUC) 0.625 versus 0.628; p=0.93), KCL and Rockwood Clinical Frailty Scale (AUC 0.625 versus 0.542; p=0.15), and KCL and Short Physical Performance Battery (AUC 0.625 versus 0.612; p=0.91). The first and second tertiles of the total KCL score were 8 and 12, respectively. The multivariate Cox regression model indicated that the total KCL score [hazard ratio (HR), 1.104; 95% confidence interval (CI), 1.034-1.179; p=0.003], presence of diabetes mellitus (HR, 1.993; CI, 1.055-3.766; p=0.03), and presence of liver disease (HR, 3.007; CI, 1.067-8.477; p=0.04) were independently associated with 3-year all-cause mortality. CONCLUSIONS: The KCL is a simple and useful tool for evaluating frailty status and predicting 3-year all-cause mortality in patients undergoing TAVI.

Artificial intelligence-based detection of aortic stenosis from chest radiographs.

Aims: We aimed to develop models to detect aortic stenosis (AS) from chest radiographs-one of the most basic imaging tests-with artificial intelligence. Methods and results: We used 10 433 retrospectively collected digital chest radiographs from 5638 patients to train, validate, and test three deep learning models. Chest radiographs were collected from patients who had also undergone echocardiography at a single institution between July 2016 and May 2019. These were labelled from the corresponding echocardiography assessments as AS-positive or AS-negative. The radiographs were separated on a patient basis into training [8327 images from 4512 patients, mean age 65 ± (standard deviation) 15 years], validation (1041 images from 563 patients, mean age 65 ± 14 years), and test (1065 images from 563 patients, mean age 65 ± 14 years) datasets. The soft voting-based ensemble of the three developed models had the best overall performance for predicting AS with an area under the receiver operating characteristic curve, sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of 0.83 (95% confidence interval 0.77-0.88), 0.78 (0.67-0.86), 0.71 (0.68-0.73), 0.71 (0.68-0.74), 0.18 (0.14-0.23), and 0.97 (0.96-0.98), respectively, in the validation dataset and 0.83 (0.78-0.88), 0.83 (0.74-0.90), 0.69 (0.66-0.72), 0.71 (0.68-0.73), 0.23 (0.19-0.28), and 0.97 (0.96-0.98), respectively, in the test dataset. Conclusion: Deep learning models using chest radiographs have the potential to differentiate between radiographs of patients with and without AS. Lay Summary: We created artificial intelligence (AI) models using deep learning to identify aortic stenosis (AS) from chest radiographs. Three AI models were developed and evaluated with 10 433 retrospectively collected radiographs and labelled from echocardiography reports. The ensemble AI model could detect AS in a test dataset with an area under the receiver operating characteristic curve of 0.83 (95% confidence interval 0.78-0.88). Since chest radiography is a cost-effective and widely available imaging test, our model can provide an additive resource for the detection of AS.

The Impact of Aorto-Mitral Angle on New-Onset Atrial Arrhythmia after Mitral Valve Repair in Patients with Mitral Regurgitation.

In this study, we hypothesized that post-operative aorto-mitral angle might be associated to the occurrence of post-operative atrial arrhythmia (AA), including atrial fibrillation and atrial tachycardia, after mitral valve repair in patients with mitral regurgitation (MR). Thus, this present study aims to determine the effects of post-operative aorto-mitral angle on new-onset AA after mitral valve repair with mitral annuloplasty for the treatment of MR.In total, 172 patients without any history of AA underwent mitral valve repair with mitral annuloplasty in our institution between 2008 and 2017. Patient information, including medical records and echocardiographic data, were retrospectively studied.As per our findings, AA occurred in 15 (8.7%) patients during the follow-up period (median, 35.7 months; range, 0.5-132 months). The patients with AA were noted to have a longer cardiopulmonary bypass time and a smaller aorto-mitral angle at post-operative TTE than the others (119 ± 6° versus 125 ± 10°, P = 0.003). No significant difference was noted in the degree of post-operative residual MR or functional MS between the groups. In a multivariate Cox proportional hazards analysis, the longer cardiopulmonary bypass time and the smaller post-operative aorto-mitral angle were independent predictors of the occurrence of AA during the follow-up period (odds ratio per 10 minutes 1.11; 95% CI 1.02-1.22, P = 0.019: odds ratio 0.91; 95% CI 0.85-0.98, P = 0.012).A small aorto-mitral angle at post-operative TTE was determined to be a predictor of new-onset AA after a mitral valve repair for treating MR.

Increased oxidative stress during exercise predicts poor prognosis in patients with acute decompensated heart failure.

AIMS: Oxidative stress plays an important role in the development and progression of heart failure (HF). Although exercise and oxidative stress are closely related, the effect of acute exercise on reactive oxygen species production and the fluctuation on prognosis are unclear. METHODS AND RESULTS: We enrolled 94 patients who were hospitalized for worsening HF (mean age 68.0 ± 14.5 years old, 63.8% male). The changes in diacron-reactive oxygen metabolites (d-ROM) values, a marker of oxidative stress, before and after a cardiopulmonary exercise test were considered as Δd-ROM. The mean follow-up period was 24 ± 13 months, during which 15 patients had all-cause death or left ventricular assist system implantation. Kaplan-Meier analysis demonstrated that all-cause death or left ventricular assist system implantation was significantly higher in the Δd-ROM-positive group than in the Δd-ROM-negative group (log-rank P = 0.047). Elevated Δd-ROM levels were associated with increased mortality risk. Multivariate analysis adjusted for body mass index and peak oxygen uptake revealed that Δd-ROM was an independent prognostic factor of adverse events (Tertile 3 vs. 1; hazard ratio: 4.57; 95% confidence interval: 1.21-29.77; P = 0.022). CONCLUSIONS: Patients with HF who underwent a cardiopulmonary exercise test and had an increased oxidative stress marker level had a poor prognosis. The appropriate exercise intensity could be determined by evaluating the changes in oxidative stress status in response to acute exercise in patients with HF.

Enhancement patterns detected by multidetector computed tomography are associated with the long-term prognosis of patients with acute myocardial infarction.

The present study investigated the clinical value of myocardial contrast-delayed enhancement (DE) with multidetector computed tomography (MDCT) without iodine re-injection immediately after primary percutaneous coronary intervention (PCI) for predicting future cardiovascular events after acute myocardial infarction (AMI). We performed a prospective study in which 263 consecutive patients with first AMI successfully treated with primary PCI were enrolled. Sixty-four-slice MDCT without the re-injection of contrast medium was performed immediately after PCI. Myocardial DE was considered to be transmural when involving myocardial thickness ≥ 75% (Group A; n = 104), subendocardial (< 75%, Group B; n = 108), or normal (Group C; n = 51). A semiquantitative scale score was defined for 17 left ventricular segments to investigate the extent of the DE area assessed. We examined the relationship between the presence or absence of transmural DE and long-term cardiovascular event rates. The median follow-up period was 3.5 years. Kaplan-Meier survival curves showed that patient prognosis was poorer in the group with Group A than that in the group with Group B, which was equivalent to that with Group C. A multivariate analysis identified the presence of transmural DE as the strongest predictor for future cardiovascular events (hazard ratio: 3.7; P = 0.023). Transmural myocardial DE immediately following primary PCI without an iodine re-injection for AMI is a major risk factor for future cardiovascular events.

Difference in risk factors of silent brain infarction between paroxysmal and persistent atrial fibrillation.

BACKGROUND: Although silent brain infarction is an independent risk factor for subsequent symptomatic stroke and dementia in patients with nonvalvular atrial fibrillation, little is known regarding differences in risk factors for silent brain infarction between patients with paroxysmal and persistent nonvalvular atrial fibrillation. METHODS: This study population consisted of 190 neurologically asymptomatic patients (mean age, 64 ± 11 years) with nonvalvular atrial fibrillation (119 paroxysmal, 71 persistent) who were scheduled for catheter ablation. All patients underwent brain magnetic resonance imaging to screen for silent brain infarction prior to ablation. Transthoracic and transesophageal echocardiography was performed to screen for left atrial abnormalities (left atrial enlargement, spontaneous echo contrast, or left atrial appendage emptying velocity) and complex plaques in the aortic arch. RESULTS: Silent brain infarction was detected in 50 patients (26%) [26 patients (22%) in paroxysmal vs. 24 patients (34%) in persistent, p = 0.09]. Multiple logistic regression analysis indicated that age and diabetes mellitus or chronic kidney disease (estimated glomerular filtration rate < 60 mL/min/1.73 m2) were associated with silent brain infarction in patients with paroxysmal nonvalvular atrial fibrillation (p < 0.05), whereas no modifiable risk factors of silent brain infarction were observed in patients with persistent nonvalvular atrial fibrillation. CONCLUSIONS: These findings suggest that intensive intervention for diabetes mellitus and renal impairment from the paroxysmal stage or ablation therapy at the time of paroxysmal stage to prevent progression to persistent nonvalvular atrial fibrillation may prevent silent brain infarction and consequently reduce the risk of future symptomatic stroke.

Comparative Effects of Etelcalcetide and Maxacalcitol on Serum Calcification Propensity in Secondary Hyperparathyroidism: A Randomized Clinical Trial.

BACKGROUND AND OBJECTIVES: Vitamin D receptor activators and calcimimetics (calcium-sensing receptor agonists) are two major options for medical treatment of secondary hyperparathyroidism. A higher serum calcification propensity (a shorter T50 value) is a novel surrogate marker of calcification stress and mortality in patients with CKD. We tested a hypothesis that a calcimimetic agent etelcalcetide is more effective in increasing T50 value than a vitamin D receptor activator maxacalcitol. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A randomized, multicenter, open-label, blinded end point trial with active control was conducted in patients with secondary hyperparathyroidism undergoing hemodialysis in Japan. Patients were randomly assigned to receive intravenous etelcalcetide 5 mg thrice weekly (etelcalcetide group) or intravenous maxacalcitol 5 or 10 µg thrice weekly (maxacalcitol group). The primary, secondary, and tertiary outcomes were changes in T50 value, handgrip strength, and score of the Dementia Assessment Sheet for Community-Based Integrated Care System from baseline to 12 months, respectively. RESULTS: In total, 425 patients from 23 dialysis centers were screened for eligibility, 326 patients were randomized (etelcalcetide, n=167; control, n=159), and 321 were included in the intention-to-treat analysis (median age, 66 years; 113 women [35%]). The median (interquartile range) of T50 value was changed from 116 minutes (interquartile range, 90-151) to 131 minutes (interquartile range, 102-176) in the maxacalcitol group, whereas it was changed from 123 minutes (interquartile range, 98-174) to 166 minutes (interquartile range, 127-218) in the etelcalcetide group. The increase in T50 value was significantly greater in the etelcalcetide group (difference in change, 20 minutes; 95% confidence interval, 7 to 34 minutes; P=0.004). No significant between-group difference was found in the change in handgrip strength or in the Dementia Assessment Sheet for Community-Based Integrated Care System score. CONCLUSIONS: Etelcalcetide was more effective in increasing T50 value than maxacalcitol among patients on hemodialysis with secondary hyperparathyroidism. There was no difference in handgrip strength or cognition between the two drugs. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: VICTORY; UMIN000030636 and jRCTs051180156.

Rivaroxaban Attenuates Right Ventricular Remodeling in Rats with Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive condition that frequently results in right ventricular (RV) remodeling. The objectives of this study are to investigate effects of rivaroxaban on RV remodeling in a rat model of PAH, created with Sugen5416 and chronic hypoxia, and the in vitro effects of rivaroxaban on human cardiac microvascular endothelial cells (HCMECs). To create the PAH model, male Sprague-Dawley rats were subcutaneously injected with Sugen5416 (20 mg/kg) and exposed to 2 weeks of hypoxia (10% O2), followed by 2 weeks of exposure to normoxia. The animals were then divided into 2 groups with or without administration of rivaroxaban (12 mg/kg/d) for a further 4 weeks. HCMECs were cultured under hypoxic conditions (37 °C, 1% O2, 5% CO2) with Sugen5416 and with or without rivaroxaban. In the model rats, RV systolic pressure and Fulton index increased by hypoxia with Sugen5416 were significantly decreased when treated with rivaroxaban. In HCMECs, hypoxia with Sugen5416 increased the expression of protease-activated receptor-2 (PAR-2) and the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB), while treatment with rivaroxaban significantly suppressed the expression of these proteins. Rivaroxaban attenuated RV remodeling in a rat model of PAH by reducing ERK, JNK and NF-κB activation. Rivaroxaban has the possibility of providing additive effects on RV remodeling in patients with PAH.