Low-intensity pulsed ultrasound alleviates doxorubicin-induced cardiotoxicity via inhibition of S100a8/a9-mediated cardiac recruitment of neutrophils.

Doxorubicin (DOX)-induced cardiotoxicity limits its broad use as a chemotherapy agent. The development of effective and non-invasive strategies to prevent DOX-associated adverse cardiac events is urgently needed. We aimed to examine whether and how low-intensity pulsed ultrasound (LIPUS) plays a protective role in DOX-induced cardiotoxicity. Male C57BL/6J mice were used to establish models of both acute and chronic DOX-induced cardiomyopathy. Non-invasive LIPUS therapy was conducted for four consecutive days after DOX administration. Cardiac contractile function was evaluated by echocardiography. Myocardial apoptosis, oxidative stress, and fibrosis were analyzed using terminal deoxynucleotidyl transferase-mediated dUTP nick end labelling (TUNEL) staining, dihydroethidium (DHE) staining, and picrosirius red staining assays. RNA-seq analysis was performed to unbiasedly explore the possible downstream regulatory mechanisms. Neutrophil recruitment and infiltration in the heart were analyzed by flow cytometry. The S100a8/a9 inhibitor ABR-238901 was utilized to identify the effect of S100a8/a9 signaling. We found that LIPUS therapy elicited a great benefit on DOX-induced heart contractile dysfunction in both acute and chronic DOX models. Chronic DOX administration increased serum creatine kinase and lactate dehydrogenase levels, as well as myocardial apoptosis, all of which were significantly mitigated by LIPUS. In addition, LIPUS treatment prevented chronic DOX-induced cardiac oxidative stress and fibrosis. RNA-seq analysis revealed that LIPUS treatment partially reversed alterations of gene expression induced by DOX. Gene ontology (GO) analysis of the downregulated genes between DOX-LIPUS and DOX-Sham groups indicated that inhibition of neutrophil chemotaxis might be involved in the protective effects of LIPUS therapy. Flow cytometry analysis illustrated the inhibitory effects of LIPUS on DOX-induced neutrophil recruitment and infiltration in the heart. Moreover, S100 calcium binding protein A8/A9 (S100a8/a9) was identified as a potential key target of LIPUS therapy. S100a8/a9 inhibition by ABR-238901 showed a similar heart protective effect against DOX-induced cardiomyopathy to LIPUS treatment. LIPUS therapy prevents DOX-induced cardiotoxicity through inhibition of S100a8/a9-mediated neutrophil recruitment to the heart, suggesting its potential application in cancer patients undergoing chemotherapy with DOX.

An IL-6/STAT3/MR/FGF21 axis mediates heart-liver cross-talk after myocardial infarction.

The liver plays a protective role in myocardial infarction (MI). However, very little is known about the mechanisms. Here, we identify mineralocorticoid receptor (MR) as a pivotal nexus that conveys communications between the liver and the heart during MI. Hepatocyte MR deficiency and MR antagonist spironolactone both improve cardiac repair after MI through regulation on hepatic fibroblast growth factor 21 (FGF21), illustrating an MR/FGF21 axis that underlies the liver-to-heart protection against MI. In addition, an upstreaming acute interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway transmits the heart-to-liver signal to suppress MR expression after MI. Hepatocyte Il6 receptor deficiency and Stat3 deficiency both aggravate cardiac injury through their regulation on the MR/FGF21 axis. Therefore, we have unveiled an IL-6/STAT3/MR/FGF21 signaling axis that mediates heart-liver cross-talk during MI. Targeting the signaling axis and the cross-talk could provide new strategies to treat MI and heart failure.

Periodontitis exacerbates atherosclerosis through Fusobacterium nucleatum-promoted hepatic glycolysis and lipogenesis.

AIMS: Positive associations between periodontitis (PD) and atherosclerosis have been established, but the causality and mechanisms are not clear. We aimed to explore the causal roles of PD in atherosclerosis and dissect the underlying mechanisms. METHODS AND RESULTS: A mouse model of PD was established by ligation of molars in combination with application of subgingival plaques collected from PD patients and then combined with atherosclerosis model induced by treating atheroprone mice with a high-cholesterol diet (HCD). PD significantly aggravated atherosclerosis in HCD-fed atheroprone mice, including increased en face plaque areas in whole aortas and lesion size at aortic roots. PD also increased circulating levels of triglycerides and cholesterol, hepatic levels of cholesterol, and hepatic expression of rate-limiting enzymes for lipogenesis. Using 16S ribosomal RNA (rRNA) gene sequencing, Fusobacterium nucleatum was identified as the most enriched PD-associated pathobiont that is present in both the oral cavity and livers. Co-culture experiments demonstrated that F. nucleatum directly stimulated lipid biosynthesis in primary mouse hepatocytes. Moreover, oral inoculation of F. nucleatum markedly elevated plasma levels of triglycerides and cholesterol and promoted atherogenesis in HCD-fed ApoE-/- mice. Results of RNA-seq and Seahorse assay indicated that F. nucleatum activated glycolysis, inhibition of which by 2-deoxyglucose in turn suppressed F. nucleatum-induced lipogenesis in hepatocytes. Finally, interrogation of the molecular mechanisms revealed that F. nucleatum-induced glycolysis and lipogenesis by activating PI3K/Akt/mTOR signalling pathway in hepatocytes. CONCLUSIONS: PD exacerbates atherosclerosis and impairs lipid metabolism in mice, which may be mediated by F. nucleatum-promoted glycolysis and lipogenesis through PI3K/Akt/mTOR signalling in hepatocytes. Treatment of PD and specific targeting of F. nucleatum are promising strategies to improve therapeutic effectiveness of hyperlipidaemia and atherosclerosis.

Major adverse cardiac events and functional capacity in patients at intermediate risk undergoing transcatheter versus surgical aortic valve replacement for aortic stenosis with bicuspid valves.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) is not always the optimal option for aortic valve stenosis (AS) patients with bicuspid aortic valves (BcAVs) and many studies exclude this group of patients. The aim of our study was to compare the rate of a major adverse cardiovascular event (MACE) and functional capacity in AS patients with BcAV after surgical aortic valve replacement (SAVR) and TAVR. METHODS: This study included 130 patients who underwent SAVR or TAVR from July 2013 to August 2018 at the Cheng Hsin General Hospital. The main outcome was MACE. Events recorded included noncardiovascular (CV) mortality, CV mortality, recurrent nonfatal stroke, recurrent nonfatal myocardial infarction (MI), and important events. The secondary outcome was functional recovery, which was defined according to the metabolic equivalent (MET) 6 months after the aortic procedure. RESULTS: The mean age of patients was 56.8 ± 26.9 years and the mean Society of Thoracic Surgeons score was 3.29 ± 4.69. Logistic regression analyses indicated that SAVR was a significant predictor of functional recovery. Patients who underwent SAVR had a higher rate of functional recovery (>3 METs; 87.8%, p = .000) and had a significantly higher odds ratio (3.56; 95% confidence interval, 1.19-10.63, p = .023). The Kaplan-Meier survival analysis showed that the MACE rate was not associated with the aortic procedure. CONCLUSIONS: Our analysis showed that SAVR is a significant predictor of better functional recovery and TAVR is associated with a lower level of functional capacity. In summary, TAVR is an acceptable option for AS patients with BcAV, and for a better prognosis, an early intervention aimed at improving functional capacity is highly recommended for this group of patients.

Predicting exercise capacity recovery immediately after mitral valve surgery.

BACKGROUND: This study presents the exercise capacity of postmitral valve surgery patients and determines predictors capable of affecting recovery. METHODS: A total of 302 patients with mitral regurgitation who had undergone mitral surgery at the Heart Center in Taiwan from 1 August 2013 to 31 December 2015 were included in the present study. Data related to specific predictors of operative outcome were collected, including demographic data, intraoperative factors, exercise tolerance, echocardiogram data, concurrent cardiovascular disease history, comorbidities, lifestyle risk factors, and surgery types. Postoperative exercise capacity was presented as peak oxygen consumption (VO2 ; mL of O 2 /kg/min) determined by exercise tests 3 weeks after surgery. Subjects were separated into two groups: a preserved recovery (peak VO 2 ≥ 65% of predicted VO 2max ) group and a poor recovery group (peak VO 2 < 65% of predicted VO 2max ). Preliminary univariate analysis was performed to test for possible relationships between predictive variables and exercise capacity. An analysis of all items shown to be significantly different between the two groups was then subjected to multivariate logistic regression analysis. Detected differences with P < .05 were considered significant. RESULTS: Among the 302 patients sampled, female sex (odds ratio [OR], 2.65; 95% confidence interval [95% CI], 1.58-4.47), obesity (OR, 0.26; 95% CI, 0.10-0.64), sedentary lifestyle (OR, 0.47; 95% CI, 0.28-0.79), and high preoperative New York Heart Association Functional Classification level (OR, 0.52; 95% CI, 0.31-0.87) were significant predictors of poor exercise capacity. CONCLUSIONS: Without complicated clinical procedures, physicians and medical teams could easily use these items of information to screen the exercise capacity of mitral valve surgery patients and prepare a suitable after surgery plan if needed or request a consultation as early as possible.

Elevated sodium chloride drives type I interferon signaling in macrophages and increases antiviral resistance.

Type I IFN production and signaling in macrophages play critical roles in innate immune responses. High salt (i.e. high concentrations of NaCl) has been proposed to be an important environmental factor that influences immune responses in multiple ways. However, it remains unknown whether high salt regulates type I IFN production and signaling in macrophages. Here, we demonstrated that high salt promoted IFNß production and its signaling in both human and mouse macrophages, and consequentially primed macrophages for strengthened immune sensing and signaling when challenged with viruses or viral nucleic acid analogues. Using both pharmacological inhibitors and RNA interference we showed that these effects of high salt on IFNß signaling were mediated by the p38 MAPK/ATF2/AP1 signaling pathway. Consistently, high salt increased resistance to vesicle stomatitis virus (VSV) infection in vitro. In vivo data indicated that a high-salt diet protected mice from lethal VSV infection. Taken together, these results identify high salt as a crucial regulator of type I IFN production and signaling, shedding important new light on the regulation of innate immune responses.

Application of the Transtheoretical Model to Exercise Behavior and Physical Activity in Patients after Open Heart Surgery.

PURPOSE: To assess exercise behavior and physical activity levels after open heart surgery. METHODS: This prospective cohort study included 130 patients (70.8% male, aged 61.0 ± 12.2 years, 53.8% coronary bypass grafting) who underwent open heart surgery. The exercise behavior and physical activity of these patients were assessed at the 3- and 6-month follow-up appointments. Additional interviews were also conducted to further assess exercise behavior. Physical activity duration and metabolic equivalents were calculated from self-reported questionnaire responses. Moreover, possible related demographic factors, clinical features, participation in cardiac rehabilitation programs, and physical activity levels were additionally evaluated. RESULTS: Six months after hospital discharge, most patients were in the action (39.2%) and maintenance (37.7%) stages. Other subjects were in the precontemplation (11.5%), contemplation (5.4%), and preparation (6.2%) stages. The average physical activity level was 332.6 ± 377.1 min/week and 1198.1 ± 1396.9 KJ/week. Subjects in the action and maintenance stages exercised an average of 399.4 ± 397.6 min/week, significantly longer than those in other stages (116.2 ± 176.2 min/week, p = 0.02). Subjects that participated in outpatient cardiac rehabilitation programs after discharge may have the better exercise habit. Gender had no significant effect on exercise behavior 6 months after hospital discharge. CONCLUSIONS: Most subjects following open heart surgery may maintain regular exercise behavior at 6 months after hospital discharge. Physical activity levels sufficient for cardiac health were achieved by subjects in the active and maintenance stages. Outpatient cardiac rehabilitation programs are valuable for encouraging exercise behavior after heart surgery. KEY WORDS: Exercise behavior; Open heart surgery; Physical activity; Transtheoretical model.