Noninvasive Stereotactic Radiotherapy for PADN in an Acute Canine Model of Pulmonary Arterial Hypertension.

This study assesses the feasibility, safety, and effectiveness of noninvasive stereotactic body radiotherapy (SBRT) as an approach for pulmonary artery denervation in canine models. SBRT with CyberKnife resulted in reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance, and insignificantly increased cardiac output. In comparison to the control group, serum norepinephrine levels at 1 month and 6 months were significantly lower in the CyberKnife group. Computed tomography, pulmonary angiography, and histology analysis revealed that SBRT was associated with minimal collateral damage.

How to effectively manage the refractory coronary thrombus? A systemic mini-review.

The main management principle for patients with coronary thrombus should be "more removal and less implantation". Routine thrombus aspiration (TA) is ineffective for intracoronary thrombus or high residual thrombus burden after TA and may result in a refractory coronary thrombus. It is unwise to implant a stent in the vessel with high residual thrombus, which is associated with no-reflow, impaired microvascular perfusion, and consequently worse clinical outcomes. Therefore, increasing the efficiency of TA during percutaneous coronary intervention procedures, especially under some conditions of refractory coronary thrombus, is very important to restore myocardial reperfusion and improve microvascular dysfunction early. In the present work, we aimed to demonstrate the factors that may affect TA efficiency and introduce several highly effective approaches to treat refractory coronary thrombus.

Bacteroides fragilis prevents aging-related atrial fibrillation in rats via regulatory T cells-mediated regulation of inflammation.

BACKGROUND: Aging plays a critical role in the genesis of atrial fibrillation (AF) and also changes the gut microbes. Whether the aging-associated gut dysbiosis contributes to the development of aging-related AF and whether the gut microbes can be a target to prevent aging-related AF remains unknown. METHODS AND RESULTS: 16S rRNA gene sequencing was performed to reveal the changes of gut microbes in elderly patients with AF, and the result showed that the intestinal abundance of B. fragilis was significantly decreased in elderly patients with AF. Subsequently, we examined the impact of B. fragilis supplementation on AF promotion, atrial structural remodeling and inflammation response in D-galactose induced aging rats. We found that oral administration of B. fragilis prevented AF inducibility and duration, which was associated with attenuation of atrial senescence, apoptosis and fibrosis. Furthermore, B. fragilis significantly diminished the systemic and atrial inflammation, which is accompanied by an increase in the number of Treg cells in the spleen and blood. More importantly, we found that the circulation level of polysaccharide A (PSA), the metabolite synthesized by B. fragilis, was reduced in elderly patients with AF and could predict the occurrence of AF, and B. fragilis increased the circulation concentration of PSA in D-galactose induced aging rats. CONCLUSIONS: The abundance of B. fragilis was lower in elderly patients with AF. Oral administration of B. fragilis significantly attenuated inflammatory response by increasing Treg cells, thereby preventing atrial structural remodeling and inhibiting AF promotion in D-galactose induced aging rats. This study provides experimental evidence for the effectiveness of targeting gut microbes in the prevention of aging-related AF.

Gut microbiota dysbiosis promotes age-related atrial fibrillation by lipopolysaccharide and glucose-induced activation of NLRP3-inflammasome.

AIMS: Ageing is the most significant contributor to the increasing prevalence of atrial fibrillation (AF). The gut microbiota dysbiosis is involved in age-related diseases. However, whether the aged-associated dysbiosis contributes to age-related AF is still unknown. Direct demonstration that the aged gut microbiota is sufficient to transmit the enhanced AF susceptibility in a young host via microbiota-intestinal barrier-atria axis has not yet been reported. This study aimed to determine whether gut microbiota dysbiosis affects age-related AF. METHODS AND RESULTS: Herein, by using a faecal microbiota transplantation (FMT) rat model, we demonstrated that the high AF susceptibility of aged rats could be transmitted to a young host. Specially, we found the dramatically increased levels of circulating lipopolysaccharide (LPS) and glucose led to the up-regulated expression of NOD-like receptor protein (NLRP)-3 inflammasome, promoting the development of AF, which depended on the enhanced atrial fibrosis in recipient host. Inhibition of inflammasome by a potent and selective inhibitor of the NLRP3 inflammasome, MCC950, resulted in a lower atrial fibrosis and AF susceptibility. Then, we conducted cross-sectional clinical studies to explore the effect of ageing on the altering trends with glucose levels and circulating LPS among clinical individuals in two China hospitals. We found that both of serum LPS and glucose levels were progressively increased in elderly patients as compared with those young. Furthermore, the ageing phenotype of circulating LPS and glucose levels, intestinal structure and atrial NLRP3-inflammasome of rats were also confirmed in clinical AF patients. Finally, aged rats colonized with youthful microbiota restored intestinal structure and atrial NLRP3-inflammasome activity, which suppressed the development of aged-related AF. CONCLUSIONS: Collectively, these studies described a novel causal role of aberrant gut microbiota in the pathogenesis of age-related AF, which indicates that the microbiota-intestinal barrier-atrial NLRP3 inflammasome axis may be a rational molecular target for the treatment of aged-related arrhythmia disease.

Functional Evaluation of Intermediate Coronary Lesions with Integrated Computed Tomography Angiography and Invasive Angiography in Patients with Stable Coronary Artery Disease.

Background and objectives: The hemodynamic evaluation of coronary stenoses undergoes a transition from wire-based invasive measurements to image-based computational assessments. However, fractional flow reserve (FFR) values derived from coronary CT angiography (CCTA) and angiography-based quantitative flow ratio have certain limitations in accuracy and efficiency, preventing their widespread use in routine practice. Hence, we aimed to investigate the diagnostic performance of FFR derived from the integration of CCTA and invasive angiography (FFRCT-angio) with artificial intelligence assistance in patients with stable coronary artery disease (CAD). Methods: Forty stable CAD patients with 67 target vessels (50%-90% diameter stenosis) were included in this single-center retrospective study. All patients underwent CCTA followed by coronary angiography with FFR measurement within 30 days. Both CCTA and angiographic images were combined to generate a three-dimensional reconstruction of the coronary arteries using artificial intelligence. Subsequently, functional assessment was performed through a deep learning algorithm. FFR was used as the reference. Results: FFRCT-angio values were significantly correlated with FFR values (r = 0.81, P < 0.001, Spearman analysis). Per-vessel diagnostic accuracy of FFRCT-angio was 92.54%. Sensitivity and specificity in identifying ischemic lesions were 100% and 88.10%, respectively. Positive predictive value and negative predictive value were 83.33% and 100%, respectively. Moreover, the diagnostic performance of FFRCT-angio was satisfactory in different target vessels and different segment lesions. Conclusions: FFRCT-angio exhibits excellent diagnostic performance of identifying ischemic lesions in patients with stable CAD. Combining CCTA and angiographic imaging, FFRCT-angio may represent an effective and practical alternative to invasive FFR in selected patients.

Lnc-C2orf63-4-1 Confers VSMC Homeostasis and Prevents Aortic Dissection Formation via STAT3 Interaction.

Emerging evidence indicates that long non-coding RNAs (lncRNAs) serve as a critical molecular regulator in various cardiovascular diseases. Here, we aimed to identify and functionally characterize lncRNAs as potential mediators in the development of thoracic aortic dissection (TAD). We identified that a novel lncRNA, lnc-C2orf63-4-1, was lowly expressed in aortic samples of TAD patients and angiotensin II (Ang II)-challenged vascular smooth muscle cells (VSMCs), which was correlated with clinically aortic expansion. Besides, overexpression of lnc-C2orf63-4-1 significantly attenuated Ang II-induced apoptosis, phenotypic switching of VSMCs and degradation of extracellular matrix both in vitro and in vivo. A customized transcription factor array identified that signal transducer and activator of transcription 3 (STAT3) functioned as the main downstream effector. Mechanistically, dual-luciferase report analysis and RNA antisense purification (RAP) assay indicated that lnc-C2orf63-4-1 directly decreased the expression of STAT3, which was depend on the reduced stabilization of STAT3 mRNA. Importantly, up-regulation of STAT3 efficiently reversed the protective role of lnc-C2orf63-4-1 against Ang II-mediated vascular remodeling. Therefore, lnc-C2orf63-4-1 negatively regulated the expression of STAT3 and prevented the development of aortic dissection. Our study revealed that lnc-C2orf63-4-1 played a critical role in vascular homeostasis, and its dysfunction exacerbated Ang II-induced pathological vascular remodeling.

Efficacy and safety of different ticagrelor regimens versus clopidogrel in patients with coronary artery disease: a retrospective multicenter study (SUPERIOR).

Current guidelines favor dual anti-platelet therapy with ticagrelor 90 mg BID (T90BID) over clopidogrel 75 mg QD (C75QD) in addition to aspirin for acute coronary syndrome. However, an increased risk of ticagrelor-related adverse events prompted the evaluation of low-dose regimens. This study (NCT03381742) retrospectively analyzed the data from 11 hospitals on 3,043 patients with coronary artery disease, who received C75QD, T90BID, ticagrelor 45 mg BID (T45BID), or ticagrelor 90 mg QD (T90QD). Compared with C75QD, both T45BID and T90QD showed significantly higher inhibition of platelet aggregation (P < .0001) and lower platelet-fibrin clot strength (P < .0001) induced by adenosine diphosphate. Furthermore, compared with T90BID, two low-dose regimens had a much lower minor bleeding rate and a significantly higher proportion of patients within the therapeutic window for P2Y12 receptor reactivity. There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite. Similar efficacy and safety outcomes were observed in the propensity score-matched analysis. In conclusion, the low-dose ticagrelor regimen, either T45BID or T90QD, may provide a more attractive benefit-risk profile than C75QD or T90BID.

Novel Findings and Therapeutic Targets on Cardioprotection of Ischemia/ Reperfusion Injury in STEMI.

Acute ST-segment elevation myocardial infarction (STEMI) remains a leading cause of morbidity and mortality around the world. A large number of STEMI patients after the infarction gradually develop heart failure due to the infarcted myocardium. Timely reperfusion is essential to salvage ischemic myocardium from the infarction, but the restoration of coronary blood flow in the infarct-related artery itself induces myocardial injury and cardiomyocyte death, known as ischemia/reperfusion injury (IRI). The factors contributing to IRI in STEMI are complex, and microvascular obstruction, inflammation, release of reactive oxygen species, myocardial stunning, and activation of myocardial cell death are involved. Therefore, additional cardioprotection is required to prevent the heart from IRI. Although many mechanical conditioning procedures and pharmacological agents have been identified as effective cardioprotective approaches in animal studies, their translation into the clinical practice has been relatively disappointing due to a variety of reasons. With new emerging data on cardioprotection in STEMI over the past few years, it is mandatory to reevaluate the effectiveness of "old" cardioprotective interventions and highlight the novel therapeutic targets and new treatment strategies of cardioprotection.

Effects of different doses of ticagrelor on platelet aggregation and endothelial function in diabetic patients with stable coronary artery disease.

We performed this study to observe the effects of different doses of ticagrelor and standard-dose clopidogrel on platelet reactivity and endothelial function in diabetic patients with stable coronary artery disease (CAD). Sixty type 2 diabetic patients were assigned to one-quarter standard-dose ticagrelor, half standard-dose ticagrelor, standard-dose ticagrelor and standard-dose clopidogrel groups. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. Endothelial function was assessed by measurement of flow-mediated vasodilation (FMD) and plasma von Willebrand factor (VWF) levels were detected. Enzyme-linked immunosorbent assay (ELISA) examined the Interleukin-8(IL-8) and IL-10. The results suggested that the one-quarter dose (34.0%± 14.7%), half-dose (26.9%± 11.6%) and standard-dose (17.3%± 10.3%) ticagrelor showed lower platelet aggregation rate than clopidogrel (52.8%± 18.3%; P ï¼œ0.0001). PRU values in three ticagrelor groups were lower than that in clopidogrel group (102 (76-184)；75 (33-88)；38 (11-52) versus 194 (138-271) and；P ï¼œ0.0001). FMD levels were higher in ticagrelor groups compared with baseline levels while lower in clopidogrel group after treatment. However, no significant differences were found in the percentage increase in the FMD between ticagrelor groups and clopidogrel group. The levels of VWF after treatment were lower than the baseline levels, but there was no statistically significant difference between ticagrelor group and clopidogrel group after treatment. The concentration of IL-8 and IL-10 were decreased in patients with half and standard-dose ticagrelor group. In conclusion, one-quarter standard-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose clopidogrel in diabetic patients with stable CAD. The half standard-dose ticagrelor had a similar inhibitory effect on platelet inhibition as standard-dose ticagrelor, which was stronger than that of clopidogrel. Moreover, the half-dose ticagrelor had equal protection of endothelial function and inhibition of inflammatory factor as standard-dose ticagrelor.

Metoprolol has a similar therapeutic effect as amlodipine on BP lowering in hypertensive patients with obstructive sleep apnea.

PURPOSE: ß-Blocker use has been controversial for a long time in the management of hypertensive patients with obstructive sleep apnea (OSA). The aim of present study was to compare the effects of metoprolol on BP lowering with amlodipine in hypertensive OSA patients. METHODS: Hypertensive subjects with OSA were randomly assigned to metoprolol and amlodipine groups, receiving 12 weeks of oral either metoprolol (47.5 mg once daily) or amlodipine (5 mg once daily) treatment. At baseline and after the 12-week treatment period, 24-h ambulatory blood pressure monitoring was performed in both groups. RESULTS: Both of metoprolol and amlodipine treatments significantly lowered 24-h blood pressure (BP) (from 143/88 to 132.3/81.6 mmHg; from 141.3/84.5 to 133.7/80.8 mmHg), daytime BP (from 146/90.2 to 136.4/84.6 mmHg; from 145.1/87.6 to 138.2/84.1 mmHg), and nighttime BP (from 139.1/83.9 to 125.7/76.2 mmHg; from 134.5/78.5 to 125.8/74.1 mmHg) (all P < 0.05). But there were no significant differences between the groups in BP variability (P > 0.05). Besides, metoprolol significantly reduced daytime heart rate (HR) (P < 0.05), while 24-h and nighttime HR values had no remarkable changes compared with baseline (P > 0.05). CONCLUSIONS: Metoprolol had similar therapeutic effects on BP lowering as amlodipine and could not decrease HR during the nighttime in hypertensive patients with OSA.

"Seesaw balloon-wire cutting" technique is superior to Tornus catheter in balloon uncrossable chronic total occlusions.

BACKGROUND: Inability to advance a balloon is a well-recognized cause leading to a failure in recanalization of chronic total occlusions (CTOs) despite successfully passing a guidewire. A few techniques and devices have been introduced to facilitate balloon passage, especially the use of Tornus catheter. However, complex manipulation, expensive cost, and availability limit the application of these methods. This study was to evaluate the efficiency and safety of "seesaw balloon-wire cutting" technique in comparison with Tornus catheter for balloon uncrossable CTOs. METHODS: Eighty patients with balloon uncrossable CTOs were enrolled in this study. Among them, 40 patients treated with "seesaw balloon-wire cutting" technique were consecutively investigated and 40 patients treated with Tornus catheter before were matched retrospectively. A rotablator or retrograde strategy was taken as a bail-out strategy. Success rates of device and procedure and complication rate were assessed. Complications included coronary dissection, cardiac tamponade, death, Q-wave myocardial infarction (MI), non-Q-wave MI, emergency PCI and bypass surgery. RESULTS: Compared with the Tornus catheter, device success rate was significantly higher with the "seesaw balloon-wire cutting" technique (87.5% vs. 45.0%, P<0.001), and the mean procedural time was much shorter (90.5±8.3min vs. 141.5±21.3min, P<0.001). The procedural success rate was also higher with the "seesaw balloon-wire cutting" technique (92.5% vs.72.5%, P=0.037). There were no differences in complication rate. CONCLUSION: The "seesaw balloon-wire cutting" technique is superior to the Tornus catheter in treating balloon uncrossable CTOs.

Presence of Severe Stenosis in Most Culprit Lesions of Patients with ST-segment Elevation Myocardial Infarction.

BACKGROUND: Previous studies revealed that culprit vessels of ST-segment elevation myocardial infarction (STEMI) were often related to mild or moderate stenosis. However, recent studies suggested that severe stenosis was primarily found in culprit lesions. The objective of this study was to analyze the stenosis severity of culprit lesions in STEMI patients and to clarify the paradoxical results. METHODS: A total of 489 consecutive STEMI patients who underwent primary percutaneous coronary intervention were retrospectively studied from January 2012 to December 2014. The patients were divided into three groups based on stenosis severity using quantitative coronary analysis: Group A, 314 cases, stenosis ≥70%; Group B, 127 cases, stenosis 50-70%; and Group C, 48 cases, stenosis ≤50%. The clinical, demographic, and angiographic data of all groups were analyzed. RESULTS: Patients in Group A exhibited a significantly higher prevalence of history of angina pectoris (95.9% vs. 62.5%, P< 0.001), multivessel disease (73.2% vs. 54.2%, P = 0.007), and lower cardiac ejection fraction (53.3 ± 8.6 vs. 56.8 ± 8.4, P= 0.009) than those in Group C. Multivariable analysis revealed that history of angina pectoris (odds ratio [OR]: 13.89, 95% confidence interval [CI]: 6.21-31.11) and multivessel disease (OR: 2.32, 95% CI: 1.25-4.31) were correlated with severe stenosis of the culprit lesion in Group A. CONCLUSIONS: Most culprit lesions in STEMI patients were severe stenosis. These patients exhibited a higher prevalence of angina history and multivessel diseases.

One-quarter standard-dose ticagrelor better than standard-dose clopidogrel in Chinese patients with stable coronary artery disease: A randomized, single-blind, crossover clinical study.

BACKGROUND: Ticagrelor has been demonstrated to provide a more rapid and powerful inhibition of platelet aggregation compared with clopidogrel in coronary artery disease (CAD) patients. In our previous study, we found that half-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose ticagrelor and exerted significantly stronger effects than clopidogrel in Chinese patients with non-ST-elevation ACS. Therefore, we performed this study to observe the efficacy of one-quarter standard-dose ticagrelor in comparison to standard-dose clopidogrel in Chinese patients with stable CAD. METHODS: In a randomized, single-blind, crossover trial, 30 patients with stable CAD were randomized to one-quarter standard-dose ticagrelor (22.5mg BID for 7days) or standard-dose clopidogrel (75mg QD for 7days). Following a 2-week washout period, patients switched regimens. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. RESULTS: The platelet aggregation rate (PAgR) was obviously lower with ticagrelor than clopidogrel (17.70%±12.67% versus 27.63%±13.10%, P<0.05). The % inhibition levels in the ticagrelor group exhibited significantly greater than that in the clopidogrel group (65.33%±21.31% versus 36.23%±23.01%, P<0.01). PRU values in the ticagrelor group were dramatically lower than that in the clopidogrel group (87.03±51.38 versus 163.77±58.66, P<0.01). High-platelet reactivity (HPR) (≥208 PRU) was 0% with ticagrelor and 16.67% with clopidogrel. CONCLUSIONS: One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard-dose clopidogrel in Chinese patients with stable CAD.