Prevention of neointimal hyperplasia after coronary artery bypass graft via local delivery of sirolimus and rosuvastatin: network pharmacology and in vivo validation.

BACKGROUND: Coronary artery bypass graft (CABG) is generally used to treat complex coronary artery disease. Treatment success is affected by neointimal hyperplasia (NIH) of graft and anastomotic sites. Although sirolimus and rosuvastatin individually inhibit NIH progression, the efficacy of combination treatment remains unknown. METHODS: We identified cross-targets associated with CABG, sirolimus, and rosuvastatin by using databases including DisGeNET and GeneCards. GO and KEGG pathway enrichment analyses were conducted using R studio, and target proteins were mapped in PPI networks using Metascape and Cytoscape. For in vivo validation, we established a balloon-injured rabbit model by inducing NIH and applied a localized perivascular drug delivery device containing sirolimus and rosuvastatin. The outcomes were evaluated at 1, 2, and 4 weeks post-surgery. RESULTS: We identified 115 shared targets between sirolimus and CABG among databases, 23 between rosuvastatin and CABG, and 96 among all three. TNF, AKT1, and MMP9 were identified as shared targets. Network pharmacology predicted the stages of NIH progression and the corresponding signaling pathways linked to sirolimus (acute stage, IL6/STAT3 signaling) and rosuvastatin (chronic stage, Akt/MMP9 signaling). In vivo experiments demonstrated that the combination of sirolimus and rosuvastatin significantly suppressed NIH progression. This combination treatment also markedly decreased the expression of inflammation and Akt signaling pathway-related proteins, which was consistent with the predictions from network pharmacology analysis. CONCLUSIONS: Sirolimus and rosuvastatin inhibited pro-inflammatory cytokine production during the acute stage and regulated Akt/mTOR/NF-κB/STAT3 signaling in the chronic stage of NIH progression. These potential synergistic mechanisms may optimize treatment strategies to improve long-term patency after CABG.

Sustained drug release behavior of captopril-incorporated chitosan/carboxymethyl cellulose biomaterials for antihypertensive therapy.

Captopril (CTP) is an oral drug widely used to treat high blood pressure and congestive heart failure. In this study, CTP-incorporated biomaterials for antihypertensive therapy were synthesized from chitosan, carboxymethyl cellulose, and plasticizers. The physicochemical properties of the prepared biomaterials were characterized using FE-SEM, FT-IR analysis, and physical properties. CTP release experiments were carried out in buffer solutions at various pH values and temperatures. Results indicated that above 99.0 % of CTP was released within 180 min. Optimization of the experimental conditions for CTP release was analyzed by using response surface methodology (RSM). Results of CTP release through artificial skin indicated that CTP was continuously released above 95.0 % from the prepared biomaterials for 36.0 h. The CTP release mechanisms into a buffer and through artificial skin followed pseudo-Fickian diffusion mechanism and non-Fickian diffusion mechanisms, respectively. Moreover, angiotensin-converting enzyme (ACE) inhibition (related to cardiovascular disease) via the released CTP clearly reveals that the prepared biomaterials have a high potential as a transdermal drug delivery agent in antihypertensive therapy.

Adipose Derived Stromal Vascular Fraction and Mesenchymal Stem Cells Improve Angiogenesis in a Rat Hindlimb Ischaemia Model.

OBJECTIVE: This study aimed to investigate the effect of human adipose tissue derived stromal vascular fraction (AD-SVF) and mesenchymal stem cells (AD-MSCs) on blood flow recovery and neovascularisation in a rat hindlimb ischaemia model. METHODS: SVF was isolated using an automated centrifugal system, and AD-MSCs were obtained from adherent cultures of SVF cells. Rats were divided into four groups of six rats each: non-ischaemia (Group 1); saline treated ischaemia (Group 2); SVF treated ischaemia (Group 3); and AD-MSC treated ischaemia (Group 4). Unilateral hindlimb ischaemia was induced in Sprague-Dawley rats via femoral artery ligation. Saline, SVF, or AD-MSCs were injected intramuscularly into the adductor muscle intra-operatively. Cell viability was calculated as the percentage of live cells relative to total cell number. Blood flow improvement, muscle fibre injury, and angiogenic properties were validated using thermal imaging and histological assessment. RESULTS: The viabilities of SVF and AD-MSCs were 83.3% and 96.7%, respectively. Group 1 exhibited no significant temperature difference between hindlimbs, indicating a lack of blood flow changes. The temperature gradient gradually decreased in SVF and AD-MSC treated rats compared with saline treated rats. In addition, only normal muscle fibres with peripherally located nuclei were observed in Group 1. Groups 3 and 4 exhibited significantly fewer centrally located nuclei, indicating less muscle damage compared with Group 2. Regarding angiogenic properties, CD31 staining of endothelial cells showed similar patterns among all groups, whereas expression of vascular endothelial growth factor, as a crucial angiogenesis factor, was enhanced in the SVF and AD-MSC treated groups. CONCLUSION: SVF and AD-MSCs improved blood flow and neovascularisation in a rat hindlimb ischaemia model, suggesting their potential ability to promote angiogenesis. Further extensive research is warranted to explore their potential applications in the treatment of severe lower extremity arterial disease.

Effect of sequential release of sirolimus and rosuvastatin using silk fibroin microneedle to prevent intimal hyperplasia.

Intimal hyperplasia (IH) is a major cause of vascular restenosis after bypass surgery, which progresses as a series of processes from the acute to chronic stage in response to endothelial damage during bypass grafting. A strategic localized drug delivery system that reflects the pathophysiology of IH and minimizes systemic side effects is necessary. In this study, the sequential release of sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, and statin, an HMG-COA inhibitor, was realized as a silk fibroin-based microneedle device in vivo. The released sirolimus in the acute stage reduced neointima (NI) and vascular fibrosis through mTOR inhibition. Furthermore, rosuvastatin, which was continuously released from the acute to chronic stage, reduced vascular stiffness and apoptosis through the inactivation of Yes-associated protein (YAP). The sequential release of sirolimus and rosuvastatin confirmed the synergistic treatment effects on vascular inflammation, VSMC proliferation, and ECM degradation remodeling through the inhibition of transforming growth factor (TGF)-beta/NF-κB pathway. These results demonstrate the therapeutic effect on preventing restenosis with sufficient vascular elasticity and significantly reduced IH in response to endothelial damage. Therefore, this study suggests a promising strategy for treating coronary artery disease through localized drug delivery of customized drug combinations.

Bilateral versus Single Internal Thoracic Artery Grafting Strategies Supplemented by Radial Artery Grafting.

PURPOSE: It is unclear if a second or third arterial graft can improve clinical outcomes in coronary artery bypass graft surgery. We compared the outcomes of bilateral internal thoracic artery (BITA) plus radial artery (RA) grafting versus left internal thoracic artery (LITA) plus RA grafting after off-pump coronary artery bypass grafting. MATERIALS AND METHODS: Between January 2009 and December 2020, a total of 3007 patients with three-vessel coronary artery disease who underwent off-pump coronary artery bypass were analyzed. Among them, 971 patients received total arterial grafting using LITA. We divided the patients into two groups [group A, BITA+RA grafting (n=227) and group B, LITA+RA grafting (n=744)], and compared the survival and major adverse cardiac and cerebrovascular event (MACCE) rates between the two groups at 10 years. RESULTS: After risk adjustment with inverse probability treatment weighting methods, the freedom from all-cause mortality was 93.1% and 88.3% in groups A and B, respectively (p=0.140). The freedom from MACCE rates were 68.3% and 89.0%, respectively (p<0.0001). LITA plus RA grafting [hazard ratio (HR): 1.3, 95% confidence interval (CI): 1.05-2.37, p=0.025] and incomplete revascularization (HR 1.2, 95% CI: 0.70-2.15, p=0.046) were significant risk factors for MACCEs in multivariable Cox regression analysis. CONCLUSION: The rates of MACCEs were lower with LITA plus RA grafting than with BITA plus RA grafting in total arterial revascularization. Furthermore, complete revascularization improved long-term outcomes following total arterial grafting.

Hemostatic efficacy of a flowable collagen-thrombin matrix during coronary artery bypass grafting: a double-blind randomized controlled trial.

BACKGROUND: Flowable hemostatic agents have the advantage of being able to be applied to irregular wound surfaces and difficult to reach areas. We sought to compare the effectiveness and safety of the flowable hemostatic sealants Collastat® (collagen hemostatic matrix, [CHM]) and Floseal® (gelatin hemostatic matrix, [GHM]) during off-pump coronary artery bypass (OPCAB). METHODS: In this prospective, double-blind, randomized controlled trial, 160 patients undergoing elective OPCAB surgery were enrolled between March 2018 and February 2020. After primary suture of the aortocoronary anastomosis, an area of hemorrhage was identified, and patients received either CHM or GHM (n = 80, each). Study endpoints were the following: proportion of successful intraoperative hemostasis and time required for hemostasis overall postoperative bleeding, proportion of transfusion of blood products, and surgical revision for bleeding. RESULTS: Of the total patients, 23% were female, and the mean age was 63 years (range 42-81 years). Successful hemostasis proportion within 5 min was achieved for 78 patients (97.5%) in the GHM group, compared to 80 patients (100%) in the CHM group (non-inferiority p = 0.006). Two patients receiving GHM required surgical revision to achieve hemostasis. There were no differences in the mean time required to obtain hemostasis [GHM vs. CHM, mean 1.49 (SD 0.94) vs. 1.35 (0.60) min, p = 0.272], as confirmed by time-to-event analysis (p = 0.605). The two groups had similar amounts of mediastinal drainage for 24 h postoperatively [538.5 (229.1) vs. 494.7 (190.0) ml, p = 0.298]. The CHM group required less packed red blood cells, fresh frozen plasma, and platelets for transfusion than the GHM group (0.5 vs. 0.7 units per patient, p = 0.047; 17.5% vs. 25.0%, p = 0.034; 7.5% vs. 15.0%, p = 0.032; respectively). CONCLUSIONS: CHM was associated with a lower need for FFP and platelet transfusions. Thus, CHM is a safe and effective alternative to GHM. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04310150.

Effect of Preoperative Administration of Intravenous Ferric Carboxymaltose in Patients with Iron Deficiency Anemia after Off-Pump Coronary Artery Bypass Grafting: A Randomized Controlled Trial.

Patients scheduled for cardiac surgery often have anemia and iron deficiency. We investigated the effect of the preoperative administration of intravenous ferric carboxymaltose (IVFC) in patients with iron deficiency anemia (IDA) who were due to undergo off-pump coronary artery bypass grafting (OPCAB). Patients who were due to undergo elective OPCAB between February 2019 and March 2022 who had IDA (n = 86) were included in this single center, randomized, parallel-group controlled study. The participants were randomly assigned (1:1) to receive either IVFC or placebo treatment. Postoperative hematologic parameters [hemoglobin (Hb), hematocrit, serum iron concentration, total iron-binding capacity, transferrin saturation, transferrin concentration, and ferritin concentration] and the changes in these parameters during the follow-up period were the primary and secondary outcomes, respectively. The tertiary endpoints were early clinical outcomes, such as the volume of mediastinal drainage and the need for blood transfusions. IVFC treatment significantly reduced the need for red blood cell (RBC) and platelet transfusions. Despite receiving fewer RBC transfusions, patients in the treatment group had higher levels of Hb, hematocrit, and serum iron and ferritin concentrations during weeks 1 and 12 after surgery. No serious adverse events occurred during the study period. Preoperative IVFC treatment in patients with IDA undergoing OPCAB improved the values of the hematologic parameters and iron bioavailability. Therefore, is a useful strategy for stabilizing patients prior to OPCAB.

Clinical Validation of a Wearable Piezoelectric Blood-Pressure Sensor for Continuous Health Monitoring.

Wearable blood-pressure sensors have recently attracted attention as healthcare devices for continuous non-invasive arterial pressure (CNAP) monitoring. However, the accuracy of wearable blood-pressure (BP) monitoring devices has been controversial due to the low signal quality of sensors, the absence of an accurate transfer function to convert the sensor signals into BP values, and the lack of clinical validation regarding measurement precision. Here, a wearable piezoelectric blood-pressure sensor (WPBPS) is reported, which achieves a high normalized sensitivity (0.062 kPa-1 ), and fast response time (23 ms) for CNAP monitoring. The transfer function of a linear regression model is designed, offering a simple solution to convert the flexible piezoelectric sensor signals into BP values. In order to verify the measurement accuracy of WPBPS, clinical trials are performed on 35 subjects aged from 20 to 80 s after screening. The mean difference between the WPBPS and a commercial sphygmomanometer of 175 BP data pairs is -0.89 ± 6.19 and -0.32 ± 5.28 mmHg for systolic blood pressure (SBP) and diastolic blood pressure (DBP), respectively. By building a WPBPS-embedded wristwatch, the potentially promising use of a convenient, portable, continuous BP monitoring system for cardiovascular disease diagnosis is demonstrated.

Hemodynamic management during off-pump coronary artery bypass surgery: a narrative review of proper targets for safe execution and troubleshooting.

Off-pump coronary surgery requires mechanical cardiac displacement, which results in bi-ventricular systolic and diastolic dysfunction. Although transient, subsequent hemodynamic deterioration can be associated with poor prognosis and, in extreme cases, emergency conversion to on-pump surgery, which is associated with high morbidity and mortality. Thus, appropriate decision-making regarding whether the surgery can be proceeded based on objective hemodynamic targets is essential before coronary arteriotomy. For adequate hemodynamic management, avoiding myocardial oxygen supply-demand imbalance, which includes maintaining mean arterial pressure above 70 mmHg and preventing an increase in oxygen demand beyond the patient's coronary reserve, must be prioritized. Maintaining mixed venous oxygen saturation above 60%, which reflects the lower limit of adequate global oxygen supply-demand balance, is also essential. Above all, severe mechanical cardiac displacement incurring compressive syndromes, which cannot be overcome by adjusting major determinants of cardiac output, should be avoided. An uncompromising form of cardiac constraint can be ruled out as long as the central venous pressure is not equal to or greater than the pulmonary artery diastolic (or occlusion) pressure, as this would reflect tamponade physiology. In addition, transesophageal echocardiography should be conducted to rule out mechanical cardiac displacement-induced ventricular interdependence, dyskinesia, severe mitral regurgitation, and left ventricular outflow tract obstruction with or without systolic motion of the anterior leaflet of the mitral valve, which cannot be tolerated during grafting. Finally, the ascending aorta should be carefully inspected for gas bubbles to prevent hemodynamic collapse caused by a massive gas embolism obstructing the right coronary ostium.

Sirolimus-Embedded Silk Microneedle Wrap to Prevent Neointimal Hyperplasia in Vein Graft Model.

We investigated the role of a sirolimus-embedded silk microneedle (MN) wrap as an external vascular device for drug delivery efficacy, inhibition of neointimal hyperplasia, and vascular remodeling. Using dogs, a vein graft model was developed to interpose the carotid or femoral artery with the jugular or femoral vein. The control group contained four dogs with only interposed grafts; the intervention group contained four dogs with vein grafts in which sirolimus-embedded silk-MN wraps were applied. After 12-weeks post-implantation, 15 vein grafts in each group were explanted and analyzed. Vein grafts applied with the rhodamine B-embedded silk-MN wrap showed far higher fluorescent signals than those without the wrap. The diameter of vein grafts in the intervention group decreased or remained stable without dilatation; however, it increased in the control group. The intervention group had femoral vein grafts with a significantly lower mean neointima-to-media ratio, and had vein grafts with an intima layer showing a significantly lower collagen density ratio than the control group. In conclusion, sirolimus-embedded silk-MN wrap in a vein graft model successfully delivered the drug to the intimal layer of the vein grafts. It prevented vein graft dilatation, avoiding shear stress and decreasing wall tension, and it inhibited neointimal hyperplasia.

Clinical Outcomes of Endoscope-Assisted Pulmonary Endarterectomy for Chronic Thromboembolic Pulmonary Hypertension.

PURPOSE: Pulmonary thromboembolism is a potentially life-threatening condition in patients with heart disease; however, limited studies discussing long-term outcomes exist. This study aimed to investigate the long-term outcomes of pulmonary endarterectomy (PEA) in patients with chronic thromboembolic pulmonary hypertension (CTEPH), focusing on the improvement of functional class and right ventricular (RV) pressure. MATERIALS AND METHODS: Clinical data of patients with CTEPH were obtained from Yonsei Hospital between May 2012 and December 2021, and reviewed retrospectively. Twenty-six patients underwent endoscope-guided PEA during the study period, and the mean follow-up duration was 24.8±23.4 months. RESULTS: After PEA, most patients (88.5%) were weaned from inotropes without extracorporeal membrane oxygenation support during the first few days. Two patients (7.6%) had cerebrovascular accidents without neurological deficits. On echocardiography, the RV systolic pressure and tricuspid regurgitation grades significantly improved (p<0.001). Furthermore, the mean left ventricle end-diastolic diameter was significant increased (p=0.003), and the left ventricular end-systolic diameter increased (p<0.001). The median intensive care unit stay was 3.0±9.4 days, and median hospital stay 16.0±26.5 days. The 5-year survival rate was 95.5%, and the 5-year freedom rate of cardiac death was 100%. There was a marked improvement in New York Heart Association (NYHA) status (p<0.001). Cox regression suggested that the main pulmonary artery (MPA) involvement is a significant predictor of non-improvement in functional class post-PEA. CONCLUSION: Mortality rates are low and patients experience a marked improvement in NYHA class and health status after PEA. Moreover, MPA involvement may affect functional outcomes.

A Randomized Trial of Clopidogrel vs Ticagrelor After Off-Pump Coronary Bypass.

BACKGROUND: This study aimed to compare the outcomes of aspirin in combination with either ticagrelor or clopidogrel after off-pump coronary artery bypass (OPCAB) in patients with clopidogrel resistance. METHODS: Between November 2014 and November 2020, 1739 patients underwent OPCAB. Aspirin and clopidogrel treatment was initiated the day after surgery. On postoperative days 7 to 9, clopidogrel resistance was evaluated using a point-of-care assay. A total of 278 (18.9%) patients had clopidogrel resistance ( platelet reaction unit >208) and were enrolled in the study. The study investigators excluded patients with coresistance to aspirin (n = 74) and divided the remaining patients (mean age, 67.4 ± 8.5 years) into 2 groups (an aspirin and ticagrelor group [AT group; n = 102] and an aspirin and clopidogrel group [AC group; n = 102]), randomly assigned using a 1:1 ratio block table. The primary end point was graft patency and major adverse cardiovascular events (MACEs; defined as the composite of cardiovascular mortality, myocardial infarction, and repeat revascularization at 1 year after OPCAB), and the coprimary end point was the graft patency rate. The data were analyzed using the intent-to-treat method. RESULTS: The graft occlusion rates in the AT and AC groups were 3.9% and 5.9%, respectively (P = .52). Neither death from cardiovascular causes (1.0% vs 2.9%; P = .32) nor myocardial infarction showed significant differences (1.0% vs 3.9%; P = .18). No significant difference in the rates of major bleeding were found between the 2 groups (P = .75). However, the AT group was associated with a lower rate of MACEs after OPCAB (hazard ratio, 0.77; 95% CI, 0.684-0.891; P = .01). CONCLUSIONS: These results suggest that ticagrelor may be associated with reducing MACEs in patients with clopidogrel resistance after OPCAB.

Transit-Time Flow Measurement and Outcomes in Coronary Artery Bypass Graft Patients.

Transit-time flowmetry (TTFM) is commonly used during coronary artery bypass grafting for intraoperative graft assessment. This study aimed to investigate whether TTFM values were predictive of graft failure and major adverse cardiac and cerebrovascular events (MACCEs). Between 2011 and 2018, 1933 patients with 3-vessel coronary artery disease who underwent off-pump coronary artery bypass were retrospectively analyzed. Among them, 1288 sequential venous grafts in 538 consecutive patients were measured using TTFM's 2 parameters, pulsatility index (PI) and flow (mL/min). The anastomoses were divided in the 3 groups depending on the anastomotic site: group A, first side-to-side anastomoses (n = 538), group B; second side-to-side (n = 212), group C; end-to-side (n = 538). MACCEs were related to TTFM. The mean clinical follow-up time was 64.8 ± 21.2 months. Postoperative graft patency was confirmed with multi-slice computed tomography or coronary angiography (follow-up interval: 64.8 ± 50.4 and 27.8 ± 20.5 months based on the date of examination). The 5-year survival rate was 93.7%. The mean graft flow was 59.1 ± 31.3, 41.0 ± 25.2, and 38.9 ± 22.8 mL/minute, and the PI was 2.2 ± 1.3, 2.5 ± 3.4, and 2.4 ± 2.5, in groups A, B, and C, respectively. Graft failure occurred in 23/1055 (2.2%) anastomoses. The 5-year MACCE rate was 6.9% (37/538 patients). Kaplan-Meier analysis revealed that graft patency was significantly lower in low MGF (p = 0.044) and high PI (p < 0.001). Multivariable logistic analysis showed that high PI (>5; HR 2.276; 95%CI 2.188-2.406, p < 0.001) was an independent risk factor for MACCEs. The cutoff values for PI of sequential grafts were 3.65, 3.55, and 3.17 in groups A, B, and C, respectively for the prediction of MACCE. A high PI predicts more predictive poor outcomes of sequential venous grafts after surgery than the low mean graft blood flow.

Effects of Residual Arch Tears on Late Outcomes After Hemiarch Replacement for DeBakey I Dissection.

BACKGROUND: This study evaluated the effect of residual arch tears on late reinterventions and arch dilatation after hemiarch replacement for patients with acute DeBakey type I aortic dissection. METHODS: Between January 1995 and October 2018, 160 consecutive patients who underwent hemiarch replacement for DeBakey type I dissection were retrospectively enrolled. They were divided into patients with (n = 73) and without (n = 87) residual arch tears. The arch tears group was subdivided into the proximal/middle arch (n = 26) and distal arch (n = 47) groups to evaluate arch growth rates according to the locations of residual arch tears. The endpoints were arch growth rate and late arch and composite events. RESULTS: The arch diameter increased significantly over time in patients with residual arch tears (1.620 mm/y, P < .001). The increase occurred more rapidly when residual tears occurred at the distal arch than at the proximal/middle arch level (2.101 vs 1.001 mm/y). In the adjusted linear mixed model, residual arch tears or luminal communications at the distal arch level were significant factors associated with increases in the arch diameter over time. The 10-year freedom from late arch and composite event rate was significantly lower for patients with residual arch tears than for those without (82.4% vs 95.5%, P = .001; and 68.0% vs 89.3%, P = .002, respectively). CONCLUSIONS: Residual arch tears are significant factors associated with late arch dilatation and reinterventions, especially for patients with distal arch tears. Extensive arch replacement during the initial surgery to avoid residual arch tears may improve long-term outcomes.

Long-Term Outcomes of Preoperative Atrial Fibrillation in Cardiac Surgery.

Background: Atrial fibrillation (Afib) is a marker of increased cardiovascular morbidity and mortality. Owing to the increased prevalence of Afib in patients undergoing cardiac surgery, assessing the effect of Afib on postsurgical outcomes is important. We aimed to analyze the effect of preoperative Afib on clinical outcomes in patients undergoing cardiac surgery using a large surgical database. Methods: This retrospective cohort study was based on the national health claims database established by the National Health Insurance Service of the Republic of Korea from 2009 to 2015. Diagnosis and procedure codes were used to identify diseases according to the International Statistical Classification of Diseases, 10th revision. Results: We included 1,037 patients (0.1%) who had undergone cardiac surgery from a randomized 1,000,000-patient cohort, and 15 patients (1.5%) treated with isolated surgical Afib ablation were excluded. Of these 1,022 patients, 412 (39.7%), 303 (29.2%), and 92 (9.0%) underwent coronary artery bypass, heart valve surgery, and Cox-maze surgery, respectively. Preoperative Afib was associated with higher patient mortality (p=0.028), regardless of the surgical procedure. Patients with preoperative Afib (n=190, 18.6%) experienced a higher cumulative risk of overall mortality (hazard ratio [HR], 1.435; 95% confidence interval [CI], 1.263-2.107; p=0.034). Subgroup analysis revealed a reduced risk of overall mortality with Cox-maze surgery in Afib patients (HR, 0.500; 95% CI, 0.266-0.938; p=0.031). Postoperative cerebral ischemia or hemorrhage events were not related to Afib. Conclusion: Preoperative Afib was independently associated with worse long-term postoperative outcomes after cardiac surgery. Concomitant Cox-maze surgery may improve the survival rate.

Role of False Lumen Area Ratio in Late Aortic Events After Acute Type I Aortic Dissection Repair.

BACKGROUND: The aim of this study was to investigate whether distal aortic maximum false lumen area (MFLA) ratio predicts late aortic dilation and reintervention after open repair of acute type I aortic dissection. METHODS: We analyzed 309 nonsyndromic acute type I aortic dissection patients who were treated with a repair to the proximal aorta between 1994 and 2017. In 230 patients who did not show completely thrombosed false lumen on postoperative computed tomography, the MFLA ratio (MFLA/aortic area) on the descending thoracic aorta (DTA) was measured with postoperative computed tomography. Patients were divided into 3 groups according to the quartile range of MFLA ratio: low MFLA, <0.62 (n = 57); intermediate MFLA, 0.62 to 0.81 (n = 116); and high MFLA, ≥0.82 (n = 57). RESULTS: The aortic expansion rate was significantly higher in the high MFLA group (11.1 ± 21.2 mm/y) compared with intermediate (3.0 ± 7.4 mm/y; P < .01) and low (0.6 ± 6.6 mm/y; P < .01) MFLA groups. High MFLA was found to be an independent risk factor for significant aortic expansion (adjusted hazard ratio, 5.26; 95% CI, 1.53-18.12; P < .01) and aorta-related reintervention (hazard ratio, 4.99; 95% CI, 2.23-11.13; P < .01), and the MFLA ratio was significantly related to proximal DTA reentry tears (adjusted odds ratio, 12974.3; P < .001; area under curve, 0.807). CONCLUSIONS: A high MFLA ratio on the DTA after acute type I aortic dissection repair is associated with increased risk of late aortic reintervention and distal aortic dilation. A high MFLA ratio is strongly associated with proximal DTA reentry tears.

Small extracellular vesicles derived from patients with persistent atrial fibrillation exacerbate arrhythmogenesis via miR-30a-5p.

Small extracellular vesicles (sEVs) are nanometer-sized membranous vesicles that contribute to the pathogenesis of atrial fibrillation (AF). Here, we investigated the role of sEVs derived from patients with persistent AF in the pathophysiology of AF. First, we evaluated the pathological effects of sEVs derived from the peripheral blood of patients with persistent AF (AF-sEVs). AF-sEVs treatment reduced cell viability, caused abnormal Ca2+ handling, induced reactive oxygen species (ROS) production and led to increased CaMKII activation of non-paced and paced atrial cardiomyocytes. Next, we analyzed the miRNA profile of AF-sEVs to investigate which components of AF-sEVs promote arrhythmias, and we selected six miRNAs that correlated with CaMKII activation. qRT-PCR experiment identified that miR-30a-5p was significantly down-regulated in AF-sEVs, paced cardiomyocytes, and atrial tissues of patients with persistent AF. CaMKII was predicted by bioinformatics analysis as a miR-30a-5p target gene and validated by a dual luciferase reporter; hence, we evaluated the effects of miR-30a-5p on paced cardiomyocytes and validated miR-30a-5p as a pro-arrhythmic signature of AF-sEVs. Consequently, AF-sEVs-loaded with miR-30a-5p attenuated pacing-induced Ca2+-handling abnormalities, whereas AF-sEVs-loaded with anti-miR-30a-5p reversed the change in paced cardiomyocytes. Taken together, the regulation of CaMKII by miR-30a-5p revealed that miR-30a-5p is a major mediator for AF-sEVs-mediated AF pathogenesis. Accordingly, these findings suggest that sEVs derived from patients with persistent AF exacerbate arrhythmogenesis via miR-30a-5p.