Circulating mitochondria promoted endothelial cGAS-derived neuroinflammation in subfornical organ to aggravate sympathetic overdrive in heart failure mice.

BACKGROUND: Sympathoexcitation contributes to myocardial remodeling in heart failure (HF). Increased circulating pro-inflammatory mediators directly act on the Subfornical organ (SFO), the cardiovascular autonomic center, to increase sympathetic outflow. Circulating mitochondria (C-Mito) are the novel discovered mediators for inter-organ communication. Cyclic GMP-AMP synthase (cGAS) is the pro-inflammatory sensor of damaged mitochondria. OBJECTIVES: This study aimed to assess the sympathoexcitation effect of C-Mito in HF mice via promoting endothelial cGAS-derived neuroinflammation in the SFO. METHODS: C-Mito were isolated from HF mice established by isoprenaline (0.0125 mg/kg) infusion via osmotic mini-pumps for 2 weeks. Structural and functional analyses of C-Mito were conducted. Pre-stained C-Mito were intravenously injected every day for 2 weeks. Specific cGAS knockdown (cGAS KD) in the SFO endothelial cells (ECs) was achieved via the administration of AAV9-TIE-shRNA (cGAS) into the SFO. The activation of cGAS in the SFO ECs was assessed. The expression of the mitochondrial redox regulator Dihydroorotate dehydrogenase (DHODH) and its interaction with cGAS were also explored. Neuroinflammation and neuronal activation in the SFO were evaluated. Sympathetic activity, myocardial remodeling, and cardiac systolic dysfunction were measured. RESULTS: C-Mito were successfully isolated, which showed typical structural characteristics of mitochondria with double-membrane and inner crista. Further analysis showed impaired respiratory complexes activities of C-Mito from HF mice (C-MitoHF) accompanied by oxidative damage. C-Mito entered ECs, instead of glial cells and neurons in the SFO of HF mice. C-MitoHF increased the level of ROS and cytosolic free double-strand DNA (dsDNA), and activated cGAS in cultured brain endothelial cells. Furthermore, C-MitoHF highly expressed DHODH, which interacted with cGAS to facilitate endothelial cGAS activation. C-MitoHF aggravated endothelial inflammation, microglial/astroglial activation, and neuronal sensitization in the SFO of HF mice, which could be ameliorated by cGAS KD in the ECs of the SFO. Further analysis showed C-MitoHF failed to exacerbate sympathoexcitation and myocardial sympathetic hyperinnervation in cGAS KD HF mice. C-MitoHF promoted myocardial fibrosis and hypertrophy, and cardiac systolic dysfunction in HF mice, which could be ameliorated by cGAS KD. CONCLUSION: Collectively, we demonstrated that damaged C-MitoHF highly expressed DHODH, which promoted endothelial cGAS activation in the SFO, hence aggravating the sympathoexcitation and myocardial injury in HF mice, suggesting that C-Mito might be the novel therapeutic target for sympathoexcitation in HF.

lncRNA DLX6-AS1 Promotes Myocardial Ischemia-Reperfusion Injury through Mediating the miR-204-5p/FBXW7 Axis.

Myocardial ischemia-reperfusion (IR) injury is the restoration of blood flow post ischemia, which threatens the human life. Long noncoding RNA distal-less homeobox 6 antisense 1 (DLX6-AS1) has been found to take part in the IR-induced cerebral injury. Here, we determined the functional role of DLX6-AS1 in IR-induced myocardial injury. We ligated the left anterior descending coronary artery of rats to induce IR injury. IR injury rats exhibited severe tissue damage and increase of infraction size. The levels of lactate dehydrogenase (LDH), creatine kinase (CK), proinflammatory factors including MCP-1, IL-6, and IL-1ß, and cell apoptosis were also enhanced in IR rats, indicating that IR induced significant myocardial injury in rats. DLX6-AS1 expression was elevated in the myocardial tissues of IR injury rats, while DLX6-AS1 deficiency alleviated IR-induced myocardial injury in rats by reducing inflammatory response and cell apoptosis. Moreover, rat embryonic cardiomyocyte cell line H9c2 was subjected to hypoxia reoxygenation (HR). DLX6-AS1 was upregulated in the HR-treated H9c2 cells, and DLX6-AS1 enhanced the expression of F-box and WD40 repeat domain-containing 7 (FBXW7) by sponging miR-204-5p. Inhibition of DLX6-AS1 inhibited inflammatory response and cell apoptosis in H9c2 cells via miR-204-5p/FBXW7 axis. In conclusion, this work demonstrates that DLX6-AS1 accelerates myocardial IR injury through regulating miR-204-5p/FBXW7 axis. Thus, this work provides a novel ceRNA DLX6-AS1/miR-204-5p/FBXW7 axis in myocardial IR injury, and DLX6-AS1 may be a potential target for the treatment of myocardial IR injury.

Giant cardiac myxoma presenting with exertional angina: Coronary steal due to neovascularization?

Myxoma is the most common benign tumor of the heart. Most patients present with no symptoms, only a few patients present with exertional dyspnea and stroke. We introduce this rare case presenting with exertional angina, which was caused by coronary steal due to neovascularization, proved by coronary angiography and cardiac stress testing.

Enlargement of left ventricular outflow tract using an autologous pericardial patch for anterior mitral valve leaflet and septal myectomy through trans-mitral approach for the treatment of hypertrophic obstructive cardiomyopathy.

OBJECTIVE: Modified Morrow procedure is the gold standard of surgical intervention for hypertrophic obstructive cardiomyopathy (HOCM). However, there are certain cases without complete relief of obstruction through trans-aortic approach, we, therefore, described an unusual technique. We aimed to retrospectively analyze this series of patients to reveal its safety and efficiency. METHODS: We retrospectively analyzed a total of 247 consecutive HOCM patients in our center from January 2016 to December 2019. Sixteen of them who underwent enlargement of left ventricular outflow tract (LVOT) using an autologous pericardial patch for anterior mitral valve leaflet and septal myectomy through trans-mitral approach were recruited in this study. Baseline characteristics, perioperative data, and the outcomes were studied. RESULTS: Of the 16 patients, there was no operative mortality. No permanent pacemaker implantation and ventricular septal defects formation were observed. The peak pressure gradient of LVOT decreased from 97.56 ± 23.81 mmHg to 7.56 ± 2.13 mmHg (p < .01) after operation and 10.19 ± 2.93 mmHg (p < .01) 3 months later. The average septal thickness decreased from 18.38 ± 3.56 mm to 10.00 ± 2.74 mm (p < .01). During a mean follow-up of 34.25 ± 12.85 months (range, 15-57), no patient required cardiac reoperation. At the last follow up, the mean peak pressure gradient of LVOT was 10.12 ± 2.03 mmHg and no patient had more than moderate mitral regurgitation. CONCLUSION: Enlargement of LVOT using an autologous pericardial patch for anterior mitral valve leaflet and septal myectomy through trans-mitral approach is feasible and reliable for the treatment of certain types of HOCM cases.

MiR-590-3p regulates cardiomyocyte P19CL6 proliferation, apoptosis and differentiation in vitro by targeting PTPN1 via JNK/STAT/NF-kB pathway.

Cardiomyocyte differentiation is a multi-step process which involves a number of signalling pathways. microRNAs exhibit regulatory functions in various diseases and are involved in the signalling pathways in multiple physiological processes, but the specific functions of particular mRNAs is often not fully understood. of an example of this is that the role of miR-590-3p in the differentiation of cardiomyocytes remains unclear. In the current study, RT-qPCR was used to determine the expression of miR-590-3p in cardiomyocytes differentiated from the embryonic carcinoma cell line P19CL6. MTT, EdU, caspase-3 activity and flow cytometry assays were performed to examine the influence of miR-590-3p on cell behaviour. A luciferase assay was used to confirm binding between miR-590-3p and PTPN1. Western blotting was used to determine the relationship between the JNK/STAT/NF-kB pathway and PTPN1. The results inferred that miR-590-3p became heavily expressed in differentiated P19CL6. Knockdown miR-590-3p suppressed the cell proliferation while at the same time, accelerated apoptosis. Moreover, PTPN1 was identified as the target of miR-590-3p. More importantly, PTPN1 overexpression activated the JNK/STAT/NF-kB pathway and limited the differentiation of P19CL6. Thus the conclusions from this study are that miR-590-3p has the potential to regulate the proliferation, apoptosis and differentiation of cardiomyocyte P19CL6 in vitro by targeting PTPN1 via the JNK/STAT/NF-kB pathway.

Type A Aortic Dissection Occurring After Previous Cardiac Surgery.

BACKGROUND: We retrospectively reviewed our experience of total arch replacement in patients undergoing repair of an ascending aortic dissection following previous cardiac surgery. METHODS: Data were collected for patients with acute type A aortic dissection following previous cardiac surgery between January 2005 and December 2014. Clinical and prognostic features were retrospectively analyzed. RESULTS: Twenty-eight eligible patients (nonelective: 10, elective: 18) were identified. There was a mean period of 44.5 months between the first operation and the subsequent surgery. The overall 30-day mortality rate was 21.4%; 30.0% for nonelective patients and 16.7% for elective patients. Postoperative morbidity rate was higher among nonelective patients versus elective group. During follow-up, two patients died: one from intracranial hemorrhage and the other from a noncardiac cause. One patient received endografting as a result of the true lumen being compressed by the false lumen following aortic repair. CONCLUSIONS: When hemodynamically stable, patients with acute ascending aortic dissection following previous cardiac surgery may have improved outcomes if the surgery can be performed on an elective basis.

Perioperative variation in serum FGF-23 level and its correlation with MACCE risk in unprotected left main coronary artery disease patients receiving coronary artery bypassing grafting.

Objective: Fibroblast growth factor-23 (FGF-23) mediates vascular endothelial injury, inflammatory infiltration, and atherosclerosis, which could reflect major adverse cardiac and cerebrovascular event (MACCE) risk in several cardiovascular diseases. This study aims to further investigate the perioperative change of FGF-23, as well as its association with clinical characteristics and MACCE risk in unprotected left main coronary artery disease (ULMCAD) patients receiving coronary artery bypass grafting (CABG). Methods: A total of 226 ULMCAD patients who underwent CABG were enrolled. Serum samples of the patients were collected on the day before CABG, the third day (D3) after CABG, and at discharge; then, the FGF-23 level was determined by enzyme-linked immunosorbent assay. The MACCE rate was recorded during a median follow-up of 25.5 (range: 2.0-46.0) months. Results: The median, interquartile range (IQR), and range of FGF-23 level in ULMCAD patients receiving CABG were 717.0, 582.5-869.8, and 407.0-1765.0 pg/ml, respectively. FGF-23 level was increased in patients with both previous heart failure (P = 0.046) and chronic renal failure (P = 0.009) compared to those without. FGF-23 level increased from before surgery [median (IQR): 712.5 (574.5-879.8) pg/ml] to D3 [median (IQR): 844.0 (666.0-1072.5) pg/ml], then declined at discharge [median (IQR): 764.5 (569.3-986.8) pg/ml] (P < 0.001). Meanwhile, the preoperative FGF-23 level (P = 0.028), but not the FGF-23 level at discharge (P = 0.067) was positively correlated with the cumulative MACCE rate. Multivariable Cox's analyses found that preoperative FGF-23 level could independently predict cumulative MACCE rate [P = 0.015, hazards ratio (HR) = 2.940]. Conclusion: Preoperative FGF-23 level predicts higher MACCE risk in ULMCAD patients undergoing CABG surgery.

Plasma Exosomal Mir-423-5p Is Involved in the Occurrence and Development of Bicuspid Aortopathy via TGF-ß/SMAD2 Pathway.

OBJECTIVES: Patients with bicuspid aortic valve (BAV) are at increased risk for ascending aortic dilation (AAD). Our study was aimed at systemically analyzing the expression profile and mechanism of circulating plasma exosomal microRNAs (miRNAs) related to BAV and AAD. METHODS: We isolated plasma exosomes from BAV patients (n=19), BAV patients with AAD (BAVAD, n=26), and healthy tricuspid aortic valve individuals with low cardiovascular risk (TAVnon, n=16). We applied a small RNA sequencing approach to identify the specific plasma exosomal miRNAs associated with BAV (n=8) and BAVAD (n=10) patients compared with healthy TAVnon (n=6) individuals. The candidate differentially expressed (DE) miRNAs were selected and validated by RT-qPCR in the remaining samples. GO and KEGG pathway enrichment analyses were performed to illustrate the functions of target genes. Western blot analysis and luciferase reporter assay were conducted in human aortic vascular smooth muscle cells (VSMCs) to verify the results of target gene prediction in vitro. Results: The expression levels of three up-regulated (miR-151a-3p, miR-423-5p, and miR-361-3p) and two down-regulated (miR-16-5p and miR-15a-5p) exosomal miRNAs were significantly altered in BAV disease. Additionally, miR-423-5p could be functionally involved in the occurrence and development of BAV and its complication BAVAD by regulating TGF-ß signaling. miR-423-5p could target to SMAD2 and decreased the protein levels of SMAD2 and P-SMAD2. CONCLUSION: Plasma exosomal miR-423-5p regulated TGF-ß signaling by targeting SMAD2, thus exerting functions in the occurrence and development of BAV disease and its complication bicuspid aortopathy.

Tricuspid annular plane systolic excursion (TAPSE) can predict the outcome of isolated tricuspid valve surgery in patients with previous cardiac surgery?

BACKGROUND: Isolated tricuspid valve replacement is rare when performed as a re-operation after a left side operation. It is important to know the factors that determine mortality and morbidity. Tricuspid Annular Plane Systolic Excursion (TAPSE) is a scoring system that is used with non-invasive Doppler echocardiography to determine right ventricular (RV) function. This study analyzed TAPSE scores and adverse outcomes of isolated tricuspid valve surgery in patients with previous cardiac surgery. METHODS: All patients who underwent tricuspid valve replacement between January 2014 and December 2015 were retrospectively reviewed. Patients having concomitant mitral or aortic valve surgery were excluded. These patients were divided into two groups: TAPSE >14 mm and TAPSE ≤14 mm. In-hospital outcomes were compared. RESULTS: A total of 26 patients with severe tricuspid valve regurgitation underwent tricuspid valve replacement. There were 5 males (19.2%) and 21 females (80.8%). The average age at operation was 54.77±9.61 years (range, 27-69 years). There were 16 patients in the TAPSE >14 mm group and 10 patients in the TAPSE ≤14 mm group. The BNP in the TAPSE >14 mm group was significant (TAPSE >14 mm 672.34±229.98 versus TAPSE ≤14 mm 1,054.79±684.69, P=0.03). The median cardiopulmonary bypass (CPB) time and red blood cell (RBC) transfusions in the two groups were not different. The need for prolonged ventilatory support (>48 h) in the two groups was also not different (TAPSE> 14 mm 91.2±12.31 vs. TAPSE ≤14 mm 39.00±36.80, P=0.46). Moreover, hospital stays were similar between the two groups. No differences were found in postoperative renal and respiratory complications. CONCLUSIONS: It is important to determine the right ventricule function quantitatively. The TAPSE score is an important parameter that determines the cardiac index and right ventricle function. It should be used for the prediction of mortality and morbidity with all the other parameters as a whole.