In vitro immuno-prevention of nitration/dysfunction of myogenic stem cell activator HGF, towards developing a strategy for age-related muscle atrophy.

In response to peroxynitrite (ONOO-) generation, myogenic stem satellite cell activator HGF (hepatocyte growth factor) undergoes nitration of tyrosine residues (Y198 and Y250) predominantly on fast IIa and IIx myofibers to lose its binding to the signaling receptor c-met, thereby disturbing muscle homeostasis during aging. Here we show that rat anti-HGF monoclonal antibody (mAb) 1H41C10, which was raised in-house against a synthetic peptide FTSNPEVRnitroY198EV, a site well-conserved in mammals, functions to confer resistance to nitration dysfunction on HGF. 1H41C10 was characterized by recognizing both nitrated and non-nitrated HGF with different affinities as revealed by Western blotting, indicating that the paratope of 1H41C10 may bind to the immediate vicinity of Y198. Subsequent experiments showed that 1H41C10-bound HGF resists peroxynitrite-induced nitration of Y198. A companion mAb-1H42F4 presented similar immuno-reactivity, but did not protect Y198 nitration, and thus served as the control. Importantly, 1H41C10-HGF also withstood Y250 nitration to retain c-met binding and satellite cell activation functions in culture. The Fab region of 1H41C10 exerts resistivity to Y250 nitration possibly due to its localization in the immediate vicinity to Y250, as supported by an additional set of experiments showing that the 1H41C10-Fab confers Y250-nitration resistance which the Fc segment does not. Findings highlight the in vitro preventive impact of 1H41C10 on HGF nitration-dysfunction that strongly impairs myogenic stem cell dynamics, potentially pioneering cogent strategies for counteracting or treating age-related muscle atrophy with fibrosis (including sarcopenia and frailty) and the therapeutic application of investigational HGF drugs.

"Kyushu-style" collaboration between the implantable ventricular assist device implantation and management centers: a republication of the article published in Japanese journal of artificial organs.

Collaboration between the implantation centers, management centers, and regional core hospitals is a key factor in securing long-term implantable ventricular assist device (VAD) management. In Kyushu, a management system for patients with implantable VADs has been established at the prefectural and regional levels. Presently, six implantable VAD implantation centers and seven management centers exists in the eight prefectures of Kyushu and Okinawa, with at least one specialized VAD centers in each prefecture. This collaborative management system allows patients with VADs to receive seamless treatment based on the same management concept wherever they live. In fact, approximately half of the present outpatients treated at our center reside outside the prefecture and are managed in collaboration with management centers and regional core hospitals. Among our patients, there were no significant differences in survival or rehospitalization-free rates between patients with VADs in and out of the prefecture, suggesting that the place of residence did not affect the outcome. With the increase in the number of patients with VADs and the diversification of patients, patient management has become more complex. Mutual collaboration between the implantation centers, management centers, and regional core hospitals, is essential to improve the quality of VAD management. This review was created based on a translation of the Japanese review written in the Japanese Journal of Artificial Organs in 2023 (Vol. 52, No. 1, pp. 85-88), with some modifications.

Acute Dapagliflozin Administration Ameliorates Cardiac Surgery-Associated Acute Kidney Injury in a Rabbit Model.

BACKGROUND: Several studies have shown that sodium-glucose cotransporter-2 inhibitors have a renoprotective effect on acute kidney injury (AKI), but their effect on cardiac surgery-associated AKI is unknown. METHODS AND RESULTS: AKI was induced in 25 rabbits without diabetes mellitus by cardiopulmonary bypass (CPB) for 2 h and they were divided into 5 groups: sham; dapagliflozin-treated sham; CPB; dapagliflozin-treated CPB; and furosemide-treated CPB (n=5 in each group). Dapagliflozin was administered via the femoral vein before initiating CPB. Kidney tissue and urine and blood samples were collected after the surgical procedure. There were no differences in the hemodynamic variables of each group. Dapagliflozin reduced serum creatinine and blood urea nitrogen concentrations, and increased overall urine output (all P<0.05). Hematoxylin and eosin staining showed that the tubular injury score was improved after dapagliflozin administration (P<0.01). Dapagliflozin administration mitigated reactive oxygen species and kidney injury molecule-1 as assessed by immunohistochemistry (both P<0.0001). Protein expression analysis showed improvement of inflammatory cytokines and apoptosis, and antioxidant enzyme expression was elevated (all P<0.05) through activation of the nuclear factor erythroid 2-related factor 2 pathway (P<0.01) by dapagliflozin. CONCLUSIONS: Acute intravenous administration of dapagliflozin protects against CPB-induced AKI. Dapagliflozin may have direct renoprotective effects in renal tubular cells.

Cannula to Femoral Artery Diameter Ratio Predicts Potential Lower-Limb Ischemia in Minimally Invasive Cardiac Surgery With Femoral Cannulation.

OBJECTIVE: Lower-limb ischemia is a complication of minimally invasive cardiac surgery with femoral cannulation. Herein, we verified our strategy using distal perfusion cannulation (DPC) against this complication. METHODS: We retrospectively assessed 91 cases of aortic valve replacement with femoral cannulation between January 2019 and March 2023. DPC was applied when lower-limb tissue oxygenation index declined by ≥20%. The cannula to femoral artery diameter ratio (C/FA) was calculated by dividing the cannula size (Fr) divided by 3 by the femoral artery inner diameter (mm). Postoperative maximum creatinine kinase (CKmax), lactate dehydrogenase (LDHmax), and lactate levels were analyzed, and univariable logistic regression and receiver operating characteristic curve analyses were employed to determine DPC predictors and the cutoff C/FA for DPC, respectively. Patients without DPC were divided into 2 subgroups based on the cutoff C/FA for further comparisons. RESULTS: DPC was required in 9 patients. Symptomatic ischemia was not observed. All laboratory data were similar in the DPC and non-DPC groups. C/FA was significantly associated with DPC (odds ratio = 1.27, 95% confidence interval: 1.09 to 1.47, P = 0.002), and the cutoff C/FA was 0.70 (sensitivity = 0.89, specificity = 0.80). In the non-DPC group, CKmax (P = 0.027) and LDHmax (P = 0.041) were significantly higher in patients with C/FA ≥0.7 (n = 16) than in those with C/FA <0.7 (n = 66). CONCLUSIONS: Our strategy for preventing symptomatic ischemia is reasonable and could be almost achieved without DPC when C/FA is <0.7. C/FA also predicts asymptomatic potential ischemia, and proactive DPC is preferable when C/FA is ≥0.7.

Veno-venous extracorporeal membrane oxygenation support of pulmonary insufficiency using Avalon Elite® cannula in pediatric patients.

The "Avalon Elite®" cannula is a double-lumen cannula used to establish veno-venous extracorporeal membrane oxygenation support. The reported advantages are that extracorporeal circulation can be established by cannulating through the right internal jugular vein only, and there is less re-circulation than with a two-cannula technique. It is available in a wide range of cannula sizes and can be used in a variety of patients, from children to adults. We herein report three pediatric cases in which an Avalon Elite® cannula was useful. The first was a case of acute mitral regurgitation due to idiopathic chordal rupture for postoperative severe lung injury and atelectasis due to cardiogenic pulmonary edema. The second was a case of end-stage radiation pneumonitis for safe transfer to facility of lung transplantation. The third was a convalescent case of fulminant myocarditis with severe atelectasis due to cardiogenic pulmonary edema. In each case, veno-venous extracorporeal membrane oxygenation using an Avalon Elite® cannula was established, the expected sufficient support was secured, and a good clinical course was obtained without major complications associated with an Avalon Elite® cannula.

Necrostatin-1 Attenuates Delayed Paraplegia after Transient Spinal Cord Ischemia in Rabbits by Inhibiting the Upregulation of Receptor-Interacting Protein Kinase 1 and 3.

BACKGROUND: Delayed-onset paraplegia is a disastrous complication after thoracoabdominal aortic open surgery and thoracic endovascular aortic repair. Studies have revealed that transient spinal cord ischemia caused by temporary occlusion of the aorta induces delayed motor neuron death owing to apoptosis and necroptosis. Recently, necrostatin-1 (Nec-1), a necroptosis inhibitor, has been reported to reduce cerebral and myocardial infarction in rats or pigs. In this study, we investigated the efficacy of Nec-1 in delayed paraplegia after transient spinal cord ischemia in rabbits and assessed the expression of necroptosis- and apoptosis-related proteins in motor neurons. METHODS: This study used rabbit transient spinal cord ischemia models using a balloon catheter. They were divided into a vehicle-treated group (n = 24), Nec-1-treated group (n = 24), and sham-controls (n = 6). In the Nec-1-treated group, 1 mg/kg of Nec-1 was intravascularly administered immediately before ischemia induction. Neurological function was assessed using the modified Tarlov score, and the spinal cord was removed 8 hr and 1, 2, and 7 days after reperfusion. Morphological changes were examined using hematoxylin and eosin staining. The expression levels of necroptosis-related proteins (receptor-interacting protein kinase [RIP] 1 and 3) and apoptosis-related proteins (Bax and caspase-8) were assessed using western blotting and histochemical analysis. We also performed double-fluorescence immunohistochemical studies of RIP1, RIP3, Bax, and caspase-8. RESULTS: Neurological function significantly improved in the Nec-1-treated group compared with that in the vehicle-treated group 7 days after reperfusion (median 3 and 0, P = 0.025). Motor neurons observed 7 days after reperfusion were significantly decreased in both groups compared with the sham group (vehicle-treated, P < 0.001; Nec-1-treated, P < 0.001). However, significantly more motor neurons survived in the Nec-1-treated group than in the vehicle-treated group (P < 0.001). Western blot analysis revealed RIP1, RIP3, Bax, and caspase-8 upregulation 8 hr after reperfusion in the vehicle-treated group (RIP1, P = 0.001; RIP3, P = 0.045; Bax, P = 0.042; caspase-8, P = 0.047). In the Nec-1-treated group, the upregulation of RIP1 and RIP3 was not observed at any time point, whereas that of Bax and caspase-8 was observed 8 hr after reperfusion (Bax, P = 0.029; caspase-8, P = 0.021). Immunohistochemical study revealed the immunoreactivity of these proteins in motor neurons. Double-fluorescence immunohistochemistry revealed the induction of RIP1 and RIP3, and that of Bax and caspase-8, in the same motor neurons. CONCLUSIONS: These data suggest that Nec-1 reduces delayed motor neuron death and attenuates delayed paraplegia after transient spinal cord ischemia in rabbits by selectively inhibiting necroptosis of motor neurons with minimal effect on their apoptosis.

Quadruple Valve Replacement for Repaired Transposition of the Great Arteries.

A 37-year-old man with repaired transposition of the great arteries had extensive infective endocarditis, and a multidisciplinary therapeutic strategy was planned based on surgical indications, invasiveness, and future prospects. After adequate antibiotic treatment, simultaneous replacement of quadruple valve and aortic root using mechanical valves was performed to intervene in the healed valvular disease and the concurrent anatomic and functional abnormalities. We believe that this extensive one-stage surgery contributed to maximizing the quality of life and minimizing the number of future reoperations. Our approach can provide suggestions for the management of adult patients with repaired congenital heart disease.

Endovascular therapy for intracranial infectious aneurysms associated with a left ventricular assist device: illustrative case.

BACKGROUND: Cerebrovascular events and infection are among the most common complications of left ventricular assist device (LVAD) therapy. The authors reported on a patient with an infectious intracranial aneurysm (IIA) associated with LVAD infection that was successfully occluded by endovascular therapy. OBSERVATIONS: A 37-year-old man with severe heart failure received an implantable LVAD. He was diagnosed with candidemia due to driveline infection 44 months after LVAD implantation, and empirical antibiotic therapy was started. After 4 days of antibiotic treatment, the patient experienced sudden dizziness. Computed tomography (CT) revealed subarachnoid hemorrhage in the right frontal lobe, and CT angiography revealed multiple aneurysms in the peripheral lesion of the anterior cerebral artery (ACA) and middle cerebral artery. Two weeks and 4 days after the first bleeding, aneurysms on the ACA reruptured. Each aneurysm was treated with endovascular embolization using n-butyl cyanoacrylate. Subsequently, the patient had no rebleeding of IIAs. The LVAD was replaced, and bloodstream infection was controlled. He received a heart transplant and was independent 2 years after the heart transplant. LESSONS: LVAD-associated IIAs have high mortality and an increased risk of surgical complications. However, endovascular obliteration may be safe and thus improve prognosis.

[The Trend of Minimally Invasive Cardiac Surgery:Where Robot-assisted Cardiac Surgery in Japan is Now].

The trend in cardiac surgery is moving toward minimally invasive procedures worldwide. In Japan, robot-assisted cardiac surgery has started simultaneously with the insurance coverage of minimally invasive cardiac surgery in April 2018. Technology innovations such as the miniaturization of the robot arm, the development of various type of instruments have improved operability and has contributed to the spread of robot-assisted cardiac surgery. On the other hand, there are several issues that may be barriers to its widespread use. The number of facilities for robot-assisted cardiac surgery has not increased as expected probably due to the current insurance system, that is still being developed, the requirement for implementation, and the cost. The current status and issues of robot-assisted cardiac surgery in Japan will be discussed.

Redo Aortic Valve Replacement With Perceval Prosthesis via Minithoracotomy in a Patient With Permanent Tracheostoma and Tracheoesophageal Shunt.

A 76-year-old male patient had undergone aortic valve replacement with a 19-mm Carpentier-Edwards Perimount valve 12 years prior and underwent laryngopharyngo-esophagectomy for hypopharyngeal carcinoma followed by permanent tracheostomy and tracheoesophageal shunt creation 2 years later. Echocardiography showed exacerbated structural valve deterioration of the bioprosthesis, necessitating redo surgery. A permanent tracheostoma, located just above the upper edge of the sternum, seemed to be at high risk of serious infections when median resternotomy was performed. To minimize the risk of infection, we performed implantation of a Perceval prosthesis via the right anterior minithoracotomy after sufficient anatomical assessments. There was no evidence of mediastinitis or wound infection during the follow-up period. This report highlights that the less invasive Perceval implantation strategically allowed reduction in the resternotomy-associated infection risks in this patient.

Case Report: Bronchogenic Cyst in the Right Atrium of a Young Woman.

A 31-year-old woman was referred to our hospital for evaluation of a cardiac mass in the right atrium. Cardiac magnetic resonance imaging indicated a cystic mass filled with fluid accumulation in the right atrium. The mass was identified as a cardiac cyst and was surgically removed. Pathological examination revealed an extremely rare bronchogenic cyst. Bronchogenic cysts are benign congenital abnormalities of primitive foregut origins that form in the mediastinum during embryonic development. There is unusual clinical dilemmas surrounding the treatment plan for cardiac surgery or biopsy of cardiac masses, especially in patients with rare cardiac cysts. The anatomical location of the cyst can be related to various clinical symptoms and complications. In cases of indeterminate cardiac cysts, direct cyst removal without prior biopsy is of utmost importance.

Fulminant necrotizing eosinophilic myocarditis after COVID-19 vaccination survived with mechanical circulatory support.

A 69-year-old man was hospitalized for heart failure 7 days after coronavirus disease 2019 (COVID-19) mRNA vaccination. Electrocardiography showed ST-segment elevation and echocardiography demonstrated severe left ventricular dysfunction. Venoarterial extracorporeal membrane oxygenation and Impella 5.0 were instituted because of cardiogenic shock and ventricular fibrillation. Endomyocardial biopsy demonstrated necrotizing eosinophilic myocarditis (NEM). Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) PCR test was negative. He had no infection or history of new drug exposure. NEM was likely related to COVID-19 vaccination. He was administered 10 mg/kg of prednisolone following methylprednisolone pulse treatment (1000 mg/day for 3 days). Left ventricular function recovered and he was weaned from mechanical circulatory support (MCS). Follow-up endomyocardial biopsy showed no inflammatory cell infiltration. This is the first report of biopsy-proven NEM after COVID-19 vaccination survived with MCS and immunosuppression therapy. It is a rare condition but early, accurate diagnosis and early aggressive intervention can rescue patients.

Potential of the EVAHEART 2 Double-Cuff Tipless Inflow Cannula for Prevention of Thromboembolic Events.

A 32-year-old man, who had developed fulminant myocarditis leading to asystole, underwent implantation of an EVAHEART 2 left ventricular assist system with a double-cuff tipless inflow cannula and a concurrent Fontan operation. Approximately 2 years after the simultaneous EVAHEART 2 implantation and the Fontan operation, the patient underwent heart transplantation. There was no device-related thromboembolism or pump malfunction under adequate antithrombotic management during the postoperative support period. Computed tomography showed no malposition of the inflow cannula irrespective of the left ventricular chamber size. Macroscopically, the left ventricular cavity of the excised heart revealed a smooth inflow ostium with appropriate intimal proliferation and without pannus or wedge thrombus formation. These findings suggest the utility of the double-cuff tipless inflow cannula for long-term clinical applications, which may lead to favorable outcomes during long-term patient management. The double-cuff tipless inflow cannula, which does not protrude into the left ventricular cavity, potentially contributes to the prevention of suction events and the collision of the inflow cannula with the interventricular septum and left ventricular free wall. Further investigation is required to confirm the role of the unique EVAHEART 2 inflow cannula in reducing thromboembolic events.