Effect of mechanical tension on fibroblast transcriptome profile and regulatory mechanisms of myocardial collagen turnover.

Excess deposition of extracellular matrix in the myocardium is a predictor of reduced left ventricular function. Although reducing the hemodynamic load is known to improve myocardial fibrosis, the mechanisms underlying the reversal of the fibrosis have not been elucidated. We focused on the elasticity of myocardial tissue, which is assumed to influence the fibroblast phenotype. Normal and fibrotic myocardium were cultured in 16 kPa and 64 kPa silicone gel-coated dishes supplemented with recombinant TGFß protein, respectively. Matrix-degrading myocardium was cultured in 64 kPa silicone gel-coated dishes with recombinant TGFß protein and then in 16 kPa silicone gel-coated dishes. Cardiac fibroblasts were cultured in this three-part in vitro pathological models and compared. Fibroblasts differentiated into activated or matrix-degrading types in response to the pericellular environment. Comprehensive gene expression analysis of fibroblasts in each in vitro condition showed Selenbp1 to be one of the genes responsible for regulating differentiation of fibroblasts. In vitro knockdown of Selenbp1 enhanced fibroblast activation and inhibited conversion to the matrix-degrading form. In vivo knockdown of Selenbp1 resulted in structural changes in the left ventricle associated with progressive tissue fibrosis and left ventricular diastolic failure. Selenbp1 is involved in regulating fibroblast differentiation and appears to be one of the major molecules regulating collagen turnover in cardiac fibrosis.

Nrg1/ErbB signaling-mediated regulation of fibrosis after myocardial infarction.

Appropriate fibrotic tissue formation after myocardial infarction (MI) is crucial to the maintenance of the heart's structure. M2-like macrophages play a vital role in post-MI fibrosis by activating cardiac fibroblasts. Because the mechanism by which post-MI cardiac fibrosis is regulated is not fully understood, we investigated, in vitro and in vivo, the cellular and molecular mechanisms of post-MI fibrotic tissue formation, especially those related to the regulation of cellular senescence and apoptosis. CD206+ F4/80+ CD11b+ M2-like macrophages collected from mouse hearts on post-MI day 7 showed increased expression of neuregulin 1 (Nrg1). Nrg1 receptor epidermal growth factor receptors ErbB2 and ErbB4 were expressed on cardiac fibroblasts in the infarct area. M2-like macrophage-derived Nrg1 suppressed both hydrogen peroxide-induced senescence and apoptosis of fibroblasts, whereas blockade of ErbB function significantly accelerated both processes. M2-like macrophage-derived Nrg1/ErbB/PI3K/Akt signaling, shown to be related to anti-senescence, was activated in damaged cardiac fibroblasts. Interestingly, systemic blockade of ErbB function in MI model mice enhanced senescence and apoptosis of cardiac fibroblasts and exacerbated inflammation. Further, increased accumulation of M2-like macrophages resulted in excessive post-MI progression of fibrosis in mice hearts. The molecular mechanism underlying the regulation of fibrotic tissue formation in the infarcted myocardium was shown in part to be attenuation of apoptosis and senescence of cardiac fibroblasts by the activation of Nrg1/ErbB/PI3K/Akt signaling. M2-like macrophage-mediated regulation of Nrg1/ErbB signaling has a substantial effect on fibrotic tissue formation in the infarcted adult mouse heart and is critical for suppressing the progression of senescence and apoptosis of cardiac fibroblasts.

[Surgical Outcomes of Prosthetic Valve Endocarditis].

Prosthetic valve endocarditis is a fatal complication after valve replacement surgery. Early surgical intervention is recommended for patients who suffer from complications such as heart failure, valve dysfunction, and abscesses. In the present study, we evaluated the clinical characteristics of 18 patients who underwent surgery for prosthetic valve endocarditis at our institution between December 1990 and August 2022, and examined the appropriateness of the timing and method of surgery, and whether there was improvement in cardiac function. Guidelines-based surgical intervention resulted in improved survival and improved cardiac function in the early and late postoperative period.

[Non-A Non-B Aortic Dissection Complicated with Right Aortic Arch Treated by Extended Thoracic Aortic Repair].

A 44-year old man with a history of Stanford type B acute aortic dissection was admitted for the treatment of acute aortic dissection. Computed tomography( CT) scan showed a descending entry-type non-A non-B aortic dissection with a maximum diameter of 65 mm occurring in a patient with Edwards typeⅢ right aortic arch whose left subclavian artery was obliterated. The patient was initially treated conservatively and underwent one-stage extended aortic repair from the ascending aorta to the descending thoracic aorta via median sternotomy 22 days after the symptom onset. Although the patient suffered from right empyema postoperatively, he was discharged from the hospital on postoperative day 64 after 4 weeks antibiotics therapy. The patient was also complicated by right recurrent nerve palsy, hoarseness improved over the 8 months after surgery.

Early cardiac contractility outcome of reoperative coronary artery bypass grafting using right gastroepiploic artery.

BACKGROUND AND AIM OF THE STUDY: Reoperative coronary artery bypass grafting (redo CABG) still carries higher mortality and increased morbidity compared with primary CABG. In this study, we retrospectively reviewed our operative outcome of redo CABG to evaluate the impact of the left anterolateral thoracotomy approach using the right gastroepiploic artery (RGEA). METHODS: Between 1994 and 2020, 11 patients (mean age 60.3 ± 13.1 years; nine men, two women) underwent isolated redo CABG using the RGEA via the left anterolateral thoracotomy. RESULTS: The mean duration from the initial CABG was 128.3 ± 88.4 months. Redo CABG was performed because of graft occlusion in six patients (54.5%), graft stenosis in one patient (9.1%), and progressive disease of previously ungrafted vessels in four patients (36.4%). The total number of bypasses using RGEA (including Y-composite vein grafts) was 16 (four left anterior descending branches, two diagonal branches, five circumflex branches, five right coronary arteries). No residual graft injury, major comorbidity, or in-hospital death was observed. Changes in echocardiographic values before and after redo CABG were 210.9 ± 48.2 ml and 175.0 ± 41.4 ml in left ventricular end-diastolic volume, 130.2 ± 49.2 ml and 94.4 ± 33.0 ml in left ventricular end-systolic volume, and 45.6 ± 11.0% and 52.2 ± 10.7% in left ventricular ejection fraction, respectively. These parameters significantly improved after redo CABG. CONCLUSIONS: Redo CABG with RGEA grafting via the left anterolateral thoracotomy approach is a safe and effective surgical procedure especially in improving cardiac contractility in patients who required revascularization.

[Surgical Resection Papillary Fibroelastoma Arising from Left Atrium:Report of a Case].

A 75-year-old man was admitted for cerebral infarction. Magnetic resonance imaging revealed parietal lobe cerebral infarction. Transesophageal echo and contrast-enhanced computed tomography indicated mobile and speckled mass arising from left atrium. He was diagnosed with cardiogenic cerebral embolism. Under cardiopulmonary bypass, resection of the mass including endocardium tissue was per formed. The resected specimen showed multiple small fronds resembling a sea anemone. Microscopic examination showed multiple branching fronds of paucicellular and avascular fibroelastic tissue lined by a single layer of endocardium. Pathological diagnosis was papillary fibroelastoma. Three years passed without recurrence.

[Subacute Pseudoaneurysm Formation after Sutureless Repair for Postinfarction Left Ventricular Rupture:Report of a Case].

A 71-year-old woman was admitted for cardiac tamponade due to left ventricular free wall rupture after acute myocardial infarction. Sutureless repair was performed for bleeding from the inferior wall. Fifteen days later, computed tomography demonstrated enlargement of a left ventricular pseudoaneurysm. Patch closure using a vascular prosthesis was performed through left thoracotomy. No recurrence of the left ventricular aneurysm has been observed since.

[Rapid Growing Thoracic Aortic Aneurysm in a Patient with Relapsing Polychondritis].

A 26-year-old man with relapsing polychondritis was admitted for the treatment of multiple thoracic aortic aneurysms in the ascending and descending aorta. Descending thoracic aortic aneurysm showed rapid expansion, therefore, the patient underwent an extended thoracic aortic repair from the ascending aorta to the descending aorta via anterolateral thoracotomy and partial sternotomy. Although postoperative course was uneventful, aortic root enlargement and severe aortic insufficiency progressed over the next two years. He and his family refused redo surgical intervention and the patient died of heart failure. Careful perioperative follow-up may be mandatory in a patient with relapsing polychondritis complicated by cardiovascular disease.

Early superior mesenteric artery revascularization for acute type A aortic dissection with cardiac tamponade and mesenteric malperfusion.

We report herein the successful treatment of a case of acute type A aortic dissection complicated by cardiac tamponade and mesenteric malperfusion. The patient was a 60-year-old man with back and abdominal pain and in shock, who was transported to our hospital 2 h after symptom onset. Computed tomography revealed DeBakey type I dissection with massive hemopericardium and obstruction of both the celiac artery and superior mesenteric artery. After emergency pericardiotomy and removal of the hematoma, superior mesenteric artery-external iliac artery bypass was constructed with a vein graft, and this restored mesenteric perfusion. Open distal hemiarch replacement was then performed. The postoperative course was uneventful. Superior mesenteric artery revascularization achieved immediately after release of the cardiac tamponade prevented further mesenteric ischemia and paved the way for the aortic repair.

[Bioprosthetic Mitral Valve Thrombosis in Patient with Antiphospholipid Antibody Syndrome;Report of a Case].

A 66-year-old woman with primary antiphospholipid antibody syndrome (APS) was admitted due to severe dyspnea. Eight months prior to admission, she underwent bioprosthetic mitral valve replacement for mitral valve stenosis and regurgitation. Transthoracic echocardiogram showed thickening bioprosthetic valve leaflets and severe valve stenosis. Emergency reoperation for artificial valve failure was performed. The explanted bioprosthetic valve showed massive thrombus formation. After the operation, she started strict anticoagulant and antiplatelet therapies and was discharged without recurrence of valve thrombosis.

[Hybrid Repair of Distal Arch Aortic Aneurysm:Total Aortic Arch Repair with the Lupiae Vascular Graft and Thoracic Endovascular Aortic Repair;Report of Two Cases].

Surgical treatment for distal arch aortic aneurysm is generally invasive, and there is no definitive approach for it. We report 2 cases of men who was admitted for the treatment of aortic aneurysm. First case is a 78-year-old man. Two saccular aneurysm were observed on distal aortic arch and descending aorta by contrast-enhanced computed tomography. Two staged-repair was performed with using the Lupiae vascular graft and thoracic endovascular aortic repair(TEVAR). The postoperative course was uneventful, and he was discharged on day 21 after 1st operation. Second case is a 68-yearold man. Dessecting aneurysm was observed on distal aortic arch and descending aorta 3 months after incidence of type B aortic dissection. Two staged-repair was performed with using the Lupiae vascular graft and TEVAR. However, additional TEVAR was performed for enlargement of descending aorta half a year after 1st operation. Two staged-repair using Lupiae vascular graft and TEVAR was useful for alleviating a burden of a patient and avoiding paraplegia.

[Successful Surgical Repair of the Aortic Annular Infective Endocarditis with Subvalvular Abscess;Report of a Case].

A 49-year-old female was admitted to our hospital with a history of fever for 2 weeks and consciousness disorder.Transthoracic echocardiography demonstrated aortic regurgitation with a mobile fibrous band adhering to the right cusp. Infective endocarditis was diagnosed by positive blood culture and echocardiographic findings. Emergent aortic valve surgery was performed because of uncontrollable infection. A destroyed aortic annulus and subvalvular abscess was found during the operation. Removal of abscess tissue and annuloplasty with self-pericardium were successfully performed.

[Total Aortic Arch Replacement by Minimally Invasive Approach in a Patient with Permanent Tracheostomy;Report of a Case].

Standard full median sternotomy for total aortic arch replacement in patients with tracheostomy has higher risks for mediastinitis and graft infection. To avoid surgical site infection, it is necessary to keep a sufficient distance between the tracheostomy and the site of surgical skin incision. We herein report a case of a 74-year-old man with permanent tracheostomy after total laryngectomy, who underwent total aortic arch replacement for an aneurysm. Antero-lateral thoracotomy in the 2nd intercostal space with lower partial sternotomy( ALPS approach) provided an enough distance between the tracheostomy and the surgical field. It also provided a good view for surgical procedure and enabled the standard setup of cardiopulmonary bypass with ascending aortic cannulation, venous drainage from the right atrium and the left ventricular venting through the upper right pulmonary vein. The operation was completed in 345 minutes and the patient was discharged on the 11th postoperative day without any complications.

Epicardial placement of mesenchymal stromal cell-sheets for the treatment of ischemic cardiomyopathy; in vivo proof-of-concept study.

Transplantation of bone marrow mesenchymal stromal cells (MSCs) is an emerging treatment for heart failure. We have reported that epicardial placement of MSC-sheets generated using temperature-responsive dishes markedly increases donor MSC survival and augments therapeutic effects in an acute myocardial infarction (MI) model, compared to intramyocardial (IM) injection. This study aims to expand this knowledge for the treatment of ischemic cardiomyopathy, which is likely to be more difficult to treat due to mature fibrosis and chronically stressed myocardium. Four weeks after MI, rats underwent either epicardial MSC-sheet placement, IM MSC injection, or sham treatment. At day 28 after treatment, the cell-sheet group showed augmented cardiac function improvement, which was associated with over 11-fold increased donor cell survival at both days 3 and 28 compared to IM injection. Moreover, the cell-sheet group showed improved myocardial repair, in conjunction with amplified upregulation of a group of reparative factors. Furthermore, by comparing with our own previous data, this study highlighted similar dynamics and behavior of epicardially placed MSCs in acute and chronic stages after MI, while the acute-phase myocardium may be more responsive to the stimuli from donor MSCs. These proof-of-concept data encourage further development of the MSC-sheet therapy for ischemic cardiomyopathy toward clinical application.

Successful non-operative management of left atrioesophageal fistula following catheter ablation.

Atrioesophageal fistula (AEF) is a potentially lethal complication of catheter radiofrequency ablation for atrial fibrillation. A 49-year-old man with paroxysmal atrial fibrillation who underwent catheter ablation around the pulmonary vein was admitted 31 days after the procedure, suffering seizures and fever. Magnetic resonance imaging of the brain showed ischemia and multiple lesions of acute infarction in the right occipital lobe of the cerebrum. Computed tomography (CT) of the chest showed a small accumulation of air between the posterior left atrium and the esophagus, suggesting an AEF. Endoscopic snaring of the esophageal mucosa, repeated a few times, supported by nil by mouth and antibiotic therapy, resulted in improvement of his condition with no recurrence of symptoms. Subsequent chest CT scans confirmed disappearance of the leaked air and the patient was discharged home 45 days after admission with no neurological compromise.

[Emergency stent placement after descending aortic replacement with chronic aortic dissection].

A 49-year-old man with asymptomatic chronic aneurysmal dissection was admitted to our hospital. He had undergone ascending aortic replacement for type A aortic dissection 7 months before. We performed descending aortic replacement for chronic aneurysmal dissection. Renal dysfunction appeared 1 day after the operation. Contrast-enhanced computed tomography indicated that the true lumen was severely compressed by a false lumen, and that the origins of the renal artery were occluded. We performed emergency endovascular stent placement to dilate the true lumen. Immediately after this procedure, renal ischemia improved. The postoperative course was uneventful. An endovascular approach using bare stent can be a treatment option that is less invasive and prompter for a patient with renal ischemia resulting from aortic dissection.

Cell barrier function of resident peritoneal macrophages in post-operative adhesions.

Post-operative adhesions are a leading cause of abdominal surgery-associated morbidity. Exposed fibrin clots on the damaged peritoneum, in which the mesothelial barrier is disrupted, readily adhere to surrounding tissues, resulting in adhesion formation. Here we show that resident F4/80HighCD206- peritoneal macrophages promptly accumulate on the lesion and form a 'macrophage barrier' to shield fibrin clots in place of the lost mesothelium in mice. Depletion of this macrophage subset or blockage of CD11b impairs the macrophage barrier and exacerbates adhesions. The macrophage barrier is usually insufficient to fully preclude the adhesion formation; however, it could be augmented by IL-4-based treatment or adoptive transfer of this macrophage subset, resulting in robust prevention of adhesions. By contrast, monocyte-derived recruited peritoneal macrophages are not involved in the macrophage barrier. These results highlight a previously unidentified cell barrier function of a specific macrophage subset, also proposing an innovative approach to prevent post-operative adhesions.

Effects of Obesity on Outcomes of Acute Type A Aortic Dissection Repair in Japan.

Background: The prevalence of obesity among Japanese acute type A aortic dissection (ATAAD) patients and its effect on repair outcomes remain to be elucidated. Methods and Results: The prevalence of obesity (body mass index [BMI] ≥30.0 kg/m2) among 1,059 patients (mean [±SD] age 64.3±12.7 years) who underwent ATAAD repair between 1990 and 2018 was compared with that among the general Japanese population (National Health and Nutrition Survey data). The prevalence of obesity among male patients (17.1% [6/35], 20.0% [18/90], and 14.4% [20/139] for those aged 20-39, 40-49, and 50-59 years, respectively) was significantly higher than that among the age- and sex-matched general population. The 1,059 patients were divided into groups according to weight (normal [BMI <25.0 kg/m2; n=742], overweight [BMI 25.0-29.9 kg/m2; n=248], or obese [BMI ≥30.0 kg/m2; n=69]). Comparing the normal weight, overweight, and obese groups revealed significant differences among the 3 groups in median cardiopulmonary bypass time (143, 167, and 183 min, respectively), ventilation >48 h (44.5%, 60.1%, and 78.3%, respectively), and in-hospital mortality (7.0%, 7.3%, and 17.4%, respectively), but not in 30-day survival. Shock, visceral malperfusion, operation time >360 min, obesity, and coronary malperfusion were identified as predictors of in-hospital mortality. Conclusions: The prevalence of obesity is increased among Japanese male patients with ATAAD aged ≤59 years. Obesity may increase these patients' operative risk; overweight does not.

IL-4 as a Repurposed Biological Drug for Myocardial Infarction through Augmentation of Reparative Cardiac Macrophages: Proof-of-Concept Data in Mice.

Recent research has shown that reparative (alternatively activated or M2) macrophages play a role in repair of damaged tissues, including the infarcted hearts. Administration of IL-4 is known to augment M2 macrophages. This translational study thus aimed to investigate whether IL-4 administration is useful for the treatment of myocardial infarction. Long-acting IL-4 complex (IL-4c; recombinant IL-4 mixed with anti-IL-4 monoclonal antibody as a stabilizer) was administered after coronary artery ligation in mice. It was observed that IL-4c administration increased accumulation of CD206+F4/80+ M2-like macrophages predominantly in the injured myocardium, compared to the control. Sorted cardiac M2-like macrophages highly expressed wide-ranging tissue repair-related genes. Indeed, IL-4c administration enhanced cardiac function in association with reduced infarct size and enhanced tissue repair (strengthened connective tissue formation, improved microvascular formation and attenuated cardiomyocyte hypertrophy). Experiments using Trib1 -/- mice that had a depleted ability to develop M2 macrophages and other in-vitro studies supported that these IL-4-mediated effects were induced via M2-like macrophages. On the other hand, when administered at Day 28 post-MI, the effects of IL-4c were diminished, suggesting a time-frame for IL-4 treatment to be effective. These data represent proof-of-concept of efficacy of IL-4 treatment for acute myocardial infarction, encouraging its further development.