Endogenous interleukin-22 prevents cardiac rupture after myocardial infarction in mice.

Myocardial infarction (MI) can result in fatal myocardial rupture or heart failure due to adverse remodeling and dysfunction of the left ventricle. Although recent studies have shown that exogenous interleukin (IL)-22 shows cardioprotective effect after MI, the pathophysiological significance of endogenous IL-22 is unknown. In this study, we investigated the role of endogenous IL-22 in a mouse model of MI. We produced MI model by permanent ligation of the left coronary artery in wild-type (WT) and IL-22 knock-out (KO) mice. The post-MI survival rate was significantly worse in IL-22KO mice than in WT mice due to a higher rate of cardiac rupture. Although IL-22KO mice exhibited a significantly greater infarct size than WT mice, there was no significant difference in left ventricular geometry or function between WT and IL-22KO mice. IL-22KO mice showed increase in infiltrating macrophages and myofibroblasts, and altered expression pattern of inflammation- and extracellular matrix (ECM)-related genes after MI. While IL-22KO mice showed no obvious changes in cardiac morphology or function before MI, expressions of matrix metalloproteinase (MMP)-2 and MMP-9 were increased, whereas that of tissue inhibitor of MMPs (TIMP)-3 was decreased in cardiac tissue. Protein expression of IL-22 receptor complex, IL-22 receptor alpha 1 (IL-22R1) and IL-10 receptor beta (IL-10RB), were increased in cardiac tissue 3 days after MI, regardless of the genotype. We propose that endogenous IL-22 plays an important role in preventing cardiac rupture after MI, possibly by regulating inflammation and ECM metabolism.

Rapidly Moving Vanishing Tumor of the Lung After Open-heart Surgery.

Vanishing tumor of the lung, also known as phantom tumor, is uncommonly observed in congestive heart failure. We report a case of a vanishing tumor that rapidly disappeared and reappeared in just a few minutes due to repositioning in a patient after open-heart surgery.

Discontinuation of Intravenous Catecholamine by Oral Ivabradine in a Patient with Decompensated Heart Failure with Low Cardiac Output Syndrome.

Ivabradine has been shown to improve heart failure with sinus tachycardia by reducing the heart rate without affecting left ventricular systolic function or blood pressure. Here we report a case of a catecholaminedependent patient, New York Heart Association (NYHA) class IV, LVEF of 18%, and low cardiac output, who was able to discontinue intravenous catecholamine by oral administration of ivabradine.

Effects of Low-Dose Tadalafil in a Patient with Biventricular Heart Failure: A Case Report.

Phosphodiesterase type 5 (PDE5) inhibitors such as tadalafil, can improve cardiac output by increasing left ventricular preload; however, there are concerns that this can increase the risk of heart failure due to pulmonary congestion in patients with elevated left ventricular end-diastolic pressure. We encountered a case in which low dose tadalafil improved the hemodynamics of a 66-year-old male patient with dilated cardiomyopathy (DCM) with congestion and low cardiac output due to biventricular dysfunction. The patient received a cardiac resynchronization therapy defibrillator (CRT-D) and appropriate medical therapy for heart failure. During a hemodynamic evaluation after heart failure symptoms were alleviated, we attempted to increase the dose of renin-angiotensin-aldosterone system (RAAS) inhibitors, which contribute to low cardiac output, hypotension, and worsening of renal function. However, the administration of a low dose of tadalafil for the patient's benign prostatic hyperplasia allowed for the increase in the dose of RAAS inhibitors and markedly improved his subjective symptoms and hemodynamics. Because of the biventricular dysfunction in severe cases, we often experience further promotion of low cardiac output by standard treatments such as RAAS inhibitors, in which low doses of PDE5 inhibitors may be effective in maintaining biventricular linkage. PDE5 inhibitors may be effective in patients, who are not able to increase the dose of RAAS inhibitors due to low cardiac output.

Successful laparoscopic pheochromocytoma resection in an adult patient with Fontan physiology: a case report.

Background: Pheochromocytoma is a rare tumour producing catecholamines and has been more frequently reported than expected in patients with a Fontan physiology. Case summary: The patient was a 39-year-old woman born with a univentricular atrioventricular connection and pulmonary valve stenosis. A Fontan operation was performed when she was 22 years old. At the age of 38, she was diagnosed with pheochromocytoma. The most serious problem was the increased occurrence of supraventricular arrhythmias, which easily caused heart failure. We decided to perform a laparoscopic resection. Postoperative recovery was good. There were no findings of malignancy and all postoperative catecholamine levels normalized. She was discharged home on the 14th day after the surgery, walking unaided. Discussion: Diagnosis and treatment by tumour resection in the early phase are crucial in patients who undergo the Fontan procedure. However, patients after Fontan surgery have a very low cardiac reserve. Thus, the decision to perform a surgical treatment is a very difficult one to take. In this case, fenestration had been naturally closed. As fenestration provides a consistent source of systemic ventricular preload, we performed transcatheter fenestration dilatation to improve heart failure management before surgical pheochromocytoma removal. Although laparoscopic surgery is generally considered to be less invasive, pneumoperitoneum may interfere with venous return in Fontan physiology patients. There is also a risk of thrombosis via fenestration. Here, we reported the case of a successful laparoscopic pheochromocytoma resection in an adult Fontan patient.

Multidisciplinary Team-Based Palliative Care for Heart Failure and Food Intake at the End of Life.

Traditionally, patients with end-stage heart failure (HF) have rarely been involved in end-of-life care (EOLC) discussions in Japan. The purpose of this study was to examine the impact of HF-specific palliative care team (HF-PCT) activities on EOLC discussions with patients, HF therapy and care, and food intake at the end of life. We retrospectively analyzed 52 consecutive patients with HF (mean age, 70 ± 15 years; 42% female) who died at our hospital between May 2013 and July 2020 and divided them into two groups: before (Era 1, n = 19) and after (Era 2, n = 33) the initiation of HF-PCT activities in June 2015. Compared to Era 1, Era 2 showed a decrease in invasive procedures, an increase in opioid and non-intubating sedative use for symptom relief, improved quality of meals at the end of life, and an increase in participation in EOLC discussions. The administration of artificial nutrition in the final three days was associated with non-ischemic cardiomyopathy etiology, the number of previous hospitalizations for HF, and multidisciplinary EOLC discussion support. HF-PCT activities may provide an opportunity to discuss EOLC with patients, reduce the burden of physical and psychological symptoms, and shift the goals of end-of-life nutritional intake to ensure comfort and quality of life.

SOCS3 deficiency in cardiomyocytes elevates sensitivity of ischemic preconditioning that synergistically ameliorates myocardial ischemia reperfusion injury.

Ischemic preconditioning (IPC) is the most powerful endogenous cardioprotective form of cellular adaptation. However, the inhibitory or augmenting mechanism underlying cardioprotection via IPC remains largely unknown. Suppressor of cytokine signaling-3 (SOCS3) is a cytokine-inducible potent negative feedback regulator of the signal transducer and activator of transcription-3 (STAT3) signaling pathway. Here, we aimed to determine whether cardiac SOCS3 deficiency and IPC would synergistically reduce infarct size after myocardial ischemia reperfusion injury. We evaluated STAT3 activation and SOCS3 induction after ischemic conditioning (IC) using western blot analysis and real-time PCR, and found that myocardial IC alone transiently activated myocardial STAT3 and correspondingly induced SOCS3 expression in wild-type mice. Compared with wild-type mice, cardiac-specific SOCS3 knockout (SOCS3-CKO) mice showed significantly greater and more sustained IC-induced STAT3 activation. Following ischemia reperfusion, IPC substantially reduced myocardial infarct size and significantly enhanced STAT3 phosphorylation in SOCS3-CKO mice compared to in wild-type mice. Real-time PCR array analysis revealed that SOCS3-CKO mice after IC exhibited significantly increased expressions of several anti-apoptotic genes and SAFE pathway-related genes. Moreover, real-time PCR analysis revealed that myocardial IC alone rapidly induced expression of the STAT3-activating cytokine erythropoietin in the kidney at 1 h post-IC. We also found that the circulating erythropoietin level was promptly increased at 1 h after myocardial IC. Myocardial SOCS3 deficiency and IPC exert synergistic effects in the prevention of myocardial injury after ischemia reperfusion. Our present results suggest that myocardial SOCS3 is a potent inhibitor of IPC-induced cardioprotection, and that myocardial SOCS3 inhibition augment IPC-mediated cardioprotection during ischemia reperfusion injury.

Effective Use of Keishibukuryogan in Subcutaneous Hematoma after Implantable Cardiac Device Surgery in Two Cases.

Keishibukuryogan is a Kampo medicine that induces vasodilation and improves the blood flow velocity in subcutaneous blood vessels. We herein report two cases in which keishibukuryogan completely diminished subcutaneous hematoma after cardiac resynchronization therapy pacemaker implantation and defibrillator battery replacement within a month. Keishibukuryogan can be a good option for treating or preventing subcutaneous hematoma after surgical procedures for devices.

Interleukin-22 Directly Activates Myocardial STAT3 (Signal Transducer and Activator of Transcription-3) Signaling Pathway and Prevents Myocardial Ischemia Reperfusion Injury.

BACKGROUND Interleukin (IL)-22, a member of the IL-10 cytokine family, is the only known cytokine that is secreted by immune cells but does not target immune cells; it mainly targets epithelial cells. In this study, we aimed to determine whether IL-22 administration could activate the myocardial STAT3 (signal transducer and activator of transcription-3) signaling pathway, and thus prevent myocardial injury, in a mouse model of ischemia reperfusion injury. METHODS AND RESULTS We evaluated the STAT3 activation after IL-22 injection by Western blot analysis and immunostaining for phosphorylated STAT3 in the heart and found that STAT3 activation in heart tissue rapidly peaked after IL-22 injection. Coimmunostaining of phosphorylated STAT3 and α-actinin revealed that STAT3 activation occurred in cardiomyocytes after IL-22 administration. In heart tissue from intact mice, real-time PCR demonstrated significant expression of IL-22 receptor subunit 1, and coimmunostaining of IL-22 receptor subunit 1 and α-actinin showed IL-22 receptor subunit 1 expression in cardiomyocytes. In cultured cardiomyocytes, IL-22 activated STAT3, and we detected IL-22 receptor subunit 1 expression. Overall, these results indicated that IL-22 directly activated the myocardial IL-22-receptor subunit 1-STAT3 signaling pathway. Following ischemia reperfusion, compared with PBS-treated mice, IL-22-treated mice exhibited a significantly reduced infarct size, significantly reduced myocardial apoptosis, and significantly enhanced phosphorylated STAT3 expression. Moreover, heart tissue from IL-22-treated mice exhibited a significantly reduced expression ratio of phosphorylated p53 to p53. CONCLUSIONS Our present findings suggest that IL-22 directly activated the myocardial STAT3 signaling pathway and acted as a cardioprotective cytokine to ameliorate acute myocardial infarction after ischemia reperfusion.

Cardiac-Specific SOCS3 Deletion Prevents In Vivo Myocardial Ischemia Reperfusion Injury through Sustained Activation of Cardioprotective Signaling Molecules.

Myocardial ischemia reperfusion injury (IRI) adversely affects cardiac performance and the prognosis of patients with acute myocardial infarction. Although myocardial signal transducer and activator of transcription (STAT) 3 is potently cardioprotective during IRI, the inhibitory mechanism responsible for its activation is largely unknown. The present study aimed to investigate the role of the myocardial suppressor of cytokine signaling (SOCS)-3, an intrinsic negative feedback regulator of the Janus kinase (JAK)-STAT signaling pathway, in the development of myocardial IRI. Myocardial IRI was induced in mice by ligating the left anterior descending coronary artery for 1 h, followed by different reperfusion times. One hour after reperfusion, the rapid expression of JAK-STAT-activating cytokines was observed. We precisely evaluated the phosphorylation of cardioprotective signaling molecules and the expression of SOCS3 during IRI and then induced myocardial IRI in wild-type and cardiac-specific SOCS3 knockout mice (SOCS3-CKO). The activation of STAT3, AKT, and ERK1/2 rapidly peaked and promptly decreased during IRI. This decrease correlated with the induction of SOCS3 expression up to 24 h after IRI in wild-type mice. The infarct size 24 h after reperfusion was significantly reduced in SOCS3-CKO compared with wild-type mice. In SOCS3-CKO mice, STAT3, AKT, and ERK1/2 phosphorylation was sustained, myocardial apoptosis was prevented, and the expression of anti-apoptotic Bcl-2 family member myeloid cell leukemia-1 (Mcl-1) was augmented. Cardiac-specific SOCS3 deletion led to the sustained activation of cardioprotective signaling molecules including and prevented myocardial apoptosis and injury during IRI. Our findings suggest that SOCS3 may represent a key factor that exacerbates the development of myocardial IRI.

Renal Nerve-Mediated Erythropoietin Release Confers Cardioprotection During Remote Ischemic Preconditioning.

BACKGROUND: Remote ischemic preconditioning (RIPC) induced by transient limb ischemia is a powerful innate mechanism of cardioprotection against ischemia. Several described mechanisms explain how RIPC may act through neural pathways or humoral factors; however, the mechanistic pathway linking the remote organ to the heart has not yet been fully elucidated. This study aimed to investigate the mechanisms underlying the RIPC-induced production of Janus kinase (JAK)-signal transducer and activator of the transcription (STAT)-activating cytokines and cardioprotection by using mouse and human models of RIPC. METHODS AND RESULTS: Screened circulating cardioprotective JAK-STAT-activating cytokines in mice unexpectedly revealed increased serum erythropoietin (EPO) levels after RIP induced by transient ischemia. In mice, RIPC rapidly upregulated EPO mRNA and its main transcriptional factor, hypoxia-inducible factor-1α (HIF1α), in the kidney. Laser Doppler blood flowmetry revealed a prompt reduction of renal blood flow (RBF) after RIPC. RIPC activated cardioprotective signaling pathways and the anti-apoptotic Bcl-xL pathway in the heart, and reduced infarct size. In mice, these effects were abolished by administration of an EPO-neutralizing antibody. Renal nerve denervation also abolished RIPC-induced RBF reduction, EPO production, and cardioprotection. In humans, transient limb ischemia of the upper arm reduced RBF and increased serum EPO levels. CONCLUSIONS: Based on the present data, we propose a novel RIPC mechanism in which inhibition of infarct size by RIPC is produced through the renal nerve-mediated reduction of RBF associated with activation of the HIF1α-EPO pathway.