Current Immunosuppressive Treatment for Takayasu Arteritis.

Takayasu arteritis (TAK) is a rare disease characterized by inflammation of large blood vessels, which results in vascular stenosis, occlusion, and aneurysm formation. The principal treatment has been glucocorticoids, but the recent emergence of biological disease-modifying anti-rheumatic drugs (bDMARDs), represented by tocilizumab (TCZ), has significantly changed the treatment landscape. Both cardiologists and cardiovascular surgeons will encounter patients receiving these drugs who require catheterization, other invasive procedures, or surgery. Several bDMARDs have shown promise against TAK in clinical studies and their use is expected to increase in the future. Janus kinase inhibitors may also be effective. Here, we review the evidence supporting the use of TCZ and other immunosuppressants in TAK and provides an update on their status as well as the relevant guidelines.

Perm1 promotes cardiomyocyte mitochondrial biogenesis and protects against hypoxia/reoxygenation-induced damage in mice.

Normal contractile function of the heart depends on a constant and reliable production of ATP by cardiomyocytes. Dysregulation of cardiac energy metabolism can result in immature heart development and disrupt the ability of the adult myocardium to adapt to stress, potentially leading to heart failure. Further, restoration of abnormal mitochondrial function can have beneficial effects on cardiac dysfunction. Previously, we identified a novel protein termed Perm1 (PGC-1 and estrogen-related receptor (ERR)-induced regulator, muscle 1) that is enriched in skeletal and cardiac-muscle mitochondria and transcriptionally regulated by PGC-1 (peroxisome proliferator-activated receptor gamma coactivator 1) and ERR. The role of Perm1 in the heart is poorly understood and is studied here. We utilized cell culture, mouse models, and human tissue, to study its expression and transcriptional control, as well as its role in transcription of other factors. Critically, we tested Perm1's role in cardiomyocyte mitochondrial function and its ability to protect myocytes from stress-induced damage. Our studies show that Perm1 expression increases throughout mouse cardiogenesis, demonstrate that Perm1 interacts with PGC-1α and enhances activation of PGC-1 and ERR, increases mitochondrial DNA copy number, and augments oxidative capacity in cultured neonatal mouse cardiomyocytes. Moreover, we found that Perm1 reduced cellular damage produced as a result of hypoxia and reoxygenation-induced stress and mitigated cell death of cardiomyocytes. Taken together, our results show that Perm1 promotes mitochondrial biogenesis in mouse cardiomyocytes. Future studies can assess the potential of Perm1 to be used as a novel therapeutic to restore cardiac dysfunction induced by ischemic injury.

Interleukin-6/interleukin-21 signaling axis is critical in the pathogenesis of pulmonary arterial hypertension.

IL-6 is a multifunctional proinflammatory cytokine that is elevated in the serum of patients with pulmonary arterial hypertension (PAH) and can predict the survival of patients with idiopathic PAH (IPAH). Previous animal experiments and clinical human studies indicate that IL-6 is important in PAH; however, the molecular mechanisms of IL-6-mediated pathogenesis of PAH have been elusive. Here we identified IL-21 as a downstream target of IL-6 signaling in PAH. First, we found that IL-6 blockade by the monoclonal anti-IL-6 receptor antibody, MR16-1, ameliorated hypoxia-induced pulmonary hypertension (HPH) and prevented the hypoxia-induced accumulation of Th17 cells and M2 macrophages in the lungs. Consistently, the expression levels of IL-17 and IL-21 genes, one of the signature genes for Th17 cells, were significantly up-regulated after hypoxia exposure in the lungs of mice treated with control antibody but not in the lungs of mice treated with MR16-1. Although IL-17 blockade with an anti-IL-17A neutralizing antibody had no effect on HPH, IL-21 receptor-deficient mice were resistant to HPH and exhibited no significant accumulation of M2 macrophages in the lungs. In accordance with these findings, IL-21 promoted the polarization of primary alveolar macrophages toward the M2 phenotype. Of note, significantly enhanced expressions of IL-21 and M2 macrophage markers were detected in the lungs of IPAH patients who underwent lung transplantation. Collectively, these findings suggest that IL-21 promotes PAH in association with M2 macrophage polarization, downstream of IL-6-signaling. The IL-6/IL-21-signaling axis may be a potential target for treating PAH.

Pilsicainide Toxicity-Induced Brugada-Like ST Segment Elevation and Increased Pacing Voltage Threshold.

Pilsicainide is a class Ic antiarrhythmic agent that exhibits fully selective sodium channel blockade. In Japan, it is one of the most prescribed medicines for rhythm control in atrial fibrillation. Pilsicainide is mainly excreted by the kidney. Therefore, the plasma concentration of pilsicainide is likely to be increased in patients with renal insufficiency. In this case report, a 90-year-old woman presented with generalized fatigue and loss of appetite. Her ECG showed marked bradycardia and coved-type ST-segment elevation similar to that of the Brugada type 1 pattern. Owing to dehydration, her renal function indices worsened compared with those measured four months prior. The plasma pilsicainide concentration was elevated to 2.67 µg/mL (therapeutic range: 0.20-0.90 µg/mL), indicating pilsicainide toxicity. A transvenous temporary pacemaker was placed; however, the pacing voltage threshold was increased at several sites within the right ventricle. Pilsicainide administration was immediately discontinued. On day 2 of admission, ventricular backup pacing was no longer required, and there was an improvement in renal function and heart failure symptoms, such as pulmonary edema and cardiomegaly. The ECG changes improved alongside the renal function and as the plasma concentration of pilsicainide decreased. In conclusion, elevated plasma concentrations of pilsicainide can induce life-threatening arrhythmias and pacing failure. Therefore, clinicians should prescribe pilsicainide cautiously, particularly in older patients.

Repeated Syncope Following COVID-19 Infection.

A 74-year-old woman presented to our hospital with syncope after a coronavirus disease 2019 (COVID-19) infection. Upon admission, she passed out, and an 8 second sinus arrest was detected during telemetry monitoring. During the next syncope episode, telemetry monitoring showed that her heart rate decreased from 80 to 36 bpm, accompanied by a 2.4 second pause. A permanent pacemaker was implanted; however, the patient still experienced syncope. The head-up tilt test revealed a vasodepressor reflex syncope. The need for permanent pacemakers in patients with syncope following COVID-19 therefore remains controversial.

Docking protein Gab1 is an essential component of postnatal angiogenesis after ischemia via HGF/c-met signaling.

RATIONALE: Grb2-associated binder (Gab) docking proteins, consisting of Gab1, Gab2, and Gab3, have crucial roles in growth factor-dependent signaling. Various proangiogenic growth factors regulate angiogenesis and endothelial function. However, the roles of Gab proteins in angiogenesis remain elusive. OBJECTIVE: To elucidate the role of Gab proteins in postnatal angiogenesis. METHODS AND RESULTS: Endothelium-specific Gab1 knockout (Gab1ECKO) mice were viable and showed no obvious defects in vascular development. Therefore, we analyzed a hindlimb ischemia (HLI) model of control, Gab1ECKO, or conventional Gab2 knockout (Gab2KO) mice. Intriguingly, impaired blood flow recovery and necrosis in the operated limb was observed in all of Gab1ECKO, but not in control or Gab2KO mice. Among several proangiogenic growth factors, hepatocyte growth factor (HGF) induced the most prominent tyrosine phosphorylation of Gab1 and subsequent complex formation of Gab1 with SHP2 (Src homology-2-containing protein tyrosine phosphatase 2) and phosphatidylinositol 3-kinase subunit p85 in human endothelial cells (ECs). Gab1-SHP2 complex was required for HGF-induced migration and proliferation of ECs via extracellular signal-regulated kinase (ERK)1/2 pathway and for HGF-induced stabilization of ECs via ERK5. In contrast, Gab1-p85 complex regulated activation of AKT and contributed partially to migration of ECs after HGF stimulation. Microarray analysis demonstrated that HGF upregulated angiogenesis-related genes such as KLF2 (Krüppel-like factor 2) and Egr1 (early growth response 1) via Gab1-SHP2 complex in human ECs. In Gab1ECKO mice, gene transfer of vascular endothelial growth factor, but not HGF, improved blood flow recovery and ameliorated limb necrosis after HLI. CONCLUSION: Gab1 is essential for postnatal angiogenesis after ischemia via HGF/c-Met signaling.

Tocilizumab for the treatment of patients with refractory Takayasu arteritis.

Treatment of refractory Takayasu arteritis (TA) remains an unresolved clinical issue. Patients usually respond to glucocorticoid (GC) therapy, but often relapse on tapering of the GC dose. The aim of the present study was to assess the safety and efficacy of the interleukin-6 (IL-6) receptor antibody tocilizumab (TCZ) in patients with TA refractory to conventional therapies including GC. Four patients with TA who had shown GC resistance received TCZ infusions (8 mg/kg) every 4 weeks a total of at least 24 times (range, 24 to 51). Clinical symptoms, the serum levels of acute phase proteins and IL-6, GC dosage necessary to maintain remission, and cross-sectional imaging by enhanced CT and MRI were assessed. All patients achieved good clinical response and rapid normalization of the acute phase proteins such as C-reactive protein and serum amyloid A during the therapy with TCZ. The mean dosage of prednisolone could be reduced from 21.3 mg/day to 1.5 mg/day. Although the serum IL-6 level was transiently elevated in all patients after several TCZ infusions, it gradually recovered to the initial level. Along with the decrease of serum IL-6, two patients exhibited significant reduction in thickened arterial lesions. No drug-related adverse effects were noted. In this small group of patients with refractory TA, TCZ therapy was effective and well-tolerated. Further larger studies should be conducted to confirm this finding.

Slow-flow phenomenon after drug-coated balloon angioplasty for lower-extremity arteries is associated with lack of prescribing of calcium channel blockers.

This study aimed to investigate the relationship between prescription drugs and the slow-flow phenomenon after drug-coated balloon angioplasty. Of 30 patients, five (17%) presented with the slow-flow phenomenon. Patients with the slow-flow phenomenon were significantly less commonly prescribed calcium channel blockers than those without the slow-flow phenomenon (P = 0.03). There was no intergroup difference in the prescription of angiotensin II receptor blockers and ß-blockers. The clinical outcomes, including restenosis, thrombosis, target lesion revascularization, and death, did not differ between groups during the 10-month observation period.

Effect of Constant vs. Variable Moderate-Intensity Load on Peak Oxygen Uptake in Outpatient Cardiac Rehabilitation.

Background: In outpatient center-based cardiac rehabilitation (O-CBCR), moderate-intensity continuous training (MICT) based on the anaerobic threshold (AT) determined by cardiopulmonary exercise stress testing is recommended. However, it is unclear whether differences in exercise intensity within the MICT domain affect peak oxygen uptake (%peakV̇O2). Methods and Results: We retrospectively evaluated patients who underwent O-CBCR at Japan Community Healthcare Organization Osaka Hospital. Those treated with the constant-load method were designated as Group A (n=38), whereas those treated with the variable-load method were designated as Group B (n=48). Although the change in exercise intensity was significantly greater in Group B by approximately 4.5 W, the change in %peakV̇O2 was not significantly different between groups. Group A had a significantly longer exercise time than Group B (by approximately 4-5 min). No deaths or hospitalizations occurred in either group. The percentage of episodes with exercise cessation was similar between the 2 groups, but the percentage of episodes with load reduction was significantly higher in Group B, mostly because of the increased heart rate. Conclusions: In supervised MICT based on AT, the variable-load method increased exercise intensity more than the constant-load method without severe complications, but did not improve %peakV̇O2.

Clinical Characteristics of the Patient With Unmeasurable Ankle-Brachial Index in Endovascular Treatment.

Introduction Ankle-brachial index (ABI) is an important indicator to diagnose lower extremity arterial disease (LEAD). However, patients with unmeasurable ABI are sometimes excluded from the analysis and their clinical characteristics are poorly understood. Methods One hundred twenty-two consecutive Japanese subjects (mean age, 72 years), who underwent successful endovascular treatment (EVT) for lower extremity arteries at our hospital were retrospectively studied. Results Of the 122 patients, 23 (19%) patients presented an unmeasurable ABI before EVT. Five of 23 (22%) had still an unmeasurable ABI one day after EVT. Comorbidities including hypertension, diabetes, dyslipidemia, hemodialysis, smoking, ischemic heart disease, atrial fibrillation, and past-EVT history were not different between ABI measurable and unmeasurable patients. However, patients with unmeasurable ABI presented a significantly higher degree of Rutherford category and a smaller number of tibial vessel runoff than patients with measurable ABI before EVT (p<0.05 and p<0.01, respectively). There was no difference in the lesion site between the two groups. The event rate including all-cause mortality, re-EVT, lower limb amputation, and bypass surgery did not differ between two groups four years after EVT. ABI after four years of initial EVT did not differ between pre-EVT measurable and unmeasurable patients (0.96 vs. 0.84, p=0.48). Conclusions Patients with unmeasurable ABI before EVT were characterized by higher degree of Rutherford categorization and a small number of tibial vessel runoff, but there was no significant difference in outcomes during the follow-up period.

Endothelial Gab1 deletion accelerates angiotensin II-dependent vascular inflammation and atherosclerosis in apolipoprotein E knockout mice.

BACKGROUND: Docking protein Grb2-associated binder 1 (Gab1) has critical roles in signal transduction of various growth factors, cytokines, and numerous other molecules. Our previous reports show that Gab1 is essential for postnatal angiogenesis through the analysis of endothelium-specific Gab1 knockout (Gab1ECKO) mice. However, the role of Gab1 in atherosclerosis remains unknown. The aim of the present study was to elucidate the role of endothelial Gab1 in vascular inflammation and atherosclerosis. METHODS AND RESULTS: We intercrossed Gab1ECKO mice with apolipoprotein E (ApoE) knockout (ApoEKO) mice. Six-month-old male ApoEKO/Gab1ECKO and littermate control (ApoEKO) mice were treated with angiotensin II (AngII) via an osmotic infusion mini-pump. After AngII treatment, ApoEKO/Gab1ECKO mice showed significantly enhanced atherosclerosis and aneurysm formation compared with control mice. The production of proinflammatory cytokines in the aorta was significantly enhanced in ApoEKO/Gab1ECKO mice compared with control mice. Furthermore, the expression levels of Krüppel-like factor (KLF) 2 (KLF2) and KLF4, key transcription factors for endothelial homeostasis, were significantly reduced in the aortic endothelium of ApoEKO/Gab1ECKO mice compared with those of control mice. Consistently, both vascular cell adhesion molecule-1 expression and macrophage infiltration on the aortic walls were enhanced in ApoEKO/Gab1ECKO mice compared with control mice. CONCLUSIONS: Collectively, endothelial Gab1 deletion accelerates AngII-dependent vascular inflammation and atherosclerosis on ApoE-null background presumably in association with downregulation of KLF2 and KLF4.

Myocarditis Following the Second Dose of COVID-19 Vaccination in a Japanese Adolescent.

As COVID-19 vaccines continue to be deployed worldwide, countries are now planning to vaccinate their pediatric populations as well. However, several vaccine-related adverse events, including myocarditis, have been reported. Although the incidence of myocarditis after BNT162b2 vaccination is low, it is higher, particularly after receiving the second dose, among young male recipients. A 13-year-old male adolescent presented with chest pain after the second dose of the BNT162b2 vaccination. Electrocardiography, echocardiography, cardiac magnetic resonance imaging, and blood examinations were consistent with myocarditis. He was treated conservatively because his symptoms were relatively mild. In Japan, it is expected that the chances of diagnosing vaccine-related myocarditis will increase as more children are getting vaccinated. Our case report raises concerns to physicians that the COVID-19 vaccination may cause rare cases of myocarditis, which must always be considered as a differential diagnosis.

Septic Shock Due to Urinary Tract Infection in an Immunosuppressed Patient Prescribed Dapagliflozin.

Urinary tract infection (UTI) is one of the adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors. We describe a rare case of septic shock due to UTI in an immunosuppressed patient prescribed dapagliflozin. A 69-year-old woman was admitted to our hospital for the treatment of pyelonephritis. She was prescribed immunosuppressive drugs for systemic lupus erythematosus and was newly prescribed dapagliflozin for heart failure two weeks prior. One hour after admission, the patient developed hypotension and was diagnosed with septic shock due to UTI. She was administered norepinephrine, hydrocortisone and meropenem. Afterward, she underwent emergent transurethral lithotomy for her right urinary tract stones. The following clinical course was uneventful, and she was discharged on day 17. She had no recurrence of UTI or exacerbation of heart failure without dapagliflozin administration. This case report emphasizes the importance of considering the possibility of UTIs and cases in which SGLT2 inhibitors should be used. If a patient is female and immunocompromised, dapagliflozin should be prescribed more carefully after considering the increased risk of UTIs.

Multiple Cardiac Calcified Amorphous Tumors.

A 61-year-old woman who underwent hemodialysis presented with heart failure. Echocardiography revealed multiple mobile masses in the left atrium. The masses were excised, and histopathologic examination revealed calcified amorphous tumors. Here, we present several echocardiography images, including 3-dimensional transesophageal echocardiography, demonstrating the revolving masses in the left atrium. (Level of Difficulty: Intermediate.).

Clinical implication of the brachial-ankle pulse wave velocity for endovascular treatment.

This study aimed to evaluate the clinical implication of the brachial-ankle pulse wave velocity (baPWV) for endovascular treatment (EVT). Eighty-four patients who underwent EVT for aortoiliac and femoropopliteal artery were included. In these patients, 36 (43 %) had an ABI improvement above 0.9 a day after EVT. The baPWV in patients who received re-EVT afterwards was significantly higher than that of patients who did not. The area under the receiver operating characteristic curve for the baPWV for predicting re-EVT was 0.788. The optimal cut-off values of the baPWV for re-EVT, specificity, and sensitivity were 2220 cm/s, 93.1 %, and 57.1 %, respectively.

Delayed-onset constrictive pericarditis associated with trauma.

A 59-year-old man presented with exertional dyspnoea and pretibial oedema that had lasted 6 months. He was referred to our hospital with suspected constrictive pericarditis (CP). Several examinations, including CT, echocardiography and cardiac catheterisation, indicated heart failure associated with CP that had been induced by trauma 13 years prior. The CP and heart failure were unresponsive to medical treatment, therefore, a surgical pericardiectomy was performed, which is considered the only definitive treatment. Pathological examination of the resected pericardium revealed a fatty texture and dense fibrous connective tissues, which are associated with old haemorrhage and focal calcification. The patient's symptoms were improved to New York Heart Association Class I, and his peripheral oedema disappeared 6 months after leaving hospital.

Long COVID presenting with intermittent fever after COVID-19 pneumonia.

A 72-year-old man presented to our hospital with a fever. Chest computed tomography showed typical coronavirus disease 2019 (COVID-19) pneumonia. The fever normalized after a few days, and the pneumonia was alleviated. However, the intermittent fever subsequently re-occurred and persisted for over a month. Various tests, including blood tests, culture tests, and image evaluations, were performed. However, the conclusion was that long COVID was the cause of the intermittent fever as an exclusion diagnosis. Many patients suffer from persistent symptoms of COVID-19, but the symptoms and their durations vary. Here we report a case of prolonged fever after COVID-19 pneumonia.

SHP2 mediates gp130-dependent cardiomyocyte hypertrophy via negative regulation of skeletal alpha-actin gene.

Morphological and biochemical phenotypes of cardiomyocyte hypertrophy are determined by neurohumoral factors. Stimulation of G protein-coupled receptor (GPCR) results in uniform cell enlargement in all directions with an increase in skeletal alpha-actin (alpha-SKA) gene expression, while stimulation of gp130 receptor by interleukin-6 (IL-6)-related cytokines induces longitudinal elongation with no increase in alpha-SKA gene expression. Thus, alpha-SKA is a discriminating marker for hypertrophic phenotypes; however, regulatory mechanisms of alpha-SKA gene expression remain unknown. Here, we clarified the role of SH2-containing protein tyrosine phosphatase 2 (SHP2) in alpha-SKA gene expression. In neonatal rat cardiomyocytes, endothelin-1 (ET-1), a GPCR agonist, but not leukemia inhibitory factor (LIF), an IL-6-related cytokine, induced RhoA activation and promotes alpha-SKA gene expression via RhoA. In contrast, LIF, but not ET-1, induced activation of SHP2 in cardiomyocytes, suggesting that SHP2 might negatively regulate alpha-SKA gene expression downstream of gp130. Therefore, we examined the effect of adenovirus-mediated overexpression of wild-type SHP2 (SHP2(WT)), dominant-negative SHP2 (SHP2(C/S)), or beta-galactosidase (beta-gal), on alpha-SKA gene expression. LIF did not upregulate alpha-SKA mRNA in cardiomyocytes overexpressing either beta-gal or SHP2(WT). In cardiomyocytes overexpressing SHP2(C/S), LIF induced upregulation of alpha-SKA mRNA, which was abrogated by concomitant overexpression of either C3-toxin or dominant-negative RhoA. RhoA was activated after LIF stimulation in the cardiomyocytes overexpressing SHP2(C/S), but not in myocytes overexpressing beta-gal. Furthermore, SHP2 mediates LIF-induced longitudinal elongation of cardiomyocytes via ERK5 activation. Collectively, these findings indicate that SHP2 negatively regulates alpha-SKA expression via RhoA inactivation and suggest that SHP2 implicates ERK5 in cardiomyocyte elongation downstream of gp130.