Kazuko Tajiri

Prevention of atrial fibrillation recurrence with corticosteroids after radiofrequency catheter ablation: a randomized controlled trial.

OBJECTIVES We sought to clarify the efficacy of corticosteroid therapy for preventing atrial fibrillation (AF) recurrence after pulmonary vein isolation (PVI). BACKGROUND The inflammatory process may cause acute AF recurrence after PVI. However, no studies have examined the relationship between corticosteroid administration and AF recurrence after PVI. METHODS A total of 125 patients with paroxysmal AF were randomized to receive either corticosteroids (corticosteroid group) or a placebo (placebo group). In the corticosteroid group, intravenous hydrocortisone (2 mg/kg) was given the day of the procedure, and oral prednisolone (0.5 mg/kg/day) was administered for 3 days after the PVI. The body temperature and high-sensitivity C-reactive protein level were measured before and on each of the first 3 days after ablation. RESULTS The prevalence of immediate AF recurrence (≤3 days after the PVI) was significantly lower in the corticosteroid group (7%) than in the placebo group (31%). The maximum body temperature and C-reactive protein during the initial 3 days after ablation and the increase in the body temperature and C-reactive protein level from baseline were significantly lower in the corticosteroid group than in the placebo group. Corticosteroid treatment did not decrease AF recurrences between 4 and 30 days after ablation. The AF-free rate at 14 months post-ablation was greater in the corticosteroid group (85%) than in the placebo group (71%, p=0.032 by the log-rank test). CONCLUSIONS Transient use of small amounts of corticosteroids shortly after AF ablation may be effective and safe for preventing not only immediate AF recurrences but also AF recurrences during the mid-term follow-up period after PVI.

Comparison of Characteristics and Significance of Immediate Versus Early Versus No Recurrence of Atrial Fibrillation After Catheter Ablation

Atrial fibrillation (AF) recurrences after catheter ablation are common within the first month after AF ablation, and inflammatory processes may be related to AF genesis. This study aimed to clarify the relation between inflammatory processes and recurrence of AF after ablation and to characterize AF recurring within 3 days after ablation (immediate AF recurrence).The study included 186 patients with drug-refractory paroxysmal AF who underwent extensive pulmonary vein isolation. Body temperature and C-reactive protein level were measured before and consecutively on the first 3 days after ablation. Signs of pericarditis or atrial arrhythmias within 3 days after ablation were also monitored. Forty-five patients (24%) had immediate AF recurrence (immediate-AF-recurrence group), 27 (14%) had early recurrence 4 to 30 days after ablation (early-AF-recurrence group), and the remaining 114 (61%) had no AF recurrence within 1 month after ablation (no-AF-recurrence group). Increases in body temperature and C-reactive protein level from baseline in the immediate-AF-recurrence group were the highest among the 3 groups, and signs of pericarditis were observed in 15 of the 45 patients (33%) in the immediate-AF-recurrence group. Atrial premature contractions and nonsustained AF occurred most frequently in the early-AF-recurrence group. After 6-month follow-up, the AF-free rate was greater in the immediate-AF-recurrence group (76%) than in the early-AF-recurrence group (30%). In conclusion, immediate AF recurrence has an apparently different mechanism and impact on midterm outcomes than does early AF recurrence. Acute inflammatory changes after ablation may be responsible for immediate AF recurrence.

Suppressor of Cytokine Signaling 1 DNA Administration Inhibits Inflammatory and Pathogenic Responses in Autoimmune Myocarditis

Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Myocarditis in humans is highly heterogeneous in etiology. Recent studies have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies, because autoimmunity plays an important role in myocarditis as well as contributing to the progression to cardiomyopathy and heart failure. Suppressor of cytokine signaling (SOCS) 1 plays a key role in the negative regulation of both TLR- and cytokine receptor-mediated signaling, which is involved in innate immunity and subsequent adaptive immunity. In this study, we investigated the therapeutic effect of SOCS1 DNA administration on experimental autoimmune myocarditis (EAM) in mice. EAM was induced by s.c. immunization with cardiac-specific peptides derived from α myosin H chain in BALB/c mice. In contrast to control myocarditis mice, SOCS1 DNA-injected mice were protected from development of EAM and heart failure. SOCS1 DNA administration was effective for reducing the activation of autoreactive CD4+ T cells by inhibition of the function of Ag-presenting dendritic cells. Our findings suggest that SOCS1 DNA administration has considerable therapeutic potential in individuals with autoimmune myocarditis and dilated cardiomyopathy.

Tenascin‐C Aggravates Autoimmune Myocarditis via Dendritic Cell Activation and Th17 Cell Differentiation

Background Tenascin‐C (TN‐C), an extracellular matrix glycoprotein, appears at several important steps of cardiac development in the embryo, but is sparse in the normal adult heart. TN‐C re‐expresses under pathological conditions including myocarditis, and is closely associated with tissue injury and inflammation in both experimental and clinical settings. However, the pathophysiological role of TN‐C in the development of myocarditis is not clear. We examined how TN‐C affects the initiation of experimental autoimmune myocarditis, immunologically. Methods and Results A model of experimental autoimmune myocarditis was established in BALB/c mice by immunization with murine α‐myosin heavy chains. We found that TN‐C knockout mice were protected from severe myocarditis compared to wild‐type mice. TN‐C induced synthesis of proinflammatory cytokines, including interleukin (IL)‐6, in dendritic cells via activation of a Toll‐like receptor 4, which led to T‐helper (Th)17 cell differentiation and exacerbated the myocardial inflammation. In the transfer experiment, dendritic cells loaded with cardiac myosin peptide acquired the functional capacity to induce myocarditis when stimulated with TN‐C; however, TN‐C‐stimulated dendritic cells generated from Toll‐like receptor 4 knockout mice did not induce myocarditis in recipients. Conclusions Our results demonstrated that TN‐C aggravates autoimmune myocarditis by driving the dendritic cell activation and Th17 differentiation via Toll‐like receptor 4. The blockade of Toll‐like receptor 4‐mediated signaling to inhibit the proinflammatory effects of TN‐C could be a promising therapeutic strategy against autoimmune myocarditis.

Involvement of peptidyl-prolyl isomerase Pin1 in the inhibitory effect of fluvastatin on endothelin-1-induced cardiomyocyte hypertrophy

AIMS Cardiac hypertrophy is elicited by endothelin (ET)-1 as well as other neurohumoral factors, hemodynamic overload, and oxidative stress; HMG-CoA reductase inhibitors (statins) were shown to inhibit cardiac hypertrophy partly via the anti-oxidative stress. One of their common intracellular pathways is the phosphorylation cascade of MEK signaling. Pin1 specifically isomerizes the phosphorylated protein with Ser/Thr-Pro bonds and regulates their activity through conformational changes. There is no report whether the Pin1 activation contributes to ET-1-induced cardiomyocyte hypertrophy and whether the Pin1 inactivation contributes to the inhibitory effect of statins. The aim of this study was to reveal these questions. MAIN METHODS We assessed neonatal rat cardiomyocyte hypertrophy using ET-1 and fluvastatin by the cell surface area, ANP mRNA expression, JNK and c-Jun phosphorylation, and [(3)H]-leucine incorporation. KEY FINDINGS Fluvastatin inhibited ET-1-induced increase in the cell surface area, ANP expression, and [(3)H]-leucine incorporation; and it suppressed the signaling cascade from JNK to c-Jun. The phosphorylated Pin1 level, an inactive form, was decreased by ET-1; however, it reached basal level by fluvastatin. Furthermore, Pin1 overexpression clearly elicited cardiomyocyte hypertrophy, which was inhibited by fluvastatin. SIGNIFICANCE This is the first report that ET-1-induced cardiomyocyte hypertrophy is mediated through the Pin1 activation and that the inhibitory effect of fluvastatin on cardiomyocyte hypertrophy would partly be attributed to the suppression of the Pin1 function. This study firstly suggests that Pin1 determines the size of hypertrophied cardiomyocyte by regulating the activity of phosphorylated molecules and that statins exert their pleiotropic effects partly via Pin1 inactivation.

Impact of rivaroxaban compared with warfarin on the coagulation status in Japanese patients with non-valvular atrial fibrillation: a preliminary analysis of the prothrombin fragment 1+2 levels.

BACKGROUND Rivaroxaban is an oral anticoagulant that effectively prevents thromboembolic complications using fixed doses without requiring laboratory monitoring. In this study, we aimed to examine the coagulation status in patients with non-valvular atrial fibrillation (NVAF) treated with rivaroxaban compared with warfarin. METHODS AND RESULTS The study group consisted of 85 consecutive Japanese patients with NVAF who received rivaroxaban (n=33) or warfarin (n=52) from June 2013 to February 2014. We compared the coagulation status between the rivaroxaban and warfarin treatments. The prothrombin time (PT) values did not significantly differ between the two groups. However, the prothrombin fragment 1+2 (F1+2) level, a marker of thrombin generation, was significantly higher in the rivaroxaban group than the warfarin group (202±88pmol/l vs. 114±79pmol/l, p<0.001). Next, we collected blood samples from 18 patients taking rivaroxaban at 3h and 15h after the drug intake and evaluated the time-dependent changes in the coagulation status. The PT values at 3h after the drug intake were significantly more prolonged than those at 15h (p<0.001). However, there were no significant differences in the F1+2 levels between the two time points (194±73pmol/l [at 3h] vs. 165±61pmol/l [at 15h], p=0.112). CONCLUSIONS Our preliminary results suggest that the thrombin generation level is stable regardless of the time elapsed after rivaroxaban intake, and warfarin treatment may inhibit thrombin generation more aggressively than rivaroxaban.

Cardiovascular toxic effects of targeted cancer therapy

Over the past decade, there has been a major shift in chemotherapy from non-specific cytotoxic drugs to molecular targeted drug therapies. As more molecular targeted therapies are developed, new types of cardiovascular toxicities induced by targeted therapies are a growing problem. Cardiotoxicity induced by the human epidermal growth factor receptor-2 inhibitor trastuzumab manifests as decreased left ventricular ejection fraction. In contrast to anthracycline treatment, most cardiac events occur during trastuzumab treatment, but are reversed quickly when treatment is interrupted and cardiac intervention is established. Vascular endothelial growth factor pathway inhibitors decrease vascular tone, leading to hypertension. After drug initiation, the early detection and aggressive pharmacological management of hypertension are necessary to avoid severe complications. Cardiovascular safety is an emerging challenge in patients treated with newer generations of BCR-ABL inhibitors. Although rare, dasatinib-induced pulmonary hypertension is potentially fatal. Vascular events including cardiac and cerebral ischemic events and peripheral arterial occlusive disease have emerged as a new type of toxicity in patients treated with ponatinib and nilotinib. Thus, a wide variety of cardiovascular toxicities have been observed in patients treated with targeted drugs and have become a critically important topic of discussion for the practicing oncologist and cardiologists. Awareness of the potential side effects, recognition of signs and symptoms, and the establishment of therapeutic strategies are all crucial to providing quality patient care.

Immune checkpoint inhibitor-related myocarditis

Immune checkpoint inhibitors have demonstrated significant clinical benefit in many cancers. The clinical benefit afforded by these treatments can be accompanied by a unique and distinct spectrum of adverse events. Recently, several fatal cases of immune checkpoint inhibitor-related myocarditis were reported. Although its frequency is comparatively lower than that of other immune-related adverse events, myocarditis can lead to circulatory collapse and lethal ventricular arrhythmia. Immune checkpoints, cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1), play important roles in establishing peripheral tolerance to the heart. Evidence from studies using genetically engineered mouse models suggests that CTLA-4 signaling terminates proliferation and promotes anergy during the primary response to cardiac self-peptide recognition. PD-1 signaling restrains autoreactive T cells that enter the peripheral tissues and recognize cardiac-peptide, maintaining them in an anergic state. Patients affected by immune checkpoint inhibitor-related myocarditis often experience rapid onset of profound hemodynamic compromise progressing to cardiogenic shock. Early diagnosis is mandatory to address specific therapy and correct the timing of circulatory support. However, the diagnosis of myocarditis is challenging due to the heterogeneity of clinical presentations. Owing to its early onset, nonspecific symptomatology and fulminant progression, especially when these drugs are used in combination, oncologists should be vigilant for immune checkpoint inhibitor-related myocarditis. With many questions yet to be answered, from basic immune biology to clinical management, future research should aim to optimize the use of these drugs by identifying predictive biomarkers of either a response to therapy or the risks of myocarditis development.

Endothelin receptor antagonist exacerbates autoimmune myocarditis in mice

AIMS Myocarditis and subsequent dilated cardiomyopathy are major causes of heart failure in young adults. Experimental autoimmune myocarditis (EAM) is a mouse model of post-infectious myocarditis and inflammatory cardiomyopathy. The pathological role of endothelin (ET) in myocarditis has not been elucidated. MAIN METHODS EAM was induced by immunization of cardiac myosin peptide with complete Freunds adjuvant on days 0 and 7 in BALB/c mice. An ETA/ETB dual receptor antagonist, SB209670, was administered by a continuous infusion from a subcutaneous pump for 2 weeks. KEY FINDINGS An increase in the heart-to-body weight ratio was observed in SB209670-treated mice compared with vehicle-treated mice. Heart pathology in SB209670-treated mice was remarkable for gross inflammatory infiltration, in contrast to the lesser inflammation in the hearts of vehicle-treated mice. We found that an ET blockade decreased the number of Foxp3(+) regulatory T cells in the heart. The ET blockade also inhibited the expression of the suppressor of cytokine signaling 3 that plays a key role in the negative regulation of both Toll-like receptor- and cytokine receptor-mediated signaling. EAM is a CD4(+) T cell-mediated disease. CD4(+) T cells isolated from SB209670-treated EAM mice produced less IL-10 and more inflammatory cytokines, IL-6 and IL-17, than those isolated from vehicle-treated mice. SIGNIFICANCE The ET receptor antagonist exacerbated autoimmune myocarditis in mice. Our novel findings suggest that ET may play an important role in the regulation of inflammation in myocarditis.

Recent advances in the management of autoimmune myocarditis: insights from animal studies.

A growing body of evidence has been accumulating to demonstrate that human myocarditis and dilated cardiomyopathy involve a complex interaction with autoimmunity triggered by cardiotropic microbial infections. Animal experiments have provided direct evidence that infections with a particular microbe can incite autoimmune myocarditis, and this autoimmune response can be mimicked by immunization with the cardiac autoantigen, α- myosin. Animal models greatly advanced our understanding of the molecular mechanisms of myocarditis, and various novel therapeutic strategies have been reported during the last two decades. In this review we present animal models of autoimmune myocarditis and describe the outlook of possible drug targets by showing the latest findings from animal studies.