Secondary cardiac involvement in anti-SRP-antibody-positive myopathy: an 87-year-old woman with heart failure symptoms as the first clinical presentation.

BACKGROUND: Necrotizing myopathy (NM) is defined by the dominant pathological feature of necrosis of muscle fibers without substantial lymphocytic inflammatory infiltration. Anti-signal recognition particle (SRP)-antibody-positive myopathy is related to NM. Anti-SRP-antibody-positive myopathy can comorbid with other disorders in some patients, however, comorbidity with malignant tumor and myopericarditis has still not been reported. CASE PRESENTATION: An 87-year-old woman with dyspnea on exertion and leg edema was referred to our hospital because of suspected heart failure and elevated serum creatine kinase level. Upon hospitalization, she developed muscle weakness predominantly in the proximal muscles. Muscle biopsy and immunological blood test led to the diagnosis of anti-SRP-antibody-positive myopathy. A colon carcinoma was also found and surgically removed. The muscle weakness remained despite the tumor resection and treatment with methylprednisolone. Cardiac screening revealed arrhythmia and diastolic dysfunction with pericardial effusion, which recovered with intravenous immunoglobulin (IVIg) treatment. CONCLUSIONS: We reported the first case of anti-SRP-positive myopathy comorbid with colon carcinoma and myopericarditis. This case is rare in the point that heart failure symptoms were the first clinical presentation. The underlying mechanism is still not clear, however, physicians should be carefully aware of the neoplasm and cardiac involvement in anti-SRP-antibody positive-myopathy patients and should consider farther evaluation and management.

Novel Mapping Technique for Localization of Focal and Reentrant Activation During Atrial Fibrillation.

INTRODUCTION: Identification of wavefront propagation pattern during AF remains challenging in ablation procedures. We sought to test a novel combination of a new mapping technology called Ripple Map and high-density mapping to distinguish focal and reentrant activation during atrial fibrillation (AF). METHODS AND RESULTS: Subjects were patients undergoing ablation for persistent AF. If AF remained after isolation of the pulmonary veins, the left atrium (LA) was mapped by a high-density mapping catheter for later analysis, after which ablation was continued using a conventional stepwise approach. After the procedure, electrograms from the high-density mapping catheter were analyzed using Ripple Map, which is a new feature in the CARTO®3, and type of activation on ≥3 consecutive AF cycles was determined. High-density mapping was performed on 569 sites in 45 patients (13 ± 3 sites per patient). AF wavefront propagation determined by Ripple Map was in good agreement with analysis of manual annotation of bipolar electrograms. Ripple Map's representation of wavefront activation pattern, which could include local as well as far-field activity, allowed us to identify focal activation in 64 (11%) sites and 1 (0.2%) reentrant activation site. Radiofrequency delivery in atrial regions with activation sites identified as focal by Ripple Map resulted in termination of AF more often than regions without focal activation (22% vs. 7%, P = 0.015). CONCLUSION: This study demonstrated that Ripple Map enabled quick identification of AF wavefront activation pattern, potentially being helpful for determining ablation targets in persistent AF.

Occurrence of Focal Atrial Tachycardia During the Ablation Procedure Is Associated With Arrhythmia Recurrence After Termination of Persistent Atrial Fibrillation.

INTRODUCTION: Catheter ablation can terminate persistent atrial fibrillation (AF). However, atrial tachycardia (AT) often arises after termination of AF. METHODS AND RESULTS: Of 215 patients who underwent index stepwise ablation for persistent AF, 141 (66%) patients (64 ± 9 years) in whom AF terminated during the ablation procedure were studied. If AF converted into AT, ablation for AT was subsequently performed. ATs were categorized as focal or macroreentrant AT. We assessed whether type of AT occurring after conversion of AF during the ablation procedure was associated with freedom from atrial tachyarrhythmia (AF or AT) during follow-up. Sinus rhythm was directly restored from AF in 37 patients, while 34, 37, and 33 patients had focal AT alone, a mix of focal and macroreentrant AT, and macroreentrant AT alone after termination of AF, respectively. Arrhythmia-free survival rates at 1 year after the index procedure were 30%, 34%, 61%, and 59% in the patients with focal AT alone, a mix of focal AT and macroreentrant AT, macroreentrant AT alone, and direct restoration of sinus rhythm, respectively (P = 0.004). Type of AT occurring during the index procedure was associated with type of recurrent AT (P = 0.03), but the origin of focal AT occurring during the index ablation differed from that of the recurrent AT in 85% of patients. CONCLUSION: In patients who had AF termination by ablation, occurrence of focal AT during the ablation procedure was associated with worse clinical outcome than occurrence of macroreentrant AT, likely due to ATs arising from other foci during follow-up.

Mechanisms of Diuresis for Acute Decompensated Heart Failure by Tolvaptan.

Tolvaptan, a vasopressin type 2 receptor antagonist, does not affect kidney circulation or cause worsening of renal function (WRF) in patients with acute decompensated heart failure (ADHF). Bioelectrical impedance analysis (BIA) can be used to evaluate intravascular volume by calculating the ratio of extracellular water (ECW) to intracellular water (ICW). There have been no reports examining the mechanisms of tolvaptan-induced diuresis using BIA. We investigated whether tolvaptan decreases excess volume while maintaining intravascular volume in ADHF patients.Study patients included 29 ADHF patients (age 48-95, men 69%) diagnosed between April 2013 and May 2016 and who underwent BIA before and after treatment. Fifteen patients were treated with tolvaptan in addition to conventional diuresis therapy (tolvaptan group), and 14 patients were treated with conventional diuresis therapy only (control group). In the control group, the numerical value of serum creatinine (Cre) significantly increased from 0.89 ± 0.22 mg/ dL to 1.07 ± 0.29 mg/dL (P = 0.004), and the ECW/ICW significantly decreased from 0.696 ± 0.036 to 0.673 ± 0.032 (P = 0.004). These values were not significantly different from those obtained for the tolvaptan group. Furthermore, regression analysis showed a negative correlation between ΔCre and ΔECW/ICW, which are the differences between values before and after treatment (ΔCre = -0.002-5.668 × ΔECW/ICW, r2 = 0.306, P = 0.002).Our findings suggest that WRF is caused by a reduction in intravascular volume and that tolvaptan treatment can decrease the excess volume while maintaining intravascular volume.

Different roles of PPAR-γ activity on physiological and pathological alteration after myocardial ischemia.

BACKGROUND: Telmisartan is an angiotensin II receptor blocker, which acts as a partial agonist of peroxisome proliferator activator receptor-γ (PPAR-γ). Because PPAR-γ initiates a variety of antiinflammatory responses, the effect on myocardial ischemia is to be elucidated. METHODS AND RESULTS: The left anterior descending arteries were ligated to induce myocardial infarction in rats. The animals were assigned to 4 groups: (1) control (saline, n = 6), (2) telmisartan (10 mg·kg·d, n = 6), (3) telmisartan + GW9662 (PPAR-γ-antagonist) (10 mg·kg·d of telmisartan and 1 mg·kg·d of GW9662, n = 6), and (4) amlodipine (10 mg·kg·d, n = 8) groups. Telmisartan reduced mean blood pressure compared with that in the control group. There was no statistical difference among the telmisartan, telmisartan + GW9662 and amlodipine groups. The end-diastolic left ventricular diameter was smaller in telmisartan group compared with that in the control group; GW9662 negated the effect of telmisartan. The thickness of the ventricular septum was kept in the telmisartan group compared with that in the control group; GW9662 negated the effect. Histopathologic analyses showed that telmisartan suppressed myocardial fibrosis compared with that of the control, whereas GW9662 negated the telmisartan effect. CONCLUSIONS: Telmisartan suppresses pathological remodeling by PPAR-γ agonistic activities independent of its antihypertensive effects.

[A case of antisynthetase syndrome with anti-EJ antibody complicated by pericarditis].

A 69-year-old man was admitted with neck muscle weakness, symmetric proximal muscle weakness, skin rash and elevated serum creatine kinase levels. Muscle biopsy showed perifascicular necrosis and perimysial alkaline phosphatase activity. Chest CT revealed interstitial lung disease and colorectal cancer was diagnosed on colonoscopy. He was serologically positive for anti-EJ antibody, leading to the diagnosis of antisynthetase syndrome (ASS). After laparoscopic low anterior resection of the rectum, he received intravenous methylprednisolone (1,000 mg/d for 3 days) followed by oral prednisolone (50 mg/d). Although his muscle weakness improved after corticosteroid therapy, he developed pericardial effusion with resultant asymptomatic hypotension and arrhythmia possibly due to pericarditis. Corticosteroid monotherapy was insufficient to control the disease, and, we decided to use oral cyclosporin concurrently. After this combined therapy started, pericardial effusion and arrhythmia were improved. We should keep in mind that pericarditis can occur in patients with anti-EJ antibody-positive ASS, and early combined therapy with corticosteroid and immunosuppressive drugs for ASS may improve the patient's prognosis.

Anti-salusin-ß antibody enhances angiogenesis after myocardial ischemia reperfusion injury.

BACKGROUNDS: Salusins are multifunctional endogenous bioactive peptides simultaneously biosynthesized from their precursor prosalusin. Salusin-ß stimulates proliferation of vascular smooth muscle cells and fibroblasts and regulates myocardial growth and hypertrophy. Salusin-ß has potent hypotensive, bradycardic and proatherosclerotic effects. OBJECTIVES: To investigate whether salusin-ß plays a role in myocardial remodeling after myocardial ischemia reperfusion (I/R) injury, rat I/R models were created by the left anterior descending coronary artery occlusion for 30 min, followed by 24 h or 7 days of reperfusion (control, n = 6 each). RESULTS AND CONCLUSION: Immunohistochemical double staining showed the enhanced expression of salusin-ß in the macrophages around myocardial ischemic area. Anti-salusin-ß treated groups were administered the neutralizing salusin-ß antibody (10 µl/day, i.p.) once daily from day -1 to day 1 or from day -1 to day 7 (anti-salusin-ß, n = 6 each). The anti-salusin-ß therapy enhanced myocardial angiogenesis in the peri-ischemic area of reperfusion. The small vessels (< 40 µm in diameter) of I/R hearts treated with anti-salusin-ß were more densely populated than those of control animals (108.5 ± 19.7 vs 47.5 ± 2.4, p < 0.05). Real-time PCR revealed that the anti-salusin-ß therapy-induced angiogenesis was not associated with enhanced vascular endothelial growth factor A expression. The authors, for the first time, have clarified that endogenous salusin-ß suppresses angiogenesis which is critical in the development of cardiac remodeling following I/R injury.

Clarithromycin attenuates myocardial ischemia-reperfusion injury.

BACKGROUND: MMP activity is upregulated in the heart after myocardial ischemia reperfusion, and its activation contributes to the changes in left ventricular (LV) dysfunction. A major macrolide antibiotic, clarithromycin has many biological functions including MMP regulation. However, little is known about the effect of clarithromycin in myocardial reperfusion injury via MMPs. Our objective was to clarify the role of MMPs regulated by clarithromycin in the progression of myocardial reperfusion injury. METHODS: We administered clarithromycin to rats with ischemia-reperfusion injury twice a day for 7 days before and 14 days after reperfusion. RESULTS: Clarithromycin resulted in a significant reduction of the infarction area:area at risk ratio and preserved fractional shortening ratio after 14 days of reperfusion. Immunohistochemical analysis revealed that macrophages were the primary cellular source of MMPs. Fewer macrophages were detected in the ischemic area of the hearts following ischemia reperfusion in the clarithromycin-treated group compared with the vehicle-treated group. Although ischemia-reperfusion injury resulted in LV fibrosis with increasing MMP activities, clarithromycin significantly reduced these changes. CONCLUSION: Clarithromycin is effective for attenuating myocardial ischemia-reperfusion injury by suppressing MMPs.

Early treatment with clarithromycin attenuates rat autoimmune myocarditis via inhibition of matrix metalloproteinase activity.

BACKGROUND: Matrix metalloproteinase (MMP) activity is upregulated in the hearts with myocarditis, and its activation contributes to the changes in left ventricular function. A major macrolide antibiotic, clarithromycin (CAM), has many biological functions including MMP regulation. However, little is known about the effect of CAM in myocarditis via MMPs. OBJECTIVE: To clarify the role of MMPs regulated by CAM in the progression of myocarditis. Design CAM was given to experimental rats with autoimmune myocarditis (EAM) from day -7 to day 21 (early treated group, n=6) or from day 1 to day 21 (late treated group, n=6) twice a day. RESULTS: Although the non-treated rats showed blood pressure decline and impaired cardiac function, early CAM treatment prevented this progression. Pathologically, severe myocardial cell infiltration (30.5+/-4.2%) and fibrosis (32.2+/-1.1%) were detected in the non-treated group, while early CAM treatment significantly suppressed these changes (infiltration 6.5+/-0.2%, fibrosis 5.9+/-3.9%). Zymography showed that non-treated EAM resulted in enhanced ventricular activities of MMP-9, while early CAM treatment reduced the alteration. However, late CAM treatment was less effective than the early treatment. CONCLUSIONS: Early CAM treatment is effective to attenuate myocarditis by suppressing MMP-9.

A novel IKK inhibitor suppresses heart failure and chronic remodeling after myocardial ischemia via MMP alteration.

OBJECTIVE: Amplification of inflammatory response in the non-infarct area plays an important role in the pathogenesis of ventricular remodeling after myocardial ischemia. Activation of nuclear factor-kappa B (NF-kappaB) is involved in this amplification through a positive feedback loop of pro- inflammatory cytokines. We investigated the efficacy of IKK blockade with IMD-0560, a novel inhibitor of IKK, in a rat myocardial ischemia model. METHODS/RESULTS: Left coronary artery occlusion (28 days) was carried out in Sprague-Dawley rats. Daily intraperitoneal injections of IMD-0560 (5 mg/kg) were done after the operation. Treatment with IMD-0560 significantly improved cardiac function as indicated by the preservation of fractional shortening and lower serum brain natriuretic peptide level. Histological analysis showed that IMD-0560 treatment suppressed thinning in the infarcted area compared with vehicle-treated hearts. Moreover, in situ zymography showed matrix metalloprotease-9 activity was inhibited in the infarct area. CONCLUSION: We revealed that the IKK blockade is potent for the suppression of chronic ventricular remodeling after myocardial ischemia.