Subcutaneous air entrapment after subcutaneous implantable cardioverter defibrillator implantation evaluated by computed tomography.

BACKGROUND: Inappropriate shock (IAS) caused by subcutaneous air entrapment (AE) in an early period after subcutaneous implantable cardioverter defibrillator (S-ICD) implantation has been reported, however, no detailed data on air volume are available. We evaluated the subcutaneous air volume after implantation and its absorption rate one week after implantation. METHODS: Patients who underwent S-ICD implantation in our hospital received chest CT scans immediately after implantation and followed up 1 week later. The total subcutaneous air volume, air around the generator, the distal electrode, and the proximal electrode within 3 cm were calculated using a three-dimensional workstation. Fat areas at the level of the lower edge of the generator were also analyzed. RESULT: Fifteen patients received CT immediately after implantation. The mean age was 45.6 ± 17.9 (66.7% of men), and the mean body mass index was 24.3 ± 3.3. The three-incision technique was applied in seven patients and two-incision technique was in the latter eight patients. The mean total subcutaneous air volume was 18.54 ± 7.50 mL. Air volume around the generator, the distal electrode, and the proximal electrode were 11.05 ± 5.12, 0.72 ± 0.72, and 0.88 ± 0.87 mL, respectively. Twelve patients received a follow-up CT 1 week later. The mean total subcutaneous air was 0.25 ± 0.45 mL, showing a 98.7% absorption rate. CONCLUSION: Although subcutaneous air was observed in all patients after S-ICD implantation, most of the air was absorbed within 1 week, suggesting a low occurrence of AE-related IAS after a week postoperation.

Significance of Ventricular Arrhythmia Based on Stored Electrogram Analysis in a Pacemaker Population.

The incidence of ventricular arrhythmia in patients with an implanted pacemaker is not yet known. The aim of this study was to analyze non-sustained ventricular tachycardia (NSVT) episodes based on stored electrograms (EGM) and determine the occurrence rate and risk factors for NSVT in a pacemaker population.This study included 302 consecutive patients with a dual-chamber pacemaker. A total of 1024 EGMs stored in pacemakers as ventricular high-rate episodes were analyzed. The definition of NSVT was ≥ 5 consecutive ventricular beats at ≥ 150 bpm lasting < 30 seconds.In baseline, most patients (94.8%) had ≥ 60% left ventricular ejection fraction. Of 1024 EGMs, 420 (41.0%) showed appropriate NSVT episodes, as well as premature atrial contractions, atrial tachyarrhythmia, or atrial fibrillation with a rapid ventricular response, whereas other EGMs did not show an actual ventricular arrhythmia. On EGM analysis, during a mean follow-up period of 46.1 months, NSVT occurred one or more times in 82 patients (33.1%). On multivariate analysis, ≥ 50% right ventricular pacing was an independent risk factor for NSVT (odds ratios, 4.519; P < 0.001), but NSVT was not associated with increased all-cause mortality.Moreover, in the pacemaker population, ≥ 50% right ventricular pacing is an independent risk factor for NSVT; however, NSVT was not associated with increased all-cause mortality because of the preserved left ventricular function.

The iron chelating agent, deferoxamine detoxifies Fe(Salen)-induced cytotoxicity.

Iron-salen, i.e., µ-oxo-N,N'-bis(salicylidene)ethylenediamine iron (Fe(Salen)) was a recently identified as a new anti-cancer compound with intrinsic magnetic properties. Chelation therapy has been widely used in management of metallic poisoning, because an administration of agents that bind metals can prevent potential lethal effects of particular metal. In this study, we confirmed the therapeutic effect of deferoxamine mesylate (DFO) chelation against Fe(Salen) as part of the chelator antidote efficacy. DFO administration resulted in reduced cytotoxicity and ROS generation by Fe(Salen) in cancer cells. DFO (25 mg/kg) reduced the onset of Fe(Salen) (25 mg/kg)-induced acute liver and renal dysfunction. DFO (300 mg/kg) improves survival rate after systematic injection of a fatal dose of Fe(Salen) (200 mg/kg) in mice. DFO enables the use of higher Fe(Salen) doses to treat progressive states of cancer, and it also appears to decrease the acute side effects of Fe(Salen). This makes DFO a potential antidote candidate for Fe(Salen)-based cancer treatments, and this novel strategy could be widely used in minimally-invasive clinical settings.

Successful implantation of left ventricular lead for a cardiac resynchronization therapy defibrillator through a persistent left superior vena cava using the anchor balloon technique.

A 69-year-old woman was referred for upgrading implantable cardioverter defibrillator (ICD) to cardiac resynchronization therapy defibrillator (CRT-D) because of symptomatic heart failure due to dilated cardiomyopathy. Her electrocardiogram showed left bundle branch block and echocardiography showed severe left ventricular dysfunction. Venography confirmed the presence of persistent left superior vena cava (PLSVC), and occlusion of innominate vein and the coronary sinus (CS) ostium. We tried to insert the left ventricular (LV) lead through the PLSVC. Because the PLSVC was narrow, there was concern that insertion of the guiding catheter through the PLSVC might cause vascular damage. Therefore, we planned to implant the LV lead without a guiding catheter. Although the LV lead did not advance to the CS due to the acute angle, using a second wire (buddy wire system), the tip of the first wire was trapped by an inflated balloon delivered by a second wire (anchor balloon technique). This technique allowed us to reinforce the support of the other wire. The LV lead was easily advanced along with the fixed first wire and was delivered to the lateral vein of the CS. Thus, we successfully performed minimally invasive implantation of an LV lead through a PLSVC approach. .

A case report of pulmonary vein isolation with radiofrequency catheter using superior vena cava approach in patient with paroxysmal atrial fibrillation and inferior vena cava filter.

BACKGROUND: Transseptal puncture and pulmonary vein isolation (PVI) in patients with atrial fibrillation (AF) are generally performed via the inferior vena cava (IVC). However, in cases where the IVC is inaccessible, a specific strategy may be needed. CASE SUMMARY: An 86-year-old woman with paroxysmal AF and an IVC filter in situ was referred to our hospital for ablation therapy. An IVC filter for pulmonary embolism and deep venous thrombosis had been implanted 15 years prior, therefore we selected a transoesophageal echocardiography (TOE)-guided transseptal puncture using a superior vena cava (SVC) approach. After the single transseptal puncture, we performed fast anatomical mapping, voltage mapping by multipolar mapping catheter, and then PVI by contact force-guided radiofrequency catheter using a steerable sheath. Following the ablation, bidirectional conduction block between the four pulmonary veins and the left atrium was confirmed by both radiofrequency and mapping catheter. No complications occurred and no recurrence of AF was documented in the 12 months after the procedure. DISCUSSION: When performing a transseptal puncture during AF ablation, an SVC approach, via access through the right internal jugular vein, enables the sheath to directly approach the left atrium without angulation and improves operability of the ablation catheter. Combining the use of general anaesthesia, TOE, a steerable sheath, and contact force-guided ablation may contribute to achieving minimally invasive PVI with a single transseptal puncture via an SVC approach.

[Doxorubicin directly induced fibrotic change of cardiac fibroblasts].

Doxorubicin (DOX)-induced cardiomyopathy has a poor prognosis. No early detection or effective treatment methods are available in clinical. The mechanisms of cardiotoxicity were considered as oxidative stress and apoptosis in cardiomyocytes. However, the effect of DOX on cardiac fibroblasts remains to be developed. We investigated the direct effect of DOX on the function of human cardiac fibroblasts (HCFs) independently of cell death pathway. Animal study showed that lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulate dose, induced perivascular fibrosis without cell death in hear of mice. DOX increased the protein expression of α-SMA (a marker of trans-differentiation) in HCFs culture cells, indicating that DOX promoted the trans-differentiation of HCFs into myofibroblast. DOX also increased the mRNA and protein expression of matrix metalloproteinase (MMP)-1 in less than 0.1 µM which did not induce cell apoptosis of HCFs cells via PI3K/Akt pathway in HCFs. DOX increased Interleukin-6 (IL-6) via transforming growth factor (TGF)-ß/Smad pathway. In addition, DOX induced the mitochondrial damage and increased the expression of Interleukin-1 (IL-1) via stress-activated protein kinases (SAPK)/ c-Jun NH-2termial kinase (JNK). A peroxisome proliferator-activated receptor gamma (PPARγ) agonist, pioglitazone hydrochloride attenuated the expression of fibrotic marker such as α-SMA and galectin-3 and collagen1 via SAPK/JNK signaling. Pioglitazone also suppressed DOX-induced early fibrotic response in vivo. In conclusion, these findings suggested that low dose DOX induced reactive fibrotic change of cardiac fibroblasts via cell death-independent pathway. There may be potentially new mechanisms of DOX induced cardiotoxicity in clinical usage.

Reactive fibrosis precedes doxorubicin-induced heart failure through sterile inflammation.

AIMS: Doxorubicin (DOX)-induced heart failure has a poor prognosis, and effective treatments have not been established. Because DOX shows cumulative cardiotoxicity, we hypothesized that minimal cardiac remodelling occurred at the initial stage in activating cardiac fibroblasts. Our aim was to investigate the initial pathophysiology of DOX-exposed cardiac fibroblasts and propose prophylaxis. METHODS AND RESULTS: An animal study was performed using a lower dose of DOX (4 mg/kg/week for 3 weeks, i.p.) than a toxic cumulative dose. Histological analysis was performed with terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling assay, picrosirius red staining, and immunohistochemical staining. The mechanism was analysed in vitro with a low dose of DOX, which did not induce cell apoptosis. Microarray analysis was performed. Differentially expressed genes were confirmed by enrichment analysis. Mitochondrial damage was assessed by mitochondrial membrane potential. The production of inflammatory cytokines and fibrosis markers was assessed by western blot, quantitative polymerase chain reaction, and ELISA. A phosphokinase antibody array was performed to detect related signalling pathways. Low-dose DOX did not induced cell death, and fibrosis was localized to the perivascular area in mice. Microarray analysis suggested that DOX induced genes associated with the innate immune system and inflammatory reactions, resulting in cardiac remodelling. DOX induced mitochondrial damage and increased the expression of interleukin-1. DOX also promoted the expression of fibrotic markers, such as alpha smooth muscle actin and galectin-3. These responses were induced through stress-activated protein kinase/c-Jun NH2-terminal kinase signalling. A peroxisome proliferator-activated receptor (PPARγ) agonist attenuated the expression of fibrotic markers through suppressing stress-activated protein kinase/c-Jun NH2-terminal kinase. Furthermore, this molecule also suppressed DOX-induced early fibrotic responses in vivo. CONCLUSIONS: Low-dose DOX provoked reactive fibrosis through sterile inflammation evoked by the damaged mitochondria.

Doxorubicin induces trans-differentiation and MMP1 expression in cardiac fibroblasts via cell death-independent pathways.

Although doxorubicin (DOX)-induced cardiomyopathy causes lethal heart failure (HF), no early detection or effective treatment methods are available. The principal mechanisms of cardiotoxicity are considered to involve oxidative stress and apoptosis of cardiomyocytes. However, the effect of DOX on cardiac fibroblasts at non-lethal concentrations remains unknown. The aim of this study was to investigate the direct effect of doxorubicin on the activation of cardiac fibroblasts independent of cell death pathways. We first found that DOX induced α-SMA expression (marker of trans-differentiation) at a low concentration range, which did not inhibit cell viability. DOX also increased MMP1, IL-6, TGF-ß and collagen expression in human cardiac fibroblasts (HCFs). In addition, DOX promoted Akt and Smad phosphorylation. A Smad inhibitor prevented DOX-induced α-SMA and IL-6 protein expression. An PI3K inhibitor also prevented MMP1 mRNA expression in HCFs. These findings suggest that DOX directly induces fibrotic changes in HCFs via cell death-independent pathways. Furthermore, we confirmed that these responses are organ- and species-specific for HCFs based on experiments using different types of human and murine fibroblast cell lines. These results suggest potentially new mechanisms of DOX-induced cardiotoxicity from the viewpoint of fibrotic changes in cardiac fibroblasts.

Acute Hyperthermia Inhibits TGF-ß1-induced Cardiac Fibroblast Activation via Suppression of Akt Signaling.

Transforming growth factor-ß1 (TGF-ß1) induces phenotypic changes in fibroblasts to become myofibroblasts with increased production of extracellular matrix (ECM) components and cytokines. It is also known that excessive activation of myofibroblasts accelerates cardiac fibrosis, remodeling, and thus cardiac dysfunction. However, no effective therapy has been established to prevent this process although recent clinical studies have demonstrated the effectiveness of hyperthermia in cardiac dysfunction. The aim of this study was to examine the molecular mechanism of hyperthermia on TGF-ß1-mediated phenotypic changes in cardiac fibroblasts. TGF-ß1 increased the expression of IL-6, α-smooth muscle actin (α-SMA), and collagen in human cardiac fibroblasts (HCFs). Hyperthermia (42 °C) significantly prevented these changes, i.e., increases in IL-6, α-SMA, and collagen, as induced by TGF-ß1 in a time-dependent manner. Immunoblotting showed that hyperthermia decreased Akt/S6K signaling, but did not affect Smad2 and Smad3 signaling. Pharmacological inhibition of Akt signaling mimicked these effects of hyperthermia. Furthermore, hyperthermia treatment prevented cardiac fibrosis in Ang II infusion mice model. Putting together, our findings suggest that hyperthermia directly inhibits TGF-ß-mediated activation of HCFs via suppressing Akt/S6K signaling.

Hydrostatic pressure suppresses fibrotic changes via Akt/GSK-3 signaling in human cardiac fibroblasts.

Mechanical stresses play important roles in the process of constructing and modifying heart structure. It has been well established that stretch force acting on cardiac fibroblasts induces fibrosis. However, the effects of compressive force, that is, hydrostatic pressure (HP), have not been well elucidated. We thus evaluated the effects of HP using a pressure-loading apparatus in human cardiac fibroblasts (HCFs) in vitro. In this study, high HP (200 mmHg) resulted in significant phosphorylation of Akt in HCFs. HP then greatly inhibited glycogen synthase kinase 3 (GSK-3)α, which acts downstream of the PI3K/Akt pathway. Similarly, HP suppressed mRNA transcription of inflammatory cytokine-6, collagen I and III, and matrix metalloproteinase 1, compared with an atmospheric pressure condition. Furthermore, HP inhibited collagen matrix production in a three-dimensional HCF culture. Taken together, high HP suppressed the differentiation of fibroblasts into the myofibroblast phenotype. HP under certain conditions suppressed cardiac fibrosis via Akt/GSK-3 signaling in HCFs. These results might help to elucidate the pathology of some types of heart disease.

Transient receptor potential cation 3 channel regulates melanoma proliferation and migration.

Melanoma has an extremely poor prognosis due to its rapidly progressive and highly metastatic nature. Several therapeutic drugs have recently become available, but are effective only against melanoma with specific BRAF gene mutation. Thus, there is a need to identify other target molecules. We show here that Transient receptor potential, canonical 3 (TRPC3) is widely expressed in human melanoma. We found that pharmacological inhibition of TRPC3 with a pyrazole compound, Pyr3, decreased melanoma cell proliferation and migration. Similar inhibition was observed when the TRPC3 gene was silenced with short-hairpin RNA (shRNA). Pyr3 induced dephosphorylation of signal transducer and activator of transcription (STAT) 5 and Akt. Administration of Pyr3 (0.05 mg/kg) to mice implanted with human melanoma cells (C8161) significantly inhibited tumor growth. Our findings indicate that TRPC3 plays an important role in melanoma growth, and may be a novel target for treating melanoma in patients.

Beneficial effect of early infusion of landiolol, a very short-acting beta-1 adrenergic receptor blocker, on reperfusion status in acute myocardial infarction.

BACKGROUND: An early IV beta blocker during primary percutaneous coronary intervention (PCI) has been shown to reduce infarct size in ST-segment elevation acute myocardial infarction (STEMI), although the underlying mechanism is unknown. The aim of this study was to investigate the efficacy of early infusion of landiolol, the short-acting beta-1 adrenergic receptor blocker, on the reperfusion status in a STEMI. METHODS: We conducted a prospective, single-group trial of landiolol during the primary PCI for a STEMI. Landiolol was started intravenously just before reperfusion. The reperfusion status and outcomes in 55 treated patients were compared with those in 60 historical controls treated without landiolol. The optimal reperfusion was assessed by an ST-segment resolution (STR), coronary flow, and myocardial brush grade (MBG) after reperfusion. RESULTS: Patients in the landiolol group achieved a higher rate of an STR (64% vs. 42%, p=0.023) and MBG 2/3 (64% vs. 45%, p=0.045), whereas coronary flow was comparable between the two groups. A multivariate analysis showed that landiolol use was an independent predictor of an STR (odds ratio 2.99, 95% confidence interval 1.25-7.16, p=0.014). The incidence of non-sustained ventricular tachycardia (27% vs. 50%, p=0.014), hypotension (15% vs. 32%, p=0.046), and progression to Killip class grade III or IV (0% vs. 10%, p=0.028) were lower in the landiolol group. CONCLUSION: Early infusion of landiolol during the primary PCI was associated with optimal reperfusion and a lower incidence of adverse events in comparison with the control group.