Therapeutic efficacy of lenvatinib in nonviral unresectable hepatocellular carcinoma.

AIM: To investigate the therapeutic effect of lenvatinib (LEN) in liver disease etiology, especially nonviral hepatocellular carcinoma (HCC). METHODS AND RESULTS: Sixty-seven patients with unresectable advanced HCC (u-HCC) treated with LEN and consisting of 26 hepatitis C virus (HCV), 19 hepatitis B virus (HBV), 11 alcohol, and 11 nonalcoholic steatohepatitis (NASH) cases were retrospectively recruited. Univariate and multivariate Cox proportional hazard models were used to determine predictive factors for survival. The objective response rate in the nonviral (alcohol and NASH) group was higher than that in the viral group (59.1% [13/22] vs. 46.7% [21/45]). Progression-free survival was significantly longer in the nonviral group than in the viral group (13.7 vs. 6.6 months; hazard ratio [HR] 0.324; 95% confidence interval [CI] 0.174-0.602; P < 0.01). Similarly, median overall survival (OS) was significantly longer in the nonviral group than in the viral group (not evaluable vs. 15.9 months; HR = 0.277; 95% CI = 0.116-0.662; P < 0.01). Multivariate analysis revealed that portal vein invasion (HR = 5.327, P = 0.0025), treatment line (HR = 0.455, P = 0.023), and etiology (HR = 0.180, P = 0.00055) were significant independent factors associated with OS in u-HCC patients treated with LEN. CONCLUSION: Our results suggest that LEN is more effective against nonviral u-HCC than against viral u-HCC.

Late presentation of arrhythmogenic right ventricular cardiomyopathy in an octogenarian associated with a pathogenic variant in the plakophilin 2 gene: a case report.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by fibrofatty replacement and ventricular arrhythmias. ARVC is believed to be a disease of the young, with most cases being diagnosed before the age of 40 years. We report here a case of newly diagnosed ARVC in an octogenarian associated with a pathogenic variant in the plakophilin 2 gene (PKP2). CASE PRESENTATION: An 80-year-old Japanese man was referred for sustained ventricular tachycardia. His baseline electrocardiogram showed negative T waves in V1-V4. Right ventriculography showed right ventricular aneurysm. Because this case met three major criteria, ARVC was diagnosed. He was successfully treated with radiofrequency ablation and oral amiodarone. Genetic analysis identified an insertion mutation in exon 8 of PKP2 (1725_1728dupGATG), which caused a frameshift and premature termination of translation (R577DfsX5). CONCLUSIONS: To the best of our knowledge, this is the first report of newly diagnosed ARVC in an octogenarian associated with a loss-of-function PKP2 pathogenic variant. Although the late clinical presentation of ARVC is rare, it should be included in the differential diagnosis when treating older patients with ventricular tachyarrhythmias.

Clinical characteristics associated with pacing-induced cardiac dysfunction: a high incidence of undiagnosed cardiac sarcoidosis before permanent pacemaker implantation.

Previous studies suggested that right ventricular pacing was associated with pacing-induced cardiac dysfunction (PICD). The purpose of this study was to investigate the clinical characteristics including the incidence of undiagnosed cardiac sarcoidosis (CS) in patients with atrioventricular block (AVB) who manifest PICD. We retrospectively investigated consecutive patients with permanent pacemaker (PPM) undergoing a first-generator replacement surgery with a new PPM or an upgrade procedure to a cardiac resynchronization therapy (CRT) device between December 1, 2011 and June 30, 2017. Patients with AVB showing normal echocardiographic findings before PPM implantation were included and divided into 2 groups: patients with post-PPM left ventricular ejection fraction (LVEF) < 40% and/or undergoing an upgrade procedure to CRT (PICD group) and patients with post-PPM LVEF ≥ 40% who underwent replacement surgery with a new PPM (no-PICD group). There were 15 and 41 patients in the PICD and no-PICD groups, respectively. A wider-paced QRS duration just after the PPM implantation and/or lower pre-PPM LVEF was observed in the PICD group. Furthermore, 46.7% of the PICD patients (7/15) satisfied the diagnostic criteria for CS according to the guideline of the Japanese Circulation Society, although no patients fulfilled these criteria before PPM implantation. In conclusion, a high incidence of CS was observed in patients with AVB who had PICD. However, none of these patients was diagnosed with CS before PPM implantation.

Endothelial Nitric Oxide Synthase-Independent Pleiotropic Effects of Pitavastatin Against Atherogenesis and Limb Ischemia in Mice.

AIM: Statins have a protective impact against cardiovascular diseases through not only lipid-lowering effects but also pleiotropic effects, including activation of the endothelial nitric oxide synthase (eNOS) system. We aimed to clarify the protective effects of a statin against atherogenesis and ischemia in eNOS－/－ mice. METHODS: Study 1. eNOS－/－ Apolipoprotein E (ApoE)－/－ mice were treated with a vehicle or pitavastatin (0.3 mg/kg/day) for 4 weeks. Study 2. eNOS－/－ mice were also treated with a vehicle or the same dose of pitavastatin for 2 weeks prior to hind-limb ischemia. RESULTS: In Study 1, pitavastatin attenuated plaque formation and medial fibrosis of the aortic root with decreased macrophage infiltration in eNOS－/－ ApoE－/－ mice. PCR array analysis showed reductions in aortic gene expression of proatherogenic factors, including Ccl2 and Ccr2 in pitavastatin-treated double mutant mice. In addition, pitavastatin activated not only atherogenic p38MAPK and JNK but also anti-atherogenic ERK1/2 and ERK5 in the aorta of the double mutant mice. In Study 2, pitavastatin prolonged hind-limb survival after the surgery with increased BCL2-to-BAX protein ratio and inactivated JNK. Enhanced expression of anti-apoptotic genes, including Vegf, Api5, Atf5, Prdx2, and Dad1, was observed in the ischemic limb of pitavastatin-treated eNOS－/－ mice. Furthermore, pitavastatin activated both aortic and skeletal muscle AMPK in the eNOS-deficient vascular injury models. CONCLUSION: Pitavastatin exerts eNOS-independent protective effects against atherogenesis and hind-limb ischemia in mice, which may occur via modifications on key molecules such as AMPK and diverse molecules.

Peri-Mitral Atrial Tachycardia Using the Marshall Bundle Epicardial Connections.

OBJECTIVES: The aim of this study was to determine whether re-entrant circuits were associated with the ligament of Marshall (LOM). BACKGROUND: Peri-mitral atrial tachycardias (PMATs) following pulmonary vein isolation (PVI) or mitral valve surgery are common. METHODS: Six PMATs involving epicardial circuits were identified from 38 patients. Of these, 4 PMATs involved the LOM (PMAT-LOM, mean cycle length 308 ± 53 ms), as confirmed by the insertion of a 2-F electrode in the vein of Marshall (VOM). All patients underwent PVI and mitral isthmus ablation. The PMAT-LOMs were diagnosed based on left atrium (LA) activation maps that covered <90% of tachycardia cycle length (TCL), and a difference between the post-pacing interval and TCL that was: 1) ≤20 ms at the VOM, the ridge between the left pulmonary vein and appendage, the anterior wall of the LA, and along the 6 to 11 o'clock direction of the mitral annulus; and 2) >20 ms at the distal coronary sinus (CS), the posterior wall of the LA, and the mitral isthmus ablation line (or noncapture). Catheter ablation was performed at the ridge for all PMAT-LOMs. RESULTS: Three tachycardias were successfully terminated at the ridge, which showed continuous fractionated potential lasting >100 ms, confirming the bidirectional block of Marshall bundle (MB)-LA connections. The remaining tachycardia required ablation for the CS-MB connections, confirming bidirectional block of CS-MB connections. CONCLUSIONS: PMAT-LOMs following PVI or valve surgery accounted for up to 11% of PMATs. The bidirectional block of either MB-LA or CS-MB connections is required to eliminate PMAT-LOMs.

Major adverse cardiac and bleeding events associated with non-cardiac surgery in coronary artery disease patients with or without prior percutaneous coronary intervention.

BACKGROUND: The optimal preoperative therapeutic strategy for patients with coronary artery disease (CAD) is an important concern in the era of drug-eluting stents and antiplatelet therapy. However, there are few studies about the impact of prior percutaneous coronary intervention (PCI) on perioperative major adverse cardiac events (MACEs) and bleeding events associated with oral antiplatelet therapy. The aim of this study was to examine the risks and benefits of performing PCI before non-cardiac surgery (NCS) in patients with CAD. METHODS: We investigated 130 patients who had angiographically significant and stable CAD and underwent NCS after index coronary angiography. We divided the patients into two groups: patients undergoing PCI with coronary stenting (PCI group), and those not undergoing PCI before NCS (no-PCI group), and compared the MACEs and bleeding events within 30 days from NCS between the groups. RESULTS: There were 53 and 77 patients in the PCI and no-PCI groups, respectively. MACEs were observed in 2 patients (3.8%) in the PCI group and 3 patients (3.9%) in the no-PCI group (p=0.97), whereas bleeding events were observed in 10 (18.9%) and 8 patients (10.4%) in the PCI and no-PCI groups, respectively (p=0.17). There were no significant differences between the two groups in terms of MACEs and bleeding events. CONCLUSIONS: The rate of MACEs following NCS was not significantly different between the PCI and no-PCI groups, while the rate of bleeding events was higher in the PCI group without reaching statistical significance. This study suggests that patients with stable CAD may be able to safely undergo NCS without revascularization even in the presence of significant coronary artery stenosis.

Cardiovascular and bleeding risk of non-cardiac surgery in patients on antiplatelet therapy.

BACKGROUND: The perioperative risk of non-cardiac surgery (NCS) in the patients on antiplatelet therapy after percutaneous coronary intervention (PCI) remains unclear. METHODS: This study was a retrospective and single center study. Between January 2008 and December 2011, 198 patients who had already received PCI underwent NCS in our hospital. Among them, 63 patients underwent surgery on dual antiplatelet therapy (DAPT group) and 88 patients on single antiplatelet therapy (SAPT group). We compared bleeding events and cardiovascular events during perioperative period between the two groups. RESULTS: There was no stent thrombosis in either group. The bleeding events in the DAPT group were significantly higher than that in the SAPT group (9.5% vs 2.3%, p=0.049). There was no difference in events between with or without heparin-bridge in the SAPT group. CONCLUSIONS: The frequency of bleeding events was higher in the DAPT group. Both bleeding and cardiovascular events with aspirin alone were low in our study. It may be safe to undergo NCS with SAPT after PCI.

[Relationship between redox state of whole arterial blood glutathione and left ventricular function after acute myocardial infarction].

OBJECTIVES: To investigate the role of oxidative stress in left ventricular function after acute myocardial infarction. METHODS: We studied 41 patients with acute myocardial infarction (30 men and 11 women, mean age 61.7 +/- 11.6 years) with Thrombolysis in Myocardial Infarction grade 3 recanalization of occluded coronary arteries within 12 hr after onset. Cardiac catheterization was performed at the time of admission and before discharge. Three markers for oxidative stress were measured: plasma lipid hydroperoxide, plasma creatol and whole arterial blood glutathione at the time of admission. RESULTS: Mean time from onset to recanalization was 5.2 +/- 0.6 hr. The patients were divided into two groups according to the changes in left ventricular wall motion (LVWM); patients who showed improvement in LVWM and those without improvement. There were no significant differences in age, sex, coronary risk factors, severity of coronary artery disease, time from onset to recanalization or ejection fraction between two groups. Maximum creatine kinase and C-reactive protein levels in patients without LVWM improvement were significantly higher than in patients with improvement. Plasma levels of lipid hydroperoxide and creatol did not differ significantly between two groups. On the other hand, reduced glutathione/oxidized glutathione ratio in arterial blood in patients without LVWM improvement was significantly lower than in patients with LVWM improvement (69.8 +/- 3.4 vs 85.5 +/- 2.9, p < 0.05). CONCLUSIONS: Our results suggest that whole arterial blood glutathione is more oxidized in acute myocardial infarction patients without LVWM improvement than in patients with improvement. Redox state of arterial blood can be a predicting factor for left ventricular function after acute myocardial infarction.