The coronavirus disease 2019 (COVID-19) pandemic with high infectivity and mortality has caused severe social and economic impacts worldwide. Growing reports of COVID-19 patients with multi-organ damage indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) may also disturb the cardiovascular system. Herein, we used human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iCMs) as the in vitro platform to examine the consequence of SARS-CoV2 infection on iCMs. Differentiated iCMs expressed the primary SARS-CoV2 receptor angiotensin-converting enzyme-II (ACE2) and the transmembrane protease serine type 2 (TMPRSS2) receptor suggesting the susceptibility of iCMs to SARS-CoV2. Following the infection of iCMs with SARS-CoV2, the viral nucleocapsid (N) protein was detected in the host cells, demonstrating the successful infection. Bioinformatics analysis revealed that the SARS-CoV2 infection upregulates several inflammation-related genes, including the proinflammatory cytokine tumor necrosis factor-α (TNF-α). The pretreatment of iCMs with TNF-α for 24 h, significantly increased the expression of ACE2 and TMPRSS2, SASR-CoV2 entry receptors. The TNF-α pretreatment enhanced the entry of GFP-expressing SARS-CoV2 pseudovirus into iCMs, and the neutralization of TNF-α ameliorated the TNF-α-enhanced viral entry. Collectively, SARS-CoV2 elevated TNF-α expression, which in turn enhanced the SARS-CoV2 viral entry. Our findings suggest that, TNF-α may participate in the cytokine storm and aggravate the myocardial damage in COVID-19 patients.

Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase and plays a significant role in the pathogenesis of arteriovenous fistula (AVF) dysfunction. The aim of this study is to evaluate the effect of far-infrared (FIR) therapy on the maturation and patency of newly-created AVFs in patients with advanced diabetic kidney disease (DKD) as well as the concurrent change in plasma ADMA. The study enrolled 144 participants with advanced DKD where 101 patients were randomly allocated to the FIR therapy group (N = 50) and control group (N = 51). Patients receiving FIR therapy had a decreased AVF failure rate within 12 months (16% versus 35.3%; p = 0.027); decreased incremental change of ADMA concentration at the 3rd and 12th month; increased AVF blood flow at the 1st, 3rd, and 12th month; increased 3-month physiologic maturation rate (88% versus 68.6%; p = 0.034); increased 1-year unassisted AVF patency rate (84% versus 64.7%; p = 0.017); and increased clinical AVF maturation rate within 12 months (84% versus 62.7%; p = 0.029) compared to the control group. The study demonstrates that FIR therapy can reduce the incremental changes in plasma ADMA concentration, which may be associated with the improvement of AVF prognosis in patients with advanced DKD.

Introduction Despite improvements in endovascular interventions and multidisciplinary approaches, improving clinical outcomes and increasing limb salvage have become increasingly challenging. This prospective study investigated the associations of cilostazol treatment with clinical outcomes and predictive factors in patients with diabetes mellitus (DM) and critical limb ischemia (CLI) after endovascular revascularization of the affected angiosome. Methods In this study, 172 consecutive patients with CLI (Fontaine levels III–IV) received cilostazol treatment after successful endovascular intervention according to the angiosome concept, and their primary patency rates and cardiovascular and amputation events during a 24-month follow-up period were assessed. Result The 24-month primary patency rate, mortality rate, and amputation rate were better in the patients under long-term cilostazol treatment (P < 0.001, P = 0.029, and P = 0.014). Weighted multivariate Cox analyses with a propensity scoring-based method showed that long-term cilostazol treatment [hazard ratio (HR) 0.2, 95% confidence interval (CI) 0.11–0.36, P < 0.001], direct revascularization (DR) (HR 0.46, 95% CI 0.28–0.74, P = 0.002), and supervised exercise (HR 0.4, 95% CI 0.24–0.66, P < 0.001) were independently associated with primary patency. Patients with lower-extremity amputation (LEA) had a higher risk of coronary artery disease (CAD) and mortality. Cellulitis and neuropathy were independently associated with LEA events (cellulitis: HR 2.89, 95% CI 1.66–5.05, P < 0.001; neuropathy: HR 2.2, 95% CI 1.31–3.7, P = 0.003). Conclusion Our results showed that patients with DM who received cilostazol treatment for more than 3 months had significantly better outcomes and decreased amputation and mortality rates after DR, and cellulitis and neuropathy were highly associated with the risk of limb loss. A large-scale randomized trial should be conducted in the future to confirm these results. Trial Registration Taipei Veterans General Hospital (TVGH) IRB no. 2013-08-020B. Registered 30 August 2013.

Background: Since novel oral anticoagulants (NOACs) have been introduced in the past decade, the first option of deep vein thrombosis (DVT) treatment is toward NOACs. However, aggressive and early thrombus removal strategy is widely used for treating acute iliofemoral DVT. Consequently, optimal treatment duration, efficacy, and safety of rivaroxaban alone or in combination with catheter-directed intrathrombus thrombolysis (CDT) in acute iliofemoral DVT patients should be investigated. Methods: Patients with recent acute iliofemoral DVT treated with combined CDT–rivaroxaban (CDT) or rivaroxaban alone (control) were followed for mean (standard deviation) of 25.7 (2.5) months. DVT evolution, treatment efficacy and safety, and predisposing factors for patency and postthrombotic syndrome (PTS) development were analyzed through duplex ultrasonography, plethysmography, venography, and computed tomographic venography. Results: 43.2%, 64.9%, 75.7%, and 72.2% of the CDT patients showed complete patency at 3, 6, 12, and 24 months of treatment compared with the control patients having 8.5%, 36.2%, 55.3%, and 57.4% of cumulative patency at 3, 6, 12, and 24 months, respectively (p = 0.001, 0.017, 0.088, and 0.081, respectively). The p value of the log-rank test comparing patency rates of the two groups was 0.009. The median (interquartile range, IQR) Villalta scores at 24 months were 3 (2-5) and 6 (4-8) in CDT and control patients, respectively (p = 0·001). PTS and bleeding events during therapy were, respectively, found in 35.1% and 63.8% (p = 0.017) and in 27% and 17% of CDT and control patients (p = 0.4). The Kaplan–Meier curve analysis of cumulative patency at 24 months for 6 months of rivaroxaban treatment was significant (p = 0.016). Conclusion: Treatment therapy and treatment duration with rivaroxaban alone or in combination with CDT are potentially associated with vein patency at 24 months, and a 6-month lysis rate and obstructive vein can influence PTS development. A larger randomized trial is warranted to confirm these findings.

Original Article Safety and efficiency of femoral artery access closure using QuikClot Combat Gauze in patients with severe arterial calcification of access sites Fan-Chieh Meng, Chiu-Yang Lee

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has been associated with severe cardiovascular complications. However, the role of epitranscriptional modulation involved in SARS-CoV-2-infected myocarditis is still unclear. Ten-eleven translocation 2 (TET2), a methylcytosine dioxygenase, plays key roles in DNA demethylation during viral infection and host–virus interactions. Using human-induced-pluripotent-stem-cell-derived cardiomyocytes (hiPSC-CMs) as a platform, our data revealed the epitranscriptomic role of TET2 during SARS-CoV-2 infection. First, our RNA sequencing analysis revealed the alterations of the messenger-RNA-expression profiles of epitranscriptomic regulators, including TET2, in hiPSC-CMs during SARS-CoV-2 infection. Second, silencing TET2 markedly reduced both the messenger RNA and protein levels of the viral nucleocapsid (N) protein, leading to attenuated viral replication in infected hiPSC-CMs. Furthermore, RNA dot-blotting analysis revealed that TET2 knockdown suppressed the levels of 5-hydroxymethylcytosine in SARS-CoV-2-infected hiPSC-CMs. To further explore the therapeutic relevance of TET2 inhibition in suppressing SARS-CoV-2 infection, we screened and compared 3 structurally distinct TET2 enzymatic inhibitors: Bobcat339, TETi76, and TFMB-2HG. Among these, Bobcat339 demonstrated the most potent antiviral effect, markedly suppressing SARS-CoV-2 replication and N-protein expression. Molecular docking analysis revealed that Bobcat339 exhibited a high binding affinity for multiple viral targets, including nsp16, RdRp, and N protein, indicating a multitarget mechanism of action. In addition, our data demonstrated that treatment with Bobcat339 can suppress SARS-CoV-2 infectious activity and N-protein expression in infected hiPSC-CMs. Together, our findings highlight the regulatory role of TET2 in SARS-CoV-2 infection and identify Bobcat339 as a promising therapeutic compound. Understanding TET2-driven epitranscriptomics and the functions of TET-targeting inhibitors may provide a novel strategy for mitigating viral infection in SARS-CoV-2-induced cardiomyopathy.