The aim of the study was to examine frequency, size, and localization of peri-device leaks after percutaneous left atrial appendage (LAA)-closure with the AMPLATZER-Cardiac-Plug (ACP) by using a multimodal imaging approach, i.e. combined cardiac-CT and TEE follow-up.Catheter-based LAA-occlusion using ACP aims to reduce the risk of stroke in patients with atrial fibrillation. Detection of peri-device leaks after ACP implantation by TEE is challenging, the few available data are inconsistent and the frequency of LAA leaks after ACP implantation remains therefore unclear.Cardiac-CT using a multi-phase protocol and a second-generation dual-source-CT-system was performed in 24 patients with non-valvular atrial fibrillation starting 3 months after LAA-closure by ACP. Color Doppler multiplane TEE was used to evaluate peri-device flow.Cardiac-CT follow-up detected any persistent LAA contrast filling in 62% of patients (n = 15), but leak-sizes were small (1.5 ± 1.4 mm). Peri-device leaks were almost exclusively localized at the posterior portion of the LAA-orifice (>90%). TEE follow-up revealed peri-device flow in 36% of patients (jet-sizes: ≤ 4 mm). ACP-lobe compression (>10%) and perpendicular ACP-lobe orientation to the LAA-neck axis, that was also dependent on LAA anatomy, were substantially more frequent in patients with complete LAA closure.The present study evaluates for the first time peri-device flow after LAA closure by ACP using a combined cardiac-CT and TEE follow-up. Persistent LAA-perfusion was frequently detected, leak-sizes were small and were less frequent when lobe compression was >10% and lobe orientation was perpendicular to the LAA-neck axis, that was also related to the LAA anatomy. The clinical significance of these small leaks after LAA-closure using ACP needs to be further evaluated in future studies.
Abstract Background Few studies have assessed whether the increased SARS-CoV-2 risk of healthcare workers (HCW) is carried on to their household contacts. Within a prospective HCW cohort, we assessed the SARS-CoV-2 risk of household contacts of HCW depending on the HCWs cumulative exposure to COVID-19 patients and identified factors influencing this association. Methods HCW aged ≥ 16 years from nine Swiss healthcare networks participated. HCW without any household contacts were excluded. For HCW, cumulative patient exposure (number of COVID-19 patient contacts times average contact duration during a 12-month follow-up) was calculated. During follow-up, HCW reported SARS-CoV-2 nasopharyngeal swab results and positive swab results of their household contacts. We used multivariable logistic regression to identify variables associated with SARS-CoV-2 household positivity. Results Of 2406 HCW, 466 (19%) reported ≥ 1 SARS-CoV-2 positive household. In multivariable analysis, patient exposure of HCW (adjusted OR [aOR] 1.08 per category, 95% CI 1.04–1.12), household size (aOR 1.53 per household member, 95% CI 1.35–1.73) and having children (aOR 0.70, 95% CI 0.53–0.94) remained associated with household positivity. Vaccinated HCW had a lower risk (aOR 0.54, 95% CI 0.38–0.77) of reporting a positive contact, as were those using respirator masks in contact with COVID-19 patients (aOR 0.65, 95% CI 0.49–0.86). Among vaccinated HCW, delayed first vaccination was associated with increased household SARS-CoV-2 positivity (aOR 1.14 per month, 95% CI 1.08–1.21). Conclusions SARS-CoV-2 positivity in household contacts of HCW increases with higher cumulative COVID-19 patient exposure of HCWs. Measures reducing the SARS-CoV-2 risk in HCW might indirectly reduce the infection risk of their households.
Inflammasomes are crucial gatekeepers of the immune response, but their maladaptive activation associates with inflammatory pathologies. Besides canonical activation, monocytes can trigger non-transcriptional or rapid inflammasome activation that has not been well defined in the context of acute myocardial infarction (AMI). Rapid transcription-independent inflammasome activation induced by simultaneous TLR priming and triggering stimulus was measured by caspase-1 (CASP1) activity and interleukin release. Both classical and intermediate monocytes from healthy donors exhibited robust CASP1 activation, but only classical monocytes produced high mature interleukin-18 (IL18) release. We also recruited a limited number of coronary artery disease (CAD, n=31) and AMI (n=29) patients to evaluate their inflammasome function and expression profiles. Surprisingly, monocyte subpopulations isolated from blood collected during percutaneous coronary intervention (PCI) from AMI patients presented diminished CASP1 activity and abrogated IL18 release despite increased NLRP3 gene expression. This unexpected attenuated rapid inflammasome activation was accompanied by a significant increase of TNFAIP3 and IRAKM expression. Moreover, TNFAIP3 protein levels of circulating monocytes showed positive correlation with high sensitive troponin T (hsTnT), implying an association between TNFAIP3 upregulation and the severity of tissue injury. We suggest this monocyte attenuation to be a protective phenotype aftermath following a very early inflammatory wave in the ischemic area. Damage-associated molecular patterns (DAMPs) or other signals trigger a transitory negative feedback loop within newly recruited circulating monocytes as a mechanism to reduce post-injury tissue damage.
Aggravated endothelial injury and impaired endothelial repair capacity contribute to the high cardiovascular risk in patients with type 2 diabetes (T2D), but the underlying mechanisms are still incompletely understood. Here we describe the functional role of a mature form of miRNA (miR) 483-3p, which limits endothelial repair capacity in patients with T2D. Expression of human (hsa)-miR-483-3p was higher in endothelial-supportive M2-type macrophages (M2MΦs) and in the aortic wall of patients with T2D than in control subjects without diabetes. Likewise, the murine (mmu)-miR-483* was higher in T2D than in nondiabetic murine carotid samples. Overexpression of miR-483-3p increased endothelial and macrophage apoptosis and impaired reendothelialization in vitro. The inhibition of hsa-miR-483-3p in human T2D M2MΦs transplanted to athymic nude mice (NMRI-Foxn1ν/Foxn1ν) or systemic inhibition of mmu-miR-483* in B6.BKS(D)-Leprdb/J diabetic mice rescued diabetes-associated impairment of reendothelialization in the murine carotid-injury model. We identified the endothelial transcription factor vascular endothelial zinc finger 1 (VEZF1) as a direct target of miR-483-3p. VEZF1 expression was reduced in aortae of diabetic mice and upregulated in diabetic murine aortae upon systemic inhibition of mmu-483*. The miRNA miR-483-3p is a critical regulator of endothelial integrity in patients with T2D and may represent a therapeutic target to rescue endothelial regeneration after injury in patients with T2D.
Background: HDL-raising therapies are currently intensely evaluated as a potential novel therapeutic strategy in patients with CAD. However, vascular effects of HDL have been observed to be highly variable. The aim of the present study was therefore to characterize mechanisms leading to altered endothelial-vasoprotective properties of HDL in patients with CAD. Methods: HDL was isolated from patients with stable CAD (sCAD), an acute coronary syndrome (ACS) and healthy subjects (HS; n=20 –25) by sequential ultracentrifugation. The effects of HDL on endothelial nitric oxide (NO) production, endothelium-dependent, NO-mediated vasodilation, signaling pathways leading to eNOS activation and endothelial superoxide production (ESR spectroscopy analysis) were examined. HDL-associated paraoxonase (PON) activity/content and endothelial binding of HDL (radioactive 125I-labelling of HDL) were characterized. Moreover, the role of eNOS and PON for anti-inflammatory properties of HDL were determined. Results: HDL from HS, but not HDL from sCAD/ACS patients, potently stimulated endothelial NO production. HDL from HS increased endothelial Akt, eNOS-Ser1177-phosphorylation and eNOS-Thr495-dephosphorylation, that was not observed with HDL from sCAD/ACS patients. Endothelial binding capacity of HDL was markedly reduced in patients with CAD. PON activity was reduced (−62.2% and −70.4% vs. HS, P<0.001), whereas PON1 content was increased in HDL from sCAD/ACS patients as compared to HDL from HS, suggesting inactivation of HDL-associated PON in CAD. Inhibition of PON activity prevented the capacity of HDL from HS to stimulate Akt/eNOS phosphorylation, endothelial NO production, NO-dependent vasodilation and to exert anti-inflammatory effects. eNOS siRNA knockdown prevented anti-inflammatory effects of HDL from HS. Conclusion: The present study demonstrates that reduced endothelial binding of HDL and inactivation of HDL-associated paraoxonase are major mechanisms leading to impaired endothelial-vasoprotective and anti-inflammatory effects of HDL in CAD patients. HDL-targeted treatment approaches should therefore not only increase HDL levels, but likely more important, restore endothelial-vasoprotective properties of HDL.
Accumulating evidence suggests a critical role for increased reactive oxygen species (ROS) production in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). Increased expression of xanthine oxidase (XO), a major source of ROS, has recently been demonstrated in experimental and clinical heart failure; however, a potential role for LV remodeling processes remains unclear. We therefore studied the effect of long-term treatment with allopurinol, a potent XO inhibitor, on myocardial ROS production and LV remodeling and dysfunction after MI.Mice with extensive anterior MI (n=105) were randomized to treatment with either vehicle or allopurinol (20 mg x kg(-1) x d(-1) by gavage) for 4 weeks starting on day 1 after surgery. Infarct size was similar among the groups. XO expression and activity were markedly increased in the remote myocardium of mice after MI, as determined by electron spin resonance spectroscopy. Myocardial ROS production was increased after MI but markedly reduced after allopurinol treatment. Importantly, allopurinol treatment substantially attenuated LV cavity dilatation and dysfunction after MI, as assessed by echocardiography, and markedly reduced myocardial hypertrophy and interstitial fibrosis.The present study reveals a novel beneficial effect of treatment with allopurinol, ie, a marked attenuation of LV remodeling processes and dysfunction after experimental MI. Allopurinol treatment therefore represents a potential novel strategy to prevent LV remodeling and dysfunction after MI.
