LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosis

COVID-19 related acro-ischemic neuropathic-like painful lesions in pediatric patients: A case seriese

Background: A variety of skin manifestations have been associated with COVID-19 infection. Acral lesions on hands and feet, closely resembling chilblains, have been reported in association with COVID-19, which are nonspecific. These acro-ischemic painful lesions have been described mainly in asymptomatic and mildly symptomatic pediatric COVID-19 positive patients, without a precise patho-genetic mechanism.COVID-19-induced chilblains may portend an indolent course and a good outcome. In young patients, the IFN-1 response induces microangiopathic changes and produces a chilblain lupus erythematosus-like eruption with vasculitic neuro-pathic pain features. Objectives: This paper presented a case series of pediatric patients with COVID-19-related skin lesions and neuropathic-like pain. Methods: Clinical outcomes were collected from 11 patients diagnosed with painful erythematous skin lesions with neuropathic-like pain and positive IgG for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Results: It is a mildly symptomatic condition not related to severe pain rates, and it is treated with paracetamol due to the transitory nature of the problem, which provides good results. Conclusions: A particular point of interest is skin lesion manifestation as a further indirect sign of SARS-CoV-2 infection. Due to the initial manifestation of chilblains in pauci-symptomatic pediatric patients, they need to be immediately tested and isolated. Chilblains can be considered a clinical clue to suspect SARS-CoV-2 infection and help in early diagnosis, patient triage, and infection control. © 2021, Author(s)

LRP1-Mediated AggLDL Endocytosis Promotes Cholesteryl Ester Accumulation and Impairs Insulin Response in HL-1 Cells

The cardiovascular disease (CVD) frequently developed during metabolic syndrome and type-2 diabetes mellitus is associated with increased levels of aggregation-prone small LDL particles. Aggregated LDL (aggLDL) internalization is mediated by low-density lipoprotein receptor-related protein-1 (LRP1) promoting intracellular cholesteryl ester (CE) accumulation. Additionally, LRP1 plays a key function in the regulation of insulin receptor (IR) and glucose transporter type 4 (GLUT4) activities. Nevertheless, the link between LRP1, CE accumulation, and insulin response has not been previously studied in cardiomyocytes. We aimed to identify mechanisms through which aggLDL, by its interaction with LRP1, produce CE accumulation and affects the insulin-induced intracellular signaling and GLUT4 trafficking in HL-1 cells. We demonstrated that LRP1 mediates the endocytosis of aggLDL and promotes CE accumulation in these cells. Moreover, aggLDL reduced the molecular association between IR and LRP1 and impaired insulin-induced intracellular signaling activation. Finally, aggLDL affected GLUT4 translocation to the plasma membrane and the 2-NBDG uptake in insulin-stimulated cells. We conclude that LRP1 is a key regulator of the insulin response, which can be altered by CE accumulation through LRP1-mediated aggLDL endocytosisThis work was funded by Secretaría de Ciencia y Tecnología de la Universidad Nacional de Córdoba (SECyT-UNC) grants 2016 and 2017 (to GAC); Fondo para la Investigación Científica y Tecnológica (FONCyT), Préstamo BID Proyecto de Investigación en Ciencia y Tecnología (PICT) grant 2012-2607 and grant 2015-0807 (to GAC); FISPI18/01584 (to VLl-C) from Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.) and by Project 201521-10 from Fundació MARATÓ TV3 (to VLl-C). CIBER Cardiovascular (CB16/11/00403 to VLl-C and DdG-C) is a project from Instituto de Salud Carlos III. VAD and MV are doctoral fellows at CONICET, and GRB and GAC are members of the Research Career of CONICET. DdG-C was a recipient of a Juan de la Cierva-Incorporación grant from the Ministerio de Economía y Competitividad (IJCI-2016-29393). DdG, AB-A are members and VLl-C is the PI of Quality Research Group (2017-SGR-946) from Generalitat de Catalunya. VLl-C anPeer reviewe

Permanent pacemaker implantation following transcatheter aortic valve implantation using self-expandable, balloon-expandable, or mechanically expandable devices: a network meta-analysis

Aims Permanent pacemaker implantation (PPI) still limits the expansion of indications for transcatheter aortic valve implantation (TAVI). Comparison between different systems remains scarce. We aimed to determine the impact of the device type used on post-TAVI PPI.Methods and results A systematic literature review was performed to identify studies reporting the use of balloon-expandable valve (BEV), self-expandable valve (SEV), and mechanically expandable valve (MEV) and post-TAVI PPI. A network meta-analysis was used to compare TAVI mechanisms (Analysis A) and transcatheter heart valves (Analysis B) with respect to post-TAVI PPI. Analysis A included 40 181 patients with a pooled PPI rate of 19.2% in BEV, 24.7% in SEV, and 34.8% in MEV. Balloon-expandable valve showed lower risk compared to either SEV or MEV and SEV demonstrated lower risk for PPI than MEV. Implantation of BEV was associated with 39% and 62% lower PPI rate with respect to SEV and MEV. Implantation of SEV was associated with 38% lower PPI rate with respect to MEV. Analysis B included 36.143 patients with the lowest pooled PPI rate of 9.6% for Acurate Neo or others, and the highest pooled PPI rate of 34.3% for Lotus. CoreValve, Evolut Portico, and Lotus influenced significantly PPI rate, while Sapien group did not.Conclusion Implantation of BEV and also SEV were associated with lower post-TAVI PPI rate, while MEV were associated with higher post-TAVI PPI. Patient tailored-approach including devices characteristics may help to reduce post-TAVI PPI and to allow TAVI to take the leap towards extension of use in younger patients.[GRAPHICS]

Permanent pacemaker implantation following transcatheter aortic valve implantation using self-expandable, balloon-expandable, or mechanically expandable devices: a network meta-analysis

Aims Permanent pacemaker implantation (PPI) still limits the expansion of indications for transcatheter aortic valve implantation (TAVI). Comparison between different systems remains scarce. We aimed to determine the impact of the device type used on post-TAVI PPI.Methods and results A systematic literature review was performed to identify studies reporting the use of balloon-expandable valve (BEV), self-expandable valve (SEV), and mechanically expandable valve (MEV) and post-TAVI PPI. A network meta-analysis was used to compare TAVI mechanisms (Analysis A) and transcatheter heart valves (Analysis B) with respect to post-TAVI PPI. Analysis A included 40 181 patients with a pooled PPI rate of 19.2% in BEV, 24.7% in SEV, and 34.8% in MEV. Balloon-expandable valve showed lower risk compared to either SEV or MEV and SEV demonstrated lower risk for PPI than MEV. Implantation of BEV was associated with 39% and 62% lower PPI rate with respect to SEV and MEV. Implantation of SEV was associated with 38% lower PPI rate with respect to MEV. Analysis B included 36.143 patients with the lowest pooled PPI rate of 9.6% for Acurate Neo or others, and the highest pooled PPI rate of 34.3% for Lotus. CoreValve, Evolut Portico, and Lotus influenced significantly PPI rate, while Sapien group did not.Conclusion Implantation of BEV and also SEV were associated with lower post-TAVI PPI rate, while MEV were associated with higher post-TAVI PPI. Patient tailored-approach including devices characteristics may help to reduce post-TAVI PPI and to allow TAVI to take the leap towards extension of use in younger patients.[GRAPHICS]

Surgery for Bentall endocarditis: Short- And midterm outcomes from a multicentre registry

Objectives: Endocarditis after the Bentall procedure is a severe disease often complicated by a pseudoaneurysm or mediastinitis. Reoperation is challenging but conservative therapy is not effective. The aim of this study was to assess short- and midterm outcomes of patients reoperated on for Bentall-related endocarditis. Methods: Seventy-three patients with Bentall procedure-related endocarditis were recorded in the Italian registry. The mean age was 57 \ub1 14 years and 92% were men; preoperative comorbidities included hypertension (45%), diabetes (12%) and renal failure (11%). The logistic EuroSCORE was 25%; the EuroSCORE II was 8%. Results: Preoperatively, 12% of the patients were in septic shock; left ventricular-aortic discontinuity was present in 63% and mitral valve involvement occurred in 12%. The most common pathogens were Staphylococcus aureus (22%) and Streptococci (14%). Reoperations after a median interval of 30months (1-221 months) included a repeat Bentall with a bioconduit (41%), a composite mechanical (33%) or biological valved conduit (19%) and a homograft (6%). In 1 patient, a heart transplant was required (1%); in 12%, a mitral valve procedure was needed. The hospital mortality rate was 15%. The postoperative course was complicated by renal failure (19%), major bleeding (14%), pulmonary failure (14%), sepsis (11%) and multiorgan failure (8%). At multivariate analysis, urgent surgery was a risk factor for early death [hazard ratio 20.5 (1.9-219)]. Survival at 5 and 8 years was 75 \ub1 6% and 71 \ub1 7%, with 3 cases of endocarditis relapse. Conclusions: Surgery is effective in treating endocarditis following the Bentall procedure although it is associated with high perioperative mortality and morbidity rates. Endocarditis relapse seems to be uncommon

Extracorporeal life support in mitral papillary muscle rupture: Outcome of multicenter study

Background: Post-acute myocardial infarction papillary muscle rupture (post-AMI PMR) may present variable clinical scenarios and degree of emergency due to result of cardiogenic shock. Veno-arterial extracorporeal life support (V-A ECLS) has been proposed to improve extremely poor pre- or postoperative conditions. Information in this respect is scarce.Methods: From the CAUTION (meChanical complicAtion of acUte myocardial infarcTion: an InternatiOnal multiceNter cohort study) database (16 different Centers, data from 2001 to 2018), we extracted adult patients who were surgically treated for post-AMI PMR and underwent pre- or/and postoperative V-A ECLS support. The end-points of this study were in-hospital survival and ECLS complications.Results: From a total of 214 post-AMI PMR patients submitted to surgery, V-A ECLS was instituted in 23 (11%) patients. The median age was 61.7 years (range 46-81 years). Preoperatively, ECLS was commenced in 10 patients (43.5%), whereas intra/postoperative in the remaining 13. The most common V-A ECLS indication was post-cardiotomy shock, followed by preoperative cardiogenic shock and cardiac arrest. The median duration of V-A ECLS was 4 days. V-A ECLS complications occurred in more than half of the patients. Overall, in-hospital mortality was 39.2% (9/23), compared to 22% (42/219) for the non-ECLS group.Conclusions: In post-AMI PMR patients, V-A ECLS was used in almost 10% of the patients either to promote bridge to surgery or as postoperative support. Further investigations are required to better evaluate a potential for increased use and its effects of V-A ECLS in such a context based on the still high perioperative mortality

Surgical Treatment of Postinfarction Ventricular Septal Rupture

IMPORTANCE Ventricular septal rupture (VSR) is a rare but life-threatening mechanical complication of acute myocardial infarction associated with high mortality despite prompt treatment. Surgery represents the standard of care; however, only small single-center series or national registries are usually available in literature, whereas international multicenter investigations have been poorly carried out, therefore limiting the evidence on this topic.OBJECTIVES To assess the clinical characteristics and early outcomes for patients who received surgery for postinfarction VSR and to identify factors independently associated with mortality.DESIGN, SETTING, AND PARTICIPANTS The Mechanical Complications of Acute Myocardial Infarction: an International Multicenter Cohort (CAUTION) Study is a retrospective multicenter international cohort study that includes patients who were treated surgically for mechanical complications of acute myocardial infarction. The study was conducted from January 2001 to December 2019 at 26 different centers worldwide among 475 consecutive patients who underwent surgery for postinfarction VSR.EXPOSURES Surgical treatment of postinfarction VSR, independent of the technique, alone or combined with other procedures (eg, coronary artery bypass grafting).MAIN OUTCOMES AND MEASURES The primary outcome was early mortality; secondary outcomes were postoperative complications.RESULTS Of the 475 patients included in the study, 290 (61.1%) were men, with a mean (SD) age of 68.5 (10.1) years. Cardiogenic shock was present in 213 patients (44.8%). Emergent or salvage surgery was performed in 212 cases (44.6%). The early mortality rate was 40.4% (192 patients), and it did not improve during the nearly 20 years considered for the study (median [IQR] yearly mortality, 41.7% [32.6%-50.0%]). Low cardiac output syndrome and multiorgan failure were the most common causes of death (low cardiac output syndrome, 70 [36.5%]; multiorgan failure, 53 [27.6%]). Recurrent VSR occurred in 59 participants (12.4%) but was not associated with mortality. Cardiogenic shock (survived: 95 [33.6%]; died, 118 [61.5%]; P = 7 days, survived: 105 [57.4%]; died, 47 [35.1%]; P < .001) were associated with lower survival. At multivariate analysis, older age (odds ratio [OR], 1.05; 95% CI, 1.02-1.08; P = .001), preoperative cardiac arrest (OR, 2.71; 95% CI, 1.18-6.27; P = .02) and percutaneous revascularization (OR, 1.63; 95% CI, 1.003-2.65; P = .048), and postoperative need for intra-aortic balloon pump (OR, 2.98; 95% CI, 1.46-6.09; P = .003) and extracorporeal membrane oxygenation (OR, 3.19; 95% CI, 1.30-7.38; P = .01) were independently associated with mortality.CONCLUSIONS AND RELEVANCE In this study, surgical repair of postinfarction VSR was associated with a high risk of early mortality; this risk has remained unchanged during the last 2 decades. Delayed surgery seemed associated with better survival. Age, preoperative cardiac arrest and percutaneous revascularization, and postoperative need for intra-aortic balloon pump and extracorporeal membrane oxygenation were independently associated with early mortality. Further prospective studies addressing preoperative and perioperative patient management are warranted to hopefully improve the currently suboptimal outcome