Severe Ischemic Events Research Articles

Advancing Human iPSC-Derived Cardiomyocyte Hypoxia Resistance for Cardiac Regenerative Therapies through a Systematic Assessment of In Vitro Conditioning.

Acute myocardial infarction (MI) is a sudden, severe cardiac ischemic event that results in the death of up to one billion cardiomyocytes (CMs) and subsequent decrease in cardiac function. Engineered cardiac tissues (ECTs) are a promising approach to deliver the necessary mass of CMs to remuscularize the heart. However, the hypoxic environment of the heart post-MI presents a critical challenge for CM engraftment. Here, we present a high-throughput, systematic study targeting several physiological features of human induced pluripotent stem cell-derived CMs (hiPSC-CMs), including metabolism, Wnt signaling, substrate, heat shock, apoptosis, and mitochondrial stabilization, to assess their efficacy in promoting ischemia resistance in hiPSC-CMs. The results of 2D experiments identify hypoxia preconditioning (HPC) and metabolic conditioning as having a significant influence on hiPSC-CM function in normoxia and hypoxia. Within 3D engineered cardiac tissues (ECTs), metabolic conditioning with maturation media (MM), featuring high fatty acid and calcium concentration, results in a 1.5-fold increase in active stress generation as compared to RPMI/B27 control ECTs in normoxic conditions. Yet, this functional improvement is lost after hypoxia treatment. Interestingly, HPC can partially rescue the function of MM-treated ECTs after hypoxia. Our systematic and iterative approach provides a strong foundation for assessing and leveraging in vitro culture conditions to enhance the hypoxia resistance, and thus the successful clinical translation, of hiPSC-CMs in cardiac regenerative therapies.

Platelet inhibitor withdrawal and outcomes after coronary artery surgery: an individual patient data meta-analysis.

To evaluate the association between guideline-conforming as compared to shorter than recommended withdrawal period of P2Y12 receptor inhibitors prior to isolated on-pump coronary artery bypass grafting (CABG) and the incidence of severe bleeding and ischaemic events. Randomized controlled trials are lacking in this field. We searched PUBMED, Embase and other suitable databases for studies including patients on P2Y12 receptor inhibitors undergoing isolated CABG and reporting bleeding and postoperative ischaemic events from 2013 to March 2024. The primary outcome was incidence of Bleeding Academic Research Consortium type 4 (BARC-4) bleeding defined as any of the following: perioperative intracranial bleeding, reoperation for bleeding, transfusion of ≥5 units of red blood cells, chest tube output of ≥2 l. The secondary outcome was postoperative ischaemic events according to the Academic Research Consortium 2 Consensus Document. Patient-level data provided by each observational trial were synthesized into a single dataset and analysed using a 2-stage IPD-MA. Individual data of 4837 patients from 7 observational studies were synthesized. BARC-4 bleeding, 30-day mortality and postoperative ischaemic events occurred in 20%, 2.6% and 5.2% of patients. After adjusting for EuroSCORE II and cardiopulmonary bypass time, guideline-conforming withdrawal was associated with decreased BARC-4 bleeding risk in patients on clopidogrel [adjusted odds ratio (OR) 0.48; 95% confidence intervals (CI) 0.28-0.81; P = 0.006] and a trend towards decreased risk in patients on ticagrelor (adjusted OR 0.48; 95% CI 0.22-1.05; P = 0.067). Guideline-conforming withdrawal was not significantly associated with 30-day mortality risk (clopidogrel: adjusted OR 0.70; 95% CI 0.30-1.61; ticagrelor: adjusted OR 0.89; 95% CI 0.37-2.18) but with decreased risk of postoperative ischaemic events in patients on clopidogrel (clopidogrel: adjusted OR 0.50; 95% CI 0.30-0.82; ticagrelor: adjusted OR 0.78; 95% CI 0.45-1.37). BARC-4 bleeding was associated with 30-day mortality risk (adjusted OR 4.76; 95% CI 2.67-8.47; P < 0.001). Guideline-conforming preoperative withdrawal of ticagrelor and clopidogrel was associated with a 50% reduced BARC-4 bleeding risk when corrected for EuroSCORE II and cardiopulmonary bypass time but was not associated with increased risk of 30-day mortality or postoperative ischaemic events.

Deciphering smooth muscle cell heterogeneity in atherosclerotic plaques and constructing model: a multi-omics approach with focus on KLF15/IGFBP4 axis

BackgroundRuptured atherosclerotic plaques often precipitate severe ischemic events, such as stroke and myocardial infarction. Unraveling the intricate molecular mechanisms governing vascular smooth muscle cell (VSMC) behavior in plaque stabilization remains a formidable challenge.MethodsIn this study, we leveraged single-cell and transcriptomic datasets from atherosclerotic plaques retrieved from the gene expression omnibus (GEO) database. Employing a combination of single-cell population differential analysis, weighted gene co-expression network analysis (WGCNA), and transcriptome differential analysis techniques, we identified specific genes steering the transformation of VSMCs in atherosclerotic plaques. Diagnostic models were developed and validated through gene intersection, utilizing the least absolute shrinkage and selection operator (LASSO) and random forest (RF) methods. Nomograms for plaque assessment were constructed. Tissue localization and expression validation were performed on specimens from animal models, utilizing immunofluorescence co-localization, western blot, and reverse-transcription quantitative-polymerase chain reaction (RT-qPCR). Various online databases were harnessed to predict transcription factors (TFs) and their interacting compounds, with determination of the cell-specific localization of TF expression using single-cell data.ResultsFollowing rigorous quality control procedures, we obtained a total of 40,953 cells, with 6,261 representing VSMCs. The VSMC population was subsequently clustered into 5 distinct subpopulations. Analyzing inter-subpopulation cellular communication, we focused on the SMC2 and SMC5 subpopulations. Single-cell subpopulation and WGCNA analyses revealed significant module enrichments, notably in collagen-containing extracellular matrix and cell-substrate junctions. Insulin-like growth factor binding protein 4 (IGFBP4), apolipoprotein E (APOE), and cathepsin C (CTSC) were identified as potential diagnostic markers for early and advanced plaques. Notably, gene expression pattern analysis suggested that IGFBP4 might serve as a protective gene, a hypothesis validated through tissue localization and expression analysis. Finally, we predicted TFs capable of binding to IGFBP4, with Krüppel-like family 15 (KLF15) emerging as a prominent candidate showing relative specificity within smooth muscle cells. Predictions about compounds associated with affecting KLF15 expression were also made.ConclusionOur study established a plaque diagnostic and assessment model and analyzed the molecular interaction mechanisms of smooth muscle cells within plaques. Further analysis revealed that the transcription factor KLF15 may regulate the biological behaviors of smooth muscle cells through the KLF15/IGFBP4 axis, thereby influencing the stability of advanced plaques via modulation of the PI3K-AKT signaling pathway. This could potentially serve as a target for plaque stability assessment and therapy, thus driving advancements in the management and treatment of atherosclerotic plaques.

Serial daily lactate levels association with 30-day outcome in cardiogenic shock patients treated with VA-ECMO: a post-hoc analysis of the HYPO-ECMO study

BackgroundReliable predictors of outcomes in venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy are limited. While elevated lactate levels over time have been linked to outcomes in cardiogenic shock (CS), their significance in VA-ECMO-treated patients remains inconclusive.MethodsWe conducted a post hoc analysis of data from the HYPO-ECMO trial, which compared normothermia to moderate hypothermia in CS patients supported by VA-ECMO. We examined daily lactate levels collected over a week to assess their correlation with 30-day mortality.ResultsAmong the 318 out of 334 patients (95%) with baseline lactate measurements, 66 had normal levels (< 2.2 mmol/l, 21%). No difference was found in lactate course between moderate hypothermia and normothermia groups. Lactate levels were consistently higher in non-survivors at each time point (p = 0.0002). Baseline hyperlactatemia was associated with an increased risk of death (Hazard Ratio [HR]: 1.85 (1.12–3.05), p = 0.016). When considering all time points, lactate levels during the ICU stay were significantly and gradually associated with a higher risk of death (p < 0.0001). In the overall population, a decrease in lactate levels was not linked to 30-day mortality. However, patients with baseline hyperlactatemia exhibited a more significant decrease in lactate levels from day one to seven (p < 0.0001). In this group, survivors had a significantly greater decrease in lactate levels at day 1 compared to non-survivors (63% (48–77) versus 57% (21–75), p = 0.026). Patients experiencing a secondary increase in lactate (24%) had a worse prognosis (Hazard Ratio: 1.78 (1.21–2.61), p = 0.004), regardless of both baseline lactate levels and the occurrence of severe ischemic adverse events (intestinal and/or limb ischemia).ConclusionsThe consistent and significant association between lactate levels, whether assessed at baseline or during ICU treatment, and the risk of mortality underscores the pivotal prognostic relevance of lactate levels in patients with CS undergoing VA-ECMO therapy. The study findings provide some novel insights, regarding the trend profile and the relevance of a second peak during the 7 day period after ECMO start.Trial Registration identifier NCT02754193 registered on 2016–04–12.

Unique quinoline orientations shape the modified aptamer to sclerostin for enhanced binding affinity and bone anabolic potential

Osteogenesis imperfecta is a rare genetic disease characterized by bone fragility and bone formation. Sclerostin could negatively regulate bone formation by antagonizing Wnt signal pathway, whereas impose severe cardiac ischemic events in clinic. Our team has screened an aptamer, which could promote bone anabolic potential without cardiovascular risk. However, the affinity of the aptamer is lower and needs to be improved. In the study, hydrophobic quinoline molecule with unique orientations (7 subtypes) were incorporated into key sites of a bone anabolic aptamer against sclerostin to form a modified aptamer library. Among all the quinoline modifications, 5-quinoline modification could shape the molecular recognition of modified aptamers to sclerostin to facilitate enhancing its binding to sclerostin towards the highest affinity by interacting with newly participated binding sites in sclerostin. Further, 5-quinoline modification could facilitate the modified aptamer attenuating the suppressed effect of the transfected sclerostin on both Wnt signaling and bone formation marker expression levels in vitro, promoting bone anabolism in osteogenesis imperfecta mice (Col1a2+/G610C). The proposed quinoline-oriented modification strategy could shape the molecular recognition of modified aptamers to proteins to facilitate enhancing its binding affinity and therapeutic potency.

Remote Ischemia Postconditioning Mitigates Hippocampal Neuron Impairment by Modulating Cav1.2-CaMKIIα-Aromatase Signaling After Global Cerebral Ischemia in Ovariectomized Rats

Brain-derived estrogen (BDE2) is gaining attention as an endogenous neurotransmitter. Recent research has revealed that selectively removing the aromatase gene, the pivotal enzyme responsible for BDE2 synthesis, in forebrain neurons or astrocytes can lead to synaptic loss and cognitive impairment. It is worth noting that remote ischemia post-conditioning (RIP), a non-invasive technique, has been shown to activate natural protective mechanisms against severe ischemic events. The aim of our study was to investigate whether RIP triggers aromatase-BDE2 signaling, shedding light on its neuroprotective mechanisms after global cerebral ischemia (GCI) in ovariectomized rats. Our findings are as follows: (1) RIP was effective in mitigating ischemic damage in hippocampal CA1 neurons and improved cognitive function after GCI. This was partially due to increased Aro-BDE2 signaling in CA1 neurons. (2) RIP intervention efficiently enhanced pro-survival kinase pathways, such as AKT, ERK1/2, CREB, and suppressed CaMKIIα signaling in CA1 astrocytes induced by GCI. Remarkably, inhibiting CaMKIIα activity led to elevated Aro-BDE2 levels and replicated the benefits of RIP. (3) We also identified the positive mediation of Cav1.2, an LVGCC calcium channel, on CaMKIIα-Aro/BDE2 pathway response to RIP intervention. (4) Significantly, either RIP or CaMKIIα inhibition was found to alleviate reactive astrogliosis, which was accompanied by increased pro-survival A2-astrocyte protein S100A10 and decreased pro-death A1-astrocyte marker C3 levels. In summary, our study provides compelling evidence that Aro-BDE2 signaling is a critical target for the reparative effects of RIP following ischemic insult. This effect may be mediated through the CaV1.2-CaMKIIα signaling pathway, in collaboration with astrocyte-neuron interactions, thereby maintaining calcium homeostasis in the neuronal microenvironment and reducing neuronal damage after ischemia.

In-hospital outcomes after acute myocardial infarction with obstructive coronary artery disease in critically ill patients hospitalized for non-cardiac disease

BackgroundAcute myocardial infarction (AMI) is one of the major cardiac complications in patients hospitalized in the intensive care unit (ICU) for non-cardiac disease. A better knowledge of ischemic and bleeding risks in these patients is needed to identify those most likely to benefit from specific cardiac management. We therefore assessed the incidence and predictors of a composite outcome of severe ischemic event (AMI recurrence, ischemic stroke), major bleeding, or all-cause death in this setting.MethodsIn this multicenter retrospective study, all consecutive adult patients admitted for non-cardiac disease to four French university hospital ICUs between January 2012 and December 2018 who had an AMI with obstructive coronary artery disease (OCAD) during the ICU stay were considered for inclusion. AMI with OCAD was defined as an elevated cardiac troponin value associated with at least one sign (clinical, electrocardiographic, or echocardiographic) suggestive of myocardial ischemia and presence of OCAD on coronary angiography. The primary endpoint was in-hospital occurrence of the composite outcome.ResultsNinety-six patients [median age 69 years, 22 women (23%), 59 with sepsis (61%), 35 with ST elevation (37%), median sequential organ failure assessment (SOFA) of 8 on the day of AMI] were included. The median peak cardiac troponin value was 131 (IQR 44–303) times the upper reference limit. Dual antiplatelet, therapeutic anticoagulation, and early mechanical reperfusion therapies were administered in 61 (64%), 68 (71%), and 47 (49%) patients, respectively. The composite outcome occurred in 48 (50%) patients. Severe ischemic events occurred in 17 (18%) patients and major bleeding in 26 (27%) patients; 26 patients (27%) died in the hospital. AMI management was not significantly different in patients with and without the composite outcome. A history of arterial hypertension (HR 2.05, 95% CI 1.01–4.16) and high SOFA score at the time of AMI (HR 1.07, 95% CI 1.00–1.15) were independent risk factors for the composite outcome.ConclusionsPatients who have an AMI with OCAD during an ICU stay for non-cardiac disease are at risk of a composite outcome of severe ischemia, major bleeding, and death. A history of arterial hypertension and high SOFA scores were independent hazards for poor prognosis.Graphical

Associations of microcirculation damage on nailfold capillaroscopy with supra-aortic severe ischemic events in patients with Takayasu arteritis.

To evaluate the clinical characteristics and nailfold microcirculation and explore the associations with severe ischemic events (SIEs) in Takayasu arteritis (TA) with supra-aortic involvement. Eighty-one patients with supra-aortic artery involvement who underwent nailfold video-capillaroscopy (NVC) of their hands were enrolled from the East China TA (ECTA) cohort between August and December 2021. Clinical features and capillaroscopy variables associated with supra-aortic SIEs were analyzed by multivariate logistic regression. Overall, 71 patients were female, and 42 experienced supra-aortic SIEs, among whom there was a higher prevalence of hypertension and the number of supra-aortic artery stenosis (P = 0.005, and 0.003, respectively). Furthermore, intergroup differences in capillary density (P < 0.001) and minor morphology abnormalities (P < 0.001) were significant. After adjustment for all confounders, multivariate logistic regression revealed hypertension (odds ratio [OR]: 7.3, 95% confidence interval [CI]: 1.6-33.7, P = 0.011), the number of supra-aortic arteries stenosis (≥4, OR: 6.8, 95% CI: 1.4-34.6, P = 0.020), capillary density (≤7.2/mm, OR: 43.0, 95% CI: 7.0-264.6, P < 0.001) and minor abnormalities (OR: 34.2, 95% CI: 3.6-325.1; P = 0.002) were independent risk factors for supra-aortic SIEs. capillary density (≤7.2/mm) and minor abnormalities or combined with at least two of the three items in the matrix model showed the probability of supra-aortic SIEs was 61.2-87.6%. Decreased capillary density and morphologic abnormalities indicated that hypoperfusion was more likely to be observed in supra-aortic SIEs patients. Combined NVC indicators could be instrumental for early identification of supra-aortic SIEs. Key Points • Minor morphological abnormalities and hemorrhages were only observed in supra-aortic SIEs patients. • Capillaroscopic density and minor morphological abnormalities or combined with at least two of the three items in the matrix model showed the probability occurrence of supra-aortic SIEs was 61.2-87.6%.

CT-IGFBP-4 as a Predictive Novel Biomarker of Ischemic Cardiovascular Events and Mortality: A Systematic Review.

Methods The electronic databases PubMed, medRxiv, ScienceDirect, and Google Scholar were searched for relevant literature from inception to the 10th of December, 2021. Thus, retrieved literature was screened by title and abstract, followed by full-text screening based on the eligibility criteria. The risk of bias was accessed using the quality in prognostic studies (QUIPSs) tool. The data on cardiovascular outcomes about CT-IGFBP-4 levels were studied and the results were synthesized. Results Five studies with a total of 1,417 participants were included in our study. The studies reported a low risk of bias. The mean age of the participants was 66.14 and more than 65% were males. Elevated CT-IGFBP-4 levels were associated with poor cardiovascular outcomes and increased mortality in severely ill patients. In contrast, there were no significant findings in the case of stable patients. Sandwich ELISA using lithium-heparin plasma provided a better detection limit of 0.15 ng/ml, low cross-reactivity (<2%), and generated linear results between 12 and 500 ng/ml. Conclusion CT-IGFBP-4 is an efficient biomarker for the prediction of MACE and mortality in patients with severe ischemic cardiovascular events.

Prognostic performance of GRACE and TIMI risk scores in critically ill patients with sepsis and a concomitant myocardial infarction

Identifying which patients with acute myocardial infarction (AMI) during sepsis are at risk of poor outcome is a clinical challenge. To evaluate Global Registry of Acute Coronary Events (GRACE) and Thrombolysis In Myocardial Infarction (TIMI) risk scores to predict in-hospital mortality and severe ischaemic events in this setting. In this single-centre retrospective study conducted from 2012 to 2016, all consecutive adults hospitalized in the intensive care unit for sepsis who had a concomitant AMI (within 72hours of admission) were enrolled. AMI was defined by an elevated cardiac troponin I value associated with at least one sign (clinical, electrocardiographic or echocardiographic) suggestive of myocardial ischaemia. The primary outcome was in-hospital mortality from any cause. Secondary outcomes were in-hospital occurrence of severe ischaemic events (cardiac arrest with resuscitation, ischaemic stroke and myocardial reinfarction) and major bleeding events. Among 856 patients hospitalized for sepsis, 120 (14.5%) had a concomitant AMI (37.5% women; median age 65 years; median Sequential Organ Failure Assessment [SOFA] score 8). Severe ischaemic events occurred in 15 patients (12.5%), and 39 (33%) died in hospital. Neither the GRACE score (median 192, interquartile range 154-223) nor the TIMI score (median 3, interquartile range 2-4) was associated with occurrence of severe ischaemic events. Only the GRACE score was associated with in-hospital mortality (odds ratio 1.01, 95% confidence interval 1.00-1.02 per 1 point increase). Multivariable analysis identified previous aspirin use and SOFA score as independent factors associated with in-hospital mortality. GRACE and TIMI scores did not predict in-hospital severe ischaemic events and mortality in patients with AMI during sepsis. Among individual components of both scores, previous aspirin use was associated with poor prognosis. However, because of lack of statistical power, we cannot formally rule out the usefulness of these scores in this setting.

Carotid Intima-media Thickness/Diameter Ratio and Peak Systolic Velocity as Risk Factors for Neurological Severe Ischemic Events in Takayasu Arteritis

To characterize Takayasu arteritis (TA) with supra-aortic involvement and determine the associations between clinical features, carotid ultrasonographic (US) variables, and neurological severe ischemic events (SIEs). Patients with supra-aortic involvement including brachiocephalic trunk, bilateral common carotid artery and internal carotid artery, and bilateral subclavian and vertebral artery and baseline carotid US examination were enrolled from the East China TA cohort. Bilateral carotid diameter, intima-media thickness (IMT), and peak systolic velocity (PSV) were measured by US. Then, the IMT/diameter ratio (IDR) was calculated. Risk factors associated with neurological SIEs were analyzed by multivariate logistic regression. In total, 295 patients were included, of whom 260 (88.14%) were female, and 93 (31.53%) experienced neurological SIEs. Involved supra-aortic artery distribution (P = 0.04) and number (P < 0.01) differed between subjects with neurologic and nonneurologic SIEs, showing higher prevalence of common carotid and vertebral artery involvement after Bonferroni correction and 56.99% patients having ≥ 4 involved arteries in the neurological SIE group. The bilateral IDR (P < 0.01) differed between patients with and without neurological SIEs. The carotid IDR (left: cut-off value ≥ 0.55, OR 2.75, 95% CI 1.24-6.07, P = 0.01; right: ≥ 0.58, OR 2.70, 95% CI 1.21-6.02, P = 0.01) and left carotid PSV (≤ 76.00 cm/s, OR 3.09, 95% CI 1.53-6.27, P < 0.01), as well as involved supra-aortic artery number (≥ 4, OR 2.33, 95% CI 1.15-4.72, P = 0.02) were independently associated with neurological SIEs. The carotid IDR and PSV might be performed as valuable markers for recognizing neurological SIEs in patients with TA with supra-aortic lesions.

Bullous skin lesions in cirrhotic patients receiving combination of terlipressin and noradrenaline: a case series

Background and Aim: Effect of terlipressin on systemic circulation causing severe ischemic events like myocardial ischemia, ischemic colitis and skin necrosis are rare. We present a case series of four patients, who developed blistering skin disease after administration of combination of Terlipressin and noraenalin both. We aimed to look for risk factors, onset, progress and outcome of bullous skin lesions in cirrhotic patients receiving combination of Terlipressin and Noradrenaline. Methods: We have included patients of liver cirrhosis who were started on Terlipressin for hepato-renal syndrome or variceal bleeding with Noradrenaline for shock and developed skin blisters. Results: Series includes four middle aged male patients of cirrhosis of liver with three patients had alcohol and one patient had NASH as etiology. Three patients had septic shock with HRS, while one had massive variceal bleed with hypotension. All four developed blistering within 2-4 days of starting vasopressors. Terlipressin was given in intravenous bolus doses (1 mg thrice to four times a day) while noradrenaline was given as infusion. Blisters were common in extremities, were extensive, and one even progressed to ischemic necrosis of skin. Blistering was more extensive with higher doses of terlipressin and noradrenaline. Sepsis as etiology for blisters was excluded in all by testing the fluid within the bullous lesion and negative blood cultures. Terlipressin was stopped in all, after which eruption of new lesions halted and skin lesions healed completely. Conclusions: Risk of bullous skin lesion increases when terlipressin is given as bolus doses as compared to infusion , when used in higher doses and in combination with noraenalin. In addition to the obesity, NAFLD, and ischemic heart disease, it was important to think that alcohol use was a possible risk factor for progressive ischemic necrosis due to terlipressin. Majority of patient’s skin lesions recovers after stopping terlipressin.

Therapeutic aptamer targeting sclerostin loop3 for promoting bone formation without increasing cardiovascular risk in osteogenesis imperfecta mice.

Rationale: Sclerostin inhibition demonstrated bone anabolic potential in osteogenesis imperfecta (OI) mice, whereas humanized therapeutic sclerostin antibody romosozumab for postmenopausal osteoporosis imposed clinically severe cardiac ischemic events. Therefore, it is desirable to develop the next generation sclerostin inhibitors to promote bone formation without increasing cardiovascular risk for OI.Methods and Results: Our data showed that sclerostin suppressed inflammatory responses, prevented aortic aneurysm (AA) and atherosclerosis progression in hSOSTki.Col1a2+/G610C.ApoE-/- mice. Either loop2&3 deficiency or inhibition attenuated sclerostin's suppressive effects on expression of inflammatory cytokines and chemokines in vitro, whilst loop3 deficiency maintained the protective effect of sclerostin on cardiovascular system both in vitro and in vivo. Moreover, loop3 was critical for sclerostin's antagonistic effect on bone formation in Col1a2+/G610C mice. Accordingly, a sclerostin loop3-specific aptamer aptscl56 was identified by our lab. It could recognize both recombinant sclerostin and sclerostin in the serum of OI patients via targeting loop3. PEG40k conjugated aptscl56 (Apc001PE) demonstrated to promote bone formation, increase bone mass and improve bone microarchitecture integrity in Col1a2+/G610C mice via targeting loop3, while did not show influence in inflammatory response, AA and atherosclerosis progression in Col1a2+/G610C.ApoE-/- mice with Angiotensin II infusion. Further, Apc001PE had no influence in the protective effect of sclerostin on cardiovascular system in hSOSTki.Col1a2+/G610C.ApoE-/- mice, while it inhibited the antagonistic effect of sclerostin on bone formation in hSOSTki.Col1a2+/G610C mice via targeting loop3. Apc001PE was non-toxic to healthy rodents, even at ultrahigh dose. Apc001PE for OI was granted orphan drug designation by US-FDA in 2019 (DRU-2019-6966).Conclusion: Sclerostin loop3-specific aptamer Apc001PE promoted bone formation without increasing cardiovascular risk in OI mice.

Outcomes After Transcatheter Aortic Valve Replacement in Bicuspid Versus Tricuspid Anatomy: A Systematic Review and Meta-Analysis.

The aim of this study was to compare the feasibility, safety, and clinical outcomes of transcatheter aortic valve replacement (TAVR) in bicuspid aortic valve (BAV) versus tricuspid aortic valve (TAV) stenosis. At present, limited observational data exist supporting TAVR in the context of bicuspid anatomy. Primary endpoints were 1-year survival and device success. Secondary endpoints included moderate to severe paravalvular leak (PVL) and a composite endpoint of periprocedural complications; incidence rates of individual procedural endpoints were also explored individually. In the main analysis, 17 studies and 181,433 patients undergoing TAVR were included, of whom 6,669 (0.27%) had BAV. A secondary analysis of 7,071 matched subjects with similar baseline characteristics was also performed. Device success and 1-year survival rates were similar between subjects with BAV and those with TAV (97% vs 94% [P=0.55] and 91.3% vs 90.8% [P=0.22], respectively). In patients with BAV, a trend toward a higher risk for periprocedural complications was observed in our main analysis (risk ratio [RR]: 1.12; 95% CI: 0.99-1.27; P=0.07) but not in the matched population secondary analysis (RR: 1.00; 95%CI: 0.81-1.24; P=0.99). The risk for moderate to severe PVL was higher in subjects with BAV (RR: 1.42; 95%CI: 1.29-1.58; P< 0.0001) as well as the incidence of cerebral ischemic events (2.4% vs 1.6%; P=0.015) and of annular rupture (0.3% vs 0.02%; P=0.014) in matched subjects. TAVR is a feasible option among selected patients with BAV anatomy, but the higher rates of moderate to severe PVL, annular rupture, and cerebral ischemic events observed in the BAV group warrant caution and further evidence.

Oxygenation targets in ICU patients with COVID-19: A post hoc subgroup analysis of the HOT-ICU trial.

BackgroundSupplemental oxygen is the key intervention for severe and critical COVID‐19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage.MethodsIn spring 2020, 110 COVID‐19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT‐ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID‐19 patients.ResultsAt 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58–1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end‐expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT‐ICU population were insignificant.ConclusionsTargeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID‐19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT‐ICU trial.Trial registration number: ClinicalTrials.gov number, NCT03174002.Date of registration: June 2, 2017.

Characteristics of Takayasu Arteritis Patients with Severe Ischemic Events.

Takayasu arteritis (TA) is a rare large-vessel vasculitis that puts patients at high risk of developing severe ischemic events (SIE). Outcomes for TA patients with SIE are poorly understood. We aim to describe the characteristics of TA patients experiencing SIE. All TA patients with at least 1 followup visit seen between 1988 and 2015 were included from 3 academic centers in Ontario, Canada. Diagnosis was based on American College of Rheumatology criteria, physician opinion, and vascular imaging. SIE were defined as cerebrovascular accident (CVA), acute coronary syndrome (ACS), ischemic cardiomyopathy, ischemic blindness, and/or ischemic bowel or limb requiring surgery. Of the 52 patients with TA included in the study, 51 (98%) were female and 22 (42%) were of European descent. The mean age was 31 (SD 12) at the time of diagnosis and the followup time was 6 years (SD 5). Fifteen (29%) experienced an SIE: 5 CVA, 5 ACS, 1 ischemic cardiomyopathy, and 4 limb ischemia. Thirteen out of 15 SIE (87%) occurred at or before diagnosis. Patients with SIE were more likely than those without SIE to be started on corticosteroids combined with immunosuppressants (p = 0.04) and antiplatelet agents (p = 0.004). Outcomes including disease activity and damage scores were similar between patients with and without SIE. SIE are common in patients with TA and occur early in the disease. With aggressive treatment, patients with SIE had a favorable prognosis.

A modeling and machine learning approach to ECG feature engineering for the detection of ischemia using pseudo-ECG.

Early detection of coronary heart disease (CHD) has the potential to prevent the millions of deaths that this disease causes worldwide every year. However, there exist few automatic methods to detect CHD at an early stage. A challenge in the development of these methods is the absence of relevant datasets for their training and validation. Here, the ten Tusscher-Panfilov 2006 model and the O’Hara-Rudy model for human myocytes were used to create two populations of models that were in concordance with data obtained from healthy individuals (control populations) and included inter-subject variability. The effects of ischemia were subsequently included in the control populations to simulate the effects of mild and severe ischemic events on single cells, full ischemic cables of cells and cables of cells with various sizes of ischemic regions. Action potential and pseudo-ECG biomarkers were measured to assess how the evolution of ischemia could be quantified. Finally, two neural network classifiers were trained to identify the different degrees of ischemia using the pseudo-ECG biomarkers. The control populations showed action potential and pseudo-ECG biomarkers within the physiological ranges and the trends in the biomarkers commonly identified in ischemic patients were observed in the ischemic populations. On the one hand, inter-subject variability in the ischemic pseudo-ECGs precluded the detection and classification of early ischemic events using any single biomarker. On the other hand, the neural networks showed sensitivity and positive predictive value above 95%. Additionally, the neural networks revealed that the biomarkers that were relevant for the detection of ischemia were different from those relevant for its classification. This work showed that a computational approach could be used, when data is scarce, to validate proof-of-concept machine learning methods to detect ischemic events.

Time Course of Septic Shock in Immunocompromised and Nonimmunocompromised Patients.

To address the impact of underlying immune conditions on the course of septic shock with respect to both mortality and the development of acute infectious and noninfectious complications. An 8-year (2008-2015) monocenter retrospective study. A medical ICU in a tertiary care center. Patients diagnosed for septic shock within the first 48 hours of ICU admission were included. Patients were classified in four subgroups with respect to their immune status: nonimmunocompromised and immunocompromised distributed into hematologic or solid malignancies and nonmalignant immunosuppression. Outcomes were in-hospital death and the development of ischemic and hemorrhagic complications and ICU-acquired infections. The determinants of death and complications were addressed by multivariate competing risk analysis. None. Eight hundred one patients were included. Among them, 305 (38%) were immunocompromised, distributed into solid tumors (122), hematologic malignancies (106), and nonmalignant immunosuppression (77). The overall 3-day, in-ICU, and in-hospital mortality rates were 14.1%, 37.3%, and 41.3%, respectively. Patients with solid tumors displayed increased in-hospital mortality (cause-specific hazard, 2.20 [95% CI, 1.64-2.96]; p < 0.001). ICU-acquired infections occurred in 211 of the 3-day survivors (33%). In addition, 95 (11.8%) and 70 (8.7%) patients exhibited severe ischemic or hemorrhagic complications during the ICU stay. There was no association between the immune status and the occurrence of ICU-acquired infections. Nonmalignant immunosuppression and hematologic malignancies were independently associated with increased risks of severe ischemic events (cause-specific hazard, 2.12 [1.14-3.96]; p = 0.02) and hemorrhage (cause-specific hazard, 3.17 [1.41-7.13]; p = 0.005), respectively. The underlying immune status impacts on the course of septic shock and on the susceptibility to ICU-acquired complications. This emphasizes the complexity of sepsis syndromes in relation with comorbid conditions and raises the question of the relevant endpoints in clinical studies.

Ischemic complications in Takayasu’s arteritis: A meta-analysis

Takayasu's arteritis (TAK) is a rare vasculitis affecting the large blood vessels with significant morbidity and mortality from ischemic complications. The objective of this meta-analysis is to determine the proportion of TAK patients with severe ischemic complications. We performed a literature search using MEDLINE, EMBASE, and the Cochrane library from database inception to March 2016. We included articles that reported at least one severe ischemic complication. A random effects model with inverse-variance weighting was performed to estimate the pooled proportion of TAK subjects with ischemic complications. In all, 35 studies met inclusion criteria, representing 3262 TAK patients. All studies were observational and of low to moderate quality. Mean age at symptom onset or at diagnosis ranged from 10 to 49 years and mean delay from symptom onset to diagnosis ranged from 2 months to 7.6 years. Study follow-up times were from 22 months to 17 years. The majority of studies had >70% female subjects. The pooled prevalence of stroke in TAK was 8.9% (95% CI: 7.0-10.9%) and of MI was 3.4% (95% CI: 2.1-4.8%) at any time during the disease course. There was moderate-to-severe heterogeneity across the studies (stroke: I2 = 64.9%; MI: I2 = 74.0%). Other ischemic complications were inconsistently reported. Stroke and MI are common in TAK patients. Further studies are needed to identify predictors and preventative measures for severe ischemic events in TAK patients.

Reduced Severity of Outcome of Recurrent Ipsilateral Transient Cerebral Ischemia Compared with Contralateral Transient Cerebral Ischemia in Rats

To investigate whether prior transient ischemic attack (TIA) had a preconditioning effect on subsequent cerebral infarction in a rat model using middle cerebral artery occlusion (MCAO). Thirty-six adult male Sprague-Dawley rats were divided into 3 groups: those with transient (5 minutes) left MCAO (left TIA) (n = 15), those with transient right MCAO (right TIA) (n = 15), and a sham operation group (n = 6). Seven days after the initial transient MCAO, rats in all groups underwent permanent left MCAO. After 24 hours, all rats underwent motor function measurement (the Garcia score and tilting plane test), magnetic resonance imaging, postmortem brain examination, and biomarkers of stroke. Following permanent MCAO, the Garcia score, the brain edema area of T2-weighted images, brain infarction volume, and the level of tumor necrosis factor α mRNA of the ipsilateral and contralateral TIA groups showed no significant difference. The angle of sliding off in the tilting plane test, the mean intensity of the brain edema area of T2-weighted images, levels of matrix metalloproteinase 9, interleukin-1β, inducible nitric oxide synthase mRNA, and apoptosis-related proteins, BAX, and phosphorylated-p38, were lower in the ipsilateral TIA group compared with the contralateral TIA group. The main finding of this study was that a transient, mild, unilateral focus of cerebral ischemia (or TIA) in either the left or right hemisphere, which is then followed by a second unilateral severe and focal ischemic event, results in brain injury. The severity of the brain injury following this second ischemic event will be alleviated when the second insult is ipsilateral to the first TIA.