Vitamin D deficiency among patients with pulmonary hypertension.

BACKGROUND: There is little information about vitamin D (Vit D) deficiency in patients with pulmonary hypertension (PH). The objective of this study was: 1) compare Vit D levels between patients with PH, left ventricular failure (LVF) and healthy subjects (HS); 2) correlate, in patients with PH, Vit D levels with prognosis-related variables, such as the 6-min walk test (6MWT). METHODS: Vitamin D levels were measured in a cross-sectional study in 126 patients from one of three groups: patients with PH (n = 53), patients with LVF (n = 42) and healthy subjects (n = 31). In all groups, 8-h fasting blood samples were obtained in the morning. In the PH and the LVF group, functional class (WHO criteria), metres covered in the 6MWT and echocardiographic parameters were analysed. In the PH group, plasma N terminal pro B type natriuretic peptide (NT-proBNP) level was analysed and a complete haemodynamic evaluation by right heart catheterisation was made. RESULTS: Mean Vit D levels were lower in PH than in both other groups (ng/ml, mean ± SD): PH 19.25 ± 10, LVF 25.68 ± 12, HS 28.8 ± 12 (PH vs LVF p = 0.017, PH vs HS p = 0.001 and HS vs LVF p = 0.46). Vit D deficiency prevalence was higher in PH as compared to the other groups (PH 53.8%, LVF 45.2%, HS 25%, p = 0.01). Patients with PH in functional class (FC; WHO criteria) III-IV had higher Vit D deficiency prevalence than those in FC I-II (86.7% vs 40.5%, p = 0.003). There was a significant linear correlation between the 6MWT and Vit D levels in PH (p < 0.01), but not in LVF (p = 0.69). CONCLUSIONS: Vit D levels were lower in patients with PH as compared to patients with LVF and HS and correlated directly with 6-min walk distance.

Galectin-1 as an Emerging Mediator of Cardiovascular Inflammation: Mechanisms and Therapeutic Opportunities.

Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, controls immune cell homeostasis and tempers acute and chronic inflammation by blunting proinflammatory cytokine synthesis, engaging T-cell apoptotic programs, promoting expansion of T regulatory (Treg) cells, and deactivating antigen-presenting cells. In addition, this lectin promotes angiogenesis by co-opting the vascular endothelial growth factor receptor (VEGFR) 2 signaling pathway. Since a coordinated network of immunomodulatory and proangiogenic mediators controls cardiac homeostasis, this lectin has been proposed to play a key hierarchical role in cardiac pathophysiology via glycan-dependent regulation of inflammatory responses. Here, we discuss the emerging roles of Gal-1 in cardiovascular diseases including acute myocardial infarction, heart failure, Chagas cardiomyopathy, pulmonary hypertension, and ischemic stroke, highlighting underlying anti-inflammatory mechanisms and therapeutic opportunities. Whereas Gal-1 administration emerges as a potential novel treatment option in acute myocardial infarction and ischemic stroke, Gal-1 blockade may contribute to attenuate pulmonary arterial hypertension.

Should endovascular approach be the first line of treatment for retroperitoneal bleeding with hemodynamic shock following percutaneous intervention? A case series.

OBJECTIVES: To report a series of consecutive patients that developed retroperitoneal hemorrhage (RPH) and persistent hypotension treated with endovascular approach. BACKGROUND: RPH is a rare complication of percutaneous cardiovascular interventions associated with high morbidity and mortality. The standard approach to treat this complication has been a conservative management for stable patients, and urgent vascular surgery for those with persistent hypovolemic shock. Percutaneous endovascular treatment has evolved as an alternative treatment option. METHODS: We implemented a management algorithm for patients with suspected RPH and persistent hypotension which embraced systematic use of emergency endovascular evaluation and treatment following clinical assessment without the use of non-invasive diagnostic testing. We report a series of 8 consecutive patients that developed RPH with persistent hypotension. RESULTS: Successful percutaneous treatment was achieved in all cases with the use of a covered stent. No patient required vascular surgery. The average blood transfusion was 3.4 ± 2.7 units per patient. There were no deaths; one patient experienced acute stent thrombosis that was successfully treated via endovascular approach. At 1-year follow-up, no further events were reported. CONCLUSION: The incorporation of a standardized protocol using only clinical evaluation followed by emergency percutaneous approach without delays attributed to non-invasive diagnostic work-up showed to be feasible and associated with favorable outcomes. © 2016 Wiley Periodicals, Inc.

Interleukin-18 mediates interleukin-1-induced cardiac dysfunction.

Patients with heart failure (HF) have enhanced systemic IL-1 activity, and, in the experimental mouse model, IL-1 induces left ventricular (LV) systolic dysfunction. Whether the effects of IL-1 are direct or mediated by an inducible cytokine, such as IL-18, is unknown. Recombinant human IL-18-binding protein (IL-18BP) or an IL-18-blocking antibody (IL-18AB) was used to neutralize endogenous IL-18 after challenge with the plasma of patients with HF or with recombinant murine IL-1ß in adult male mice. Plasma levels of IL-18 and IL-6 (a key mediator of IL-1-induced systemic effects) and LV fractional shortening were measured in mice sedated with pentobarbital sodium (30-50 mg/kg). Mice with genetic deletion of IL-18 or IL-18 receptors were compared with matching wild-type mice. A group of mice received murine IL-18 to evaluate the effects on LV fractional shortening. Plasma from HF patients and IL-1ß induced LV systolic dysfunction that was prevented by pretreatment with IL-18AB or IL-18BP. IL-1ß failed to induce LV systolic dysfunction in mice with genetic deletion of IL-18 signaling. IL-1ß induced a significant increase in plasma IL-18 and IL-6 levels. Genetic or pharmacological inhibition of IL-18 signaling failed to block the induction of IL-6 by IL-1ß. In conclusion, IL-1 induces a release of active IL-18 in the mouse that mediates the LV systolic dysfunction but not the induction of IL-6. IL-18 blockade may therefore represent a novel and more targeted therapeutic approach to treat HF.

Galectin-1 controls cardiac inflammation and ventricular remodeling during acute myocardial infarction.

Galectin-1 (Gal-1), an evolutionarily conserved ß-galactoside-binding lectin, plays essential roles in the control of inflammation and neovascularization. Although identified as a major component of the contractile apparatus of cardiomyocytes, the potential role of Gal-1 in modulating heart pathophysiology is uncertain. Here, we aimed to characterize Gal-1 expression and function in the infarcted heart. Expression of Gal-1 was substantially increased in the mouse heart 7 days after acute myocardial infarction (AMI) and in hearts from patients with end-stage chronic heart failure. This lectin was localized mainly in cardiomyocytes and inflammatory infiltrates in peri-infarct areas, but not in remote areas. Both simulated hypoxia and proinflammatory cytokines selectively up-regulated Gal-1 expression in mouse cardiomyocytes, whereas anti-inflammatory cytokines inhibited expression of this lectin or had no considerable effect. Compared with their wild-type counterpart, Gal-1-deficient (Lgals1(-/-)) mice showed enhanced cardiac inflammation, characterized by increased numbers of macrophages, natural killer cells, and total T cells, but reduced frequency of regulatory T cells, leading to impaired cardiac function at baseline and impaired ventricular remodeling 7 days after nonreperfused AMI. Treatment of mice with recombinant Gal-1 attenuated cardiac damage in reperfused AMI. Taken together, our results indicate a protective role for Gal-1 in normal cardiac homeostasis and postinfarction remodeling by preventing cardiac inflammation. Thus, Gal-1 treatment represents a potential novel strategy to attenuate heart failure in AMI.

The inflammasome promotes adverse cardiac remodeling following acute myocardial infarction in the mouse.

Acute myocardial infarction (AMI) initiates an intense inflammatory response that promotes cardiac dysfunction, cell death, and ventricular remodeling. The molecular events underlying this inflammatory response, however, are incompletely understood. In experimental models of sterile inflammation, ATP released from dying cells triggers, through activation of the purinergic P2X7 receptor, the formation of the inflammasome, a multiprotein complex necessary for caspase-1 activation and amplification of the inflammatory response. Here we describe the presence of the inflammasome in the heart in an experimental mouse model of AMI as evidenced by increased caspase-1 activity and cytoplasmic aggregates of the three components of the inflammasome--apoptosis speck-like protein containing a caspase-recruitment domain (ASC), cryopyrin, and caspase-1, localized to the granulation tissue and cardiomyocytes bordering the infarct. Cultured adult murine cardiomyocytes also showed the inducible formation of the inflammasome associated with increased cell death. P2X7 and cryopyrin inhibition (using silencing RNA or a pharmacologic inhibitor) prevented the formation of the inflammasome and limited infarct size and cardiac enlargement after AMI. The formation of the inflammasome in the mouse heart during AMI causes additional loss of functional myocardium, leading to heart failure. Modulation of the inflammasome may therefore represent a unique therapeutic strategy to limit cell death and prevent heart failure after AMI.

Interleukin-1ß induces a reversible cardiomyopathy in the mouse.

BACKGROUND: Inflammatory mediators play a key role in the development and progression of heart failure. Interleukin-1ß (IL-1ß) is a prototypical inflammatory cytokine that suppresses myocyte contractility following acute administration. METHODS: Healthy mice were randomly assigned to daily intraperitoneal injections of recombinant murine IL-1ß (3 µg/kg in 0.2 ml) or matching volumes of NaCl 0.9 % solution (vehicle) for 15 days. Echocardiography was performed at baseline and 4 h (acute), followed by repeat measurements immediately prior to IL-1ß or saline injections on days 5, 10, and 15 (chronic). Final echocardiography was performed on day 20 (5 days after last treatment). A subgroup of animals underwent isoproterenol challenge to evaluate contractile reserve at baseline, 4 h (acute), 15 days (chronic) and 20 days (recovery). RESULTS: IL-1ß reduced left ventricular fractional shortening (LVFS) at 4 h versus vehicle (-24 vs. 0 %, respectively, P < 0.05). This reduction was maintained throughout chronic dosing at day 15. IL-1ß-treated mice also showed impaired contractile reserve with a right shift of the dose-response curve to isoproterenol (P < 0.05) at 4 h and 15 days. By day 20, 5 days after stopping IL-1ß, LVFS and contractile reserve had returned to baseline. CONCLUSIONS: IL-1ß induces a reversible contractile dysfunction associated with impaired response to ß-receptor stimulation.

Unraveling the role of galectin-3 in cardiac pathology and physiology.

Galectin-3 (Gal-3) is a carbohydrate-binding protein with multiple functions. Gal-3 regulates cell growth, proliferation, and apoptosis by orchestrating cell-cell and cell-matrix interactions. It is implicated in the development and progression of cardiovascular disease, and its expression is increased in patients with heart failure. In atherosclerosis, Gal-3 promotes monocyte recruitment to the arterial wall boosting inflammation and atheroma. In acute myocardial infarction (AMI), the expression of Gal-3 increases in infarcted and remote zones from the beginning of AMI, and plays a critical role in macrophage infiltration, differentiation to M1 phenotype, inflammation and interstitial fibrosis through collagen synthesis. Genetic deficiency of Gal-3 delays wound healing, impairs cardiac remodeling and function after AMI. On the contrary, Gal-3 deficiency shows opposite results with improved remodeling and function in other cardiomyopathies and in hypertension. Pharmacologic inhibition with non-selective inhibitors is also protective in cardiac disease. Finally, we recently showed that Gal-3 participates in normal aging. However, genetic absence of Gal-3 in aged mice exacerbates pathological hypertrophy and increases fibrosis, as opposed to reduced fibrosis shown in cardiac disease. Despite some gaps in understanding its precise mechanisms of action, Gal-3 represents a potential therapeutic target for the treatment of cardiovascular diseases and the management of cardiac aging. In this review, we summarize the current knowledge regarding the role of Gal-3 in the pathophysiology of heart failure, atherosclerosis, hypertension, myocarditis, and ischemic heart disease. Furthermore, we describe the physiological role of Gal-3 in cardiac aging.

An Experimental Model of Myocardial Infarction for Studying Cardiac Repair and Remodeling in Knockout Mice.

Cardiovascular disease is the most prevalent cause of death in Western countries, with acute myocardial infarction (MI) being the most prevalent form. This paper describes a protocol for studying the role of galectin 3 (Gal-3) in the temporal evolution of cardiac healing and remodeling in an experimental animal model of MI. The procedures described include an experimental model of MI with a permanent coronary ligature in male C57BL/6J (control) and Gal-3 knockout (KO) mice, an echocardiography procedure to study cardiac remodeling and systolic function in vivo, a histological evaluation of interstitial myocardial fibrosis with picrosirius red-stained and rhodamine-conjugated lectin-stained sections for studying myocyte hypertrophy by the cross-sectional area (MCSA), and the quantification of infarct size and cardiac remodeling (scar thinning, septum thickness, and expansion index) by planimetry in slices stained with Masson's trichrome and triphenyl tetrazolium chloride. Gal-3 KO mice with MI showed disrupted cardiac remodeling and an increase in the scar thinning ratio and the expansion index. At the onset of MI, myocardial function and cardiac remodeling were also severely affected. At 4 weeks post MI, the natural evolution of fibrosis in infarcted Gal-3 KO mice was also affected. In summary, the experimental model of MI is a suitable model for studying the temporal evolution of cardiac repair and remodeling in mice with the genetic deletion of Gal-3 and other animal models. The lack of Gal-3 affects the dynamics of cardiac repair and disrupts the evolution of cardiac remodeling and function after MI.

Iatrogenic coronary dissection: state of the art management.

Iatrogenic coronary artery dissections (ICAD) are rare but potentially devastating complications during coronary angiography and percutaneous coronary interventions (PCI). Intima media complex separation may be produced either by the catheter tip or during PCI. Patient characteristics and procedure related risk factors are intimately linked to catheter induced ICAD over diagnostic angiography. Moreover, the increasing complexity of patients undergoing PCI, which frequently involves treatment of heavily calcified or occluded vessels, has increased the likelihood of dissections during PCI. A prompt recognition, along with a prompt management (either percutaneous, surgical or even careful watching), are key in preventing catastrophic consequences of ICAD, such as left ventricular dysfunction, cardiogenic shock, periprocedural myocardial infarction (MI) or cardiac death. This review aims to summarize the main updates concerning the pathophysiology, highlight key risk factors and suggest recommendations in management and treatment of ICAD.

Chronic systemic glucocorticoid therapy is associated with increased risk of major vascular complications and cardiac tamponade after transcatheter aortic valve implantation: a systematic review and meta-analysis.

INTRODUCTION: TAVI-related complications, such as conduction disturbances, vascular complications or death may be related to increased inflammatory response. The aim of this study was to elucidate the efficacy and safety of the systemic glucocorticoid therapy regarding the adverse events after TAVI deployment. EVIDENCE ACQUISITION: We conducted a systemic search of PubMed, a reference list of relevant articles, and Medline. The main efficacy outcomes of interest were all-cause death, cardiac and non-cardiac death, permanent pacemaker implantation (PPM), new left bundle branch block (LBBB), stroke, and myocardial infarction (MI). Safety endpoints were major vascular complications, major bleeding events, and cardiac tamponade. EVIDENCE SYNTHESIS: A total of 7 studies including data from 3439 patients with a median follow-up was 30 days. Systemic glucocorticoid compared to the control group were associated with an increased risk of non-cardiac death (Relative Risk [RR] 5.90 95%CI [2.95; 11.80], P<0.001) major vascular complications (RR 1.78, 95%CI [1.22 - 2.61], P=0.003) and cardiac tamponade (RR 3.42, 95%CI [1.69 - 6.92], P<0.001). However, there were no differences in all-cause death, cardiac death, new LBBB, stroke, MI, or major bleeding events (all P values >0.05). CONCLUSIONS: Glucocorticoid therapy before the TAVI procedure was associated with an increase in non-cardiac death, major vascular events and cardiac tamponade. There were no differences in the risk of all-cause death, cardiac death, PPM or LBBB, stroke, or MI.

Heart Failure After ST-Elevation Myocardial Infarction: Beyond Left Ventricular Adverse Remodeling.

ST-segment elevation myocardial infarction (STEMI) remains a significant source of morbidity and mortality worldwide. Despite advances in treatment leading to a significant reduction in the early complications and in-hospital mortality, a significant proportion of STEMI survivors develop heart failure (HF) at follow-up. The classic paradigm of HF after STEMI is one characterized by left ventricular adverse remodeling (LVAR) and encompasses the process of regional and global structural and functional changes that occur in the heart as a consequence of loss of viable myocardium, increased wall stress and neurohormonal activation, and results in HF with reduced ejection fraction (HFrEF). More recently, however, with further improvements in the treatment of STEMI the incidence and entity of LVAR appear to be largely reduced, yet the risk for HF following STEMI is not abolished and remains substantial, identifying a new paradigm by which patients with STEMI present with HF and preserved EF (HFpEF) characterized by reduction of diastolic or systolic reserve independent of LVAR.

Galectin-3 contributes to acute cardiac dysfunction and toxicity by increasing oxidative stress and fibrosis in doxorubicin-treated mice.

BACKGROUND: Doxorubicin (DOX) leads to cardiovascular toxicity through direct cardiomyocyte injury and inflammation. We aimed to study the role of Galectin-3 (Gal-3), a ß-galactosidase binding lectin associated with inflammation and fibrosis in DOX-induced acute cardiotoxicity in mice. METHODS: Male C57 and Gal-3 knockout (KO) mice were given a single dose of DOX (15 mg/kg, i.p) or placebo. Serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), aspartate aminotransferase (AST) and cardiac thiobarbituric acid-reactive substance (TBARS) were measured at 3 days to assess cardiac injury and oxidative stress. Cardiac remodeling and function were studied by echocardiography and catheterization at 7 days. Myocardial fibrosis was quantified in picrosirius red stained slices. RESULTS: Absence of Gal-3 tended to reduce the mortality after DOX. DOX significantly increased CPK, LDH, AST and TBARS while treated Gal-3 KO mice showed reduced injury and oxidative stress. After 7 days, adverse remodeling, fibrosis and dysfunction in treated-C57 mice were severely affected while those effects were prevented by absence of Gal-3. CONCLUSION: In summary, genetic deletion of Gal-3 prevented cardiac damage, adverse remodeling and dysfunction, associated with reduced cardiac oxidative stress and fibrosis. Understanding the contribution of GAL-3 to doxorubicin-induced cardiac toxicity reinforces its potential use as a therapeutic target in patients with several cancer types.

Dual Role of Guide Extension Catheters for the Management of High Thrombus Burden in STEMI: Case Report and Mini Review.

High thrombus burden in ST segment elevation myocardial infarction (STEMI) patients increases the risk of adverse events. In this report, we review current strategies for high thrombus burden and present a case report with the combination of two different techniques: aspiration through a guide extension catheter followed by local intracoronary thrombolysis with 'marinade' technique.

Interplay between climate, pollution and COVID-19 on ST-elevation myocardial infarction in a large metropolitan region.

BACKGROUND: Collective risk factors such as climate and pollution impact on the risk of acute cardiovascular events, including ST-elevation myocardial infarction (STEMI). There is limited data however on the precise temporal and independent association between these factors and STEMI, and the potentially interacting role of government policies against Coronavirus disease 2019 (COVID-19), especially for Latin America. METHODS: We retrospectively collected aggregate data on daily STEMI admissions at 10 tertiary care centers in the Buenos Aires metropolitan area, Argentina, from January 1, 2017 to November 30, 2020. Daily measurements for temperature, humidity, atmospheric pressure, wind direction, wind speed, and rainfall, as well as carbon monoxide (CO), nitrogen dioxide, and particulate matter <10 µm (PM10), were retrieved. Exploratory analyses focused on key COVID-19-related periods (e.g. first case, first lockdown), and Stringency Index quantifying the intensity of government policy response against COVID-19. RESULTS: A total of 1498 STEMI occurred over 1430 days, for an average of 0.12 STEMI per center (decreasing from 0.130 in 2018 to 0.102 in 2020, P=0.016). Time series analysis showed that lower temperature and higher concentration of CO and PM10 were all significantly associated with an increased rate of STEMI (all P<0.05), whereas COVID-19 outbreak, lockdown, and stringency of government policies were all inversely associated with STEMI (all P<0.05). Notably, environmental features impacted as early as 28 days before the event (all P<0.05), even if same or prior day associations proved stronger (all P<0.05). Multivariable analysis suggested that maximum temperature (P=0.001) and PM10 (P=0.033) were the strongest predictor of STEMI, even after accounting for COVID-19-related countermeasures (P=0.043). CONCLUSIONS: Lower temperature and higher concentrations of CO and PM10 are associated with significant increases in the rate of STEMI in a large Latin American metropolitan area. The reduction in STEMI cases seen during the COVID-19 pandemic is at least in part mediated by improvements in pollution, especially reductions in PM10.

Alpha-1 antitrypsin inhibits caspase-1 and protects from acute myocardial ischemia-reperfusion injury.

Alpha-1-antitrypsin (AAT) possesses anti-inflammatory and tissue-protective properties. Here, we studied the effects of exogenously administered AAT on caspase-1 activity and on the outcome of ischemia-reperfusion injury (I/R) in a mouse model of acute myocardial infarction (AMI). Adult male mice underwent 30 min of coronary artery ligation followed by reperfusion and were randomly assigned to receive clinical-grade AAT or albumin at reperfusion. Infarct size was evaluated after 1 and 7 days. Caspase-1 activity was measured in homogenates of heart tissue. Left ventricular (LV) end-diastolic diameter (EDD) and end-systolic diameter (ESD) were measured and LV fractional shortening (FS) and ejection fraction (EF) were calculated using transthoracic echocardiography. The effect of AAT on caspase-1 activity was determined in cultures of mouse HL-1 cardiomyocytes stimulated with LPS and triggered with nigericin or when HL-1 cells were exposed to simulated ischemia. AAT-treated mice had significantly smaller infarct sizes (-30% day 1 and -55% day 7) compared with mice treated with albumin. AAT treatment resulted in >90% reduction in caspase-1 activity in homogenates of hearts 24h after I/R. Seven days after AMI, AAT-treated mice exhibited a >90% smaller increase in LVEDD and LVESD and smaller reduction in LVEF. The increase in caspase-1 activity in HL-1 cells induced by LPS and nigericin or following exposure to simulated ischemia was reduced by >80% and AAT similarly reduced cell death by >50%. In conclusion, exogenous administration of clinical grade AAT reduces caspase-1 activity in the ischemic myocardium leading to preservation of viable myocardium and prevention of adverse cardiac remodeling.

Altered oxido-reductive state in the diabetic heart: loss of cardioprotection due to protein disulfide isomerase.

Diabetes is associated with an increased risk of heart failure, in part explained by endoplasmic reticulum stress and apoptosis. Protein disulfide isomerase (PDI) prevents stressed cardiomyocytes apoptosis. We hypothesized that diabetes impairs PDI function by an alteration in its oxido-reductive state. Myocardial biopsies harvested from the anterolateral left ventricular wall from diabetic (n = 7) and nondiabetic (n = 8) patients were used to assess PDI expression and cardiomyocyte death. A mouse model of diabetes (streptozotocin injection, 130 mg/mL) was used to study PDI expression and its redox state after ischemia/reperfusion injury induced by 30-min occlusion of the left anterior coronary artery followed by reperfusion. Transthoracic echocardiography was performed to assess cardiac remodeling after 1 wk. Western blot analysis was used to analyze PDI expression, and methoxy-polyethyleneglycol-maleimide was used to assess its redox state. Dehydroascorbate (DHA) administration was used to restore the PDI redox state. Diabetic patients had a greater number of transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells than nondiabetic patients despite a greater myocardial PDI expression suggesting altered PDI function. Diabetic mice had a worse postinfarction remodeling associated with an altered PDI redox state. DHA treatment restored functional PDI redox state and ameliorated post-myocardial infarction remodeling. An increase in PDI levels with a paradoxical decrease of its active form occurs in the diabetic heart after ischemia and may explain the lack of protective effects of PDI in diabetes. Restoration of PDI redox state prevents adverse remodeling. The potential significance of these findings deserves to be validated in a clinical setting.

Ascorbic acid attenuates lipopolysaccharide-induced acute lung injury.

OBJECTIVE: Sepsis-induced lung injury is a persisting clinical problem with no direct therapy. Recent work suggests that intravenously infused ascorbic acid improves the circulatory dysfunction of sepsis. We used a model of endotoxin-induced acute lung injury to determine whether parenteral ascorbic acid modulates the dysregulated proinflammatory, procoagulant state that leads to lung injury. DESIGN: C57BL/6 mice were exposed to lethal lipopolysaccharide doses (10 µg/g of body weight) to induce acute lung injury. SETTING: Laboratory investigation. SUBJECTS: Wild-type C57BL/6 mice. INTERVENTIONS: Ascorbic acid or its oxidized form (dehydroascorbic acid) was administered intraperitoneally at 200 mg/kg 30 mins after the lethal lipopolysaccharide dose. MEASUREMENTS AND MAIN RESULTS: We quantified survival, lung capillary leak, proinflammatory chemokine expression, and lung microvascular thrombosis. Lipopolysaccharide induced 100% lethality in mice within 28 hrs of exposure and in lung we observed intense neutrophil sequestration, loss of capillary barrier function, exuberant pulmonary inflammation, and extensive microthrombus formation. A time-delayed infusion protocol of both ascorbic acid and dehydroascorbic acid significantly prolonged survival. Both ascorbic acid and dehydroascorbic acid preserved lung architecture and barrier function while attenuating proinflammatory chemokine expression and microvascular thrombosis. Ascorbic acid and dehydroascorbic acid attenuated nuclear factor kappa B activation and normalized coagulation parameters. CONCLUSIONS: Ascorbic acid administered in an interventional manner following lipopolysaccharide infusion attenuates proinflammatory, procoagulant states that induce lung vascular injury in an animal model of sepsis.

Balloon aortic valvuloplasty through the novel transradial technique.

BACKGROUND: Balloon aortic valvuloplasty (BAV) has been typically performed through a femoral approach thus increasing the risk of bleeding and access site-related vascular complications. The aim of this study was to describe the safety and efficacy of transradial aortic valve valvuloplasty (TRBAV). METHODS: The present research is a retrospective, single-center study including patients undergoing TRBAV (October 2019-July 2020). BAV was performed using 18-25 mm balloons through an 8-10 French (F) radial sheath. Successful BAV was defined as ≥50% reduction in peak-to-peak gradient (efficacy endpoint). Procedural complications, including radial artery occlusion (RAO) at follow-up were evaluated (safety endpoint). RESULTS: Twenty-four patients underwent TRBAV were included, aged 81 (73-85) years, 70% males, EuroScoreII 3.1 (2.1-5.5). Aortic valve gradient was significantly reduced (pre-50±24 vs. 18.7±13 mmHg post, P<0.001), and 91% had successful BAV. Mean gradient drop was 31.4±16.8 mmHg. One patient (4%) required cross-over to femoral access for severe vasospasm and was excluded from the analysis. Most used sheaths were 8F (46%) and 9F (37%), mostly for 20 mm (50%) and 23 mm (38%) balloons. There were neither major procedural complications (neither balloon entrapment nor compartmental syndrome) nor minor complications (any access-site bleeding). RAO was observed in 2 patients (8%), both asymptomatic. CONCLUSIONS: TRBAV was safe, feasible, and efficacious with a small rate of conversion and RAO, suggesting reproducibility of this novel technique. TRBAV may represent an alternative to femoral access in selected patients although larger studies are warranted.