Colchicine therapy in acute coronary syndrome patients acts on caspase-1 to suppress NLRP3 inflammasome monocyte activation

Inflammasome activation, with subsequent release of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18, has recently been implicated in atherosclerosis-associated inflammation. This study aims to assess in acute coronary syndrome (ACS) patients (1) inflammasome activation in circulating monocytes and (2) whether short-term oral colchicine, a recognized anti-inflammatory agent that has been shown to be cardio-protective in clinical studies, might acutely suppress inflammasome-dependent inflammation. ACS patients (n=21) were randomized to oral colchicine (1 mg followed by 0.5 mg 1 h later) or no treatment, and compared with untreated healthy controls (n=9). Peripheral venous blood was sampled pre- (day 1) and 24 h post- (day 2) treatment. Monocytes were cultured and stimulated with ATP. Analysis of key inflammasome markers was performed by ELISA. IL-1β secretion increased by 580.4% (P<0.01) in ACS patients compared with controls but only with ATP stimulation. Untreated ACS patients secreted significantly higher levels of IL-18 compared with healthy controls independent of ATP stimulation (P<0.05). Colchicine treatment in ACS patients markedly reduced intracellular and secreted levels of IL-1β compared with pre-treatment levels (P<0.05 for both), as well as significantly reducing pro-caspase-1 mRNA levels by 57.7% and secreted caspase-1 protein levels by 30.2% compared with untreated patients (P<0.05 for both). Monocytes from ACS patients are ‘primed’ to secrete inflammasome-related cytokines and short-term colchicine acutely and markedly suppresses monocyte caspase-1 activity, thereby reducing monocyte secretion of IL-1β

Ejection fraction and mortality: A nationwide register-based cohort study of 499 153 women and men

Aims: We investigated the sex-based risk of mortality across the spectrum of left ventricular ejection fraction (LVEF) in a large cohort of patients in Australia. Methods and results: Quantified levels of LVEF from 237 046 women (48.1%) and 256 109 men undergoing first-time, routine echocardiography (2000–2019) were linked to 119 232 deaths (median 5.6 years of follow-up). Overall, 17.6% of men vs. 8.3% of women had an LVEF P\u3c 0.001] in women and 1.21 (95% CI 1.05–1.39; P = 0.008) in men. In women, an LVEF of 60.0–64.9% was also associated with a HR 1.33 (95% CI 1.16–1.52; P\u3c 0.001) for cardiovascular-related mortality. These associations were most striking in women and men aged Conclusions: Among patients investigated for suspected or established cardiovascular disease, we found clinically relevant sex-based differences in the distribution and mortality associated with an LVE

Brain Volumetrics, Regional Cortical Thickness and Radiographic Findings in Adults with Cyanotic Congenital Heart Disease

AbstractBackgroundChronic cyanosis in adults with congenital heart disease (CHD) may cause structural brain changes that could contribute to impaired neurological functioning. The extent of these changes has not been adequately characterized.HypothesisWe hypothesized that adults with cyanotic CHD would have widespread changes including abnormal brain volumetric measures, decreased cortical thickness and an increased burden of small and large vessel ischemic changes.MethodsTen adults with chronic cyanosis from CHD (40±4years) and mean oxygen saturations of 82±2% were investigated using quantitative MRI. Hematological and biochemical parameters were also assessed. All subjects were free from major physical or intellectual impairment. Brain volumetric results were compared with randomly selected age- and sex-matched controls from our database of normal subjects.ResultsFive of 10 cyanotic subjects had cortical lacunar infarcts. The white matter (WM) hyperintensity burden was also abnormally high (Scheltens Scale was 8±2). Quantitative MRI revealed evidence of extensive generalized WM and gray matter (GM) volumetric loss; global GM volume was reduced in cyanosed subjects (630±16 vs. 696±14mL in controls, p=0.01) as was global WM volume (471±10 vs. 564±18mL, p=0.003). Ventricular cerebrospinal fluid volume was increased (35±10 vs. 26±5mL, p=0.002). There were widespread regions of local cortical thickness reduction observed across the brain. These changes included bilateral thickness reductions in the frontal lobe including the dorsolateral prefrontal cortex and precentral gyrus, the posterior parietal lobe and the middle temporal gyrus. Sub-cortical volume changes were observed in the caudate, putamen and in the thalamus (p≤0.005 for all regions). Cortical GM volume negatively correlated with brain natriuretic peptide (R=−0.89, p=0.009), high sensitivity C-reactive protein (R=−0.964, p<0.0001) and asymmetric dimethylarginine (R=−0.75, p=0.026) but not with oxygen saturations, packed cell volume or viscosity.ConclusionsWe present the first comprehensive analysis of brain structure in adults with chronic neurocyanosis due to congenital heart disease. We demonstrate clear evidence for marked macro- and microvascular injury. Cyanotic patients show global evidence for reduced brain volume as well as specific foci of cortical thickness reduction. The GM volume loss correlated with hsCRP, BNP and ADMA suggesting that inflammation, neurohormonal activation and endothelial dysfunction may have important roles in its pathogenesis

Outcome in neonates with Ebstein's anomaly

AbstractThe presentation and outcome of 50 patients with neonatal Ebstein's anomaly seen from 1961 to 1990 were reviewed. The majority (88%) presented in the 1st 3 days of life; cyanosis (80%) was the most common presenting feature. Associated defects, present in 27 infants (54%), included pulmonary stenosis in 11 and atresia in 7. Nine patients (18%) died in the neonatal period; there were 15 late deaths (due to hemodynamic deterioration in 9, sudden death in 5 and a noncardiac cause in 1) at a mean age of 4.5 years (range 4 months to 19 years). Actuarial survival at 10 years was 61%.A new echocardiographic grade (1 to 4 in order of increasing severity of the defect) was devised with use of the ratio of the area of the right atrium and atrialized right ventricle to the area of the functional right ventricle and left heart chambers. Cardiac death occured in 0 of 4 infants with grade 1, 1 (10%) of 16 with grade 2, 4 (44%) of 9 with grade 3 and 5 (100%) of 5 with grade 4. In a multivariate analysis of clinical and investigational features at presentation, echocardiographic grade of severity was the best independent predictor of death.Neonates with Ebstein's anomaly have a high early mortality rate and those surviving the 1st month of life remain at high risk of late hemodynamic deterioration or sudden death. Echocardiographic grading of severity of the defect permits prognostic stratification

Prevalence of pulmonary hypertension in mitral regurgitation and its influence on outcomes

Objective: Pulmonary hypertension (PHT) commonly coexists with significant mitral regurgitation (MR), but its prevalence and prognostic importance have not been well characterised. In a large cohort of adults with moderate or greater MR, we aimed to describe the prevalence and severity of PHT and assess its influence on outcomes. Methods: In this retrospective study, we analysed the National Echocardiography Database of Australia (data from 2000 to 2019). Adults with an estimated right ventricular systolic pressure (eRVSP), left ventricular ejection fraction &gt;50% and with moderate or greater MR were included (n=9683). These subjects were then categorised according to their eRVSP. The relationship between PHT severity and mortality outcomes was evaluated (median follow-up of 3.2 years, IQR 1.3–6.2 years). Results: Subjects were aged 76±12 years, and 62.6% (6038) were women. Overall, 959 (9.9%) had no PHT, and 2952 (30.5%), 3167 (32.7%), 1588 (16.4%) and 1017 (10.5%) patients had borderline, mild, moderate and severe PHT, respectively. A ‘typical left heart disease’ phenotype was identified with worsening PHT, showing rising E:e′, right and left atrial sizes increasing progressively, from no PHT to severe PHT (p&lt;0.0001, for all). With increasing PHT severity, 1- and 5-year actuarial mortality increased from 8.5% and 33.0% to 39.7% and 79.8%, respectively (p&lt;0.0001). Similarly, adjusted survival analysis showed the risk of long-term mortality progressively increased with higher eRVSP levels (adjusted HR 1.20–2.86, borderline to severe PHT, p&lt;0.0001 for all). A mortality inflection was apparent at an eRVSP level &gt;34.00 mm Hg (HR 1.27, CI 1.00–1.36). Conclusions: In this large study, we report on the importance of PHT in patients with MR. Mortality increases as PHT becomes more severe from an eRVSP of 34 mm Hg onwards

Oral vitamin C and endothelial function in smokers: short-term improvement, but no sustained beneficial effect

AbstractOBJECTIVESTo test the hypothesis that antioxidant therapy would improve endothelial function in smokers.BACKGROUNDSeveral studies have documented a beneficial effect of short-term oral or parenteral vitamin C on endothelial physiology in subjects with early arterial dysfunction. Possible long-term effects of vitamin C on endothelial function, however, are not known.METHODSWe studied the effects of short- and long-term oral vitamin C therapy on endothelial function in 20 healthy young adult smokers (age 36 ± 6 years, 8 male subjects, 21 ± 10 pack-years). Each subject was studied at baseline, 2 h after a single dose of 2 g vitamin C and 8 weeks after taking 1 g vitamin C daily, and after placebo, in a randomized double-blind crossover study. Blood samples were analyzed for plasma ascorbate levels and endothelial function was measured as flow-mediated dilation of the brachial artery, using high resolution ultrasound. Nitroglycerin-mediated dilation (endothelium-independent) was also measured at each visit.RESULTSAt baseline, plasma ascorbate level was low in the smokers (42 ± 21 μmol/liter; normal range, 50 to 150 μmol/liter), increased with vitamin C therapy after 2 h to 120 ± 54 μmol/liter (p < 0.001) and remained elevated after eight weeks of supplementation at 92 ± 32 μmol/liter (p < 0.001, compared with placebo). Flow-mediated dilation, however, increased at 2 h (from 2.8 ± 2.0% to 6.3 ± 2.8%, p < 0.001), but there was no sustained beneficial effect after eight weeks (3.9 ± 3.2%, p = 0.26). Nitroglycerin-mediated dilation was unchanged throughout.CONCLUSIONOral vitamin C therapy improves endothelial dysfunction in the short term in healthy young smokers, but it has no beneficial long-term effect, despite sustained elevation of plasma ascorbate levels

Angiopoietin-2 is increased in sepsis and inversely associated with nitric oxide-dependent microvascular reactivity

IntroductionAngiopoietin-2 (ang-2), an angiogenic peptide released by endothelial cell Weibel-Palade bodies (WPBs), increases endothelial activation and vascular permeability. Ang-2 is raised in severe sepsis but the mechanisms underlying this are not known. Nitric oxide (NO) inhibits WPB exocytosis, and bioavailability of endothelial NO is decreased in sepsis. We hypothesized that endothelial NO bioavailability would be inversely correlated with ang-2 concentrations in sepsis. MethodsPlasma ang-2, vascular endothelial growth factor (VEGF) and endothelial-active cytokines were assessed in 83 patients with early sepsis and 41 hospital controls, and related to reactive hyperaemia-peripheral arterial tonometry, RH-PAT, a measure of endothelial NO bioavailability. ResultsPlasma Ang-2 was elevated in sepsis (median [interquartile range (IQR)], ng/ml: severe sepsis 12.4 [8.5-33.4], sepsis without organ failure 6.1 [5.0-10.4], controls 2.7 [2.2-3.6], P &lt; 0.0001). It correlated inversely with RH-PAT (r = -0.38, P &lt; 0.0001) and positively with IL-6 (r = 0.57, P &lt; 0.0001) and degree of organ failure (sequential organ function assessment score) (r = 0.58, P &lt; 0.0001). The correlation of ang-2 with RH-PAT persisted after controlling for sepsis severity. In a longitudinal mixed-effects model, recovery of RH-PAT over time was associated with decline in ang-2. ConclusionsAng-2 is elevated in proportion to sepsis severity, and inversely correlated with NO-dependent microvascular reactivity. Impaired endothelial NO bioavailability may contribute to increased endothelial cell release of ang-2, endothelial activation and capillary leak. Agents that increase endothelial NO bioavailability or inhibit WPB exocytosis and/or Ang-2 activity may have therapeutic potential in sepsis

Neutrophil-derived microparticles are released into the coronary circulation following percutaneous coronary intervention in acute coronary syndrome patients.

To evaluate (i) local coronary and systemic levels of microparticles (MP) in acute coronary syndrome (ACS) and stable angina pectoris (SAP) patients and (ii) their release after plaque disruption with percutaneous coronary intervention (PCI). MP are small vesicles originating from plasma membranes of cells after activation or apoptosis and are implicated in the pathogenesis of atherosclerosis. Neutrophils play a role in plaque destabilization and shed neutrophil-derived MP that have the potential to drive significant proinflammatory and thrombotic downstream effects. Eight ACS and eight SAP patients were included. Coronary sinus (CS) samples pre-intervention (CS1), 45 s following balloon angioplasty (CS2) and at 45 s intervals following stent deployment (CS3, CS4 and CS5), together with peripheral vein samples, pre- and post-PCI were analysed for neutrophil-derived (CD66b+), endothelial-derived (CD144+), platelet-derived (CD41a+), monocyte-derived (CD14+) and apoptotic (Annexin V+) MP. ELISA for interleukin (IL)-6, myeloperoxidase (MPO) and P-selectin was also performed. CD66b+ MP levels were similar in both groups pre-intervention. Post-PCI, CS levels rose significantly in ACS but not SAP patients (ACS area under the curve (AUC): 549 ± 83, SAP AUC: 24 ± 29, P<0.01). CS CD41a+, CD144+, CD14+ and Annexin V+ MP levels did not differ between groups. Acute neutrophil-derived MP release post-PCI occurs in ACS compared with stable patients, likely to be reflective of plaque MP content in vulnerable lesions