Chronic Vascular Disease Research Articles

Incidence of cardiovascular diseases among breast cancer patients: a nationwide registry study 2013-2020

Abstract Background and aims There is evidence to suggest that breast cancer (BC) treatment is associated with an increased risk of developing cardiovascular disease (CVD). Several countries have introduced clinical measures to reduce the impact of breast cancer treatment on cardiovascular function including activated breathing control during radiotherapy, lower radiation doses, and maximum anthracycline doses. The overall aim of this study was therefore to investigate whether breast cancer patients still exhibit higher rates of cardiovascular disease than the general population. Methods We conducted a registry-based cohort study using linked data from four nationwide health registries. Out study population included all Norwegian patients diagnosed with BC between 2013-2020 and matched them by age to 10 controls without BC. Health outcomes were measured from 2008 to 2021. We estimated the cumulative incidence from index date, for ten selected CVDs. For BC patients, the index date was defined as date of BC diagnosis. For controls, the index date was defined as the date of BC diagnosis for the matched BC patient. A wash-out period of 5 years was applied to identify incident cases of CVD. Results The study population included 27,535 patients with BC and 269,9994 matched controls. Median age in both groups was 62 years (IQR: 20). Prior to index date, there were no significant differences in the prevalence of heart valve disease, chronic ischemic heart disease heart failure and peripheral vascular disease in BC patients compared to controls (p>0.05) (Table 1). Hypertensive heart disease, pulmonary embolism, atrial fibrillation, and other cardiac arrythmias were more prevalent in BC patients, while angina pectoris and acute myocardial infarction were more prevalent among controls. After the index date, the incidence proportion for heart valve disease, hypertensive heart disease, pulmonary embolism, atrial fibrillation, other cardiac arrythmias, and heart failure were higher in BC patients compared to controls (p<0.001) (Table 2). No significant differences were found for angina pectoris, acute myocardial infarction, chronic ischemic heart disease, and peripheral vascular disease. Conclusion Breast cancer is still associated with an increased risk of developing several CVDs in current clinical practice, compared to matched controls without breast cancer.Baseline characteristicsIncidence of CVD

Mechanisms of Lung Endothelial Cell Injury and Survival in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive, chronic, and incurable inflammatory pulmonary vascular disease characterized by significant sex bias and largely unexplored microbial-associated molecular mechanisms that may influence its development and sex prevalence across various subgroups. PAH can be subclassified as idiopathic, heritable, or associated with conditions such as connective tissue diseases, congenital heart defects, liver disease, infections, and chronic exposure to drugs or toxins. During PAH progression, lung vascular endothelial cells (ECs) undergo dramatic morphofunctional transformations in response to acute and chronic inflammation. These transformations include the appearance and expansion of abnormal vascular cell phenotypes such as those derived from apoptosis-resistant cell growth and endothelial-to-mesenchymal transition (EndoMT). Compelling evidence indicates that these endothelial phenotypes seem to be triggered by chronic lung vascular injury and dysfunction, often characterized by reduced secretion of vasoactive molecules like nitric oxide (NO) and exacerbated response to vasoconstrictors such as Endothelin-1 (ET-1); both long-term known contributors of PAH pathogenesis. This review sheds light on the mechanisms of EC dysfunction, apoptosis, and EndoMT in PAH, aiming to unravel the intricate interactions between ECs, pathogens, and other cell types that drive the onset and progression of this devastating disease. Ultimately, we hope to provide an overview of the complex functions of lung vascular ECs in PAH, inspiring novel therapeutic strategies that target these dysfunctional cells to improve the treatment landscape for PAH, particularly in the face of current and emerging global pathogenic threats.

Longitudinal association between depressive symptoms and cognitive function: the neurological mechanism of psychological and physical disturbances on memory.

The neural correlates underlying late-life depressive symptoms and cognitive deterioration are largely unclear, and little is known about the role of chronic physical conditions in such association. This research explores both concurrent and longitudinal associations between late-life depressive symptoms and cognitive functions, with examining the neural substrate and chronic vascular diseases (CVDs) in these associations. A total of 4109 participants (mean age = 65.4, 63.0% females) were evaluated for cognitive functions through various neuropsychological assessments. Depressive symptoms were assessed by the Geriatric Depression Scale and CVDs were self-reported. T1-weighted magnetic resonance imaging (MRI), diffusion tensor imaging, and functional MRI (fMRI) data were acquired in a subsample (n = 791). Cognitively, higher depressive symptoms were correlated with poor performance across all cognitive domains, with the strongest association with episodic memory (r = ‒0.138, p < 0.001). Regarding brain structure, depressive symptoms were negatively correlated with thalamic volume and white matter integrity. Further, white matter integrity was found to mediate the longitudinal association between depressive symptoms and episodic memory (indirect effect = -0.017, 95% CI -0.045 to -0.002) and this mediation was only significant for those with severe CVDs (β = -0.177, p = 0.008). This study is one of the first to provide neural evidence elucidating the longitudinal associations between late-life depressive symptoms and cognitive dysfunction. Additionally, the severity of CVDs strengthened these associations, which enlightens the potential of managing CVDs as an intervention target for preventing depressive symptoms-related cognitive decline.

Investigation of Hemorheological Parameters in Ischemic Stroke Patients.

The aim of this study is to determine whether there are any changes in hemorheological parameters, including whole blood viscosity (WBV), plasma viscosity, erythrocyte aggregation, and erythrocyte deformability, in acute ischemic stroke patients, and to establish their relationship with stroke etiology. The study also aims to observe the changes in these parameters, if any, over time and after treatment, and to assess the correlation between risk factors for ischemic stroke and neuroimaging findings. This was a prospective observational study including 70 patients diagnosed with acute ischemic stroke within the first 3 days of the onset of symptoms and 96 healthy controls. Stroke patients were categorized based on TOAST criteria, and hemorheological parameters were measured at admission and on the fifth day post-treatment. Erythrocyte aggregation and deformability were measured using a laser ektacytometer, and viscosity assessment was conducted with a rotational viscometer. Stroke patients exhibited significant differences from the control group in aggregation amplitude, aggregation index, and aggregation half-time (p = 0.001, p = 0.013, p = 0.009, respectively) and showed elevated maximum value of elongation index (p = 0.000). No significant differences in WBV and plasma viscosity were observed between the groups. Post-treatment, the small vessel occlusion subgroup demonstrated a notable reduction in WBV. Additionally, homocysteine levels showed a positive correlation with scattered white matter lesions in basal ganglia and infratentorial regions (p = 0.002, p = 0.039, respectively). Increased predisposition to erythrocyte aggregation may contribute to the occurrence of acute ischemic stroke. Moreover, gaining the ability of erythrocytes to deform and increase blood flow may serve as a compensatory mechanism in the chronic vascular disease process. The risk factors for ischemic stroke may exhibit connections to specific areas within the brain.

Severe Skin and Soft Tissue Infection of Patients Admitted to Intensive Care Units

Skin and soft tissue infections (SSTIs) can occasionally progress to life-threatening conditions, such as septic shock, requiring intensive care unit admission. Their risk factors include diabetes mellitus, chronic renal failure, chronic vascular disease, malignancy, and acquired immune deficiency syndrome. However, early diagnosis is challenging due to initially benign skin lesions and the absence of systemic symptoms such as fever. This review focuses on severe bacterial infections such as necrotizing fasciitis, gas gangrene, and toxic shock syndrome, examining their etiology and management. These severe SSTIs should be understood for the early diagnosis, appropriate treatment, and improved patient outcomes. Dermatologists play a vital role in recognizing and managing these infections

Knockdown of USP7 alleviates atherosclerosis in ApoE-deficient mice by regulating EZH2 expression.

Atherosclerosis (AS) is a chronic vascular disease associated with lipid accumulation. Understanding the molecular mechanisms of AS is essential. Ubiquitin-specific protease 7 (USP7) is a deubiquitination enzyme involved in various cellular processes, including lipid metabolism. In this study, we aimed to elucidate the role of USP7 in AS progression and its underlying mechanism using ApoE-deficient mice. We found that USP7 ablation improved the morphological characteristics of AS in these mice. USP7 knockdown reduced inflammation, evidenced by decreases in inflammatory markers IL-6, TNF-α, and IL-1β by 35, 40, and 38%, respectively (p < 0.01). Additionally, USP7 depletion reduced oxidative stress, indicated by a 30% reduction in malondialdehyde levels and increases in superoxide dismutase and glutathione peroxidase levels by 25 and 28%, respectively (p < 0.01). Moreover, USP7 knockdown blocked lipid accumulation in aortic tissue cells. Mechanistically, USP7 knockdown inhibited enhancer of Zeste Homolog 2 (EZH2) expression, thereby suppressing AS progression. In conclusion, USP7 depletion alleviated AS progression in ApoE-deficient mice by targeting EZH2 expression. USP7 may serve as a therapeutic target for AS.

Establishment of Mouse Models of Abdominal Aortic Aneurysm.

Abdominal aortic aneurysm (AAA) is a chronic vascular disease that commonly affects elderly individuals but has recently increased in younger populations. As the aneurysm grows, it can cause compression symptoms such as abdominal pain, rupture, and bleeding, which are absent in the early stages. Once an AAA ruptures and causes bleeding, the mortality rate is alarmingly high. Currently, the pathogenesis for AAA is unknown, and therapeutic options are limited, necessitating improvement in treatment efficacy. An essential research method for studying the processes and potential treatment of AAA is establishing animal models using mice. The present study provides a detailed overview of the widely used AAA mouse animal models and their construction strategies, advantages, disadvantages, scope of applications, and prospects.

Targeting Gut Microbiota with Probiotics and Phenolic Compounds in the Treatment of Atherosclerosis: A Comprehensive Review.

Atherosclerosis (AS) is a chronic inflammatory vascular disease. Dysregulated lipid metabolism, oxidative stress, and inflammation are the major mechanisms implicated in the development of AS. In addition, evidence suggests that gut dysbiosis plays an important role in atherogenesis, and modulation of the gut microbiota with probiotics and phenolic compounds has emerged as a promising strategy for preventing and treating AS. It has been shown that probiotics and phenolic compounds can improve atherosclerosis-related parameters by improving lipid profile, oxidative stress, and inflammation. In addition, these compounds may modulate the diversity and composition of the gut microbiota and improve atherosclerosis. The studies evaluated in the present review showed that probiotics and phenolic compounds, when consumed individually, improved atherosclerosis by modulating the gut microbiota in various ways, such as decreasing gut permeability, decreasing TMAO and LPS levels, altering alpha and beta diversity, and increasing fecal bile acid loss. However, no study was found that evaluated the combined use of probiotics and phenolic compounds to improve atherosclerosis. The available literature highlights the synergistic potential between phenolic compounds and probiotics to improve their health-promoting properties and functionalities. This review aims to summarize the available evidence on the individual effects of probiotics and phenolic compounds on AS, while providing insights into the potential benefits of nutraceutical approaches using probiotic strains, quercetin, and resveratrol as potential adjuvant therapies for AS treatment through modulation of the gut microbiota.

Exploring the causal relationship between plasma lipids and varicose veins of lower extremity: A comprehensive two-sample Mendelian randomization study.

Varicose veins of the lower extremities (VVs) is a common chronic vascular disease, with high prevalence rates in some countries; however, their pathogenesis remains unclear. Some studies have identified associations between changes in specific plasma lipid molecules, such as phosphatidylethanolamine (PE), phosphatidylcholine (PC), and sphingomyelin (SM), and the onset of VVs, but due to confounders and reverse causality, the causal relationship remains unclear. Meanwhile, studies on the potential link between other plasma lipids beyond PE, PC, and SM and the risk of VVs in the lower extremities are lacking. This study aimed to explore the potential causal relationship between VVs and plasma lipid levels to provide theoretical insights into the interrelation of plasma lipids and VVs in their occurrence and progression. We conducted a two-sample Mendelian randomization (MR) analysis to assess the potential connection between genetically predicted levels of individual plasma lipids and the risk of developing VVs. We utilized data from a large-scale genome-wide association study involving 7174 Finnish individuals for 179 plasma lipidomes along with VVs genome-wide association study data from 408,455 UK individuals. MR analysis employed methods, such as inverse-variance weighting, weighted median, Bayesian Weighted Mendelian Randomization, and MR-Egger regression. The inverse-variance weighting method was primarily used to assess causality. The validity of the results was demonstrated through sensitivity analysis. In total, 12 lipids were found to have their plasma levels associated with an increased risk of VVs. This includes 3 types of PE, 7 types of PC, and 2 types of phosphatidylinositol. However, no significant causal relationship was found between the plasma levels of 11 types of SM and VVs. These results support the existence of a potential causal relationship between specific types of lipid levels and the risk of VVs, which can provide clues for further studies on biological mechanisms and the exploration of potential therapeutic targets.

Studying the Pulmonary Endothelium in Health and Disease: An Official American Thoracic Society Workshop Report.

Lung endothelium resides at the interface between the circulation and the underlying tissue, where it senses biochemical and mechanical properties of both the blood as it flows through the vascular circuit and the vessel wall. The endothelium performs the bidirectional signaling between the blood and tissue compartments that is necessary to maintain homeostasis while physically separating both, facilitating a tightly regulated exchange of water, solutes, cells, and signals. Disruption in endothelial function contributes to vascular disease, which can manifest in discrete vascular locations along the artery-to-capillary-to-vein axis. Although our understanding of mechanisms that contribute to endothelial cell injury and repair in acute and chronic vascular disease have advanced, pathophysiological mechanisms that underlie site-specific vascular disease remain incompletely understood. In an effort to improve the translatability of mechanistic studies of the endothelium, the American Thoracic Society convened a workshop to optimize rigor, reproducibility, and translation of discovery to advance our understanding of endothelial cell function in health and disease.

Emerging connectivity of programmed cell death pathways and pulmonary vascular remodelling during pulmonary hypertension.

Pulmonary hypertension (PH) is a chronic progressive vascular disease characterized by abnormal pulmonary vascular resistance and pulmonary artery pressure. The major structural alteration during PH is pulmonary vascular remodelling, which is mainly caused by the imbalance between proliferation and apoptosis of pulmonary vascular cells. Previously, it was thought that apoptosis was the only type of programmed cell death (PCD). Soon afterward, other types of PCD have been identified, including autophagy, pyroptosis, ferroptosis and necroptosis. In this review, we summarize the role of the above five forms of PCD in mediating pulmonary vascular remodelling, and discuss their guiding significance for PH treatment. The current review could provide a better understanding of the correlation between PCD and pulmonary vascular remodelling, contributing to identify new PCD-associated drug targets for PH.

NLRP3 inflammasome in atherosclerosis: Mechanisms and targeted therapies.

Atherosclerosis (AS) is the primary pathology behind various cardiovascular diseases and the leading cause of death and disability globally. Recent evidence suggests that AS is a chronic vascular inflammatory disease caused by multiple factors. In this context, the NLRP3 inflammasome, acting as a signal transducer of the immune system, plays a critical role in the onset and progression of AS. The NLRP3 inflammasome is involved in endothelial injury, foam cell formation, and pyroptosis in AS. Therefore, targeting the NLRP3 inflammasome offers a new treatment strategy for AS. This review highlights the latest insights into AS pathogenesis and the pharmacological therapies targeting the NLRP3 inflammasome, focusing on optimal targets for small molecule inhibitors. These insights are valuable for rational drug design and the pharmacological assessment of new targeted NLRP3 inflammasome inhibitors in treating AS.

Targeted delivery of berberine using bionic nanomaterials for Atherosclerosis therapy

Atherosclerosis (AS) is a prevalent chronic vascular inflammatory disease globally, initiated by injury to vascular endothelial cells (VECs). Macrophages play a pivotal role in disease pathogenesis, involving lipid metabolism and inflammation. The application of nanomaterials has been hindered by their rapid clearance by the immune system. Utilizing macrophage cell membranes can mitigate abnormal immune responses and induce a "homing" effect. Here, M2 macrophage cell membranes (M2) were coated onto berberine polylactic-hydroxylase-polylactide (PLGA) nanoparticles (BBR NPs), employing M2 macrophage immune escape, "homing" ability, and membrane coating nanotechnology, and loaded with mannose (Man) to create bionic nanoparticles (BBR NPs@Man/M2). Subsequently, the physical properties of BBR NPs@Man/M2 were characterized. The biocompatibility and biological function of BBR NPs@Man/M2 were assessed in vitro. Finally, the targeting, therapeutic efficacy, and safety of BBR NPs@M2 were investigated in an AS mouse model. The newly developed BBR NPs@Man/M2 exhibited good biocompatibility. Owing to their M2 coating, the nanoparticles effectively targeted macrophages in vitro, inducing a shift from a pro-inflammatory to an anti-inflammatory state. This transition reduced inflammation in endothelial cells and facilitated the repair of damaged endothelial cells. Moreover, M2-coated nanoparticles efficiently targeted and accumulated in atherosclerotic lesions in vivo. Following four weeks of treatment, BBR NPs@Man/M2 significantly delayed AS progression. Furthermore, BBR NPs@Man/M2 demonstrated a good safety profile after long-term administration. In conclusion, BBR NPs@Man/M2 effectively and safely inhibited AS progression. Biomimetic nanoparticles represent a promising approach for the safe and effective delivery of anti-AS drugs.

Age-associated gadolinium leakage into ocular structures in patients with acute traumatic brain injury

BackgroundGadolinium Leakage into Ocular Structures (GLOS) is common following acute cerebrovascular events. The objective of this study was to investigate the occurrence of GLOS in an acute traumatic brain injury (TBI) cohort without acute cerebrovascular injury and to explore associated factors. MethodsEnrolled acute TBI patients had a baseline MRI ≤48 h of injury (TP1) and follow-up MRI ≤72 h after baseline (TP2). Vitreous chamber enhancement and signal intensity ratios (SIRs) were calculated using pre- and post-contrast Fluid Attenuated Inversion Recovery (FLAIR). White matter hyperintensities (WMHs) were assessed using the Fazekas scale. ResultsOf the 128 TBI patients included, median age was 47 years, 70% male, and 66% presented with Glasgow Coma Scale of 15. No GLOS was detected at TP1 but was present in 23% of patients at TP2. GLOS+ patients were older (68 years [56–76] vs 39 years [27–53], p < 0.001), more likely to report falls as injury mechanism (62% vs 36%, p = 0.006), report history of hypertension (41% vs 19%, p = 0.025), and had a higher burden of WMHs (59% vs 14% with a total Fazekas ≥2, p < 0.001). Quantitative SIRs confirmed qualitative assessments: GLOS+ patients had higher SIRs at TP2 (0.43 vs 0.22, p < 0.001). Age (OR 3.28, 95%CI [1.88–5.71], p < 0.001) and prior TBI history (OR 4.99, 95%CI [1.46–17.06], p = 0.010) were independent predictors of GLOS. When age was removed, total Fazekas score (OR 2.53, 95%CI [1.60–4.00], p < 0.001) was an independent predictor of GLOS. ConclusionsGLOS is primarily associated with age and may serve as another imaging marker of chronic vascular disease.

Equisetin protects from atherosclerosis in vivo by binding to STAT3 and inhibiting its activity

Atherosclerosis is a chronic inflammatory vascular disease characterized by lipid metabolism disorder and lipid accumulation. Equisetin (EQST) is a hemiterpene compound isolated from fungus of marine sponge origin, which has antibacterial, anti-inflammatory, lipid-lowering, and weight loss effects. Whether EQST has anti-atherosclerotic activity has not been reported. In this study, we revealed that EQST displayed anti- atherosclerosis effects through inhibiting macrophage inflammatory response, lipid uptake and foam cell formation in vitro, and finally ameliorated high-fat diet (HFD)-induced atherosclerosis in AopE-/- mice in vivo. Mechanistically, EQST directly bound to STAT3 with high-affinity by forming hydrophobic bonds at GLN247 and GLN326 residues, as well as hydrogen bonds at ARG325 and THR346 residues. EQST interacted with STAT3 physically, and functionally inhibited the transcription activity of STAT3, thereby regulating atherosclerosis. Therefore, these results supports EQST as a candidate for developing anti-atherosclerosis therapeutic agent.

Simultaneous ST-elevation in lead augmented vector right (aVR) and III in non-ST-elevation acute coronary syndromes.

The value of ST-elevation in lead augmented vector right (aVR) remains controversial in clinical practice. This study aimed to investigate the association of simultaneous ST-elevation in lead aVR and III with angiographic findings and clinical outcomes in patients with non-ST-elevation acute coronary syndromes (NSTEACS). In this observational study, patients who had been diagnosed with NSTEACS and presented with ST-elevation in lead aVR and without ST-elevation in any other two contiguous leads were enrolled from January 2018 to June 2019. Demographic, baseline clinical, angiographic and interventional characteristics as well as clinical outcomes were collected and recorded on standardized case report forms. A total of 157 patients meeting the criteria were finally enrolled in this study and classified into two groups according to the presence of ST-elevation in lead III. Patients in the two groups were similar in average age and previous history of hypertension, diabetes mellitus, hyperlipidemia, chronic kidney disease, stroke, and peripheral vascular diseases (all P>0.05). Patients with ST-elevation in lead III tended to present with myocardial hypertrophy in the echocardiography (P=0.02). The cases with ST-elevation in lead III showed higher high sensitivity troponin T (hs-TnT; P=0.08) and creatinine kinase MB isoenzyme (CK-MB; P<0.01) whereas those without ST-elevation in lead III showed higher N-terminal pro brain natriuretic peptide (NT-proBNP; P=0.02). Of note, patients with ST-elevation in lead III presented with more ST-depression in multiple leads [especially in lead I, augmented vector left (aVL), V3-V6] as well as higher degree of ST-depression (all P<0.05) and were more likely to develop multi-vessel and left main trunk (LM) lesions (P=0.04), with 20% of the cases having a LM lesion and 60% having triple vessel lesions. Patients with ST-elevation in lead III were at increased risk of 3-year major adverse cardiovascular events (MACEs), despite no significant statistical difference between the two groups (hazard ratio =1.29; P=0.26). The NSTEACS cases with simultaneous ST-elevation in lead III and aVR tended to present with more multiple leads with ST-depression, higher degree of ST-depression, and more LM or multi-vessel lesions, suggesting a broader range of severe myocardial ischemia. The concurrent presentation of ST-elevation in lead III and aVR may play a vital role in the diagnosis, risk-stratification, and prediction of poor prognosis during the management of NSTEACS patients.

Atherosclerosis and inflammation: therapeutic targets and ways of correction

Atherosclerosis is a chronic inflammatory vascular disease caused by various risk factors, in particular smoking, obesity, high blood pressure, and dyslipidemia. In addition, such signaling pathways as NLRP3 inflammasome, toll-like receptors, proprotein convertase subtilisin/kexin type 9, Notch and Wnt, which are associated with the inflammatory response in the human body, are involved in the pathogenesis of atherosclerosis. Therapeutic targeting of inflammatory pathways, especially the NLRP3 inflammasome pathway and the cascade of reactions regulated by it leading to the production of inflammatory interleukin-1β, may represent a new avenue for the treatment of atherosclerotic diseases. This article summarizes knowledge of the cellular participants and key inflammatory signaling pathways in atherosclerosis, discusses preclinical studies targeting these key pathways in atherosclerosis, clinical trials that will target some of these processes, and the effects of suppressing inflammation and atherosclerosis.

Delineating excess comorbidities in idiopathic pulmonary fibrosis: an observational study

BackgroundOur study examined whether prevalent and incident comorbidities are increased in idiopathic pulmonary fibrosis (IPF) patients when compared to matched chronic obstructive pulmonary disease (COPD) patients and control subjects without IPF or COPD.MethodsIPF and age, gender and smoking matched COPD patients, diagnosed between 01/01/1997 and 01/01/2019 were identified from the Clinical Practice Research Datalink GOLD database multiple registrations cohort at the first date an ICD-10 or read code mentioned IPF/COPD. A control cohort comprised age, gender and pack-year smoking matched subjects without IPF or COPD. Prevalent (prior to IPF/COPD diagnosis) and incident (after IPF/COPD diagnosis) comorbidities were examined. Group differences were estimated using a t-test. Mortality relationships were examined using multivariable Cox proportional hazards adjusted for patient age, gender and smoking status.ResultsAcross 3055 IPF patients, 38% had 3 or more prevalent comorbidities versus 32% of COPD patients and 21% of matched control subjects. Survival time reduced as the number of comorbidities in an individual increased (p < 0.0001).In IPF, prevalent heart failure (Hazard ratio [HR] = 1.62, 95% Confidence Interval [CI]: 1.43–1.84, p < 0.001), chronic kidney disease (HR = 1.27, 95%CI: 1.10–1.47, p = 0.001), cerebrovascular disease (HR = 1.18, 95%CI: 1.02–1.35, p = 0.02), abdominal and peripheral vascular disease (HR = 1.29, 95%CI: 1.09–1.50, p = 0.003) independently associated with reduced survival. Key comorbidities showed increased incidence in IPF (versus COPD) 7–10 years prior to IPF diagnosis.InterpretationThe mortality impact of excessive prevalent comorbidities in IPF versus COPD and smoking matched controls suggests that multiorgan mechanisms of injury need elucidation in patients that develop IPF.

The glucosylamine oxidation pathway of vitamin C recycling

The proposed glucosylamine oxidation pathway (GOP) is a two-step, intraerythrocyte, thermodynamically favorable nonenzymatic reaction that first binds glucose to the N-terminal valine of beta globin (βVal1) to form a closed-chain glucosylamine that can spontaneously reduce oxidized vitamin C to its antioxidant form. This review summarizes analytical, biochemical and clinical research supporting the existence of the GOP and the surprising hypothesis that βVal1 glucosylamine is a reducing agent that works cooperatively with reduced glutathione to dynamically regulate vitamin C recycling during naturally occurring periods of transiently or chronically elevated blood glucose and oxidant production. Rationale for the existence of the GOP is presented from the perspective of the hemoglobin glycation index, a clinically practical biomarker of risk for chronic vascular disease that we propose is mechanistically explained by person-to-person variation in GOP activity.

Impact of Frailty on the Benefits of Dual Pathway Inhibition for the Secondary Prevention of Cardiovascular Events in the COMPASS Randomised Trial

BackgroundIndividuals with frailty are at higher risk of adverse cardiovascular outcomes and bleeding. The objective of this study was to determine whether the effects of 2.5 mg rivaroxaban twice daily in addition to low-dose aspirin are similar among frail compared with nonfrail patients with chronic atherosclerotic vascular disease. MethodsIn the COMPASS trial (NCT01776424), patients with chronic atherosclerotic vascular disease were randomised to receive 100 mg aspirin daily, 100 mg aspirin daily plus 2.5 mg rivaroxaban twice daily, or 5 mg rivaroxaban twice daily. In this post hoc analysis, frailty was evaluated by constructing a cumulative deficit index from 37 diseases, signs, and symptoms. The frailty index for each participant was calculated as the proportion of the 37 deficits exhibited, with values > 0.2 considered to be frail. The primary outcome was the composite of cardiovascular death, myocardial infarction, or stroke. Hazard ratios (HRs) and 95% confidence intervals (CIs) are reported. ResultsFrailty was present in 13% of the trial population. In nonfrail individuals, adding 2.5 mg rivaroxaban twice daily to aspirin reduced the primary outcome (HR 0.69, 95% CI 0.59-0.80) and mortality (HR 0.75, 95% CI 0.63-0.90), but increased major bleeding (HR 1.87, 95% CI 1.51-2.31); Among participants with frailty, its effects on the primary outcome (HR 1.06, 95% CI 0.79-1.42), mortality (HR 1.08, 0.80-1.46), and major bleeding (HR 1.10, 95% CI 0.71-1.70) were not evident (respective interaction P values 0.011, 0.049, and 0.032). ConclusionsIn adults with chronic atherosclerotic vascular disease, the benefit of adding 2.5 mg rivaroxaban twice daily to aspirin was not evident in patients with frailty. Clinical Trial RegistrationNCT01776424