Correlation of Atherosclerosis and Osteoarthritis, the Role of Inflammation in the Pathogenesis of Osteoarthritis and Atherosclerosis

Cause-specific mortality in knee, hip and hand osteoarthritis

Cardiovascular Disease in Children with Chronic Kidney Disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease mostly affecting the elderly population. It is characterized by cognitive decline that occurs due to impaired neurotransmission and neuronal death. Even though deposition of amyloid beta (Aβ) peptides and aggregation of hyperphosphorylated TAU have been established as major pathological hallmarks of the disease, other factors such as the interaction of genetic and environmental factors are believed to contribute to the development and progression of AD. In general, patients initially present mild forgetfulness and difficulty in forming new memories. As it progresses, there are significant impairments in problem solving, social interaction, speech and overall cognitive function of the affected individual. Osteoarthritis (OA) is the most recurrent form of arthritis and widely acknowledged as a whole-joint disease, distinguished by progressive degeneration and erosion of joint cartilage accompanying synovitis and subchondral bone changes that can prompt peripheral inflammatory responses. Also predominantly affecting the elderly, OA frequently embroils weight-bearing joints such as the knees, spine and hips leading to pains, stiffness and diminished joint mobility, which in turn significantly impacts the patient's standard of life. Both infirmities can co-occur in older adults as a result of independent factors, as multiple health conditions are common in old age. Additionally, risk factors such as genetics, lifestyle changes, age and chronic inflammation may contribute to both conditions in some individuals. Besides localized peripheral low-grade inflammation, it is notable that low-grade systemic inflammation prompted by OA can play a role in AD pathogenesis. Studies have explored relationships between systemic inflammatory-associated diseases like obesity, hypertension, dyslipidemia, diabetes mellitus and AD. Given that AD is the most common form of dementia and shares similar risk factors with OA-both being age-related and low-grade inflammatory-associated diseases, OA may indeed serve as a risk factor for AD. This work aims to review literature on molecular mechanisms linking OA and AD pathologies, and explore potential connections between these conditions alongside future prospects and innovative treatments.

Osteoarthritis is a slowly developing chronic joint disease mainly characterized by joint pain and nodes with no curative treatment available except for joint replacement. The etiology of osteoarthritis is not exactly known, but the hypothesis that osteoarthritis not only evolves from wear-and-tear but is also inherent to systemic components is widely accepted. Systemic inflammation as in obesity or dyslipidemia was shown to negatively influence osteoarthritis of non-weight bearing joints such as joints in the hands. Hand osteoarthritis develops frequently in postmenopausal women. Menopausal transition in women mainly occurs from age 45 to 54, involves changes in sex hormones, and is associated with vasomotor and genitourinary symptoms mainly treated with systemic and vaginal hormone replacement therapy, respectively. Further associated symptoms such as joint pain or osteoarthritis (symptomatically treated with painkillers) or increased lipid levels (mainly treated with statins to reduce the risk of a cardiovascular event) are less known to the general public but carry a high disease burden. By means of epidemiologic studies using women’s primary care health records in the United Kingdom, this thesis aimed to help find drugs potentially delaying hand osteoarthritis onset by describing and assessing drugs treating symptoms evolving in menopausal transition in association with hand osteoarthritis. Potential negative associations may result in a decreased burden of this incurable disease. In a first descriptive study, we described incidence rates of hand osteoarthritis and of hormone replacement therapy use in women aged 40 to 69 years. We observed that rates of hormone replacement therapy initiation and of new diagnoses of hand osteoarthritis behaved inversely over time and uniformly in 5-year age groups between 40 to 54 years but not in older age groups. Hormone replacement therapy initiation rates shaped in a skewed Gaussian curve with a tail in older age groups while onset of hand osteoarthritis plateaued from age 55. In a second nested case-control study, observing women from age 45 longitudinally, we assessed the association between systemic hormone replacement therapy initiation and hand osteoarthritis overall and in women with recorded menopause only as recorded menopause was a major confounder. Most hand osteoarthritis cases occurred shortly after menopause, therefore, we assessed the timing of hormone replacement therapy initiation relative to menopause in current users as well as of hormone replacement therapy cessation relative to hand osteoarthritis diagnoses in past users, compared to non-users. The association between hormone replacement therapy use and hand osteoarthritis yielded an increased risk of hand osteoarthritis of 32%. However, in women with recorded menopause, the risk of hand osteoarthritis in hormone replacement therapy users disappeared compared to non users. Furthermore, we observed a 28% decreased risk of hand osteoarthritis if hormone replacement therapy was initiated around menopause and used continuously, compared to non-users. This potential beneficial effect diminished the later hormone replacement therapy was initiated. However, we also observed a statistically non-significant 25% increased risk of hand osteoarthritis shortly after therapy cessation. In a third cohort study, in women aged 45 to 64 years, we assessed the association between statin initiation and hand osteoarthritis and between statin initiation and generalized osteoarthritis (i.e. multiple joints affected, hand osteoarthritis is usually part of generalized osteoarthritis), overall, stratified by age, and by pre-existing dyslipidemia. Furthermore, we used psoriasis and tinnitus as negative control outcomes to control for confounding by differential menopause onset (psoriasis) and healthcare seeking behavior (psoriasis, tinnitus). We observed that statin use was neither associated with hand osteoarthritis nor with generalized osteoarthritis irrespective of age or pre existing dyslipidemia. The use of negative control outcomes corroborated this finding. Our results support the existing hypothesis that menopause is a risk factor of hand osteoarthritis. However, it is likely not the only risk factor for hand osteoarthritis because otherwise we would have expected hand osteoarthritis incidence rates to decline similarly to those of hormone replacement therapy use among older age groups. Furthermore, our results suggest that timely initiation of hormone replacement therapy relative to menopause may be crucial for a potential delay of hand osteoarthritis onset to at least after hormone replacement therapy cessation. Finally, our results suggest that the lipid lowering effect of statins does not seem to translate into a reduced risk of hand osteoarthritis in peri to postmenopausal women.

The role of sex and systemic inflammation in the development of cardiovascular disease in osteoarthritis: A population-based cohort study using the CLSA.

Background: Knee osteoarthritis (OA) is a prevalent degenerative joint disease characterized by the degeneration of joint cartilage. Knee OA leads to pain, stiffness, swelling, and decreased mobility, significantly impacting the quality of life of affected people. Advanced-stage osteoarthritis often necessitates surgical intervention due to poor response to conventional treatments, such as intra-articular hyaluronic acid (HA). Carboxymethyl-chitosan (CM-C), an emerging therapeutic agent, has shown potential in reducing inflammation, improving lubrication, and enhancing joint function. This study aimed to evaluate the long-term efficacy of CM-C injections in patients with advanced knee osteoarthritis, non-responders to HA. Methods: This retrospective study included 16 patients (mean age: 79.56 years) with Kellgren-Lawrence grade 3-4 knee OA treated with a single intra-articular injection of CM-C. Pain and functional outcomes were assessed using the Visual Analogue Scale (VAS) and Knee Injury and Osteoarthritis Outcome Score (KOOS) at baseline (T0), one month (T1), three months (T2), six months (T3), and twelve months (T4). Results: Significant pain reduction was observed at early follow up, (VAS: T1 p = 0.0002, T2 p = 0.0265; KOOS Pain: T1 p = 0.0014). However, pain partially returned by T3 and T4. KOOS activities of daily living (p = 0.0005), QoL (p = 0.0396), and Sport and Free Time (p = 0.0367) subscales showed significant improvement at T1, though worsening trends were observed in subsequent follow up with raw values suggesting persistent benefits. Strong negative correlations were found between VAS and KOOS subscales at various follow ups. Conclusions: A single CM-C injection demonstrated early pain relief and functional improvement in advanced knee OA for non-responders to HA. However, the long-term effects may diminish over time, necessitating a careful consideration of re-treatment strategies or combined therapies.

Received October 16, 2004; revision received June 4, 2005; accepted June 7, 2005. Atherosclerosis is a multifactorial process that commences in childhood but manifests clinically later in life. Atherosclerosis is increasingly considered an immune system–mediated process of the vascular system. The presence of macrophages and activated lymphocytes within atherosclerotic plaques supports the concept of atherosclerosis as an immune system–mediated inflammatory disorder.1,2 Inflammation can aggravate atherosclerosis via different mechanisms secondary to autoimmunity, infectious diseases, and other proatherogenic changes that occur during the inflammatory state. Autoimmune rheumatic diseases (AIRDs) are associated with higher rates of cardiovascular morbidity and mortality, primarily secondary to accelerated atherosclerosis. This phenomenon can be attributed to traditional risk factors for atherosclerosis and use of specific drugs, such as corticosteroids, but also might be the result of other autoimmune and inflammatory mechanisms that are aggravated in AIRDs. Several AIRDs exhibit increased overt cardiovascular disease (CVD) prevalence as well as findings of advanced subclinical atherosclerosis, which may precede the appearance of a clinical disease and thus be a target of early identification and preventive therapy. Cells of the immune system can be found within atherosclerotic plaques, which suggests that they have a role in the atherogenic process. Their migration and activation within the plaques can be secondary to various stimuli, including infectious agents.3 These cells probably aggravate atherosclerosis, because CD4+ and CD8+ T-cell depletion reduced fatty streak formation in C57BL/6 mice. In addition, after crossing of apolipoprotein E (ApoE)-knockout mice with immunodeficient scid/scid mice, the offspring had a 73% reduction in aortic fatty streak lesions compared with the immunocompetent apoE mice. Moreover, when CD4+ T cells were transferred from the immunocompetent to the immunodeficient mice, they increased lesion area in the latter by 164%.4 It is therefore not surprising that as in autoimmune diseases, the cellular components …

Atherosclerosis is an inflammatory disease and the major cause of cardiovascular disease (CVD) in general. Atherosclerotic plaques are characterized by the presence of activated immune competent cells, but antigens and underlying mechanisms causing this immune activation are not well defined. During recent years and with improved treatment of acute disease manifestations, it has become clear that the risk of CVD is very high in a prototypic autoimmune disease, systemic lupus erythematosus (SLE). SLE-related CVD and atherosclerosis are important clinical problems but may in addition also shed light on how immune reactions are related to premature atherosclerosis and atherothrombosis. A combination of traditional and nontraditional risk factors, including dyslipidaemia (and to a varying degree hypertension, diabetes and smoking), inflammation, antiphospholipid antibodies (aPL) and lipid oxidation are related to CVD in SLE. Premature atherosclerosis in some form leading to atherothrombosis is likely to be a major underlying mechanism, though distinctive features if any, of SLE-related atherosclerosis when compared with 'normal' atherosclerosis are not clear. One interesting possibility is that factors such as inflammation or aPL make atherosclerotic lesions in autoimmune disease more prone to rupture than in 'normal' atherosclerosis. Whether premature atherosclerosis is a general feature of SLE or only affects a subgroup of patients remains to be demonstrated. Treatment of SLE patients should also include a close monitoring of traditional risk factors for CVD. In addition, attention should also be paid to nontraditional risk factors such as inflammation and SLE-related factors such as aPL. Hopefully novel therapeutic principles will be developed that target the causes of the inflammation and immune reactions present in atherosclerotic lesions.

To the Editor: Recently, an update from the Framingham study could not find uric acid to be an independent risk factor for cardiovascular disease.1 While serum uric acid levels correlated significantly with the risk for cardiovascular events and mortality in women, this relationship became insignificant after factoring for 11 additional variables including hypertension, body mass index, and diuretic use.1 Both the authors1 and an accompanying editorial2 interpreted these findings as showing that uric acid is not a true risk factor for cardiovascular disease and that it should not be routinely measured to assess cardiovascular risk. The careful analysis of the Framingham study is to be commended, but one must be cautious in the interpretation of the findings. While some epidemiologic studies such as the current one have not been able to show uric acid to be an independent risk factor for cardiovascular disease, other studies using multivariate analyses3 4 5 6 came to an opposite conclusion. Another recently completed study, the Worksite,7 also found uric acid to be an independent risk factor for cardiovascular events and mortality, especially in women. One might look for subtle explanations to account for the differences in these various studies, as Culleton et al1 have attempted, but most of the studies examined the very same variables. A more central issue is whether one should interpret the finding that a risk factor is not statistically independent to mean that it should not be considered biologically important. We would argue that this is not true in several situations. First, if the risk factors are causally linked, then one may not be able to show that they are independent of each other. For example, although smoking is a risk factor for mortality, it might no longer be independent if it is …

Osteoarthritis (OA) remains a highly prevalent disorder, both in North America and globally1,2,3. According to the US National Arthritis Data Workgroup, approximately 27 million Americans were estimated, based on the 2005 population size, to have clinical evidence of OA1. Given that the prevalence of OA rises with increasing age, the national burden of OA continues to expand4. When moderate to severe OA affects the lower extremity, particularly at the knee and hip joints, the related pain and stiffness has a tremendous influence upon virtually all ambulatory activities involved in daily living5. Further, in the circumstance when symptoms resulting from joint space narrowing, cartilage degeneration, and osteophyte formation become inadequately controlled by conventional nonmedicinal and pharmacologic interventions, the patient and physician, working together, broach the subject of surgical intervention to correct the underlying joint disorder. They seek resolution to the pain and functional impairment, and an optimal restoration to a full, vital functional capacity7. Over the last 50 years, several notable demographic variables and modifiable host factors have been examined as potential risk factors for incident and prevalent OA. For example, there is clear evidence from population-based studies that age is related to OA risk. Not only are older adults at greater risk than their younger counterparts to develop OA, but the risk of incident OA, specifically at the knee, continues to rise into the septuagenarian and octogenarian decades of the life span4. In addition, gender is clearly related to risk of disease, with women experiencing higher rates of OA than men, at the hand, knee, and hip joints, after age 40 and beyond1. … Address correspondence to Dr. Gelber. E-mail: agelber{at}jhmi.edu

- Knee osteoarthritis (OA) affects millions of individuals globally and is characterized by the degeneration of joint cartilage and underlying bone. This condition leads to pain, limited movement, and reduced mobility. Accurate and timely assessment of OA severity is critical for effective clinical management. In this study, we address the challenge of predicting knee OA severity using X-ray images by leveraging deep learning, particularly convolutional neural networks (CNNs). A novel ensemble model is proposed, combining the strengths of multiple architectures to improve diagnostic accuracy. Specifically, the model integrates feature extraction from EfficientNet and DenseNet, along with other ensemble techniques, achieving an impressive accuracy of 94.76%. The high performance of the ensemble model highlights its robustness in classifying OA severity and presents a reliable, precise approach for health assessment. This systematic methodology demonstrates the potential of deep learning to significantly enhance diagnostic accuracy and support informed clinical decision-making in knee osteoarthritis care. Keywords - Knee osteoarthritis (OA), severity grading, DenseNet, EfficientNet, Ensemble model

Objectives: Osteoarthritis (OA) is a joint disease characterized by degeneration of joint cartilage and is a significant cause of severe joint pain, physical disability, and impaired quality of life in the aging population. Celastrol, a Chinese herbal medicine, has attracted wide interests because of its anti-inflammatory effects on a variety of diseases. This study aimed to investigate the effect of celastrol on OA as well as the mechanisms in vivo and in vitro.Methods: A rat knee OA model was established using “medial collateral ligament transection (MCLT) + partial meniscectomy (pMMT)”. Eight weeks after surgery, the OA rats started to receive intra-articular injection of celastrol (1 mg/kg) once a week. Safranin O-fast green (S&F) and hematoxylin and eosin (H&E) staining were used to estimate histopathological changes. Micro-CT was used to evaluate bone volume of the subchondral bone of the knee joint. Chondrocytes were isolated from the knee cartilage of rats and OA patients. Enzyme linked immunosorbent assay (ELISA), Western Blot (WB), Polymerase Chain Reaction (PCR), and Immunohistochemistry (IHC) were used to detect the expression of inflammatory factors and stromal proteins, respectively.Results: We found that celastrol treatment significantly delayed the progression of cartilage damage with a significant reduction in osteophyte formation and bone resorption in OA rat model. In IL-1β-stimulated rat chondrocytes, celastrol significantly suppressed the production of inflammatory factors such as cyclooxygenase-2 (COX2), interleukin-6 (IL-6), and prostaglandin E2 (PEG2), and reduced IL-1β-induced matrix degradation by down-regulating the expression of matrix metalloproteinase 13 (MMP13). In addition, we found that toll-like receptor 2 (TLR2) was up-regulated in OA patients and rat knee OA models, while celastrol inhibited TLR2 signal and its downstream nuclear factor-kappa B (NF-κB) phosphorylation.Conclusion: In summary, celastrol may improve OA by inhibiting the TLR2/NF-κB signaling pathway, which provides innovative strategies for the treatment of OA.

Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e3 1. About These Statistics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .e7 2. American Heart Association's 2020 Impact Goals. . . . . . . . . . . . . . . . .e10 3. Cardiovascular Diseases . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . .e21 4. Subclinical Atherosclerosis . . . . . . . . . . . . . . . . . . . . .e45 5. Coronary Heart Disease, Acute Coronary Syndrome, and Angina Pectoris . . . . . . . . .e54 6. Stroke (Cerebrovascular Disease) . . . . . . . . . . . . . . . . . . . . . . . . . . . .e68 7. High Blood Pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . .e88 8. Congenital Cardiovascular Defects . . . . . . . . . . . . . . . . . . . . . . . . . . . .e97 9. Cardiomyopathy and Heart Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . .e102 10. Disorders …

Association between aspartic acid repeat polymorphism of the asporin gene and susceptibility to knee osteoarthritis: a genetic meta-analysis

Background: Osteoarthritis (OA) is a heterogeneous joint disorder traditionally considered mechanically driven; however, evidence indicates that inflammatory mechanisms contribute to symptom expression. Exploratory analyses of peripheral biomarkers may provide insights into systemic inflammation in symptomatic knee OA, but formal phenotypic validation requires dedicated clustering or longitudinal studies. Objective: To examine associations between clinical pain, functional impairment, and circulating inflammatory biomarkers in patients with knee OA compared with healthy controls. Methods: In this prospective, single-center study, patients aged 40–80 years with radiographically confirmed knee OA and chronic knee pain were compared with age- and sex-matched healthy controls. Pain intensity and functional status were assessed using the Visual Analogue Scale (VAS) and the Knee Injury and Osteoarthritis Outcome Score (KOOS). Circulating inflammatory biomarkers, including cytokines and matrix metalloproteinases, were quantified using multiplex immunoassays. Statistical analyses included adjusted linear regression models, with age and BMI as covariates, and multiple testing correction using the Benjamini–Hochberg procedure (FDR alpha error 5%). Results: OA patients exhibited higher circulating levels of TNF-α, IL-6, IL-8, MMP-1, MMP-3, TNFSF13, TNFSF13B, and pentraxin-3 compared with controls (p < 0.01). No significant sex differences were observed. KOOSs correlated with IL-6 and IL-10 levels, suggesting an association between systemic inflammatory activity and functional limitation. All findings are presented as exploratory and associative. Conclusions: Patients with knee OA display systemic inflammatory biomarker differences associated with pain and functional impairment. These results support the role of inflammation in OA symptoms within an exploratory framework. Larger, longitudinal studies are warranted to validate these observations.