Sex Differences in Pulmonary Hypertension and Associated Right Ventricular Dysfunction.

Background: Prior studies have established the impact of sex differences on pulmonary arterial hypertension (PAH). However, it remains unclear whether these sex differences extend to other hemodynamic subtypes of pulmonary hypertension (PH). Methods: We examined sex differences in PH and hemodynamic PH subtypes in a hospital-based cohort of individuals who underwent right heart catheterization between 2005-2016. We utilized multivariable linear regression to assess the association of sex with hemodynamic indices of RV function [PA pulsatility index (PAPi), RV stroke work index (RVSWI), and right atrial: pulmonary capillary wedge pressure ratio (RA:PCWP)]. We then used Cox regression models to examine the association between sex and clinical outcomes among those with PH. Results: Among 5208 individuals with PH (mean age 64 years, 39% women), there was no significant sex difference in prevalence of PH overall. However, when stratified by PH subtype, 31% of women vs 22% of men had pre-capillary (P<0.001), 39% vs 51% had post-capillary (P=0.03), and 30% vs 27% had mixed PH (P=0.08). Female sex was associated with better RV function by hemodynamic indices, including higher PAPi and RVSWI, and lower RA:PCWP ratio (P<0.001 for all). Over 7.3 years of follow-up, female sex was associated with a lower risk of heart failure hospitalization (HR 0.83, CI 95% CI 0.74- 0.91, p value <0.001). Conclusions: Across a broad hospital-based sample, more women had pre-capillary and more men had post-capillary PH. Compared with men, women with PH had better hemodynamic indices of RV function and a lower risk of HF hospitalization. CLINICAL PERSPECTIVE: What Is New? Although sex differences have been explored in pulmonary arterial hypertension, sex differences across pulmonary hypertension (PH) in broader samples inclusive of all hemodynamic subtypes remain less well definedWe delineate sex differences in hemodynamic subtypes of PH and associated right ventricular function in a large, heterogenous, hospital-based sample of individuals who underwent right heart catheterizationSex has a significant impact on prevalence of PH across hemodynamic subtypes as well as associated RV function What Are the Clinical Implications? Understanding sex differences across different PH hemodynamic subtypes is paramount to refining risk stratification between men and womenFurther elucidating sex differences in associated RV function and clinical outcomes may aid in developing sex-specific therapies or management strategies to improve clinical outcomes.

Uncovering Unrecognized Heart Failure With Preserved Ejection Fraction Among Individuals With Obesity and Dyspnea.

BACKGROUND: Although heart failure with preserved ejection fraction (HFpEF) has become the predominant heart failure subtype, it remains clinically under-recognized. HFpEF diagnosis is particularly challenging in the setting of obesity given the limitations of natriuretic peptides and resting echocardiography. We examined invasive and noninvasive HFpEF diagnostic criteria among individuals with obesity and dyspnea without known cardiovascular disease to determine the prevalence of hemodynamic HFpEF in the community. METHODS: Research volunteers with dyspnea and obesity underwent resting echocardiography; participants with possible pulmonary hypertension qualified for invasive cardiopulmonary exercise testing. HFpEF was defined using rest or exercise pulmonary capillary wedge pressure criteria (≥15 mm Hg or Δpulmonary capillary wedge pressure/Δcardiac output slope, >2.0 mm Hg·L-1·min-1). RESULTS: Among n=78 participants (age, 53±13 years; 65% women; body mass index, 37.3±6.8 kg/m2), 40 (51%) met echocardiographic criteria to undergo invasive cardiopulmonary exercise testing. In total, 24 participants (60% among the cardiopulmonary exercise testing group, 31% among the total sample) were diagnosed with HFpEF by rest or exercise pulmonary capillary wedge pressure (n=12) or exercise criteria (n=12). There were no differences in NT-proBNP (N-terminal pro-B-type natriuretic peptide; 79 [62-104] versus 73 [57-121] pg/mL) or resting echocardiography (mitral E/e' ratio, 9.1±3.1 versus 8.0±2.7) among those with versus without HFpEF (P>0.05 for all). Distributions of HFpEF diagnostic scores were similar, with the majority classified as intermediate risk (100% versus 93.75% [H2FPEF] and 87.5% versus 68.75% [HFA-PEFF (Heart Failure Association Pretest assessment, echocardiography and natriuretic peptide, functional testing, and final etiology)] in those with versus without HFpEF). CONCLUSIONS: Among adults with obesity and dyspnea without known cardiovascular disease, at least a third had clinically unrecognized HFpEF uncovered on invasive cardiopulmonary exercise testing. Clinical, biomarker, resting echocardiography, and diagnostic scores were similar among those with and without HFpEF. These results suggest clinical underdiagnosis of HFpEF among individuals with obesity and dyspnea and highlight limitations of noninvasive testing in the identification of HFpEF.

The association of eicosanoids and eicosanoid-related metabolites with pulmonary hypertension.

BACKGROUND: Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), yet their role remains incompletely understood. METHODS: We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients. RESULTS: Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11ß-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13(S)-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH. CONCLUSIONS: Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.

Obesity-Related Biomarkers Are Associated With Exercise Intolerance and HFpEF.

BACKGROUND: Obesity and adiposity are associated with an increased risk of heart failure with preserved ejection fraction (HFpEF); yet, specific underlying mechanisms remain unclear. We sought to examine the association of obesity-related biomarkers including adipokines (leptin, resistin, adiponectin), inflammatory markers (CRP [C-reactive protein], IL-6 [interleukin-6]), and insulin resistance (HOMA-IR) with HFpEF status, exercise capacity, and cardiovascular outcomes. METHODS: We studied 509 consecutive patients with left ventricular ejection fraction ≥50% and chronic dyspnea, who underwent clinically indicated cardiopulmonary exercise test with invasive hemodynamic monitoring between 2006 and 2017. We defined HFpEF based on the presence of elevated left ventricular filling pressures at rest or during exercise. Fasting blood samples collected at the time of the cardiopulmonary exercise test were used to assay obesity-related biomarkers. We examined the association of log-transformed biomarkers with HFpEF status and exercise traits using multivariable-adjusted logistic regression models. RESULTS: We observed associations of obesity-related biomarkers with measures of impaired exercise capacity including peak VO2 (P≤0.002 for all biomarkers). The largest effect size was seen with leptin, where a 1-SD higher leptin was associated with a 2.35 mL/kg per min lower peak VO2 (ß, -2.35±0.19; P<0.001). In addition, specific biomarkers were associated with distinct measures of exercise reserve including blood pressure (homeostatic model assessment of insulin resistance, leptin, adiponectin; P≤0.002 for all), and chronotropic response (CRP, IL-6, homeostatic model assessment of insulin resistance, leptin, and resistin; P<0.05 for all). Our findings suggest that among the obesity-related biomarkers studied, higher levels of leptin and CRP are independently associated with increased odds of HFpEF, with odds ratios of 1.36 (95% CI, 1.09-1.70) and 1.25 (95% CI, 1.03-1.52), respectively. CONCLUSIONS: Specific obesity-related pathways including inflammation, adipokine signaling, and insulin resistance may underlie the association of obesity with HFpEF and exercise intolerance.

Identifying high risk clinical phenogroups of pulmonary hypertension through a clustering analysis.

INTRODUCTION: The classification and management of pulmonary hypertension (PH) is challenging due to clinical heterogeneity of patients. We sought to identify distinct multimorbid phenogroups of patients with PH that are at particularly high-risk for adverse events. METHODS: A hospital-based cohort of patients referred for right heart catheterization between 2005-2016 with PH were included. Key exclusion criteria were shock, cardiac arrest, cardiac transplant, or valvular surgery. K-prototypes was used to cluster patients into phenogroups based on 12 clinical covariates. RESULTS: Among 5208 patients with mean age 64±12 years, 39% women, we identified 5 distinct multimorbid PH phenogroups with similar hemodynamic measures yet differing clinical outcomes: (1) "young men with obesity", (2) "women with hypertension", (3) "men with overweight", (4) "men with cardiometabolic and cardiovascular disease", and (5) "men with structural heart disease and atrial fibrillation." Over a median follow-up of 6.3 years, we observed 2182 deaths and 2002 major cardiovascular events (MACE). In age- and sex-adjusted analyses, phenogroups 4 and 5 had higher risk of MACE (HR 1.68, 95% CI 1.41-2.00 and HR 1.52, 95% CI 1.24-1.87, respectively, compared to the lowest risk phenogroup 1). Phenogroup 4 had the highest risk of mortality (HR 1.26, 95% CI 1.04-1.52, relative to phenogroup 1). CONCLUSIONS: Cluster-based analyses identify patients with PH and specific comorbid cardiometabolic and cardiovascular disease burden that are at highest risk for adverse clinical outcomes. Interestingly, cardiopulmonary hemodynamics were similar across phenogroups, highlighting the importance of multimorbidity on clinical trajectory. Further studies are needed to better understand comorbid heterogeneity among patients with PH.

Plasma Proteomics of COVID-19-Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

To gain insights into the mechanisms driving cardiovascular complications in COVID-19, we performed a case-control plasma proteomics study in COVID-19 patients. Our results identify the senescence-associated secretory phenotype, a marker of biological aging, as the dominant process associated with disease severity and cardiac involvement. FSTL3, an indicator of senescence-promoting Activin/TGFß signaling, and ADAMTS13, the von Willebrand Factor-cleaving protease whose loss-of-function causes microvascular thrombosis, were among the proteins most strongly associated with myocardial stress and injury. Findings were validated in a larger COVID-19 patient cohort and the hamster COVID-19 model, providing new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Association of 71 cardiovascular disease-related plasma proteins with pulmonary function in the community.

RATIONALE: It has been speculated that shared mechanisms underlie respiratory and cardiovascular diseases (CVD) including systemic inflammation or mutual risk factors. In this context, we sought to examine the associations of CVD-related plasma proteins with lung function as measured by spirometry in a large community-based cohort of adults. METHODS: The study included 5777 Framingham Heart Study participants who had spirometry and measurement of 71 CVD-related plasma proteins. The association of plasma proteins with lung function was assessed cross-sectionally and longitudinally using models accounting for familial correlations. Linear mixed models were used for the following measurements: FEV1%predicted, FVC%predicted, and FEV1/FVC ratio with secondary analyses examining obstructive and restrictive physiology at baseline and their new onset during follow up. MEASUREMENTS AND MAIN RESULTS: Among the 71 CVD-related plasma proteins, 13 proteins were associated in cross-sectional analyses with FEV1%predicted, 17 proteins were associated with FVC%predicted, and 1 protein was associated with FEV1/FVC. The proteins with the greatest inverse relations to FEV1%predicted and FVC%predicted included leptin, adrenomedullin, and plasminogen activator inhibitor-1; in contrast there were three proteins with positive relations to FEV1%predicted and FVC%predicted including insulin growth factor binding protein 2, tetranectin, and soluble receptor for advanced glycation end products. In longitudinal analyses, three proteins were associated with longitudinal change in FEV1 (ΔFEV1) and four with ΔFVC; no proteins were associated with ΔFEV1/FVC. CONCLUSION: Our findings highlight CVD-related plasma proteins that are associated with lung function including markers of inflammation, adiposity, and fibrosis, representing proteins that may contribute both to respiratory and CVD risk.

Association of Pulmonary Artery Pulsatility Index With Adverse Cardiovascular Events Across a Hospital-Based Sample.

BACKGROUND: The pulmonary artery pulsatility index (PAPi), calculated from the ratio of the pulmonary artery pulse pressure to right atrial pressure, is a predictor of right ventricular failure after inferior myocardial infarction and left ventricular assist device implantation. Whether PAPi is associated with adverse outcomes across a heterogeneous population is unknown. METHODS: We examined consecutive patients undergoing right heart catheterization between 2005 and 2016 in a hospital-based cohort. Multivariable Cox models were utilized to examine the association between PAPi and all-cause mortality, major adverse cardiac events, and heart failure hospitalizations. RESULTS: We studied 8285 individuals (mean age 63 years, 39% women) with median PAPi across quartiles 1.7, 2.8, 4.2, and 8.7, who were followed over a mean follow-up of 6.7±3.3 years. Patients in the lowest PAPi quartile had a 60% greater risk of death compared with the highest quartile (multivariable-adjusted hazard ratio, 1.60 [95% CI, 1.36-1.88], P<0.001) and a higher risk of major adverse cardiac events and heart failure hospitalizations (hazard ratio, 1.80 [95% CI, 1.56-2.07], P<0.001 and hazard ratio, 2.08 [95% CI, 1.76-2.47], P<0.001, respectively). Of note, patients in quartiles 2 and 3 also had increased risk of cardiovascular events compared with quartile 4 (multivariable P<0.05 for all). CONCLUSIONS: Compared with the highest PAPi quartile, patients in PAPi quartiles 1 to 3 had a greater risk of all-cause mortality, major adverse cardiac events, and heart failure hospitalizations, with greatest risk observed in the lowest quartile. A low PAPi, even at values higher than previously reported, may serve an important role in identifying high-risk individuals across a broad spectrum of cardiovascular disease.

The association of lung function and pulmonary vasculature volume with cardiorespiratory fitness in the community.

BACKGROUND: Cardiorespiratory fitness is not limited by pulmonary mechanical reasons in the majority of adults. However, the degree to which lung function contributes to exercise response patterns among ostensibly healthy individuals remains unclear. METHODS: We examined 2314 Framingham Heart Study participants who underwent cardiopulmonary exercise testing (CPET) and pulmonary function testing. We investigated the association of forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), FEV1/FVC and diffusing capacity of the lung for carbon monoxide (D LCO) with the primary outcome of peak oxygen uptake (V'O2 ) along with other CPET parameters using multivariable linear regression. Finally, we investigated the association of total and peripheral pulmonary blood vessel volume with peak V'O2 . RESULTS: We found lower FEV1, FVC and D LCO were associated with lower peak V'O2 . For example, a 1 L lower FEV1 and FVC was associated with a 7.1% (95% CI 5.1-9.1%) and 6.0% (95% CI 4.3-7.7%) lower peak V'O2 , respectively. By contrast, FEV1/FVC was not associated with peak V'O2 . Lower lung function was associated with lower oxygen uptake efficiency slope, oxygen pulse slope, V'O2 at anaerobic threshold (AT), minute ventilation (V'E) at AT and breathing reserve. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V'O2 . CONCLUSIONS: In a large, community-based cohort of adults, we found lower FEV1, FVC and D LCO were associated with lower exercise capacity, as well as oxygen uptake efficiency slope and ventilatory efficiency. In addition, lower total and peripheral pulmonary blood vessel volume were associated with lower peak V'O2 . These findings underscore the importance of lung function and blood vessel volume as contributors to overall exercise capacity.

Plasma Proteomics of COVID-19 Associated Cardiovascular Complications: Implications for Pathophysiology and Therapeutics.

Cardiovascular complications are common in COVID-19 and strongly associated with disease severity and mortality. However, the mechanisms driving cardiac injury and failure in COVID-19 are largely unknown. We performed plasma proteomics on 80 COVID-19 patients and controls, grouped according to disease severity and cardiac involvement. Findings were validated in 305 independent COVID-19 patients and investigated in an animal model. Here we show that senescence-associated secretory proteins, markers of biological aging, strongly associate with disease severity and cardiac involvement even in age-matched cohorts. FSTL3, an indicator of Activin/TGFß signaling, was the most significantly upregulated protein associated with the heart failure biomarker, NTproBNP (ß = 0.4;p adj =4.6x10 - 7 ), while ADAMTS13, a vWF-cleaving protease whose loss-of-function causes microvascular thrombosis, was the most downregulated protein associated with myocardial injury (ß=-0.4;p adj =8x10 - 7 ). Mendelian randomization supported a causal role for ADAMTS13 in myocardial injury. These data provide important new insights into the pathophysiology of COVID-19 cardiovascular complications with therapeutic implications.

Association of obesity-related inflammatory pathways with lung function and exercise capacity.

BACKGROUND: Obesity has multifactorial effects on lung function and exercise capacity. The contributions of obesity-related inflammatory pathways to alterations in lung function remain unclear. RESEARCH QUESTION: To examine the association of obesity-related inflammatory pathways with pulmonary function, exercise capacity, and pulmonary-specific contributors to exercise intolerance. METHOD: We examined 695 patients who underwent cardiopulmonary exercise testing (CPET) with invasive hemodynamic monitoring at Massachusetts General Hospital between December 2006-June 2017. We investigated the association of adiponectin, leptin, resistin, IL-6, CRP, and insulin resistance (HOMA-IR) with pulmonary function and exercise parameters using multivariable linear regression. RESULTS: Obesity-related inflammatory pathways were associated with worse lung function. Specifically, higher CRP, IL-6, and HOMA-IR were associated with lower percent predicted FEV1 and FVC with a preserved FEV1/FVC ratio suggesting a restrictive physiology pattern (P ≤ 0.001 for all). For example, a 1-SD higher natural-logged CRP level was associated with a nearly 5% lower percent predicted FEV1 and FVC (beta -4.8, s.e. 0.9 for FEV1; beta -4.9, s.e. 0.8 for FVC; P < 0.0001 for both). Obesity-related inflammatory pathways were associated with worse pulmonary vascular distensibility (adiponectin, IL-6, and CRP, P < 0.05 for all), as well as lower pulmonary artery compliance (IL-6 and CRP, P ≤ 0.01 for both). INTERPRETATION: Our findings highlight the importance of obesity-related inflammatory pathways including inflammation and insulin resistance on pulmonary spirometry and pulmonary vascular function. Specifically, systemic inflammation as ascertained by CRP, IL-6 and insulin resistance are associated with restrictive pulmonary physiology independent of BMI. In addition, inflammatory markers were associated with lower exercise capacity and pulmonary vascular dysfunction.

Sex differences in inflammatory markers in patients hospitalized with COVID-19 infection: Insights from the MGH COVID-19 patient registry.

BACKGROUND: Men are at higher risk for serious complications related to COVID-19 infection than women. More robust immune activation in women has been proposed to contribute to decreased disease severity, although systemic inflammation has been associated with worse outcomes in COVID-19 infection. Whether systemic inflammation contributes to sex differences in COVID-19 infection is not known. STUDY DESIGN AND METHODS: We examined sex differences in inflammatory markers among 453 men (mean age 61) and 328 women (mean age 62) hospitalized with COVID-19 infection at the Massachusetts General Hospital from March 8 to April 27, 2020. Multivariable linear regression models were used to examine the association of sex with initial and peak inflammatory markers. Exploratory analyses examined the association of sex and inflammatory markers with 28-day clinical outcomes using multivariable logistic regression. RESULTS: Initial and peak CRP were higher in men compared with women after adjustment for baseline differences (initial CRP: ß 0.29, SE 0.07, p = 0.0001; peak CRP: ß 0.31, SE 0.07, p<0.0001) with similar findings for IL-6, PCT, and ferritin (p<0.05 for all). Men had greater than 1.5-greater odds of dying compared with women (OR 1.71, 95% CI 1.04-2.80, p = 0.03). Sex modified the association of peak CRP with both death and ICU admission, with stronger associations observed in men compared with women (death: OR 9.19, 95% CI 4.29-19.7, p <0.0001 in men vs OR 2.81, 95% CI 1.52-5.18, p = 0.009 in women, Pinteraction = 0.02). CONCLUSIONS: In a sample of 781 men and women hospitalized with COVID-19 infection, men exhibited more robust inflammatory activation as evidenced by higher initial and peak inflammatory markers, as well as worse clinical outcomes. Better understanding of sex differences in immune responses to COVID-19 infection may shed light on the pathophysiology of COVID-19 infection.

The role of obesity in inflammatory markers in COVID-19 patients.

Obesity has emerged as a significant risk factor for severe COVID-19 worldwide. Given both COVID-19 infection and obesity have been associated with increased systemic inflammation, we evaluated inflammatory markers in obese and non-obese individuals hospitalized for COVID-19 at Massachusetts General Hospital. We hypothesized that obese patients would have a more exuberant inflammatory response as evidenced by higher initial and peak inflammatory markers along with worse clinical outcomes. Of the 781 patients, 349 were obese (45%). Obese individuals had higher initial and peak levels of CRP and ESR as well as higher peak d-dimer (P < 0.01 for all) in comparison to non-obese individuals, while. IL-6 and ferritin were similar. In addition, obese individuals had a higher odds of requiring vasopressor use (OR 1.54, 95% CI 1.00-2.38, P = 0.05), developing hypoxemic respiratory failure (OR 1.58, 95% CI 1.04-2.40, P = 0.03) and death (OR 2.20, 95% CI 1.31-3.70, P = 0.003) within 28 days of presentation to care. Finally, higher baseline levels of CRP and D-dimer were associated with worse clinical outcomes even after adjustment for BMI. Our findings suggest greater disease severity in obese individuals is characterized by more exuberant inflammation.

Use of Fellow as Clinical Teacher (FACT) Curriculum for Teaching During Consultation: Effect on Subspecialty Fellow Teaching Skills.

BACKGROUND: Subspecialty consultation in inpatient care is increasing. Teaching by subspecialty fellows in a consultation setting may be an important source of work-based learning for students and residents. However, teaching and evaluation of learners in this context may be challenging due to personal and systems-based barriers. OBJECTIVE: We developed and evaluated a framework designed to overcome barriers to teaching and to improve fellow teaching skills during inpatient consultation. METHODS: The PARTNER (Partner with resident, Assess the learner, Reinforce positives, Teaching objectives, New knowledge, Execute recommendations, Review) framework was delivered to rheumatology and pulmonary and critical care medicine fellows at 3 academic medical centers as part of a 2-session Fellow as Clinical Teacher (FACT) curriculum. Fellows' teaching skills were evaluated using an objective structured teaching exercise (OSTE) pre- and postcurriculum, and at the end of the academic year. Self-assessment surveys were used to evaluate fellows' self-perception of teaching skills. RESULTS: Twelve of 16 eligible fellows (75%) participated in the program and completed 73 OSTE cases. Teaching skills measured by OSTEs and self-assessment surveys improved after administration of the FACT curriculum. There was no significant skill decay at the end-of-year evaluation. The curriculum was rated highly, and 73% (8 of 11) of fellows stated they would teach more frequently as a result of the intervention. CONCLUSIONS: The FACT curriculum was practical and feasible, and significantly improved fellows' teaching skills teaching during inpatient consultation.

Conditional Macrophage Depletion Increases Inflammation and Does Not Inhibit the Development of Osteoarthritis in Obese Macrophage Fas-Induced Apoptosis-Transgenic Mice.

OBJECTIVE: To investigate whether short-term, systemic depletion of macrophages can mitigate osteoarthritis (OA) following injury in the setting of obesity. METHODS: CSF-1R-GFP+ macrophage Fas-induced apoptosis (MaFIA)-transgenic mice that allow conditional depletion of macrophages were placed on a high-fat diet and underwent surgery to induce knee OA. A small molecule (AP20187) was administrated to deplete macrophages in MaFIA mice. The effects of macrophage depletion on acute joint inflammation, OA severity, and arthritic bone changes were evaluated using histology and micro-computed tomography. Immunohistochemical analysis was performed to identify various immune cells. The levels of serum and synovial fluid cytokines were also measured. RESULTS: Macrophage-depleted mice had significantly fewer M1 and M2 macrophages in the surgically operated joints relative to controls and exhibited decreased osteophyte formation immediately following depletion. Surprisingly, macrophage depletion did not attenuate the severity of OA in obese mice; instead, it induced systemic inflammation and led to a massive infiltration of CD3+ T cells and particularly neutrophils, but not B cells, into the injured joints. Macrophage-depleted mice also demonstrated a markedly increased number of proinflammatory cytokines including granulocyte colony-stimulating factor, interleukin-1ß (IL-1ß), IL-6, IL-8, and tumor necrosis factor in both serum and joint synovial fluid, although the mice showed a trend toward decreased levels of insulin and leptin in serum after macrophage depletion. CONCLUSION: Our findings indicate that macrophages are vital for modulating homeostasis of immune cells in the setting of obesity and suggest that more targeted approaches of depleting specific macrophage subtypes may be necessary to mitigate inflammation and OA in the setting of obesity.

Dietary fatty acid content regulates wound repair and the pathogenesis of osteoarthritis following joint injury.

OBJECTIVE: The mechanisms linking obesity and osteoarthritis (OA) are not fully understood and have been generally attributed to increased weight, rather than metabolic or inflammatory factors. Here, we examined the influence of fatty acids, adipokines, and body weight on OA following joint injury in an obese mouse model. METHODS: Mice were fed high-fat diets rich in various fatty acids (FA) including saturated FAs (SFAs), ω-6 polyunsaturated FAs (PUFAs), and ω-3 PUFAs. OA was induced by destabilising the medial meniscus. Wound healing was evaluated using an ear punch. OA, synovitis and wound healing were determined histologically, while bone changes were measured using microCT. Activity levels and serum cytokines were measured at various time-points. Multivariate models were performed to elucidate the associations of dietary, metabolic and mechanical factors with OA and wound healing. RESULTS: Using weight-matched mice and multivariate models, we found that OA was significantly associated with dietary fatty acid content and serum adipokine levels, but not with body weight. Furthermore, spontaneous activity of the mice was independent of OA development. Small amounts of ω-3 PUFAs (8% by kcal) in a high-fat diet were sufficient to mitigate injury-induced OA, decreasing leptin and resistin levels. ω-3 PUFAs significantly enhanced wound repair, SFAs or ω-6 PUFAs independently increased OA severity, heterotopic ossification and scar tissue formation. CONCLUSIONS: Our results indicate that with obesity, dietary FA content regulates wound healing and OA severity following joint injury, independent of body weight, supporting the need for further studies of dietary FA supplements as a potential therapeutic approach for OA.

Life-long caloric restriction does not alter the severity of age-related osteoarthritis.

Chronic adipose tissue inflammation and its associated adipokines have been linked to the development of osteoarthritis (OA). It has been shown that caloric restriction may decrease body mass index and adiposity. The objectives of this study were to investigate the effect of lifelong caloric restriction on bone morphology, joint inflammation, and spontaneously occurring OA development in aged mice. C57BL/NIA mice were fed either a calorie-restricted (CR) or ad libitum (AL) diet starting at 14 weeks of age. All mice were sacrificed at 24 months of age. Adipose tissue and knee joints were then harvested. Bone parameters of the joints were analyzed by micro-CT. OA and joint synovitis were determined using histology and semiquantitative analysis. Lifelong caloric restriction did not alter the severity of OA development in C57BL/NIA aged mice, and there was no difference in the total joint Mankin score between CR and AL groups (p = 0.99). Mice also exhibited similar levels of synovitis (p = 0.54). The bone mineral density of the femur and the tibia was comparable between the groups with a small increase in cancellous bone volume fraction in the lateral femoral condyle of the CR group compared with the AL group. Lifelong caloric restriction did not alter the incidence of OA or joint synovitis in C57BL/NIA mice, indicating that a reduction of caloric intake alone was not sufficient to prevent spontaneous age-related OA. Nonetheless, early initiation of CR continued throughout a life span did not negatively impact bone structural properties.