The quantity and quality of cardiovascular fat at mid-life and future cognitive performance among women: The SWAN cardiovascular fat ancillary study.

INTRODUCTION: Cardiovascular fat is a novel risk factor that may link to dementia. Fat volume and radiodensity are measurements of fat quantity and quality, respectively. Importantly, high fat radiodensity could indicate healthy or adverse metabolic processes. METHODS: The associations of cardiovascular fat (including epicardial, paracardial, and thoracic perivascular adipose tissue [PVAT]) quantity and quality assessed at mean age of 51 with subsequent cognitive performance measured repeatedly over 16 years of follow-up were examined using mixed models among 531 women. RESULTS: Higher thoracic PVAT volume was associated with a higher future episodic memory (ß[standard error (SE)] = 0.08 [0.04], P = 0.033), while higher thoracic PVAT radiodensity with lower future episodic (ß[SE] = -0.06 [0.03], P = 0.045) and working (ß[SE] = -0.24 [0.08], P = 0.003) memories. The latter association is prominent at higher volume of thoracic PVAT. DISCUSSION: Mid-life thoracic PVAT may have a distinct contribution to future cognition possibly due to its distinct adipose tissue type (brown fat) and anatomical proximity to the brain circulation. HIGHLIGHTS: Higher mid-life thoracic perivascular adipose tissue (thoracic PVAT) volume is related to a better future episodic memory in women. Higher mid-life thoracic PVAT radiodensity is related to worse future working and episodic memories. Negative association of high thoracic PVAT radiodensity with working memory is prominent at higher thoracic PVAT volume. Mid-life thoracic PVAT is linked to future memory loss, an early sign of Alzheimer's disease. Mid-life women's epicardial and paracardial fat are not related to future cognition.

Learning Clinical Concepts for Predicting Risk of Progression to Severe COVID-19.

With COVID-19 now pervasive, identification of high-risk individuals is crucial. Using data from a major healthcare provider in Southwestern Pennsylvania, we develop survival models predicting severe COVID-19 progression. In this endeavor, we face a tradeoff between more accurate models relying on many features and less accurate models relying on a few features aligned with clinician intuition. Complicating matters, many EHR features tend to be under-coded degrading the accuracy of smaller models. In this study we develop two sets of high-performance risk scores: (i) an unconstrained model built from all available features; and (ii) a pipeline that learns a small set of clinical concepts before training a risk predictor. Learned concepts boost performance over the corresponding features (C-index 0.858 vs. 0.844) and demonstrate improvements over (i) when evaluated out-of-sample (subsequent time periods). Our models outperform previous works (C-index 0.844-0.872 vs. 0.598-0.810).

Association of Hydroxychloroquine Use With Decreased Incident Atrial Fibrillation in Systemic Lupus Erythematosus.

OBJECTIVE: To study the relationship between hydroxychloroquine (HCQ) use and new-onset atrial fibrillation in patients with systemic lupus erythematosus (SLE). METHODS: A retrospective cohort of adult patients with SLE was constructed from December 1, 2014 to May 30, 2017. Patients were categorized as either HCQ users or nonusers. The primary outcome was incident atrial fibrillation. Secondary outcomes included incident ventricular arrhythmias (composite of ventricular tachycardia, ventricular fibrillation, or torsades de pointes). Outcomes were adjudicated by review of the electronic health record. Statistical analyses included simple and multivariable logistic regression tests to estimate the association between HCQ use and incident atrial fibrillation after adjusting for relevant confounders. Propensity score matching analysis was completed. RESULTS: Our study included 1,647 patients with SLE, of which 917 were HCQ users and 730 were nonusers. A total of 23 atrial fibrillation events occurred, including 3 in HCQ users and 20 in nonusers. Logistic regression analysis showed an odds ratio (OR) of 0.12 (95% confidence interval [95% CI] 0.034-0.39, P = 0.0005) for incident atrial fibrillation and 2.39 (95% CI 0.25-23.0, P = 0.45) for ventricular arrhythmias. Results remained significant in the fully adjusted and propensity score-matched models. CONCLUSION: In this exploratory study, HCQ use was associated with an 88% decrease in the risk of incident atrial fibrillation in patients with SLE. Considering the increased cardiovascular risk in SLE, incorporation of HCQ into the regimen may be beneficial for both disease manifestations and reducing the risk of atrial fibrillation. Further studies would be needed to confirm the antifibrillatory benefit of this relatively safe and low-cost medication.

Dual plate fixation results in improved union rates in comminuted distal femur fractures compared to single plate fixation.

PURPOSE: The treatment of distal femur fractures with extensive metaphyseal comminution is frequently complicated by high rates of nonunion and varus collapse. Dual plating with lateral and medial locking plates for these types of fractures has shown promising results in the recent literature. We hypothesize that dual plating of comminuted distal femur fractures leads to higher union rates and lower revision rates compared to an isolated lateral locking plate. METHODS: A retrospective medical chart review between January 2015 and December 2017 was conducted. Inclusion criteria included patients 18 years of age and older who sustained a complex distal femur fracture (AO/OTA 33-C2/33-C3 or periprosthetic fracture with significant metaphyseal comminution) and at least 6 months of follow up. Patients with simple fracture patterns, alternative fixation methods, and inadequate follow up were excluded. All patients in the single plating group were treated with a lateral distal femoral locking plate using a lateral approach. In the patients treated with dual plating, an extensile parapatellar approach was utilized for fracture reduction and placement of an adjunctive medial plate. Demographic information, fracture types, injury severity score (ISS), medical comorbidities, type of surgical fixation, union rates, complications, knee range of motion, time to follow up, and need for revision surgery were extrapolated from the medical charts for analysis. RESULTS: Twenty-one patients were included in the study. Thirteen patients underwent single plate fixation and 8 underwent dual plate fixation. There were no significant differences in demographics, number of co-morbidities, fracture classification, or ISS between single and dual plate groups (p > 0.05 for all). There was a statistically significant difference in union rates between the single plate group (6 nonunions, 4 unions, and 3 delayed unions) and the dual plate group, with no nonunions or delayed unions (p = 0.0049). Although not statistically significant, 4 patients treated with single plating underwent revision ORIF, compared to none in the dual plating group (p = 0.13). There were no significant differences in time to follow up, time to full weight bearing, or infection rates (p > 0.1 for all). CONCLUSION: Based on these results, the medial and lateral locked plating technique demonstrates a higher union rate, with possible lower rates of revision surgery, compared to a single lateral plate in highly comminuted distal femur fractures. LEVEL OF EVIDENCE: Level 3. Retrospective Cohort Study.

Risk Factors for Unnecessary Antibiotic Prescribing for Acute Respiratory Tract Infections in Primary Care.

OBJECTIVE: To determine independent risk factors for inappropriate antibiotic prescribing for acute respiratory tract infections (ARIs) in internal medicine (IM) residency-based primary care offices. PATIENTS AND METHODS: A retrospective study was conducted to measure antibiotic prescribing rates, and multivariable analysis was utilized to identify predictors of inappropriate prescribing among patients presenting to IM residency-based primary care office practices. Patients with an office visit at either of 2 IM residency-based primary care office practices from January 1, 2016, through December 31, 2016, with a primary encounter diagnosis of ARI were included. RESULTS: During the study period, 911 unique patient encounters were included with 518 for conditions for which antibiotics were considered always inappropriate. Antibiotics were not indicated in 85.8% (782 of 911) of encounters. However, antibiotics were prescribed in 28.4% (222 of 782) of these encounters. Inappropriate antibiotic prescribing occurred in 111 of 518 (21.4%) encounters for conditions for which antibiotics are always inappropriate. Using multivariable logistic regression analysis to assess for independent risk factors when adjusted for other potential risk factors for office visits at which antibiotics were not indicated, IM resident-associated visits (odds ratio, 0.25; 95% CI, 0.18-0.36) was the only variable independently associated with lower risk of inappropriate antibiotic prescribing. CONCLUSION: For ARI visits at which antibiotics were not indicated, IM resident comanagement was associated with lower rates of inappropriate prescribing.

Associations of cardiovascular fat radiodensity and vascular calcification in midlife women: The SWAN cardiovascular fat ancillary study.

BACKGROUND AND AIMS: Fat radiodensity, measured via CT Hounsfield units (HU), is a potential marker of fat quality. We sought to determine the cross-sectional associations of total heart fat (TAT) and aortic perivascular fat (PVAT) radiodensity with cardiovascular risk factors, coronary artery calcification (CAC), and aortic calcification (AC) in midlife women. METHODS: Fat radiodensity, CAC, and AC were quantified using CT scans. A total of 528 women (mean age: 50.9 ±â€¯2.9 years; 37% Black) were included in analyses. RESULTS: Women in the lowest TAT radiodensity tertile were more likely to have adverse cardiovascular risk factors. Independent of cardiovascular risk factors, women in the middle and high TAT radiodensity tertiles were less likely to have CAC (OR (95% CI): 0.32 (0.18, 0.59); 0.43 (0.24, 0.78), respectively) compared with women in the lowest TAT radiodensity tertile. Although adjusting for BMI attenuated the overall association, women in the middle TAT radiodensity tertile remained at significantly lower odds of CAC when compared to the low radiodensity tertile, 0.47 (0.24, 0.93), p=0.03. No significant associations were found for PVAT radiodensity and calcification measures in multivariable analysis. CONCLUSIONS: Lower TAT radiodensity was associated with a less favorable cardiometabolic profile. Women with mid-range TAT radiodensity values had a lower odds of CAC presence, independent of CVD risk factors and BMI. More research is necessary to understand radiodensity as a surrogate marker of fat quality in midlife women.

3D MicroCT spatial and temporal characterization of thoracic aorta perivascular adipose tissue and plaque volumes in the ApoE-/- mouse model.

Perivascular adipose tissue (PVAT) influences vascular function and pathology. We present a protocol using micro-computed tomography (microCT), a novel imaging technique typically used for hard biological tissue, to characterize the temporal and spatial development of aorta PVAT and luminal plaque soft tissue. Apolipoprotein E deficient (ApoE) and C57Bl/6J (control) mice were fed a high fat western diet up to 30 weeks. 3D microCT reconstructions were used to quantify: 1) vascular wall volume, a surrogate measure of remodeling, was greater in ApoE, 2) aorta PVAT volume was reduced in ApoE, 3) plaque volumes increased over time in ApoE, 4) plaque development co-localized with luminal ostia, origins of branching arteries, which traveled through areas of greatest PVAT volume, 5) qualitatively, the same arteries showed evidence of increased tortuosity in ApoE. This study reflects the potential of microCT analyses to assess vascular wall, PVAT and arterial trajectory modifications in relevant animal models. Abbreviations: PVAT: perivascular adipose tissue; ApoE: apolipoprotein E deficient mouse strain; Control: C57Bl/6J mouse strain; PTA: 0.3% phosphotungstic acid; microCT: micro-computed tomography; CV: cardiovascular; CVD: cardiovascular disease; IQR: interquartile range; PPARγ: peroxisome proliferator activated receptor - gamma; VV: vasa vasorum; 3D: three dimensional.

Differential Adipose Tissue Proteomics.

Differential proteomic analysis (comparative quantitative proteomics) is a robust quantitative technique used to detect and identify the proteome of selected tissues. The expression levels (upregulated vs. downregulated) of proteins in tissue samples that differ by experimental design or anatomic location are determined by a series of assays including (1) 2D difference gel electrophoresis (2D-DiGE), (2) protein spot picking based on a priori thresholds, (3) Mass Spectrometry, and (4) follow-up Western Blot for antibody validation (Chen et al., Mol Cell Proteomics 14:2466-2478, 2015). Differential proteomic analysis is a perfect method for analyzing a heterogeneous tissue such as adipose tissue with a composition spectrum consisting of white to brown adipocytes along with a stromal vascular fraction dependent on anatomical location and inflammation. The adipose tissue proteomic protocol outlined here was successful in identifying differentially expressed proteins both significantly upregulated and downregulated between the experimental and control groups (Shields et al., Pulm Circ 6:586-596, 2016).

MicroCT analysis of vascular morphometry: a comparison of right lung lobes in the SUGEN/hypoxic rat model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling within the lung. Clinical computed tomography (CT) scans are routinely used to aid in PAH diagnosis. Animal models, including the Sugen-hypoxic rat model (SU/hyp), of PAH closely mimic human PAH development. We have previously used micro-computed tomography (microCT) to find extensive right lung vascular remodeling in the SU/hyp. We hypothesized that the individual right lung lobes may not contribute equally to overall lung vascular remodeling. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) and subsequently exposed to chronic hypoxic conditions (10% O2) for three weeks. Following perfusion of the lung vasculature with an opaque resin (Microfil), the right lung lobes were microCT-imaged with a 10-µm voxel resolution and 3D morphometry analysis was performed separately on each lobe. As expected, we found a significantly lower ratio of vascular volume to total lobe volume in the SU/hyp compared with the control, but only in the distal lobes (inferior: 0.23 [0.21-0.30] versus 0.35 [0.27-0.43], P = 0.02; accessory: 0.27 [0.25-0.33] versus 0.37 [0.29-0.43], P = 0.06). Overall, we observed significantly fewer continuous blood vessels and reduced vascular density while having greater vascular lumen diameters in the distal lobes of both groups ( P < 0.05). In addition, the vascular separation within the SU/hyp lobes and the vascular surface area to volume ratio were significantly greater in the SU/hyp lobes compared with controls ( P < 0.03). Results for the examined parameters support the overall extensive vascular remodeling in the SU/hyp model and suggest this may be lobe-dependent.

In vivo Endocrine Secretion of Prostacyclin Following Expression of a Cyclooxygenase-1/Prostacyclin Fusion Protein in the Salivary Glands of Rats Via Nonviral Gene Therapy.

Pulmonary arterial hypertension (PAH) is a progressive disease that culminates in right heart failure and death. Prostacyclin (PGI2) and its derivatives are effective treatments for PAH when administered as continuous parenteral infusions. This treatment paradigm requires medical sophistication, and patients are at risk for complications from an indewelling catheter; drug interruptions may result in rebound pulmonary hypertension and death. We hypothesized that the salivary gland can be repurposed into an endogenous production site for circulating PGI2 through the expression of a fusion protein embodying cyclooxygenase-1 (Cox1) and prostacyclin synthase (PGIS) domains. We utilized ultrasound-assisted gene transfer, a nonviral gene transfer strategy that achieves robust gene transfer to the salivary gland. We initially found that Cox1-PGIS expression in livers of mice using an adenoviral vector dramatically increased circulating PGI2 relative to untreated rats or rats treated with PGIS alone. We then utilized ultrasound-assisted gene transfer to express Cox1-PGIS in the submandibular glands of rats and showed a significant elevation of circulating PGI2 that corresponded to approximately 30% of that seen in humans undergoing intravenous infusion therapy for PAH. These results suggest the feasibility of gene therapy to drive endogenous biosynthesis of PGI2 as a therapeutic strategy for the treatment of PAH.

Association of aortic perivascular adipose tissue density with aortic calcification in women with systemic lupus erythematosus.

BACKGROUND AND AIMS: Women with systemic lupus erythematosus (SLE) have an increased risk of cardiovascular disease (CVD). Perivascular adipose tissue (PVAT) surrounds the vascular wall, is associated with CVD risk factors, and may contribute to premature CVD in SLE. We previously found greater volumes of aortic PVAT associated with aortic calcification (AC) in female SLE patients. There is recent evidence that not only volume but adipose density may also be indicative of inflammation. We hypothesized that female SLE patients would have a difference in aPVAT quality associated with AC that is independent of volume. METHODS: Aorta PVAT quality was evaluated using the average radiodensity (density) of adipose tissue-specific Hounsfield Units (-190 to -30 HU) within each clinical CT scan of CVD-free, age-/race-matched SLE women (n = 143) and healthy controls (HC, n = 143). RESULTS: Aorta PVAT density was significantly higher in SLE (mean (SD): (-83.6 (1.9) HU) versus HC (-84.1 (1.8) HU), p=0.03). Increasing aPVAT volume was correlated with denser aPVAT in SLE (ρ, p-value: 0.75,<0.0001) and HC (0.74,<0.0001). Increasing AC score (log) was correlated with denser aPVAT for SLE (0.31, 0.0005) and HC (0.23, 0.008). In linear regression, denser aPVAT was more strongly associated with AC score in SLE (ß (SE): 0.445 (0.11), p<0.0001) versus HC (0.335 (0.12), p=0.006) independent of age, circulating inflammatory markers, CVD risk factors and BMI (p<0.05), but was attenuated with aPVAT volume (p=0.3). CONCLUSIONS: Denser aPVAT is associated with aPVAT volume and AC in SLE women. Adjusting for aPVAT volume attenuated the detected association between aPVAT density and AC, which may be indicative of adipose dysfunction.

Plasma complement and vascular complement deposition in patients with coronary artery disease with and without inflammatory rheumatic diseases.

PURPOSE: Inflammatory rheumatic diseases (IRD) are associated with accelerated coronary artery disease (CAD), which may result from both systemic and vascular wall inflammation. There are indications that complement may be involved in the pathogenesis of CAD in Systemic Lupus Erythematosus (SLE) and Rheumatoid Arthritis (RA). This study aimed to evaluate the associations between circulating complement and complement activation products with mononuclear cell infiltrates (MCI, surrogate marker of vascular inflammation) in the aortic media and adventitia in IRDCAD and non-IRDCAD patients undergoing coronary artery bypass grafting (CABG). Furthermore, we compared complement activation product deposition patterns in rare aorta adventitial and medial biopsies from SLE, RA and non-IRD patients. METHODS: We examined plasma C3 (p-C3) and terminal complement complexes (p-TCC) in 28 IRDCAD (SLE = 3; RA = 25), 52 non-IRDCAD patients, and 32 IRDNo CAD (RA = 32) from the Feiring Heart Biopsy Study. Aortic biopsies taken from the CAD only patients during CABG were previously evaluated for adventitial MCIs. The rare aortic biopsies from 3 SLE, 3 RA and 3 non-IRDCAD were assessed for the presence of C3 and C3d using immunohistochemistry. RESULTS: IRDCAD patients had higher p-TCC than non-IRDCAD or IRDNo CAD patients (p<0.0001), but a similar p-C3 level (p = 0.42). Circulating C3 was associated with IRD duration (ρ, p-value: 0.46, 0.03). In multiple logistic regression analysis, IRD remained significantly related to the presence and size of MCI (p<0.05). C3 was present in all tissue samples. C3d was detected in the media of all patients and only in the adventitia of IRD patients (diffuse in all SLE and focal in one RA). CONCLUSION: The independent association of IRD status with MCI and the observed C3d deposition supports the unique relationship between rheumatic disease, and, in particular, SLE with the complement system. Exaggerated systemic and vascular complement activation may accelerate CVD, serve as a CVD biomarker, and represent a target for new therapies.

Postmenopausal Women With Greater Paracardial Fat Have More Coronary Artery Calcification Than Premenopausal Women: The Study of Women's Health Across the Nation (SWAN) Cardiovascular Fat Ancillary Study.

BACKGROUND: Volumes of paracardial adipose tissue (PAT) and epicardial adipose tissue (EAT) are greater after menopause. Interestingly, PAT but not EAT is associated with estradiol decline, suggesting a potential role of menopause in PAT accumulation. We assessed whether volumes of heart fat depot (EAT and PAT) were associated with coronary artery calcification (CAC) in women at midlife and whether these associations were modified by menopausal status and estradiol levels. METHODS AND RESULTS: EAT and PAT volumes and CAC were measured using electron beam computed tomography scans. CAC was evaluated as (1) the presence of CAC (CAC Agatston score ≥10) and (2) the extent of any CAC (log CAC Agatston score >0). The study included 478 women aged 50.9 years (58% pre- or early perimenopausal, 10% late perimenopausal, and 32% postmenopausal). EAT was significantly associated with CAC measures, and these associations were not modified by menopausal status or estradiol. In contrast, associations between PAT and CAC measures were modified by menopausal status (interaction-P≤0.01). Independent of study covariates including other adiposity measures, each 1-SD unit increase in log PAT was associated with 102% higher risk of CAC presence (P=0.04) and an 80% increase in CAC extent (P=0.008) in postmenopausal women compared with pre- or early perimenopausal women. Additional adjustment for estradiol and hormone therapy attenuated these differences. Moreover, the association between PAT and CAC extent was stronger in women with lower estradiol levels (interaction P=0.004). CONCLUSIONS: The findings suggest that PAT is a potential menopause-specific coronary artery disease risk marker, supporting the need to monitor and target this fat depot for intervention in women at midlife.

CRISPR-Cas9 HDR system enhances AQP1 gene expression.

Ionizing radiation (IR) isthe primarytherapeutic tool to treat patients with cancerous lesions located in the head and neck. In many patients, IR results in irreversible and severe salivary gland dysfunction or xerostomia. Currently there are no effective treatment options to reduce the effects of xerostomia. More recently, salivary gland gene therapy utilizing the water-specific protein aquaporin 1 (AQP1) has been of great interest to potentially correct salivary dysfunction. In this study, we used CRISPR-Cas9 gene editing along with the endogenous promoter of AQP1 within theHEK293 and MDCK cell lines. The successful integration of the cytomegalovirus (CMV) promoterresultedin a significant increase of AQP1 gene transcription and translation. Additionalfunctional experiments involvingthe MDCK cell line confirmedthat over-expressed AQP1increasedtransmembrane fluid flux indicative of increased intracellular fluid flux. The off-target effect of designed guided RNA sequence was analyzed and demonstrateda high specificity for the Cas9 cleavage. Considering the development of new methods for robust DNA knock-in, our results suggest that endogenous promoter replacement may be a potential treatment forsalivary gland dysfunction.

In situ expression of Bcl-2 in pulmonary artery endothelial cells associates with pulmonary arterial hypertension relative to heart failure with preserved ejection fraction.

We have previously reported that pulmonary artery endothelial cells (PAECs) can be harvested from the tips of discarded Swan-Ganz catheters after right heart catheterization (RHC). In this study, we tested the hypothesis that the existence of an antiapoptotic phenotype in PAECs obtained during RHC is a distinctive feature of pulmonary arterial hypertension (PAH; World Health Organization group 1) and might be used to differentiate PAH from other etiologies of pulmonary hypertension. Specifically, we developed a flow cytometry-based measure of Bcl-2 activity, referred to as the normalized endothelial Bcl-2 index (NEBI). We report that higher NEBI values are associated with PAH to the exclusion of heart failure with preserved ejection fraction (HFpEF) and that this simple diagnostic measurement is capable of differentiating PAH from HFpEF without presenting addition risk to the patient. If validated in a larger, multicenter study, the NEBI has the potential to assist physicians in the selection of appropriate therapeutic interventions in the common and dangerous scenario wherein patients present a clinical and hemodynamic phenotype that makes it difficult to confidently differentiate between PAH and HFpEF.

Three-dimensional micro computed tomography analysis of the lung vasculature and differential adipose proteomics in the Sugen/hypoxia rat model of pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a rare disease characterized by significant vascular remodeling. The obesity epidemic has produced great interest in the relationship between small visceral adipose tissue depots producing localized inflammatory conditions, which may link metabolism, innate immunity, and vascular remodeling. This study used novel micro computed tomography (microCT) three-dimensional modeling to investigate the degree of remodeling of the lung vasculature and differential proteomics to determine small visceral adipose dysfunction in rats with severe PAH. Sprague-Dawley rats were subjected to a subcutaneous injection of vascular endothelial growth factor receptor blocker (Sugen 5416) with subsequent hypoxia exposure for 3 weeks (SU/hyp). At 12 weeks after hypoxia, microCT analysis showed a decrease in the ratio of vascular to total tissue volume within the SU/hyp group (mean ± standard deviation: 0.27 ± 0.066; P = 0.02) with increased vascular separation (0.37 ± 0.062 mm; P = 0.02) when compared with the control (0.34 ± 0.084 and 0.30 ± 0.072 mm). Differential proteomics detected an up-regulation of complement protein 3 (C3; SU/hyp∶control ratio = 2.86) and the adipose tissue-specific fatty acid binding protein-4 (FABP4, 2.66) in the heart adipose of the SU/hyp. Significant remodeling of the lung vasculature validates the efficacy of the SU/hyp rat for modeling human PAH. The upregulation of C3 and FABP4 within the heart adipose implicates small visceral adipose dysfunction. C3 has been associated with vascular stiffness, and FABP4 suppresses peroxisome proliferator-activated receptor, which is a major regulator of adipose function and known to be downregulated in PAH. These findings reveal that small visceral adipose tissue within the SU/hyp model provides mechanistic links for vascular remodeling and adipose dysfunction in the pathophysiology of PAH.

Complement proteins and arterial calcification in middle aged women: Cross-sectional effect of cardiovascular fat. The SWAN Cardiovascular Fat Ancillary Study.

BACKGROUND: CVD risk increases in women after menopause. Recent data suggest higher levels of complement protein C3 and cardiovascular fat (CF) in postmenopausal women. Whether complement proteins are associated with early markers of atherosclerosis in healthy midlife women has never been evaluated. Additionally, the potential impact of the local CF on these associations has never been assessed. METHODS: Participants (n = 100, age (mean(SD)):50.48(2.63), 50% premenopausal) were from the Study of Women's Health Across the Nation (SWAN). Arterial calcification (aortic-AC and coronary-CAC) and CF volumes around the heart and aorta (total heart-TAT and aortic perivascular adipose tissue-PVAT) were quantified using EBCT scans. AC and CAC were each evaluated as presence (Agatston scores >0) and extent of calcification (log (Agatston scores+1)). Logistic and linear regression models were used for statistical analysis. RESULTS: Adjusting for age, race, menopausal status and lipids, C3 was significantly associated with both presence and extent of AC and CAC, all P values <0.05. Associations between C3 and presence and extent of AC and CAC were explained by additional adjustment for log TAT and log PVAT, respectively. Association between C3 and log(AC+1) was more pronounced at higher volumes of log TAT (interaction-P = 0.013) adjusting for study variables. No associations were found with C4. CONCLUSIONS: Higher C3 was significantly associated with presence and greater extent of arterial calcification in midlife women. These associations were explained by higher volumes of CF, suggesting CF as a potential source of C3. C3 could be a potential non-invasive biomarker of early diagnosis of atherosclerosis. These findings need to be replicated in larger studies.

Cardiovascular disease biomarkers across autoimmune diseases.

Cardiovascular disease is increasingly recognized as a major cause of premature mortality among those with autoimmune disorders. There is an urgent need to identify those patients with autoimmune disease who are at risk for CVD so as to optimize therapeutic intervention and ultimately prevention. Accurate identification, monitoring and stratification of such patients will depend upon a panel of biomarkers of cardiovascular disease. This review will discuss some of the most recent biomarkers of cardiovascular diseases in autoimmune disease, including lipid oxidation, imaging biomarkers to characterize coronary calcium, plaque, and intima media thickness, biomarkers of inflammation and activated complement, genetic markers, endothelial biomarkers, and antiphospholipid antibodies. Clinical implementation of these biomarkers will not only enhance patient care but also likely accelerate the pharmaceutical pipeline for targeted intervention to reduce or eliminate cardiovascular disease in the setting of autoimmunity.

Cardiovascular Fat, Menopause, and Sex Hormones in Women: The SWAN Cardiovascular Fat Ancillary Study.

CONTEXT: Cardiovascular risk increases in women after menopause. Mounting evidence demonstrates a role of cardiovascular fat (CF) in the pathogenesis of coronary heart disease, but no research has examined CF in relation to sex hormones or menopausal status in women. OBJECTIVE: The objective was to determine the relationship between CF depots, menopausal status, and endogenous sex hormones. DESIGN: Cross-sectional and longitudinal study designs were used. SETTING: The setting included the Study of Women's Health Across the Nation (SWAN) Heart and Cardiovascular Fat Ancillary Study. PARTICIPANTS: A total of 456 women (mean age, 50.75 y); 62% premenopausal/early perimenopausal, and 38% late peri-/postmenopausal. INTERVENTION: Menopausal status, endogenous sex hormones measured simultaneously with CF volumes, and circulating estradiol available 4.80 years (median) before CF measures. MAIN OUTCOME MEASURES: Volumes of CF (epicardial adipose tissue [EAT], paracardial adipose tissue [PAT], total heart adipose tissue [TAT = EAT + PAT], and aortic perivascular adipose tissue [PVAT]). RESULTS: In final models, late peri-/postmenopausal women had 9.88% more EAT, 20.72% more PAT, and 11.69% more TAT volumes than pre-/early perimenopausal women (P < .05). PVAT was not associated with menopausal status. In final models, lower estradiol concentrations were associated with greater volumes of PAT and TAT (P < .05). Women with the greatest reduction in estradiol since baseline had greater volumes of PAT compared to women with the least reduction (P = .02). CONCLUSIONS: Late peri-/postmenopausal women have greater volumes of heart fat compared with pre-/early perimenopausal women independent of age, obesity, and other covariates. Endogenous sex hormones are associated with CF. Perhaps CF plays a role in the higher risk of coronary heart disease reported in women after menopause.

Calcified carotid artery plaques predict cardiovascular outcomes in the elderly.

BACKGROUND: Identifying plaque composition using ultrasound may aid in stratifying patients at high risk for cardiovascular disease (CVD). Calcification is an integral part of plaque progression and may contribute to plaque vulnerability. We investigated the ability of calcified carotid plaques identified using carotid ultrasound to predict cardiovascular outcomes in older adults. METHODS: Participants included 187 hypertensive and 187 normotensive adults undergoing a duplex scan to identify the presence of calcified carotid plaques. Hypertensive participants received either blood pressure treatment or placebo, and all participants were followed for incident cardiovascular events and death for a maximum of 11 years. RESULTS: The untreated hypertensive group was significantly associated with a higher time-to-any CVD event [relative risk (RR) 2.97, 95% confidence interval (CI) 2.03-4.35, P < 0.0001] and mortality (RR 3.11, 95% CI 1.92-5.04, P < 0.0001) when compared to the normotensive group. Participants with calcified carotid plaques had higher cardiovascular event rates (RR 6.22, 95% CI 1.97-19.6, P = 0.0018) and mortality (RR 6.30, 95% CI 1.55-25.7, P = 0.010) when compared to those without plaque. After controlling for age, male sex, blood pressure status, glucose, and IMT, the presence of calcified carotid plaques remained predictive of CVD events (RR 2.35, 95% CI 1.5-3.8, P = 0.0005) and mortality (RR 2.72, 95% CI 1.4-5.2, P = 0.0021). CONCLUSION: Calcified carotid plaques may predict mortality and cardiovascular outcomes independent of traditional CVD risk factors and may serve as an additional CVD risk assessment in the elderly.