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BACKGROUND: Low endogenous estrogen concentrations after menopause may contribute to higher oxidative stress and greater cardiovascular disease (CVD) risk. However, differences in oxidative stress between similarly aged premenopausal and postmenopausal women are not well-characterized on a population level. We hypothesized that urinary isoprostane concentrations, a standard measure of systemic oxidative stress, are higher in women who have undergone menopause compared to premenopausal women. METHODS AND RESULTS: We examined differences in urinary 8-isoprostane (iPF(2α)-III) and 2,3-dinor-8-isoprostane (iPF(2α)-III-M) indexed to urinary creatinine between 279 postmenopausal and 196 premenopausal women in the Coronary Artery Risk Development in Young Adults (CARDIA) study, using linear regression with progressive adjustment for sociodemographic factors and traditional CVD risk factors. Unadjusted iPF(2α)-III-M concentrations were higher among postmenopausal compared to premenopausal women (Median [25th, 75th percentile]: 1762 [1178, 2974] vs. 1535 [1067, 2462] ng/g creatinine; p = 0.01). Menopause was associated with 25.5% higher iPF(2α)-III-M (95% confidence interval [6.5–47.9]) adjusted for age, race, college education, and field center. Further adjustments for tobacco use (21.2% [2.9–42.6]) and then CVD risk factors (18.8% [0.1–39.6]) led to additional partial attenuation. Menopause was associated with higher iPF(2α)-III in Black but not White women. CONCLUSIONS: We conclude that postmenopausal women had higher oxidative stress, which may contribute to greater CVD risk. ClinicalTrials.gov Identifier: NCT00005130.

Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.

Background:People living with human immunodeficiency virus (HIV+) have greater risk for sudden arrhythmic death than HIV-uninfected (HIV–) individuals. HIV-associated abnormal cardiac repolarization may contribute to this risk. We investigated whether HIV serostatus is associated with ventricular repolarization lability by using the QT variability index (QTVI), defined as a log measure of QT-interval variance indexed to heart rate variance.Methods:We studied 1123 men (589 HIV+ and 534 HIV–) from MACS (Multicenter AIDS Cohort Study), using the ZioXT ambulatory electrocardiography patch. Beat-to-beat analysis of up to 4 full days of electrocardiographic data per participant was performed using an automated algorithm (median analyzed duration [quartile 1–quartile 3]: 78.3 [66.3–83.0] hours/person). QTVI was modeled using linear mixed-effects models adjusted for demographics, cardiac risk factors, and HIV-related and inflammatory biomarkers.Results:Mean (SD) age was 60.1 (11.9) years among HIV– and 54.2 (11.2) years among HIV+ participants (PConclusions:HIV+ men have greater beat-to-beat variability in QT interval (QTVI) than HIV– men, especially in the setting of HIV viremia and heightened inflammation. Among HIV+ men, higher QTVI suggests ventricular repolarization lability, which can increase susceptibility to arrhythmias, whereas lower heart rate variability signals a component of autonomic dysfunction.

SummaryAs health studies increasingly monitor free-living heart performance via ECG patches with accelerometers, researchers will seek to investigate cardio-electrical responses to physical activity and sedentary behavior, increasing demand for fast, scalable methods to process accelerometer data. We provide the first published analysis of tri-axial accelerometry data from Zio XT patch and introduce an extension of posture classification algorithms for use with ECG patches worn in the free-living environment. Our novel extensions to posture classification include (1) estimation of an upright posture for each individual without the reference measurements used by existing posture classification algorithms; (2) correction for device removal and re-positioning using novel spherical change-point detection; and (3) classification of upright and recumbent periods using a clustering and voting process rather than a simple inclination threshold used in other algorithms. Methods were built using data from 14 participants from the Multicenter AIDS Cohort Study (MACS), and applied to 1, 250 MACS participants. As no posture labels exist in the free-living environment, we evaluate the algorithm against labelled data from the Towson Accelerometer Study and against data labelled by hand from the MACS study.

Altered Serine/Threonine phosphorylation of the cardiac proteome is an established hallmark of heart failure (HF). However, the contribution of tyrosine phosphorylation to the pathogenesis of these diseases remains unclear. The cardiac proteome was explored by global mapping to discover and quantify site-specific tyrosine phosphorylation in two cardiac hypertrophic models; cardiac overexpression of ErbB2 (TgErbB2) and cardiac expression of α-Myosin heavy chain R403Q (R403Q-αMyHCTg) compared to control hearts. Phosphoproteomic changes found in R403Q-αMyHC Tg mice indicated EGFR1, Focal Adhesion, VEGF, ErbB signaling, and Chemokine signaling pathways activity were likely to be activated. On the other hand, TgErbB2 mice findings displayed significant overrepresentation of Right Ventricular Cardiomyopathy, Hypertrophic Cardiomyopathy (HCM), and dilated cardiomyopathy (DCM) KEGG Pathways. In silico kinase-substrate enrichment analysis (KSEA) highlighted a marked downregulation of canonical MAPK Pathway Activity downstream of k-Ras in TgErbB2 mice and activation of EGFR, PP2 inhibition of c-Src, and Hepatocyte growth factor stimulation. In vivo ErbB2 inhibition by AG-825 decreased cardiac fibrosis, cardiomyocyte disarray, and rescued contractile function on TgErbB2 mice. These results suggest that altered tyrosine phosphorylation may play a regulatory role in cardiac hypertrophic models, suggesting that tyrosine kinase inhibitors could be used therapeutically in Hypertrophic Cardiomyopathy.

Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.

Background Context Despite advances in spinal oncology, research in patient-based prognostic calculators for metastatic spine disease is lacking. Much of the literature in this area investigates the general predictive accuracy of scoring systems in heterogeneous populations, with few studies considering the accuracy of scoring systems based on patient specifics such as type of primary tumor. Purpose The aim of the present study was to compare the ability of widespread scoring systems to estimate both overall survival at various time points and tumor-specific survival for patients undergoing surgical treatment for metastatic spine disease in order to provide surgeons with information to determine the most appropriate scoring system for a specific patient and timeline. Study Design This is a retrospective study. Patient Sample Patients who underwent surgical resection for metastatic spine disease at a single institution were included. Outcome Measures Areas under the receiver operating characteristic curves were generated from comparison of actual survival of patients and survival as predicted by application of prevalent scoring systems. Methods A preoperative score for all 176 patients was retrospectively calculated utilizing the Skeletal Oncology Research Group (SORG) Classic Scoring Algorithm, SORG Nomogram, original Tokuhashi, revised Tokuhashi, Tomita, original Bauer, modified Bauer, Katagiri, and van der Linden scoring systems. Univariate and multivariate Cox proportional hazard models were constructed to assess the association of patient variables with survival. Receiver operating characteristic analysis modeling was utilized to quantify the accuracy of each test at different end points and for different primary tumor subgroups. No funds were received in support of this work. The authors have no conflicts of interest to disclose. Results Among all patients surgically treated for metastatic spine disease, the SORG Nomogram demonstrated the highest accuracy at predicting 30-day (area under the curve [AUC] 0.81) and 90-day (AUC 0.70) survival after surgery. The original Tokuhashi was the most accurate at predicting 365-day survival (AUC 0.78). Multivariate analysis demonstrated multiple preoperative factors strongly associated with survival after surgery for spinal metastasis. The accuracy of each scoring system in determining survival probability relative to primary tumor etiology and time elapsed since surgery was assessed. Conclusions Among the nine scoring systems assessed, the present study determined the most accurate scoring system for short-term (30-day), intermediate (90-day), and long-term (365-day) survival, relative to primary tumor etiology. The findings of the present study may be utilized by surgeons in a personalized effort to select the most appropriate scoring system for a given patient.

Vitamin D has traditionally been known as the "bone vitamin". However, a large body of observational data has also linked low concentrations of serum 25-hydroxyvitamin D (25[OH]D), the primary storage form of vitamin D, to an increased risk of incident cardiovascular disease (CVD) and mortality, garnering public excitement about the purported nonskeletal benefits of vitamin D. Despite this, more recent meta-analyses and randomized clinical trials have failed to find a beneficial effect of vitamin D supplements on CVD and cancer outcomes. These findings, along with the lack of consensus on optimal serum 25(OH)D concentrations, have dampened some of the initial enthusiasm for vitamin D supplements. Residual confounding or reverse causation may explain some of the discrepancy between the observational and trial results. At this time, vitamin D supplements should not be prescribed for the primary purpose of CVD prevention. Adding to this complexity is the fact that many adults take vitamin D and calcium supplements together for bone health, and there is some concern (albeit inconclusive) related to calcium use and increased CVD risk. In this light, it may be best to achieve the recommended daily allowances of calcium intake through food and reserve calcium supplementation only for those at risk for calcium intake deficiency, with the smallest dosage needed after dietary modifications have been exhausted. In this review, we discuss vitamin D and calcium supplementation and how they may affect cardiovascular health.

Background: In human heart failure, Ser199 (equivalent to Ser200 in mouse) of cTnI (cardiac troponin I) is significantly hyperphosphorylated, and in vitro studies suggest that it enhances myofilament calcium sensitivity and alters calpain-mediated cTnI proteolysis. However, how its hyperphosphorylation affects cardiac function in vivo remains unknown. Methods and Results: To address the question, 2 transgenic mouse models were generated: a phospho-mimetic cTnIS200D and a phospho-silenced cTnIS200A, each driven by the cardiomyocyte-specific α-myosin heavy chain promoter. Cardiac structure assessed by echocardiography and histology was normal in both transgenic models compared with littermate controls (n=5). Baseline in vivo hemodynamics and isolated muscle studies showed that cTnIS200D significantly prolonged relaxation and lowered left ventricular peak filling rate, whereas ejection fraction and force development were normal (n=5). However, with increased heart rate or β-adrenergic stimulation, cTnIS200D mice had less enhanced ejection fraction or force development versus controls, whereas relaxation improved similarly to controls (n=5). By contrast, cTnIS200A was functionally normal both at baseline and under the physiological stresses. To test whether either mutation impacted cardiac response to ischemic stress, isolated hearts were subjected to ischemia/reperfusion. cTnIS200D were protected, recovering 88±8% of contractile function versus 35±15% in littermate controls and 28±8% in cTnIS200A (n=5). This was associated with less cTnI proteolysis in cTnIS200D hearts. Conclusions: Hyperphosphorylation of this serine in cTnI C terminus impacts heart function by depressing diastolic function at baseline and limiting systolic reserve under physiological stresses. However, paradoxically, it preserves heart function after ischemia/reperfusion injury, potentially by decreasing proteolysis of cTnI.