Vascular calcification (VC) is a common comorbidity among patients with chronic kidney disease (CKD), indicating major cardiovascular events. This study aimed to evaluate the effects and safety of intravenous sodium thiosulphate (STS) for VC in CKD patients.Electronic databases were searched for clinical trials that provided data comparing outcomes among patients treated with and without STS. The PRISMA guidelines were followed. Efficacy was assessed using calcification scores and arterial stiffness. Safety was examined by analyzing adverse symptoms, electrolytes and bone mineral density (BMD). Random-effects models were performed. Meta-regression and sensitivity analysis were done. The risk of bias was assessed using the Cochrane tools.Among the 5601 publications, 6 studies involving 305 participants (mean age: 56 years, male: 56.6%) with all participants on maintenance hemodialysis met eligibility criteria. For efficacy, the progression in Agatston scores in the coronary arteries [107 patients, mean difference (MD): -241.27, 95% confidence interval (95% CI): -421.50 to -61.03] and iliac arteries (55 patients, MD: -382.00, 95% CI: -751.07 to -12.93) was lower in the STS treated group compared with controls. The increase in pulse wave velocity was lower in the STS group (104 patients, MD: -1.29 m/s, 95% CI: -2.24 to -0.34 m/s). No association was found between the change in calcification scores and STS regimen. For safety, gastrointestinal symptoms (e.g. nausea) and increased anion gap acidosis were noted. No reduction in BMD by STS was observed.Intravenous STS may attenuate the progression of VC and arterial stiffness in hemodialysis patients. Large and well-designed randomized controlled trials are warranted.
Background— Hypertension, a strong determinant of cardiovascular disease risk, has been documented among elite, professional American-style football (ASF) players. The risk of increased blood pressure (BP) and early adulthood hypertension among the substantially larger population of collegiate ASF athletes is not known. Methods and Results— We conducted a prospective, longitudinal study to examine BP, the incidence of hypertension, and left ventricular remodeling among collegiate ASF athletes. Resting BP and left ventricular structure were assessed before and after a single season of competitive ASF participation in 6 consecutive groups of first-year university athletes (n=113). ASF participation was associated with significant increases in systolic BP (116±8 versus 125±13 mm Hg; P <0.001) and diastolic BP (64±8 mm Hg versus 66±10 mm Hg; P <0.001). At the postseason assessment, the majority of athletes met criteria for Joint National Commission (seventh report) prehypertension (53 of 113, 47%) or stage 1 hypertension (16 of 113, 14%). Among measured characteristics, lineman field position, intraseason weight gain, and family history of hypertension were the strongest independent predictors of postseason BP. Among linemen, there was a significant increase in the prevalence of concentric left ventricular hypertrophy (2 of 64 [3%] versus 20 of 64 [31%]; P <0.001) and change in left ventricular mass correlated with intraseason change in systolic BP ( R =0.46, P <0.001). Conclusions— Collegiate ASF athletes may be at risk for clinically relevant increases in BP and the development of hypertension. Enhanced surveillance and carefully selected interventions may represent important opportunities to improve later-life cardiovascular health outcomes in this population.
Introduction: Lung cancer (LC) has been one of the most commonly diagnosed cancers worldwide, both in terms of new cases and mortality. Exponential growth of economic and industrial activities in recent decades in the Delhi urban area may have increased the incidence of LC. The primary objective of this study was to evaluate the time trend according to gender. Method: LC incidence data over 25 years were obtained from the population based urban Delhi cancer registry. Joinpoint regression analysis was applied for evaluating the time trend of age-standardized incidence rates. The age-period-cohort (APC) model was employed using Poisson distribution with a log link function and the intrinsic estimator method. Results: During the 25 years, 13,489 male and 3,259 female LC cases were registered, accounting for 9.78% of male and 2.53% of female total cancer cases. Joinpoint regression analysis revealed that LC incidence in males continued to increase during the entire period, a sharp acceleration being observed starting from 2009. In females the LC incidence rate remained a plateau during 1988-2002 and thereafter increased. The cumulative risks for 1988-2012 were 1.79% and 0.45%. The full APC (IE) model showed best fit for an age-period-cohort effect on LC incidence, with significant increase with age peaking at 70-74 years in males and 65-69 years in females. A rising period effect was observed after adjusting for age and cohort effects in both genders and a declining cohort effect was identified after controlling for age and period effects. Conclusion: The incidence of LC in urban Delhi showed increasing trend from 1988-2012. Known factors such as environmental conservation, tobacco control, physical activity awareness and medical security should be implemented more vigorously over the long term in our population.
Background: Dysregulated bone morphogenetic protein (BMP) signaling is thought to contribute to the pathogenesis of pulmonary arterial hypertension (PAH). BMP9 can be detected in the circulation at physiologically active concentrations, and is thought to serve as a vascular endothelial quiescence factor. Aim: We hypothesized that circulating levels of BMP9 might be associated with altered endothelial homeostasis, and could help predict the presence of PAH or distinguish between PAH of distinct etiologies. Methods: Circulating levels of BMP9, and its biological inhibitor, soluble Endoglin (sEng), were measured in the plasma of 96 patients with various etiologies of pulmonary hypertension and 28 healthy individuals using enzyme-linked immunoassays. Results: Patients with Group I PAH (n=44) had significantly lower levels of BMP9 compared to healthy individuals (188 ± 22 pg/mL vs 254 ± 17 pg/mL, mean ± SEM, p=0.001). BMP9 was significantly decreased in PAH associated with connective tissue disease (p=0.02), but was most profoundly decreased in patients with portopulmonary hypertension (82 ± 27 pg/mL, p<0.0001 vs controls). BMP9 was a strong predictor of concomitant liver disease (ROC AUC=0.920), correlating positively with serum albumin and platelet counts, and negatively with INR, total bilirubin, cardiac index and MELD score among Group I PAH patients (
Introduction: Atherosclerosis is a chronic inflammatory process driven by plaque formation in the major elastic arteries leading to reduced blood flow, coronary artery disease (CAD), myocardial infarction and stroke. Several single-cell RNA-seq (scRNA-seq) studies have highlighted lineage-specific transcriptomic signatures in CAD-relevant tissues; however, there remains variability on the reported cell phenotypes in humans. We evaluated the overall hypothesis that distinct smooth muscle cell (SMC) phenotypes characterized from scRNA-seq data contribute to human atherosclerotic lesion formation. Methods: Here we meta-analyzed scRNA-seq human data from four individual studies to establish a comprehensive map of cell diversity in human atherosclerosis. We applied standardized QC, processing, and integration benchmarking to harmonize datasets and generate an atlas of 118,578 high-quality cells. Results: Using this atlas we characterize vascular and immune cell diversity during atherosclerosis by identifying 100 consensus marker genes across 42 annotated cell types/subtypes. We provide insights into SMC phenotypic modulation through pseudotime, transcription factor activity inference and cell-cell communication analyses. By integrating genome-wide association study (GWAS) data we identify etiologic cell types for subclinical and clinical CAD traits, which uncovered a critical role for modulated SMC phenotypes in CAD and coronary artery calcification. Finally, we identified candidate markers of synthetic and osteochondrogenic human SMCs (e.g., LTBP1 and CRTAC1 ) that may serve as proxies of atherosclerosis progression and provide validation through bulk transcriptomics, proteomics, and immunofluorescence. Conclusions: Together, this represents an important step towards creating a unified cellular map of atherosclerosis to inform cell-specific mechanistic and translational studies of cardiovascular diseases.
Introduction: Heart failure from immunoglobulin AL amyloidosis is rapidly fatal. Serial orthotopic heart transplant (OHT) followed by high dose melphalan / autologous stem cell transplant (ASCT) improves outcomes in selected patients. Debates still focus on the appropriate selection criteria for this approach. Methods: We performed a retrospective analysis of all patients with AL amyloidosis evaluated at Massachusetts General Hospital (2000 - 2011). Demographic and clinical data were obtained at the time of evaluation for OHT and ASCT. Kaplan-Meier and Cox regression analyses were performed to identify predictors of survival to OHT. Results: Of 41 patients (age 56 ±9 years), 18 (44%) underwent OHT, of which 14 subsequently underwent ASCT. One patient died before ASCT of sepsis, and 3 are awaiting ASCT. Three-year survival is 75%. Of the 14 patients, 3 (21%) died from sepsis (n=1), progressive amyloidosis (n=1), or cardiac arrest (n=1). Of the 23 untransplanted patients, 21 (91%) died with a median time to death from initial evaluation of 55 days. Thirteen were listed for OHT but 12 died before transplant from cardiac arrest (n=5), progressive systemic amyloidosis (n=4), sepsis (n=2), and heart failure (n=1). Ten were not listed for OHT due to contra-indicating factors (severe systemic amyloidosis (n=3), cardiac arrest (n=2), coagulopathy (n=1), sepsis (n=1), heart failure (n=1), stroke (n=1), severe depression (n=1)). Of those listed for OHT (n=31), higher weight and BMI were associated with a lower likelihood of survival to transplant (189 ± 46 vs. 162 ± 20 lbs, P=0.03; Cox hazard ratio (HR) of death before OHT of 1.22 for every 10-lb increase in weight, 95% CI 1.03-1.44). For patients undergoing OHT, wait time from evaluation correlated with BMI (r=0.48, P=0.04). Of the hemodynamic variables studied, greater systemic arterial pulse pressure predicted survival to OHT (HR for death before transplant 0.43 for every 10 mmHg increase, 95% CI 0.19-0.98, P=0.045). Conclusion: Long-term survival is excellent in cardiac amyloid patients receiving serial OHT and ASCT. Mortality remains high while patients await cardiac donors. Predictors of survival to OHT include increased systemic pulse pressure and lower weight and BMI due to shorter wait time for suitable organs.
Transfusion of stored RBCs is associated with increased morbidity and mortality in trauma patients. Plasma hemoglobin scavenges nitric oxide, which can cause vasoconstriction, induce inflammation, and activate platelets. We hypothesized that transfusion of RBCs stored for prolonged periods would induce adverse effects (pulmonary vasoconstriction, tissue injury, inflammation, and platelet activation) in lambs subjected to severe hemorrhagic shock and that concurrent inhalation of nitric oxide would prevent these adverse effects.Animal study.Research laboratory at the Massachusetts General Hospital, Boston, MA.Seventeen awake Polypay-breed lambs.Lambs were subjected to 2 hours of hemorrhagic shock by acutely withdrawing 50% of their blood volume. Lambs were resuscitated with autologous RBCs stored for 2 hours or less (fresh) or 39 ± 2 (mean ± SD) days (stored). Stored RBCs were administered with or without breathing nitric oxide (80 ppm) during resuscitation and for 21 hours thereafter.We measured hemodynamic and oxygenation variables, markers of tissue injury and inflammation, plasma hemoglobin concentrations, and platelet activation. Peak pulmonary arterial pressure was higher after resuscitation with stored than with fresh RBCs (24 ± 4 vs 14 ± 2 mm Hg, p < 0.001) and correlated with peak plasma hemoglobin concentrations (R = 0.56, p = 0.003). At 21 hours after resuscitation, pulmonary myeloperoxidase activity was higher in lambs resuscitated with stored than with fresh RBCs (11 ± 2 vs 4 ± 1 U/g, p = 0.007). Furthermore, transfusion of stored RBCs increased plasma markers of tissue injury and sensitized platelets to adenosine diphosphate activation. Breathing nitric oxide prevented the pulmonary hypertension and attenuated the pulmonary myeloperoxidase activity, as well as tissue injury and sensitization of platelets to adenosine diphosphate.Our data suggest that resuscitation of lambs from hemorrhagic shock with autologous stored RBCs induces pulmonary hypertension and inflammation, which can be ameliorated by breathing nitric oxide.
Objective: Arterial stiffness is a risk factor for cardiovascular disease, including heart failure with preserved ejection fraction (HFpEF). MGP (matrix Gla protein) is implicated in vascular calcification in animal models, and circulating levels of the uncarboxylated, inactive form of MGP (ucMGP) are associated with cardiovascular disease-related and all-cause mortality in human studies. However, the role of MGP in arterial stiffness is uncertain. Approach and Results: We examined the association of ucMGP levels with vascular calcification, arterial stiffness including carotid-femoral pulse wave velocity (PWV), and incident heart failure in community-dwelling adults from the Framingham Heart Study. To further investigate the link between MGP and arterial stiffness, we compared aortic PWV in age- and sex-matched young (4-month-old) and aged (10-month-old) wild-type and Mgp +/− mice. Among 7066 adults, we observed significant associations between higher levels of ucMGP and measures of arterial stiffness, including higher PWV and pulse pressure. Longitudinal analyses demonstrated an association between higher ucMGP levels and future increases in systolic blood pressure and incident HFpEF. Aortic PWV was increased in older, but not young, female Mgp +/− mice compared with wild-type mice, and this augmentation in PWV was associated with increased aortic elastin fiber fragmentation and collagen accumulation. Conclusions: This translational study demonstrates an association between ucMGP levels and arterial stiffness and future HFpEF in a large observational study, findings that are substantiated by experimental studies showing that mice with Mgp heterozygosity develop arterial stiffness. Taken together, these complementary study designs suggest a potential role of therapeutically targeting MGP in HFpEF.
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