Project description:Racial differences in the pathophysiology of atherothrombosis are poorly understood. We explored the function and transcriptome of platelets in healthy black (n=70) and white (n=84) subjects. Numerous differentially expressed (DE) RNAs were associated with both race and PAR4 reactivity, including phosphatidylcholine transfer protein (PCTP), and platelets from blacks expressed higher levels of PC-TP protein. Purified platellets were obtained from 154 healthy volunteers not taking blood thinning medication, suffering from blood diseases or otherwise excluded for health reasons. RNA was extracted and profiled on these subjects. Simultaneously, purified platelets were phenotyped using aggregation in response to stimulation with agonist. The agonist response scores and races as ewll as gene expression values on these individuals are provided.
Project description:Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Mechanistic investigations have focused on intrarenal cellular signaling induced by ischemia/reperfusion. Additional cardiorenal connector signals have been postulated, but investigation in CRS-1 has been limited by a paucity of animal models and technical limitations precluding discovery studies of glomerular filtrate. To address these limitations, we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) in mice. Quantitative proteomics using isobaric tagging (10-plex TMT reagents, Thermo Fisher) was performed on 24h urine collections from mice with deficient tubular endocytosis and from littermate controls, before and after CA/CPR. Data acquisition used the SPS MS3 method on a Thermo Fusion Tribrid mass spectrometer for accurate reporter ion signals. The findings confirmed CA/CPR-specific cardiac proteins in urine and identified a novel CA/CPR-specific filtrate component: Cardiac LIM protein (CSRP3).
Project description:Acute cardiorenal syndrome (CRS-1) is a morbid complication of acute cardiovascular disease. Mechanistic investigations have focused on intrarenal cellular signaling induced by ischemia/reperfusion. Additional signals, “cardiorenal connectors”, have been postulated, but investigation in CRS-1 has been limited by a paucity of animal models and technical limitations precluding discovery studies of glomerular filtrate. To address these limitations we developed a translational model of CRS-1, cardiac arrest and cardiopulmonary resuscitation (CA/CPR) and now report findings from a nanoscale mass spectrometry assay allowing proteomic exploration of Bowman’s space aspirate 2h after CA/CPR or sham procedure. Imaging, molecular weight and charge distribution, and minimal contribution of proteins from surrounding cell types confirmed the acquisition of filtrate. We detected filtration of low-molecular weight proteins specific to the heart following CA/CPR. Additional mass spectrometry performed on 24h urine collections from mice with deficient tubular endocytosis confirmed CA/CPR-specific cardiac protein filtration, and identified a novel, CA/CPR-specific, filtrate component: Cardiac LIM protein. Cardiac arrest-induced plasma release of Cardiac LIM protein occurred in mice and in critically-ill human cardiac arrest survivors and administration of recombinant cardiac LIM protein to mice altered renal function. Our findings demonstrate that glomerular filtrate is accessible to nanoscale proteomics and elucidate the population of proteins filtered 2h after acute cardiovascular crisis. The presence and identification of cardiac-specific proteins in renal filtrate suggest a potential novel signaling mechanism in CRS-1. We expect these findings to advance understanding of cardiorenal syndrome.
Project description:Background and purposeThe standard for stroke risk stratification is the Framingham Stroke Risk Function (FSRF), an equation requiring an examination for blood pressure assessment, venipuncture for glucose assessment, and ECG to determine atrial fibrillation and heart disease. We assess a self-reported stroke risk function (SRSRF) to stratify stroke risk in comparison to the FSRF.MethodsParticipants from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke) were evaluated at baseline and followed for incident stroke. The FSRF was calculated using directly assessed stroke risk factors. The SRSRF was calculated from 13 self-reported questions to exclude those with prevalent stroke and assess stroke risk. Proportional hazards analysis was used to assess incident stroke risk using the FSRF and SRSRF.ResultsOver an average 8.2-year follow-up, 939 of 23 983 participants had a stroke. The FSRF and SRSRF produced highly correlated risk scores (rSpearman=0.852; 95% confidence interval, 0.849-0.856); however, the SRSRF had higher discrimination of stroke risk than the FSRF (cSRSRF=0.7266; 95% confidence interval, 0.7076-0.7457; cFSRF=0.7075; 95% confidence interval, 0.6877-0.7273; P=0.0038). The 10-year stroke risk in the highest decile of predicted risk was 11.1% for the FSRF and 13.4% for the SRSRF.ConclusionsA simple self-reported questionnaire can be used to identify those at high risk for stroke better than the gold standard FSRF. This instrument can be used clinically to easily identify individuals at high risk for stroke and also scientifically to identify a subpopulation enriched for stroke risk.
Project description:Targeted metabolomics was conducted on plasma samples from a nested case-cohort study within the biracial REasons for Geographic and Racial Differences in Stroke (REGARDS) cohort. This longitudinal study investigates health outcomes with a focus on stroke disparities across the United States, particularly in the Southeastern "Stroke Belt," where stroke risk and mortality are 2-4 times higher in the Black population. The REGARDS study recruited 30,239 Black and White participants aged 45 years or older. This dataset includes 2,377 baseline plasma samples collected between 2003 and 2007 from a stroke case-cohort sub-study, with 1,056 randomly selected cohort participants and 1,321 stroke cases. The resulting data provides a resource for investigating metabolic profiles and their potential implications for health outcomes and disparities.
Project description:Patients with combined heart and renal failure, also termed the cardiorenal syndrome (CRS), have high cardiovascular morbidity and mortality. Several key connectors between heart and kidney have been recognized, such as oxidative stress, inflammation, the renin-angiotensin system and the sympathetic nervous system. Monocytes are key players in the development of atherosclerosis and may act as a biosensor to detect changes in the systemic environment. Anemia, which occurs frequently in CRS, is partly due to an absolute and/or relative erythropoietin (EPO) deficiency. Until now, EPO treatment has largely been used to treat (renal) anemia, but recent research also showed beneficial non-hematopoietic effects such as anti-inflammatory and anti-oxidative capacities. The hypothesis of the present study was that monocyte gene expression profiles of cardiorenal patients compared to healthy controls reflect the systemic nature of CRS and are responsive to short-term treatment with Epo. The first aim was to investigate whether this short term treatment revealed non-hematopoietic EPO effects. The second aim was to address whether EPO dampens expression of genes involved in inflammation and oxidative stress. Given the variable response to EPO, the third aim was to test whether baseline gene expression profiles or the acute gene expression modulation by EPO are associated with EPO resistance.
Project description:BackgroundABO blood type is an inherited trait associated with coagulation factor levels and vascular outcomes.ObjectivesTo assess the association of blood type with stroke and whether blood type contributes to racial disparities in stroke in the United States.Patients and methodsThe REasons for Geographic And Racial Differences in Stroke (REGARDS) Study recruited 30 239 participants between 2003 and 2007. Using a case-cohort design, blood type was genotyped in 646 participants with stroke and a 1104-participant cohort random sample. Cox models that adjusted for Framingham stroke risk factors were used to assess the association of blood type with stroke.ResultsDuring 5.8 years of follow-up, blood types A or B vs. type O were not associated with stroke. Blood type AB vs. O was associated with an increased risk of stroke (adjusted hazard ratio [HR] 1.83, 95% confidence interval [CI] 1.01-3.30). The association of blood type AB vs. O was greater in those without diabetes (adjusted HR 3.33, 95% CI 1.61-6.88) than those with diabetes (adjusted HR 0.49, 95% CI 0.17-1.44) (P interaction = 0.02). Factor VIII levels accounted for 60% (95% CI 11%-98%) of the association of AB blood type and stroke risk.ConclusionBlood type AB is associated with an increased risk of stroke that is not attenuated by conventional stroke risk factors, and factor VIII levels were associated with 60% of the association. While blood type AB is rare in the US population, it is a significant stroke risk factor and may play an important role in stroke risk in these individuals.