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1.
JCI Insight ; 2021 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-33591955

RESUMO

Recent advances in proteomic technologies have made high throughput profiling of low abundance proteins in large epidemiological cohorts increasingly feasible. We investigated whether aptamer-based proteomic profiling could identify biomarkers associated with future development of type 2 diabetes (T2DM) beyond known risk factors. We identified dozens of markers with highly significant associations with future T2DM across two large longitudinal cohorts (n=2,839) followed for up to 16 years. We leveraged proteomic, metabolomic, genetic and clinical data from humans to nominate one specific candidate to test for potential causal relationships in model systems. Our studies identified functional effects of aminoacylase 1 (ACY1), a top protein association with future T2DM risk, on amino acid metabolism and insulin homeostasis in vitro and in vivo. Further, a loss-of-function variant associated with circulating levels of the biomarker WAP, Kazal, immunoglobulin, Kunitz and NTR domain-containing protein 2 (WFIKKN2) was in turn associated with fasting glucose, hemoglobin A1c and HOMA-IR measurements in humans. In addition to identifying novel disease markers and potential pathways in T2DM, we provide publicly available data to be leveraged for new insights about gene function and disease pathogenesis in the context of human metabolism. .

2.
Circ Heart Fail ; 14(1): e007275, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33464957

RESUMO

BACKGROUND: Heart failure (HF) is a heterogeneous disease characterized by significant metabolic disturbances; however, the breadth of metabolic dysfunction before the onset of overt disease is not well understood. The purpose of this study was to determine the association of circulating metabolites with incident HF to uncover novel metabolic pathways to disease. METHODS: We performed targeted plasma metabolomic profiling in a deeply phenotyped group of Black adults from the JHS (Jackson Heart Study; n=2199). We related metabolites associated with incident HF to established etiological mechanisms, including increased left ventricular mass index and incident coronary heart disease. Furthermore, we evaluated differential associations of metabolites with HF with preserved ejection fraction versus HF with reduced ejection fraction. RESULTS: Metabolites associated with incident HF included products of posttranscriptional modifications of RNA, as well as polyamine and nitric oxide metabolism. A subset of metabolite-HF associations was independent of well-established HF pathways such as increased left ventricular mass index and incident coronary heart disease and included homoarginine (per 1 SD increase in metabolite level, hazard ratio, 0.77; P=1.2×10-3), diacetylspermine (hazard ratio, 1.34; P=3.4×10-3), and uridine (hazard ratio, 0.79; P, 3×10-4). Furthermore, metabolites involved in pyrimidine metabolism (orotic acid) and collagen turnover (N-methylproline) among others were part of a distinct metabolic signature that differentiated individuals with HF with preserved ejection fraction versus HF with reduced ejection fraction. CONCLUSIONS: The integration of clinical phenotyping with plasma metabolomic profiling uncovered novel metabolic processes in nontraditional disease pathways underlying the heterogeneity of HF development in Black adults.

4.
Am J Surg ; 221(1): 134-140, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32847686

RESUMO

OBJECTIVES: Preoperative biliary stenting is required for patients with obstructive jaundice from pancreatic adenocarcinoma who are receiving neoadjuvant chemotherapy. While in most patients this approach results in durable biliary drainage, some patients develop cholangitis during neoadjuvant treatment. Further, several studies have shown that preoperative cholangitis in patients with hepatobiliary malignancies can result in substantially unfavorable outcomes. The aim of this study was to evaluate the impact of preoperative cholangitis in patients who underwent pancreaticoduodenectomy after completing neoadjuvant chemotherapy. METHODS: Participants: all adult patients (n = 449) diagnosed with pancreatic adenocarcinoma from January 1st, 2013 to March 31st, 2018 who pursued treatment at the Massachusetts General Hospital were screened. Of these 449 patients, 97 met final inclusion criteria of receiving neoadjuvant chemotherapy with intent to pursue curative surgery. Data were collected via retrospective chart review including baseline characteristics, survival, episodes of preoperative cholangitis, and surgical complications. RESULTS: In patients completing successful pancreaticoduodenectomy surgery, preoperative cholangitis is associated with increased mortality (HR 2.67, 95% CI:1.16-6.13). This finding is independent of postoperative outcomes or tumor recurrence rate. The presence of cholangitis did not impact completion of neoadjuvant chemotherapy (92% vs 85%, p = 0.5) or ability to proceed to surgery (76% vs 75%, p = 1.0). Preoperative cholangitis was not associated with postoperative morbidity (42.1% vs 45.1%, p = 1.0). CONCLUSIONS: One episode of cholangitis during neoadjuvant chemotherapy is associated with increased mortality following successful pancreaticoduodenectomy, independent of immediate postoperative outcomes or tumor recurrence. Preoperative cholangitis does not affect ability to pursue neoadjuvant chemotherapy or complete successful surgery. Patients who develop cholangitis during the neoadjuvant chemotherapy treatment phase may reflect a distinct phenotype of patients with PDAC with a complex and more challenging clinical course.


Assuntos
Adenocarcinoma/complicações , Adenocarcinoma/mortalidade , Colangite/complicações , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/mortalidade , Pancreaticoduodenectomia , Adenocarcinoma/cirurgia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/cirurgia , Estudos Retrospectivos , Fatores de Risco
5.
Brain Imaging Behav ; 2020 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-33040257

RESUMO

Subclinical cardiac dysfunction is associated with smaller total brain volume on magnetic resonance imaging (MRI). To study whether cardiac output relates to regional measurements of grey and white matter structure, older adults (n = 326) underwent echocardiogram to quantify cardiac output (L/min) and brain MRI. Linear regressions related cardiac output to grey matter volumes measured on T1 and white matter hyperintensities assessed on T2-FLAIR. Voxelwise analyses related cardiac output to diffusion tensor imaging adjusting for demographic, genetic, and vascular risk factors. Follow-up models assessed a cardiac output x diagnosis interaction with stratification (normal cognition, mild cognitive impairment). Cardiac output interacted with diagnosis, such that lower cardiac output related to smaller total grey matter (p = 0.01), frontal lobe (p = 0.01), and occipital lobe volumes (p = 0.01) among participants with normal cognition. When excluding participants with cardiovascular disease and atrial fibrillation, associations emerged with smaller parietal lobe (p = 0.005) and hippocampal volume (p = 0.05). Subtle age-related cardiac changes may disrupt neuronal homeostasis and impact grey matter integrity prior to cognitive impairment.

6.
Circulation ; 142(15): 1422-1424, 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33044857
8.
Clin Sci (Lond) ; 134(17): 2369-2379, 2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32880388

RESUMO

OBJECTIVE: Type 2 diabetes mellitus (T2DM) reduces exercise capacity, but the mechanisms are incompletely understood. We probed the impact of ischemic stress on skeletal muscle metabolite signatures and T2DM-related vascular dysfunction. METHODS: we recruited 38 subjects (18 healthy, 20 T2DM), placed an antecubital intravenous catheter, and performed ipsilateral brachial artery reactivity testing. Blood samples for plasma metabolite profiling were obtained at baseline and immediately upon cuff release after 5 min of ischemia. Brachial artery diameter was measured at baseline and 1 min after cuff release. RESULTS: as expected, flow-mediated vasodilation was attenuated in subjects with T2DM (P<0.01). We confirmed known T2DM-associated baseline differences in plasma metabolites, including homocysteine, dimethylguanidino valeric acid and ß-alanine (all P<0.05). Ischemia-induced metabolite changes that differed between groups included 5-hydroxyindoleacetic acid (healthy: -27%; DM +14%), orotic acid (healthy: +5%; DM -7%), trimethylamine-N-oxide (healthy: -51%; DM +0.2%), and glyoxylic acid (healthy: +19%; DM -6%) (all P<0.05). Levels of serine, betaine, ß-aminoisobutyric acid and anthranilic acid were associated with vessel diameter at baseline, but only in T2DM (all P<0.05). Metabolite responses to ischemia were significantly associated with vasodilation extent, but primarily observed in T2DM, and included enrichment in phospholipid metabolism (P<0.05). CONCLUSIONS: our study highlights impairments in muscle and vascular signaling at rest and during ischemic stress in T2DM. While metabolites change in both healthy and T2DM subjects in response to ischemia, the relationship between muscle metabolism and vascular function is modified in T2DM, suggesting that dysregulated muscle metabolism in T2DM may have direct effects on vascular function.

9.
Proc Natl Acad Sci U S A ; 117(40): 25026-25035, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32958645

RESUMO

In addition to their fundamental role in clearance, the kidneys release select molecules into the circulation, but whether any of these anabolic functions provides insight on kidney health is unknown. Using aptamer-based proteomics, we characterized arterial (A)-to-renal venous (V) gradients for >1,300 proteins in 22 individuals who underwent invasive sampling. Although most of the proteins that changed significantly decreased from A to V, consistent with renal clearance, several were found to increase, the most significant of which was testican-2. To assess the clinical implications of these physiologic findings, we examined proteomic data in the Jackson Heart Study (JHS), an African-American cohort (n = 1,928), with replication in the Framingham Heart Study (FHS), a White cohort (n = 1,621). In both populations, testican-2 had a strong, positive correlation with estimated glomerular filtration rate (eGFR). In addition, higher baseline testican-2 levels were associated with a lower rate of eGFR decline in models adjusted for age, gender, hypertension, type 2 diabetes, body mass index, baseline eGFR, and albuminuria. Glomerular expression of testican-2 in human kidneys was demonstrated by immunohistochemistry, immunofluorescence, and electron microscopy, while single-cell RNA sequencing of human kidneys showed expression of the cognate gene, SPOCK2, exclusively in podocytes. In vitro, testican-2 increased glomerular endothelial tube formation and motility, raising the possibility that its secretion has a functional role within the glomerulus. Taken together, our findings identify testican-2 as a podocyte-derived biomarker of kidney health and prognosis.


Assuntos
Biomarcadores/metabolismo , Rim/metabolismo , Proteoglicanas/genética , Proteômica , Afro-Americanos/genética , Aptâmeros de Peptídeos , Feminino , Taxa de Filtração Glomerular/genética , Humanos , Hipertensão/genética , Hipertensão/patologia , Rim/patologia , Testes de Função Renal , Glomérulos Renais/metabolismo , Masculino , Pessoa de Meia-Idade , Podócitos/metabolismo , Podócitos/patologia , Proteoglicanas/metabolismo
10.
Surg Endosc ; 2020 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-32886240

RESUMO

BACKGROUND AND AIMS: Gastric Access Temporary for Endoscopy (GATE), also known as EUS-Directed Trangastric ERCP (EDGE), has demonstrated advantages over device-assisted enteroscopy (DAE) and laparoscopic-assisted ERCP (LA-ERCP) for patients with Roux-en-Y gastric bypass (RYGB) anatomy. We aimed to directly compare clinical outcomes and cost utility among the three ERCP modalities. METHODS: Patients with RYGB anatomy who had DAE, LA-ERCP, or GATE from 2009 to 2019 at 2 tertiary centers were included in our review. We measured outcomes in three areas: success rate, post-procedural adverse events (AEs) and hospitalization, and cost utility per Medicare/Medicaid insurance payments. RESULTS: Cohort Total 130 patients (70 underwent DAE, 42 LA-ERCP, and 18 GATE). Success rate DAE was successful in 59% of patients, compared to success rates of 98 and 100% for LA-ERCP and GATE, respectively (p < 0.001). For DAE, 62% of unsuccessful cases required rescue therapy. Adverse events and hospitalization Patients who underwent GATE had the lowest rate of hospitalization post procedure (44% vs. 77% and 100% for DAE and LA-ERCP, respectively, p < 0.01) and spent the least amount of time hospitalized (median time 0 days vs 2 and 3 days for DAE and LA-ERCP, respectively, p < 0.0001). GATE had lower AE rates than LA-ERCP (6 vs 31%, p = 0.046), and both had similar rates to DAE. Cost utility LA-ERCP carried the highest total procedural and hospitalization cost per Medicare/ Medicaid insurance payments (median payment difference of $9.7 K vs GATE and $7.9 K vs DAE, p < 0.01 for both). Procedural and hospitalization costs were similar between GATE and DAE (p = 0.76). CONCLUSIONS: GATE is a safe modality for ERCP with high success rates in RYGB patients and exhibits the lowest hospitalization time and rate of adverse events when compared to DAE and LA-ERCP. GATE is similar to DAE from a cost utility approach, and both are less costly than LA-ERCP.

11.
J Am Coll Cardiol ; 76(12): 1455-1465, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32943164

RESUMO

BACKGROUND: Whether cardiovascular (CV) disease risk factors and biomarkers associate differentially with heart failure (HF) risk in men and women is unclear. OBJECTIVES: The purpose of this study was to evaluate sex-specific associations of CV risk factors and biomarkers with incident HF. METHODS: The analysis was performed using data from 4 community-based cohorts with 12.5 years of follow-up. Participants (recruited between 1989 and 2002) were free of HF at baseline. Biomarker measurements included natriuretic peptides, cardiac troponins, plasminogen activator inhibitor-1, D-dimer, fibrinogen, C-reactive protein, sST2, galectin-3, cystatin-C, and urinary albumin-to-creatinine ratio. RESULTS: Among 22,756 participants (mean age 60 ± 13 years, 53% women), HF occurred in 2,095 participants (47% women). Age, smoking, type 2 diabetes mellitus, hypertension, body mass index, atrial fibrillation, myocardial infarction, left ventricular hypertrophy, and left bundle branch block were strongly associated with HF in both sexes (p < 0.001), and the combined clinical model had good discrimination in men (C-statistic = 0.80) and in women (C-statistic = 0.83). The majority of biomarkers were strongly and similarly associated with HF in both sexes. The clinical model improved modestly after adding natriuretic peptides in men (ΔC-statistic = 0.006; likelihood ratio chi-square = 146; p < 0.001), and after adding cardiac troponins in women (ΔC-statistic = 0.003; likelihood ratio chi-square = 73; p < 0.001). CONCLUSIONS: CV risk factors are strongly and similarly associated with incident HF in both sexes, highlighting the similar importance of risk factor control in reducing HF risk in the community. There are subtle sex-related differences in the predictive value of individual biomarkers, but the overall improvement in HF risk estimation when included in a clinical HF risk prediction model is limited in both sexes.

12.
ESC Heart Fail ; 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32909388

RESUMO

AIMS: Heart failure (HF) is associated with several metabolic changes, but it is unknown whether distinct components of the circulating metabolome may be related to cardiac structure and function, and with incident HF in the community. METHODS AND RESULTS: We assayed 217 circulating metabolites in 2336 Framingham Study participants (mean age 55 ± 10 years, 53% women) without HF at baseline. We used linear and Cox regression to relate concentrations of metabolites to left ventricular (LV) diastolic dimension, LV wall thickness, LV ejection fraction, left atrial dimension, LV ventricular mass, and aortic root size cross-sectionally and to incident HF prospectively. Bonferroni-adjusted P-values <0.05 denoted statistical significance. Circulating concentrations of kynurenine [ß = -0.12 cm per standard deviation (SD) increment in normalized residual of metabolite, P = 7.3 × 10-8 ] and aminoadipate (-0.11 cm per SD increment, P = 2.61 × 10-5 ) were associated with left ventricular diastolic dimension, phosphatidylcholine (carbon:double bound = 38:6) with left atrial dimension (0.10 cm per SD increment, P = 9.7 × 10-6 ), and cholesterol ester (carbon:double bound = 20:5) with left atrial dimension (0.10 cm per SD increment, P = 1.4 × 10-5 ) in multivariable-adjusted models. During an average follow-up of 15.8 (range 0.02-23.2) years, 113 participants (5%) were diagnosed with HF with reduced ejection fraction and 106 individuals (5%) with HF with preserved ejection fraction. In multivariable analyses, concentrations of phosphatidylcholine (hazard ratio 0.63, P = 1.3 × 10-5 ) and ornithine (hazard ratio 1.44, P = 0.00014) were associated with HF with reduced ejection fraction. CONCLUSIONS: Several metabolites, including the vasoactive metabolite kynurenine, were related to cardiac structure and function in our sample. Additional research is warranted to confirm our observations and investigate if these metabolites can risk stratify ambulatory individuals.

14.
J Am Heart Assoc ; 9(15): e015410, 2020 Aug 04.
Artigo em Inglês | MEDLINE | ID: mdl-32698652

RESUMO

Background Current strategies for cardiovascular disease (CVD) risk assessment focus on 10-year or longer timeframes. Shorter-term CVD risk is also clinically relevant, particularly for high-risk occupations, but is under-investigated. Methods and Results We pooled data from participants in the ARIC (Atherosclerosis Risk in Communities study), MESA (Multi-Ethnic Study of Atherosclerosis), and DHS (Dallas Heart Study), free from CVD at baseline (N=16 581). Measurements included N-terminal pro-B-type natriuretic peptide (>100 pg/mL prospectively defined as abnormal); high-sensitivity cardiac troponin T (abnormal >5 ng/L); high-sensitivity C-reactive protein (abnormal >3 mg/L); left ventricular hypertrophy by ECG (abnormal if present); carotid intima-media thickness, and plaque (abnormal >75th percentile for age and sex or presence of plaque); and coronary artery calcium (abnormal >10 Agatston U). Each abnormal test result except left ventricular hypertrophy by ECG was independently associated with increased 3-year risk of global CVD (myocardial infarction, stroke, coronary revascularization, incident heart failure, or atrial fibrillation), even after adjustment for traditional CVD risk factors and the other test results. When a simple integer score counting the number of abnormal tests was used, 3-year multivariable-adjusted global CVD risk was increased among participants with integer scores of 1, 2, 3, and 4, by ≈2-, 3-, 4.5- and 8-fold, respectively, when compared with those with a score of 0. Qualitatively similar results were obtained for atherosclerotic CVD (fatal or non-fatal myocardial infarction or stroke). Conclusions A strategy incorporating multiple biomarkers and atherosclerosis imaging improved assessment of 3-year global and atherosclerotic CVD risk compared with a standard approach using traditional risk factors.

15.
Clin Transl Gastroenterol ; 11(5): e00175, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32677809

RESUMO

INTRODUCTION: Gastric variceal (GV) bleeding is a feared complication of cirrhosis. Traditional endoscopic treatment with cyanoacrylate (CYA) injection can be challenging. Alternatively, endoscopic ultrasound (EUS)-guided delivery of hemostatic coils has shown high therapeutic success without the complications profile of CYA alone. Our aim was to compare the clinical outcomes of EUS-guided coil embolization with endoscopic CYA injection for the treatment of GV. METHODS: We performed a matched cohort study using a prospective registry involving 2 tertiary centers. A total of 10 patients undergoing EUS-based coil therapy were matched in 1:3 fashion to 30 patients who underwent CYA injection. The matching criteria included type of GV, Charlson comorbidity index, and bleeding severity. Primary outcomes were technical success and complications. Secondary outcomes were rebleeding rates, reinterventions rates, total transfusion requirements, and time-to-event analysis (rebleeding, reintervention, and transfusion). RESULTS: Technical success was 100% for EUS coil therapy vs 96.7% for CYA injection (P = 1.0). Complication rates were 10% in the EUS coil group vs 20% in the CYA group; P = 0.65. At 9 months, no EUS coil patient had rebled compared with 38% of the CYA group. No EUS coil patient required blood transfusion for GV rebleed, whereas over 50% of CYA patients did. Ten percent of EUS coil patients required reintervention compared with 60% of CYA patients. The EUS coil group had superior time to reintervention, GV rebleed, and transfusions (all P < 0.05). DISCUSSION: Compared with CYA, EUS-guided coil injection appears superior for the treatment of GV and should be considered initial endoscopic treatment of choice in centers with interventional EUS expertise.

16.
Circ Heart Fail ; 13(7): e006570, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32507024

RESUMO

BACKGROUND: NPs (natriuretic peptides) are cardiac-derived hormones that promote natriuresis, diuresis, and vasodilation. Preclinical evidence suggests that nonhemodynamic triggers for NP release exist, with a few studies implicating inflammatory stimuli. We examined the association between inflammation and NP levels in humans. METHODS: The associations between inflammation and NP levels were examined in 3 independent studies. First, in 5481 MESA (Multi-Ethnic Study of Atherosclerosis) participants, the cross-sectional (exam 1) and longitudinal (exams 1 to 3) associations between circulating IL6 (interleukin-6) and NT-proBNP (N terminal pro B-type natriuretic peptide) levels were examined in multivariable-adjusted models. Second, in a prospective study of 115 healthy individuals, changes in NP levels were quantified following exposure to lipopolysaccharide as an inflammatory stimulus. Third, in 13 435 hospitalized patients, the association between acute inflammatory conditions and circulating NP levels was assessed using multivariable-adjusted models. RESULTS: At the baseline MESA exam, each 1-unit higher natural log IL6 was associated with 16% higher NT-proBNP level ([95% CI, 10%-22%]; P=0.002). Each 1-unit higher baseline natural log IL6 level also associated with 6% higher NT-proBNP level ([95% CI, 1%-11%]; P=0.02) at 4-year follow-up. In the lipopolysaccharide study, median NT-proBNP levels rose from 21 pg/mL pre-lipopolysaccharide to 54 pg/mL post-lipopolysaccharide, P<0.001. In the hospitalized patient study, acute inflammatory conditions were associated with 36% higher NP levels ([95% CI, 17%-60%]; P<0.001). CONCLUSIONS: Inflammation appears to be associated with NP release. Interpretation of NP levels should therefore take into account inflammatory conditions.


Assuntos
Inflamação/sangue , Peptídeos Natriuréticos/sangue , Ensaios Clínicos como Assunto , Humanos , Inflamação/etiologia
17.
medRxiv ; 2020 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-32577670

RESUMO

COVID-19 is one of the most consequential pandemics in the last century, yet the biological mechanisms that confer disease risk are incompletely understood. Further, heterogeneity in disease outcomes is influenced by race, though the relative contributions of structural/social and genetic factors remain unclear. Very recent unpublished work has identified two genetic risk loci that confer greater risk for respiratory failure in COVID-19: the ABO locus and the 3p21.31 locus. To understand how these loci might confer risk and whether this differs by race, we utilized proteomic profiling and genetic information from three cohorts including black and white participants to identify proteins influenced by these loci. We observed that variants in the ABO locus are associated with levels of CD209/DC-SIGN, a known binding protein for SARS-CoV and other viruses, as well as multiple inflammatory and thrombotic proteins, while the 3p21.31 locus is associated with levels of CXCL16, a known inflammatory chemokine. Thus, integration of genetic information and proteomic profiling in biracial cohorts highlights putative mechanisms for genetic risk in COVID-19 disease.

18.
Circ Heart Fail ; 13(5): e006749, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32408813

RESUMO

BACKGROUND: We used a large-scale, high-throughput DNA aptamer-based discovery proteomic platform to identify circulating biomarkers of cardiac remodeling and incident heart failure (HF) in community-dwelling individuals. METHODS: We evaluated 1895 FHS (Framingham Heart Study) participants (age 55±10 years, 54% women) who underwent proteomic profiling and echocardiography. Plasma levels of 1305 proteins were related to echocardiographic traits and to incident HF using multivariable regression. Statistically significant protein-HF associations were replicated in the HUNT (Nord-Trøndelag Health) study (n=2497, age 63±10 years, 43% women), and results were meta-analyzed. Genetic variants associated with circulating protein levels (pQTLs) were related to echocardiographic traits in the EchoGen (n=30 201) and to incident HF in the CHARGE (n=20 926) consortia. RESULTS: Seventeen proteins associated with echocardiographic traits in cross-sectional analyses (false discovery rate <0.10), and 8 of these proteins had pQTLs associated with echocardiographic traits in EchoGen (P<0.0007). In Cox models adjusted for clinical risk factors, 29 proteins demonstrated associations with incident HF in FHS (174 HF events, mean follow-up 19 [limits, 0.2-23.7] years). In meta-analyses of FHS and HUNT, 6 of these proteins were associated with incident HF (P<3.8×10-5; 3 with higher risk: NT-proBNP [N-terminal proB-type natriuretic peptide], TSP2 [thrombospondin-2], MBL [mannose-binding lectin]; and 3 with lower risk: ErbB1 [epidermal growth factor receptor], GDF-11/8 [growth differentiation factor-11/8], and RGMC [hemojuvelin]). For 5 of the 6 proteins, pQTLs were associated with echocardiographic traits (P<0.0006) in EchoGen, and for RGMC, a protein quantitative trait loci was associated with incident HF (P=0.001). CONCLUSIONS: A large-scale proteomics approach identified new predictors of cardiac remodeling and incident HF. Future studies are warranted to elucidate how biological pathways represented by these proteins may mediate cardiac remodeling and HF risk and to assess if these proteins can improve HF risk prediction.


Assuntos
Aptâmeros de Nucleotídeos , Proteínas Sanguíneas/análise , Ecocardiografia , Variação Genética , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/diagnóstico por imagem , Proteômica , Idoso , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Estudos Transversais , Feminino , Predisposição Genética para Doença , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/genética , Ensaios de Triagem em Larga Escala , Humanos , Incidência , Masculino , Massachusetts/epidemiologia , Pessoa de Meia-Idade , Noruega/epidemiologia , Fenótipo , Valor Preditivo dos Testes , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
19.
Sci Rep ; 10(1): 7561, 2020 05 05.
Artigo em Inglês | MEDLINE | ID: mdl-32372017

RESUMO

Left ventricular (LV) mass is a prognostic biomarker for incident heart disease and all-cause mortality. Large-scale genome-wide association studies have identified few SNPs associated with LV mass. We hypothesized that a polygenic discovery approach using LV mass measurements made in a clinical population would identify risk factors and diseases associated with adverse LV remodeling. We developed a polygenic single nucleotide polymorphism-based predictor of LV mass in 7,601 individuals with LV mass measurements made during routine clinical care. We tested for associations between this predictor and 894 clinical diagnoses measured in 58,838 unrelated genotyped individuals. There were 29 clinical phenotypes associated with the LV mass genetic predictor at FDR q < 0.05. Genetically predicted higher LV mass was associated with modifiable cardiac risk factors, diagnoses related to organ dysfunction and conditions associated with abnormal cardiac structure including heart failure and atrial fibrillation. Secondary analyses using polygenic predictors confirmed a significant association between higher LV mass and body mass index and, in men, associations with coronary atherosclerosis and systolic blood pressure. In summary, these analyses show that LV mass-associated genetic variability associates with diagnoses of cardiac diseases and with modifiable risk factors which contribute to these diseases.


Assuntos
Predisposição Genética para Doença , Cardiopatias/epidemiologia , Cardiopatias/etiologia , Ventrículos do Coração/patologia , Herança Multifatorial , Remodelação Ventricular , Ecocardiografia , Feminino , Estudo de Associação Genômica Ampla , Genótipo , Cardiopatias/diagnóstico , Cardiopatias/mortalidade , Ventrículos do Coração/anatomia & histologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Masculino , Razão de Chances , Tamanho do Órgão , Fenótipo , Polimorfismo de Nucleotídeo Único , Medição de Risco , Fatores de Risco , Remodelação Ventricular/genética
20.
J Am Heart Assoc ; 9(10): e014661, 2020 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-32378457

RESUMO

Background Inflammation may contribute to incident heart failure (HF). Rheumatoid arthritis (RA), a prototypic inflammatory condition, may serve as a model for understanding inflammation-related HF risk. Methods and Results Using the Vanderbilt University Medical Center electronic health record, we retrospectively identified 9889 patients with RA and 9889 control patients without autoimmune disease matched for age, sex, and race. Prevalent HF at entry into the electronic health record or preceding RA diagnosis was excluded. Incident HF was ascertained using International Classification of Diseases, Ninth Revision (ICD-9), codes and medications. Over 177 566 person-years of follow-up, patients with RA were at 21% greater risk of HF (95% CI, 3-42%) independent of traditional cardiovascular risk factors. Among patients with RA, higher CRP (C-reactive protein) was associated with greater HF risk (P<0.001), while the anti-inflammatory drug methotrexate was associated with ≈25% lower HF risk (P=0.021). In a second cohort (n=115) of prospectively enrolled patients with and without RA, we performed proteomics and cardiac magnetic resonance imaging to discover circulating markers of inflammation associated with cardiac structure and function. Artemin levels were higher in patients with RA compared with controls (P=0.009), and higher artemin levels were associated with worse ventricular end-systolic elastance and ventricular-vascular coupling ratio (P=0.044 and P=0.031, respectively). Conclusions RA, a prototypic chronic inflammatory condition, is associated with increased risk of HF. Among patients with RA, higher levels of CRP were associated with greater HF risk, while methotrexate was associated with lower risk.

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