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Cell-free hemoglobin augments acute kidney injury during experimental sepsis.
Shaver CM, Paul MG, Putz ND, Landstreet SR, Kuck JL, Scarfe L, Skrypnyk N, Yang H, Harrison FE, de Caestecker MP, Bastarache JA, Ware LB
(2019) Am J Physiol Renal Physiol 317: F922-F929
MeSH Terms: Acute Kidney Injury, Animals, Cell Line, Cell Survival, Cell-Free System, Cytokines, Female, Glomerular Filtration Rate, Hemoglobins, Hepatitis A Virus Cellular Receptor 1, Kidney Tubules, Lipocalin-2, Male, Mice, Mice, Inbred C57BL, Sepsis, Survival Analysis
Show Abstract · Added May 10, 2020
Acute kidney injury is a common complication of severe sepsis and contributes to high mortality. The molecular mechanisms of acute kidney injury during sepsis are not fully understood. Because hemoproteins, including myoglobin and hemoglobin, are known to mediate kidney injury during rhabdomyolysis, we hypothesized that cell-free hemoglobin (CFH) would exacerbate acute kidney injury during sepsis. Sepsis was induced in mice by intraperitoneal injection of cecal slurry (CS). To mimic elevated levels of CFH observed during human sepsis, mice also received a retroorbital injection of CFH or dextrose control. Four groups of mice were analyzed: sham treated (sham), CFH alone, CS alone, and CS + CFH. The addition of CFH to CS reduced 48-h survival compared with CS alone (67% vs. 97%, = 0.001) and increased the severity of illness. After 24 and 48 h, CS + CFH mice had a reduced glomerular filtration rate from baseline, whereas sham, CFH, and CS mice maintained baseline glomerular filtration rate. Biomarkers of acute kidney injury, neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 (KIM-1), were markedly elevated in CS+CFH compared with CS (8-fold for NGAL and 2.4-fold for KIM-1, < 0.002 for each) after 48 h. Histological examination showed a trend toward increased tubular injury in CS + CFH-exposed kidneys compared with CS-exposed kidneys. However, there were similar levels of renal oxidative injury and apoptosis in the CS + CFH group compared with the CS group. Kidney levels of multiple proinflammatory cytokines were similar between CS and CS + CFH groups. Human renal tubule cells (HK-2) exposed to CFH demonstrated increased cytotoxicity. Together, these results show that CFH exacerbates acute kidney injury in a mouse model of experimental sepsis, potentially through increased renal tubular injury.
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Identification of Targetable Recurrent MAP3K8 Rearrangements in Melanomas Lacking Known Driver Mutations.
Lehmann BD, Shaver TM, Johnson DB, Li Z, Gonzalez-Ericsson PI, Sánchez V, Shyr Y, Sanders ME, Pietenpol JA
(2019) Mol Cancer Res 17: 1842-1853
MeSH Terms: Algorithms, Cell Line, Tumor, Databases, Genetic, Female, Gene Amplification, Gene Expression Regulation, Neoplastic, Humans, MAP Kinase Kinase Kinases, Male, Melanoma, Protein Kinase Inhibitors, Proto-Oncogene Proteins, Sequence Analysis, RNA, Sequence Deletion, Survival Analysis, Translocation, Genetic, Up-Regulation
Show Abstract · Added March 30, 2020
Melanomas are characterized by driver and loss-of-function mutations that promote mitogen-activated protein kinase (MAPK) signaling. MEK inhibitors are approved for use in BRAF-mutated melanoma; however, early-phase clinical trials show occasional responses in driver-negative melanoma, suggesting other alterations conferring MAPK/ERK dependency. To identify additional structural alterations in melanoma, we evaluated RNA-Seq from a set of known MAPK/ERK regulators using a novel population-based algorithm in The Cancer Genome Atlas (TCGA). We identified recurrent MAP3K8 rearrangements in 1.7% of melanomas in TCGA, occurring in more than 15% of tumors without known driver mutations (, and ). Using an independent tumor set, we validated a similar rearrangement frequency by FISH. MAP3K8-rearranged melanomas exhibit a low mutational burden and absence of typical UV-mutational patterns. We identified two melanoma cell lines that harbor endogenous truncating MAP3K8 rearrangements that demonstrate exquisite dependency. Rearrangement and amplification of the MAP3K8 locus in melanoma cells result in increased levels of a truncated, active MAP3K8 protein; oncogenic dependency on the aberrant MAP3K8; and a concomitant resistance to BRAF inhibition and sensitivity to MEK or ERK1/2 inhibition. Our findings reveal and biochemically characterize targetable oncogenic MAP3K8 truncating rearrangements in driver mutation-negative melanoma, and provide insight to therapeutic approaches for patients with these tumors. These data provide rationale for using MEK or ERK inhibitors in a subset of driver-negative, MAPK/ERK-dependent melanomas harboring truncating MAP3K8 rearrangements. IMPLICATIONS: This is the first mechanistic study and therapeutic implications of truncating MAP3K8 rearrangements in driver-negative melanoma.
©2019 American Association for Cancer Research.
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Nonsteroidal Anti-inflammatory Drugs Alter the Microbiota and Exacerbate Colitis while Dysregulating the Inflammatory Response.
Maseda D, Zackular JP, Trindade B, Kirk L, Roxas JL, Rogers LM, Washington MK, Du L, Koyama T, Viswanathan VK, Vedantam G, Schloss PD, Crofford LJ, Skaar EP, Aronoff DM
(2019) mBio 10:
MeSH Terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, CD4-Positive T-Lymphocytes, Clostridium Infections, Gastrointestinal Microbiome, Indomethacin, Intestinal Mucosa, Mice, Neutrophils, Prostaglandins, Survival Analysis
Show Abstract · Added April 7, 2019
infection (CDI) is a major public health threat worldwide. The use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with enhanced susceptibility to and severity of CDI; however, the mechanisms driving this phenomenon have not been elucidated. NSAIDs alter prostaglandin (PG) metabolism by inhibiting cyclooxygenase (COX) enzymes. Here, we found that treatment with the NSAID indomethacin prior to infection altered the microbiota and dramatically increased mortality and the intestinal pathology associated with CDI in mice. We demonstrated that in -infected animals, indomethacin treatment led to PG deregulation, an altered proinflammatory transcriptional and protein profile, and perturbed epithelial cell junctions. These effects were paralleled by increased recruitment of intestinal neutrophils and CD4 cells and also by a perturbation of the gut microbiota. Together, these data implicate NSAIDs in the disruption of protective COX-mediated PG production during CDI, resulting in altered epithelial integrity and associated immune responses. infection (CDI) is a spore-forming anaerobic bacterium and leading cause of antibiotic-associated colitis. Epidemiological data suggest that use of nonsteroidal anti-inflammatory drugs (NSAIDs) increases the risk for CDI in humans, a potentially important observation given the widespread use of NSAIDs. Prior studies in rodent models of CDI found that NSAID exposure following infection increases the severity of CDI, but mechanisms to explain this are lacking. Here we present new data from a mouse model of antibiotic-associated CDI suggesting that brief NSAID exposure prior to CDI increases the severity of the infectious colitis. These data shed new light on potential mechanisms linking NSAID use to worsened CDI, including drug-induced disturbances to the gut microbiome and colonic epithelial integrity. Studies were limited to a single NSAID (indomethacin), so future studies are needed to assess the generalizability of our findings and to establish a direct link to the human condition.
Copyright © 2019 Maseda et al.
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Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis.
Rhodes CJ, Batai K, Bleda M, Haimel M, Southgate L, Germain M, Pauciulo MW, Hadinnapola C, Aman J, Girerd B, Arora A, Knight J, Hanscombe KB, Karnes JH, Kaakinen M, Gall H, Ulrich A, Harbaum L, Cebola I, Ferrer J, Lutz K, Swietlik EM, Ahmad F, Amouyel P, Archer SL, Argula R, Austin ED, Badesch D, Bakshi S, Barnett C, Benza R, Bhatt N, Bogaard HJ, Burger CD, Chakinala M, Church C, Coghlan JG, Condliffe R, Corris PA, Danesino C, Debette S, Elliott CG, Elwing J, Eyries M, Fortin T, Franke A, Frantz RP, Frost A, Garcia JGN, Ghio S, Ghofrani HA, Gibbs JSR, Harley J, He H, Hill NS, Hirsch R, Houweling AC, Howard LS, Ivy D, Kiely DG, Klinger J, Kovacs G, Lahm T, Laudes M, Machado RD, MacKenzie Ross RV, Marsolo K, Martin LJ, Moledina S, Montani D, Nathan SD, Newnham M, Olschewski A, Olschewski H, Oudiz RJ, Ouwehand WH, Peacock AJ, Pepke-Zaba J, Rehman Z, Robbins I, Roden DM, Rosenzweig EB, Saydain G, Scelsi L, Schilz R, Seeger W, Shaffer CM, Simms RW, Simon M, Sitbon O, Suntharalingam J, Tang H, Tchourbanov AY, Thenappan T, Torres F, Toshner MR, Treacy CM, Vonk Noordegraaf A, Waisfisz Q, Walsworth AK, Walter RE, Wharton J, White RJ, Wilt J, Wort SJ, Yung D, Lawrie A, Humbert M, Soubrier F, Trégouët DA, Prokopenko I, Kittles R, Gräf S, Nichols WC, Trembath RC, Desai AA, Morrell NW, Wilkins MR, UK NIHR BioResource Rare Diseases Consortium, UK PAH Cohort Study Consortium, US PAH Biobank Consortium
(2019) Lancet Respir Med 7: 227-238
MeSH Terms: Female, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Genotyping Techniques, HLA-DP alpha-Chains, HLA-DP beta-Chains, Humans, Male, Middle Aged, Polymorphism, Single Nucleotide, Pulmonary Arterial Hypertension, Risk Assessment, SOXF Transcription Factors, Signal Transduction, Survival Analysis
Show Abstract · Added March 8, 2020
BACKGROUND - Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes.
METHODS - We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses.
FINDINGS - A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity.
INTERPRETATION - This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials.
FUNDING - UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.
Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.
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Early onset oral tongue cancer in the United States: A literature review.
Campbell BR, Netterville JL, Sinard RJ, Mannion K, Rohde SL, Langerman A, Kim YJ, Lewis JS, Lang Kuhs KA
(2018) Oral Oncol 87: 1-7
MeSH Terms: Age of Onset, Humans, Incidence, Prognosis, Risk Factors, Survival Analysis, Tobacco, Smokeless, Tongue Neoplasms, United States
Show Abstract · Added March 20, 2020
The incidence of early onset oral tongue squamous cell carcinoma (OTC) has been increasing in the United States, and no clear etiology has been identified. Studies on this topic have generally been small and presented varied results. The goal of this review is to analyze and synthesize the literature regarding early onset OTC risk factors, outcomes, and molecular analyses within the US. To date, studies suggest that early onset OTC patients tend to have less heavy cigarette use than typical onset patients, but there may be an association between early onset OTC and smokeless tobacco (chewing tobacco and snuff) use. Early onset OTC is associated with similar or possibly improved survival compared to typical onset OTC. There has been no evidence to support a significant role for human papillomavirus in development of early onset OTC. Further research with larger cohorts of these patients is needed to better characterize this disease entity.
Copyright © 2018 Elsevier Ltd. All rights reserved.
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Outpatient Engagement and Predicted Risk of Suicide Attempts in Fibromyalgia.
McKernan LC, Lenert MC, Crofford LJ, Walsh CG
(2019) Arthritis Care Res (Hoboken) 71: 1255-1263
MeSH Terms: Adult, Area Under Curve, Case-Control Studies, Female, Fibromyalgia, Humans, Incidence, Male, Middle Aged, Odds Ratio, Outpatients, Predictive Value of Tests, Reproducibility of Results, Retrospective Studies, Risk Assessment, Suicidal Ideation, Suicide, Attempted, Survival Analysis, Young Adult
Show Abstract · Added March 25, 2020
OBJECTIVE - Patients with fibromyalgia (FM) are 10 times more likely to die by suicide than the general population. The purpose of this study was to externally validate published models predicting suicidal ideation and suicide attempts in patients with FM and to identify interpretable risk and protective factors for suicidality unique to FM.
METHODS - This was a case-control study of large-scale electronic health record data collected from 1998 to 2017, identifying FM cases with validated Phenotype KnowledgeBase criteria. Model performance was measured through discrimination, including the receiver operating area under the curve (AUC), sensitivity, and specificity, and through calibration, including calibration plots. Risk factors were selected by L1 penalized regression with bootstrapping for both outcomes. Secondary utilization analyses converted time-based billing codes to equivalent minutes to estimate face-to-face provider contact.
RESULTS - We identified 8,879 patients with FM, with 34 known suicide attempts and 96 documented cases of suicidal ideation. External validity was good for both suicidal ideation (AUC 0.80) and attempts (AUC 0.82) with excellent calibration. Risk factors specific to suicidal ideation included polysomatic symptoms such as fatigue (odds ratio [OR] 1.29 [95% confidence interval (95% CI) 1.25-1.32]), dizziness (OR 1.25 [95% CI 1.22-1.28]), and weakness (OR 1.17 [95% CI 1.15-1.19]). Risk factors specific to suicide attempt included obesity (OR 1.18 [95% CI 1.10-1.27]) and drug dependence (OR 1.15 [95% CI 1.12-1.18]). Per utilization analyses, those patients with FM and no suicidal ideation spent 3.5 times more time in follow-up annually, and those without documented suicide attempts spent more than 40 times more time face-to-face with providers annually.
CONCLUSION - This is the first study to successfully apply machine learning to reliably detect suicidality in patients with FM, identifying novel risk factors for suicidality and highlighting outpatient engagement as a protective factor against suicide.
© 2018, American College of Rheumatology.
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A multi-institutional review of outcomes in biopsy-proven acute invasive fungal sinusitis.
Wandell GM, Miller C, Rathor A, Wai TH, Guyer RA, Schmidt RA, Turner JH, Hwang PH, Davis GE, Humphreys IM
(2018) Int Forum Allergy Rhinol 8: 1459-1468
MeSH Terms: Adult, Aged, Aged, 80 and over, Biopsy, Cavernous Sinus, Debridement, Female, Humans, Immunization, Invasive Fungal Infections, Male, Middle Aged, Prognosis, Risk, Sinusitis, Survival Analysis, Young Adult
Show Abstract · Added July 23, 2020
BACKGROUND - Acute invasive fungal sinusitis (AIFS) is a rare, aggressive infection occurring in immunocompromised patients. In this study we examined factors that affect survival in AIFS, and whether immune-stimulating therapies (IST) improve survival.
METHODS - Pathology records of biopsy-proven AIFS were reviewed from 3 academic institutions from 1995 to 2016. Univariate and multivariate Cox regressions were performed at 1 and 3 months from diagnosis.
RESULTS - One hundred fourteen patients were included; 45 received IST. In the univariate analysis, the following factors were associated with worse survival: hematologic malignancy (3-month hazard ratio [HR], 3.7; p = 0.01); recent chemotherapy (within 1 month of AIFS diagnosis) (3-month HR, 2.3; p = 0.02); recent bone marrow transplant (BMT) (3-month HR, 2.5; p = 0.02); and infection with atypical fungi (1-month HR, 3.1; p = 0.04). The following were associated with improved survival in univariate analysis: increasing A1c% (1-month HR, 0.7; p = 0.01) and surgical debridement (1-month HR, 0.1; p = 0.001). One third of patients with a hematologic malignancy had an absolute neutrophil count (ANC) >1000 at the time of diagnosis. ANC was not associated with prognosis in these patients. The following were associated with worse survival in multivariate analyses: hematologic malignancy; recent chemotherapy; atypical organisms; and cavernous sinus extension. In multivariate analyses, IST was associated with a 70% reduction in mortality at 1 month (p = 0.02).
CONCLUSION - We presented the largest series of AIFS. Further studies are needed to examine the importance of ANC in diagnosis and prognosis. Patients diagnosed with atypical organisms may be at higher risk of death. IST likely improves short-term survival, but prospective studies are needed.
© 2018 ARS-AAOA, LLC.
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GDF-15, Galectin 3, Soluble ST2, and Risk of Mortality and Cardiovascular Events in CKD.
Tuegel C, Katz R, Alam M, Bhat Z, Bellovich K, de Boer I, Brosius F, Gadegbeku C, Gipson D, Hawkins J, Himmelfarb J, Ju W, Kestenbaum B, Kretzler M, Robinson-Cohen C, Steigerwalt S, Bansal N
(2018) Am J Kidney Dis 72: 519-528
MeSH Terms: Adult, Age Factors, Aged, Biomarkers, Cardiovascular Diseases, Cause of Death, Cohort Studies, Comorbidity, Female, Galectin 3, Growth Differentiation Factor 15, Humans, Interleukin-1 Receptor-Like 1 Protein, Kaplan-Meier Estimate, Male, Middle Aged, Prognosis, Proportional Hazards Models, Renal Insufficiency, Chronic, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Factors, Survival Analysis
Show Abstract · Added January 3, 2019
RATIONALE & OBJECTIVE - Inflammation, cardiac remodeling, and fibrosis may explain in part the excess risk for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Growth differentiation factor 15 (GDF-15), galectin 3 (Gal-3), and soluble ST2 (sST2) are possible biomarkers of these pathways in patients with CKD.
STUDY DESIGN - Observational cohort study.
SETTING & PARTICIPANTS - Individuals with CKD enrolled in either of 2 multicenter CKD cohort studies: the Seattle Kidney Study or C-PROBE (Clinical Phenotyping and Resource Biobank Study).
EXPOSURES - Circulating GDF-15, Gal-3, and sST2 measured at baseline.
OUTCOMES - Primary outcome was all-cause mortality. Secondary outcomes included hospitalization for physician-adjudicated heart failure and the atherosclerotic CVD events of myocardial infarction and cerebrovascular accident.
ANALYTIC APPROACH - Cox proportional hazards models used to test the association of each biomarker with each outcome, adjusting for demographics, CVD risk factors, and kidney function.
RESULTS - Among 883 participants, mean estimated glomerular filtration rate was 49±19mL/min/1.73m. Higher GDF-15 (adjusted HR [aHR] per 1-SD higher, 1.87; 95% CI, 1.53-2.29), Gal-3 (aHR per 1-SD higher, 1.51; 95% CI, 1.36-1.78), and sST2 (aHR per 1-SD higher, 1.36; 95% CI, 1.17-1.58) concentrations were significantly associated with mortality. Only GDF-15 level was also associated with heart failure events (HR per 1-SD higher, 1.56; 95% CI, 1.12-2.16). There were no detectable associations between GDF-15, Gal-3, or sST2 concentrations and atherosclerotic CVD events.
LIMITATIONS - Event rates for heart failure and atherosclerotic CVD were low.
CONCLUSIONS - Adults with CKD and higher circulating GDF-15, Gal-3, and sST2 concentrations experienced greater mortality. Elevated GDF-15 concentration was also associated with an increased rate of heart failure. Further work is needed to elucidate the mechanisms linking these circulating biomarkers with CVD in patients with CKD.
Copyright © 2018 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.
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Gene expression in triple-negative breast cancer in relation to survival.
Wang S, Beeghly-Fadiel A, Cai Q, Cai H, Guo X, Shi L, Wu J, Ye F, Qiu Q, Zheng Y, Zheng W, Bao PP, Shu XO
(2018) Breast Cancer Res Treat 171: 199-207
MeSH Terms: Adult, Aged, Biomarkers, Tumor, Female, Gene Expression, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Humans, Middle Aged, Neoplasm Grading, Neoplasm Staging, Population Surveillance, Prognosis, Registries, Survival Analysis, Triple Negative Breast Neoplasms
Show Abstract · Added December 6, 2018
PURPOSE - The identification of biomarkers related to the prognosis of triple-negative breast cancer (TNBC) is critically important for improved understanding of the biology that drives TNBC progression.
METHODS - We evaluated gene expression in total RNA isolated from formalin-fixed paraffin-embedded tumor samples using the NanoString nCounter assay for 469 TNBC cases from the Shanghai Breast Cancer Survival Study. We used Cox regression to quantify Hazard Ratios (HR) and corresponding confidence intervals (CI) for overall survival (OS) and disease-free survival (DFS) in models that included adjustment for breast cancer intrinsic subtype. Of 302 genes in our discovery analysis, 22 were further evaluated in relation to OS among 134 TNBC cases from the Nashville Breast Health Study and the Southern Community Cohort Study; 16 genes were further evaluated in relation to DFS in 335 TNBC cases from four gene expression omnibus datasets. Fixed-effect meta-analysis was used to combine results across data sources.
RESULTS - Twofold higher expression of EOMES (HR 0.90, 95% CI 0.83-0.97), RASGRP1 (HR 0.89, 95% CI 0.82-0.97), and SOD2 (HR 0.80, 95% CI 0.66-0.96) was associated with better OS. Twofold higher expression of EOMES (HR 0.89, 95% CI 0.81-0.97) and RASGRP1 (HR 0.87, 95% CI 0.81-0.95) was also associated with better DFS. On the contrary, a doubling of FA2H (HR 1.14, 95% CI 1.06-1.22) and GSPT1 (HR 1.33, 95% CI 1.14-1.55) expression was associated with shorter DFS.
CONCLUSIONS - We identified five genes (EOMES, FA2H, GSPT1, RASGRP1, and SOD2) that may serve as potential prognostic biomarkers and/or therapeutic targets for TNBC.
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Clinical Features Associated With Nascent Left Ventricular Diastolic Dysfunction in a Population Aged 40 to 55 Years.
Mosley JD, Levinson RT, Brittain EL, Gupta DK, Farber-Eger E, Shaffer CM, Denny JC, Roden DM, Wells QS
(2018) Am J Cardiol 121: 1552-1557
MeSH Terms: Adult, Age Distribution, Cohort Studies, Databases, Factual, Diabetes Mellitus, Type 2, Echocardiography, Female, Heart Failure, Diastolic, Humans, Hypertension, Incidence, Kaplan-Meier Estimate, Linear Models, Male, Middle Aged, Multivariate Analysis, Prognosis, Retrospective Studies, Risk Assessment, Severity of Illness Index, Sex Distribution, Stroke Volume, Survival Analysis, United States, Ventricular Dysfunction, Left
Show Abstract · Added June 7, 2018
Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction ≥50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 × 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 × 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 × 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 × 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 × 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 × 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 × 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease.
Copyright © 2018 Elsevier Inc. All rights reserved.
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