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BACKGROUND - Immune checkpoint inhibitors (ICIs) have substantially improved clinical outcomes in multiple cancer types and are increasingly being used in early disease settings and in combinations of different immunotherapies. However, ICIs can also cause severe or fatal immune-related adverse-events (irAEs). We aimed to identify and characterise cardiovascular irAEs that are significantly associated with ICIs.
METHODS - In this observational, retrospective, pharmacovigilance study, we used VigiBase, WHO's global database of individual case safety reports, to compare cardiovascular adverse event reporting in patients who received ICIs (ICI subgroup) with this reporting in the full database. This study included all cardiovascular irAEs classified by group queries according to the Medical Dictionary for Regulatory Activities, between inception on Nov 14, 1967, and Jan 2, 2018. We evaluated the association between ICIs and cardiovascular adverse events using the reporting odds ratio (ROR) and the information component (IC). IC is an indicator value for disproportionate Bayesian reporting that compares observed and expected values to find associations between drugs and adverse events. IC is the lower end of the IC 95% credibility interval, and an IC value of more than zero is deemed significant. This study is registered with ClinicalTrials.gov, number NCT03387540.
FINDINGS - We identified 31 321 adverse events reported in patients who received ICIs and 16 343 451 adverse events reported in patients treated with any drugs (full database) in VigiBase. Compared with the full database, ICI treatment was associated with higher reporting of myocarditis (5515 reports for the full database vs 122 for ICIs, ROR 11·21 [95% CI 9·36-13·43]; IC 3·20), pericardial diseases (12 800 vs 95, 3·80 [3·08-4·62]; IC 1·63), and vasculitis (33 289 vs 82, 1·56 [1·25-1·94]; IC 0·03), including temporal arteritis (696 vs 18, 12·99 [8·12-20·77]; IC 2·59) and polymyalgia rheumatica (1709 vs 16, 5·13 [3·13-8·40]; IC 1·33). Pericardial diseases were reported more often in patients with lung cancer (49 [56%] of 87 patients), whereas myocarditis (42 [41%] of 103 patients) and vasculitis (42 [60%] of 70 patients) were more commonly reported in patients with melanoma (χ test for overall subgroup comparison, p<0·0001). Vision was impaired in five (28%) of 18 patients with temporal arteritis. Cardiovascular irAEs were severe in the majority of cases (>80%), with death occurring in 61 (50%) of 122 myocarditis cases, 20 (21%) of 95 pericardial disease cases, and five (6%) of 82 vasculitis cases (χ test for overall comparison between pericardial diseases, myocarditis, and vasculitis, p<0·0001).
INTERPRETATION - Treatment with ICIs can lead to severe and disabling inflammatory cardiovascular irAEs soon after commencement of therapy. In addition to life-threatening myocarditis, these toxicities include pericardial diseases and temporal arteritis with a risk of blindness. These events should be considered in patient care and in combination clinical trial designs (ie, combinations of different immunotherapies as well as immunotherapies and chemotherapy).
FUNDING - The Cancer Institut Thématique Multi-Organisme of the French National Alliance for Life and Health Sciences (AVIESAN) Plan Cancer 2014-2019; US National Cancer Institute, National Institutes of Health; the James C. Bradford Jr. Melanoma Fund; and the Melanoma Research Foundation.
Copyright © 2018 Elsevier Ltd. All rights reserved.
Isolevuglandins are 4-ketoaldehydes formed by peroxidation of arachidonic acid. Isolevuglandins react rapidly with primary amines including the lysyl residues of proteins to form irreversible covalent modifications. This review highlights evidence for the potential role of isolevuglandin modification in the disease processes, especially atherosclerosis, and some of the tools including small molecule dicarbonyl scavengers utilized to assess their contributions to disease.
Copyright © 2018. Published by Elsevier Inc.
OBJECTIVE - Patients with rheumatoid arthritis (RA) have increased cardiovascular (CV) risk. In the general population, exercise improves several CV risk factors. In a cross-sectional study, we examined the hypothesis that more exercise is associated with protective traditional and non-traditional CV risk factor profile in patients with RA.
METHODS - Patient-reported exercise outside of daily activities was quantified by time and metabolic equivalents per week (METmin/week) and CV risk factors including blood pressure, standard lipid profiles, lipoprotein particle concentrations (NMR spectroscopy), and vascular indices were measured in 165 patients with RA. The relationship between exercise and CV risk factors was assessed according to whether patients exercised or not, and after adjustment for age, race and sex.
RESULTS - Over half (54%) of RA patients did not exercise. Among those who did exercise, median value for exercise duration was 113 min/week [IQR: 60, 210], and exercise metabolic equivalent expenditure was 484 METmin/week [IQR: 258, 990]. Disease activity (measured by DAS28 score), C-reactive protein, waist-hip ratio, and prevalence of hypertension were lower in patients who exercised compared to those who did not (all p-values < 0.05) but standard lipid profile and body mass index were not significantly different. Patients who exercised had significantly higher concentrations of HDL particles (p = 0.004) and lower vascular stiffness as measured by pulse wave velocity (p = 0.005).
CONCLUSIONS - More self-reported exercise in patients with RA was associated with a protective CV risk factor profile including lower waist-hip ratio, higher HDL particle concentration, lower vascular stiffness, and a lower prevalence of hypertension.
The completion of the Human Genome Project has unleashed a wealth of human genomics information, but it remains unclear how best to implement this information for the benefit of patients. The standard approach of biomedical research, with researchers pursuing advances in knowledge in the laboratory and, separately, clinicians translating research findings into the clinic as much as decades later, will need to give way to new interdisciplinary models for research in genomic medicine. These models should include scientists and clinicians actively working as teams to study patients and populations recruited in clinical settings and communities to make genomics discoveries-through the combined efforts of data scientists, clinical researchers, epidemiologists, and basic scientists-and to rapidly apply these discoveries in the clinic for the prediction, prevention, diagnosis, prognosis, and treatment of cardiovascular diseases and stroke. The highly publicized US Precision Medicine Initiative, also known as All of Us, is a large-scale program funded by the US National Institutes of Health that will energize these efforts, but several ongoing studies such as the UK Biobank Initiative; the Million Veteran Program; the Electronic Medical Records and Genomics Network; the Kaiser Permanente Research Program on Genes, Environment and Health; and the DiscovEHR collaboration are already providing exemplary models of this kind of interdisciplinary work. In this statement, we outline the opportunities and challenges in broadly implementing new interdisciplinary models in academic medical centers and community settings and bringing the promise of genomics to fruition.
© 2018 American Heart Association, Inc.
PURPOSE OF REVIEW - The goal of this review is to highlight the potential of induced pluripotent stem cell (iPSC)-based modeling as a tool for studying human cardiovascular diseases. We present some of the current cardiovascular disease models utilizing genome editing and patient-derived iPSCs.
RECENT FINDINGS - The incorporation of genome-editing and iPSC technologies provides an innovative research platform, providing novel insight into human cardiovascular disease at molecular, cellular, and functional level. In addition, genome editing in diseased iPSC lines holds potential for personalized regenerative therapies. The study of human cardiovascular disease has been revolutionized by cellular reprogramming and genome editing discoveries. These exceptional technologies provide an opportunity to generate human cell cardiovascular disease models and enable therapeutic strategy development in a dish. We anticipate these technologies to improve our understanding of cardiovascular disease pathophysiology leading to optimal treatment for heart diseases in the future.
BACKGROUND - We previously reported that consuming a balanced high fat diet (BHFD) wherein total saturated fat was reduced and total unsaturated fat increased by proportionately balancing the type of fat (1/3 saturated, 1/3 monounsaturated, 1/3 polyunsaturated) led to significant improvements in inflammatory burden, blood pressure, and vascular function in obese premenopausal European American (EA) and African American (AA) women.
OBJECTIVE - Here we compared changes in adipose tissue, lipoproteins, insulin resistance, and cardiovascular risk between EA and AA women.
METHODS - Dietary intakes, plasma fatty acids, lipids, apolipoproteins, lipoproteins, HOMA-IR and ASCVD risk was measured in 144 women who consumed BHFD for 16 weeks. Generalized linear modeling was performed while controlling for change in body weight.
RESULTS - EA women had greater reductions in visceral adipose tissue. Only EA women had significant reductions in fasting insulin levels (↓24.8%) and HOMA-IR (↓29%) scores. In EA women, the most significant improvements occurred in VLDL particle size (↑), apolipoprotein B levels (↑), serum TG (↓), number of plasma LDL particles (↓), and serum LDL-cholesterol (↓). In AA women, significant improvements occurred in HDL particle size (↑), number of large HDL particles (↑), and apolipoprotein AI levels (↑). Consequently, both groups had improved ASCVD risk scores (↓5.5%).
CONCLUSIONS - Consuming the balanced high fat diet led to significant reduction in cardiovascular risk factors in both groups. However, the pattern of response to BHFD differed with EA women responding more in components of the apolipoprotein B pathway versus AA women responding more in components of the apolipoprotein AI pathway.
Published by Elsevier Inc.
BACKGROUND - Acute kidney injury (AKI) is common and associated with poor outcomes. Heart failure is a leading cause of cardiovascular disease among patients with chronic kidney disease. The relationship between AKI and heart failure remains unknown and may identify a novel mechanistic link between kidney and cardiovascular disease.
STUDY DESIGN - Observational study.
SETTING & PARTICIPANTS - We studied a national cohort of 300,868 hospitalized US veterans (2004-2011) without a history of heart failure.
PREDICTOR - AKI was the predictor and was defined as a 0.3-mg/dL or 50% increase in serum creatinine concentration from baseline to the peak hospital value. Patients with and without AKI were matched (1:1) on 28 in- and outpatient covariates using optimal Mahalanobis distance matching.
OUTCOMES - Incident heart failure was defined as 1 or more hospitalization or 2 or more outpatient visits with a diagnosis of heart failure within 2 years through 2013.
RESULTS - There were 150,434 matched pairs in the study. Patients with and without AKI during the index hospitalization were well matched, with a median preadmission estimated glomerular filtration rate of 69mL/min/1.73m. The overall incidence rate of heart failure was 27.8 (95% CI, 19.3-39.9) per 1,000 person-years. The incidence rate was higher in those with compared with those without AKI: 30.8 (95% CI, 21.8-43.5) and 24.9 (95% CI, 16.9-36.5) per 1,000 person-years, respectively. In multivariable models, AKI was associated with 23% increased risk for incident heart failure (HR, 1.23; 95% CI, 1.19-1.27).
LIMITATIONS - Study population was primarily men, reflecting patients seen at Veterans Affairs hospitals.
CONCLUSIONS - AKI is an independent risk factor for incident heart failure. Future studies to identify underlying mechanisms and modifiable risk factors are needed.
Copyright © 2017 National Kidney Foundation, Inc. All rights reserved.
OBJECTIVE - To assess cross-sectionally whether lower cardiac index relates to lower resting cerebral blood flow (CBF) and cerebrovascular reactivity (CVR) among older adults.
METHODS - Vanderbilt Memory & Aging Project participants free of stroke, dementia, and heart failure were studied (n = 314, age 73 ± 7 years, 59% male, 39% with mild cognitive impairment). Cardiac index (liters per minute per meter squared) was quantified from echocardiography. Resting CBF (milliliters per 100 grams per minute) and hypercapnia-induced CVR were quantified from pseudo-continuous arterial spin-labeling MRI. Linear regressions with ordinary least-square estimates related cardiac index to regional CBF, with adjustment for age, education, race/ethnicity, Framingham Stroke Risk Profile score (systolic blood pressure, antihypertensive medication use, diabetes mellitus, current cigarette smoking, left ventricular hypertrophy, prevalent cardiovascular disease [CVD], atrial fibrillation), ε4 status, cognitive diagnosis, and regional tissue volume.
RESULTS - Lower cardiac index corresponded to lower resting CBF in the left (β = 2.4, = 0.001) and right (β = 2.5, = 0.001) temporal lobes. Results were similar when participants with prevalent CVD and atrial fibrillation were excluded (left temporal lobe β = 2.3, = 0.003; right temporal lobe β = 2.5, = 0.003). Cardiac index was unrelated to CBF in other regions assessed ( > 0.25) and CVR in all regions ( > 0.05). In secondary cardiac index × cognitive diagnosis interaction models, cardiac index and CBF associations were present only in cognitively normal participants and affected a majority of regions assessed with effects strongest in the left ( < 0.0001) and right ( < 0.0001) temporal lobes.
CONCLUSIONS - Among older adults without stroke, dementia, or heart failure, systemic blood flow correlates with cerebral CBF in the temporal lobe, independently of prevalent CVD, but not CVR.
© 2017 American Academy of Neurology.
BACKGROUND AND AIMS - Most familial hypercholesterolemia (FH) patients remain undertreated, and it is unclear what role health disparities may play for FH patients in the US. We sought to describe sex and racial/ethnic disparities in a national registry of US FH patients.
METHODS - We analyzed data from 3167 adults enrolled in the CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia (CASCADE-FH) registry. Logistic regression was used to evaluate for disparities in LDL-C goals and statin use, with adjustments for covariates including age, cardiovascular risk factors, and statin intolerance.
RESULTS - In adjusted analyses, women were less likely than men to achieve treated LDL-C of <100 mg/dL (OR 0.68, 95% CI, 0.57-0.82) or ≥50% reduction from pretreatment LDL-C (OR 0.79, 95% CI, 0.65-0.96). Women were less likely than men to receive statin therapy (OR, 0.60, 95% CI, 0.50-0.73) and less likely to receive a high-intensity statin (OR, 0.60, 95% CI, 0.49-0.72). LDL-C goal achievement also varied by race/ethnicity: compared with whites, Asians and blacks were less likely to achieve LDL-C levels <100 mg/dL (Asians, OR, 0.47, 95% CI, 0.24-0.94; blacks, OR, 0.49, 95% CI, 0.32-0.74) or ≥50% reduction from pretreatment LDL-C (Asians, OR 0.56, 95% CI, 0.32-0.98; blacks, OR 0.62, 95% CI, 0.43-0.90).
CONCLUSIONS - In a contemporary US population of FH patients, we identified differences in LDL-C goal attainment and statin usage after stratifying the population by either sex or race/ethnicity. Our findings suggest that health disparities contribute to the undertreatment of US FH patients. Increased efforts are warranted to raise awareness of these disparities.
Copyright © 2017 Elsevier B.V. All rights reserved.
INTRODUCTION - Kidney stone risk factors are understudied among Asians. Our study objective was to investigate associations of obesity and other chronic diseases with incident kidney stones among the urban Chinese.
PATIENTS AND METHODS - Included in this study are two prospective cohorts: the Shanghai Women's Health Study (N = 69,166) and Shanghai Men's Health Study (N = 58,054). Incident kidney stones were determined by self-report in 2004 and 2008. Cox regression models were used to evaluate the associations of study variables with stone risk with adjustment of demographics, medical history, and dietary intakes.
RESULTS - There were 2653 incident stones over 1,007,958 person-years of follow-up. Overall incidence rates (per 1000 person-years, 95% confidence interval [CI]) were 2.10 (1.99, 2.21) among women and 3.80 (3.59, 4.02) among men. Higher body mass index (BMI) was associated with risk (BMI ≥25 vs 18.5-24.9 kg/m, women: hazard ratio [HR] = 1.14 [95% CI 1.01, 1.28]; men: HR = 1.17 [1.03, 1.32]). High waist-hip ratio (≥0.80 and ≥0.90 for women and men, respectively) was associated with risk (HR 1.13, 95% CI 1.01, 1.27 for women; HR 1.19, 95% CI 1.05, 1.35 for men). Coronary heart disease or stroke history was associated with risk in women only (HR 1.31, 95% CI 1.10, 1.56). Hypertension history was associated with risk in men only (HR 1.27, 95% CI 1.11, 1.45). No significant association with diabetes mellitus was observed.
CONCLUSIONS - Among the Chinese, kidney stone incidence in men is almost twice that of women. Obesity is a shared risk factor. Hypertension history is associated with risk in men, whereas history of coronary heart disease or stroke is associated with risk in women.