Larson, Nicholas B.

Background Hepatocyte growth factor (HGF) is a biomarker with potential for use in the diagnosis, treatment and prognostication of cardiovascular disease (CVD). Elevated HGF is associated with calcification in the coronary arteries. However, knowledge is limited on the role HGF may play in extracoronary calcification (ECC). This study examined whether HGF is associated with ECC in the aortic valve (AVC), mitral annulus (MAC), ascending thoracic aorta and descending thoracic aortic (DTAC). Methods At baseline, adults aged 45–84 years, free of CVD, in the Multi-Ethnic Study of Atherosclerosis had HGF and ECC measured by ELISA and cardiac CT scan, respectively. ECC measurements were repeated after an average of 2.4 years of follow-up. Prevalent ECC was defined as Agatston score >0 at baseline. Incident ECC was defined as Agatston score >0 at follow-up among participants with Agatston score=0 at baseline. We used Poisson and linear mixed-effects regression models to estimate the association between HGF and ECC, adjusted for sociodemographic and CVD risk factors. Results Of 6648 participants, 53% were women. Mean (SD) age was 62 (10) years. Median (IQR) of HGF was 905 (757-1087) pg/mL. After adjustment for CVD risk factors, the highest HGF levels (tertile 3) were associated with greater prevalence and extent of AVC, MAC and DTAC at baseline compared with the lowest tertile (tertile 1). Additionally, the risk of incident AVC and MAC increased by 62% and 45%, respectively, in demographic-adjusted models. However, the associations were not statistically significant in fully adjusted models. The highest HGF levels were also associated with 10% and 13% increase in MAC and DTAC progression, respectively, even after adjustment for CVD risk factors. Conclusion Higher HGF levels were significantly associated with a greater risk of calcification at some extracoronary sites, suggesting an alternate biological pathway that could be targeted to reduce CVD risk.

Hypertension is a common bevacizumab‐induced toxicity. No markers are available to predict patients at risk of developing hypertension. We hypothesized that genetic risk of essential hypertension, as measured by a blood pressure polygenic risk score (PRS), would be associated with risk of severe bevacizumab‐induced hypertension. PRSs were calculated for 1,027 bevacizumab‐treated patients of European descent with cancer from four clinical trials (Alliance for Clinical Trials in Oncology (Alliance) / Cancer and Leukemia Group B (CALGB) 80303, 40503, 90401, 40502) using summary systolic blood pressure (SBP) and diastolic blood pressure (DBP) genome‐wide association results obtained from 757,601 individuals of European descent. The association between PRS and grade 3 bevacizumab‐induced hypertension (Common Toxicity Criteria for Adverse Events version 3) in each trial was performed by multivariable logistic regression. Fixed‐effect meta‐analyses odds ratios (ORs) per standard deviation (SD) of the association of PRS (quantitative) and hypertension across trials were estimated by inverse‐variance weighting. PRSs were additionally stratified into quintiles, with the bottom quintile as the referent group. The OR of the association between hypertension and each quintile vs. the referent group was determined by logistic regression. The most significant PRS (quantitative)‐hypertension association included up to 67 single‐nucleotide variants (SNPs) associated with SBP (P = 0.0077, OR per SD = 1.31, 95% confidence interval (CI), 1.07–1.60), and up to 53 SNPs associated with DBP (P = 0.0209, OR per SD = 1.27, 95% CI, 1.04–1.56). Patients in the top quintile had a higher risk of developing bevacizumab‐induced hypertension compared with patients in the bottom quintile using SNPs associated with SBP (P = 4.75 × 10−4, OR = 3.72, 95% CI, 1.84–8.16) and DBP (P = 0.076, OR = 1.83, 95% CI, 0.95–3.64). Genetic variants associated with essential hypertension, mainly SBP, increase the risk of severe bevacizumab‐induced hypertension.

Introduction: Heart failure (HF) is a clinical syndrome with high mortality. Left ventricular ejection fraction (EF) determines clinical phenotyping and HF is classified most often as preserved (HFpEF) or reduced (HFrEF) EF. The importance of expanding phenotyping beyond EF is recognized. We hypothesized that machine learning applied to echocardiography will provide information important for deep phenotyping. Methods: We collected clinical and echo data in a HF community cohort between 2013 and 2017. Unsupervised clustering was applied to 23 echo variables using partitioning around medoids (PAM), with Gower dissimilarity used to address the mixed variable types. Proportional hazards regression examined the association between cluster assignment and death. Results: We identified 4978 persons with HF [mean age 73.9 years (SD 13.9), 47% women] with echocardiography within 6 months of diagnosis. We identified 2 primary clusters using echo variables, as depicted using t-Distributed Stochastic Neighbor Embedding (t-SNE) applied to the dissimilarity matrix (Figure). Diastolic function variables exhibited the largest differences by clusters as shown by absolute standardized differences (Table). After 3.2 + 1.9 years of follow up, 2001 deaths occurred. Assignment to cluster 2 was associated with a near 20% excess risk of death independent of age, sex, comorbidity, and EF [HR 1.17 (1.07, 1.28) p<0.001]. Conclusions: Unsupervised clustering applied to echocardiography in a large community HF cohort identified 2 distinct clusters, which defined HF subgroups with different characteristics and were independently associated with risk of death.

Introduction: Hepatocyte growth factor (HGF) is released in response to endothelial injury, and higher levels of circulating HGF are associated with atherosclerosis. However, the association of HGF with atherosclerosis progression is unknown. Hypothesis: Circulating HGF is positively associated with atherosclerosis progression, measured as progression of 1) carotid artery plaque and 2) coronary artery calcium (CAC). Methods: The Multi-Ethnic Study of Atherosclerosis is a large, population-based cohort study of adults aged 45-84 and free of clinical cardiovascular disease. Participants had HGF measured in serum at baseline (2000-02), and were followed for progression of carotid plaque and CAC through 2012. We defined CAC and carotid plaque progression as dichotomous variables (progression, no progression). Carotid plaque progression is an increase in the number of carotid plaques. We used the Hokanson method to define CAC progression as an increase of ≥ 2.5 mm 3 in the square root-transformed calcium volume score. Relative risk regression quantified the association between HGF and carotid plaque progression. Cox regression models using inverse-probability-of-attrition weights estimated the association of HGF with progression of CAC. All effect estimates are adjusted for potential confounding variables. Results: The cohort included 6714 Americans with HGF measurements: 2593 non-Hispanic white, 797 Chinese, 1848 black, and 1476 Hispanic Americans. In 3363 participants with measurements for both carotid plaque and HGF, each standard deviation (259 pg/ml) increase in HGF was associated with a 4% greater risk (95% CI: 1.01-1.07) of carotid plaque progression (n=1875), which did not differ by race/ethnicity (interaction p = 0.3). Out of 6714 participants with measurements for both CAC and HGF, 2994 had CAC progression during follow-up. The association of HGF with CAC progression differed by race/ethnicity (interaction p = 0.01). Each standard deviation increase of HGF was associated with a 10% greater risk of CAC progression in non-Hispanic white (95% CI: 1.05-1.16) and black Americans (95% CI: 1.03-1.17), while HGF was not associated with CAC progression in Chinese (p = 0.5) nor Hispanic (p = 0.7) American participants. Conclusions: Circulating HGF was associated with a modestly increased risk of atherosclerosis progression in this large and diverse population, with the strongest associations between HGF and CAC progression in non-Hispanic white and black Americans. Our results suggest that HGF may have utility as a marker of atherosclerosis progression in some populations.

Introduction: Proton pump inhibitors (PPIs) are used by an estimated 29 million Americans. PPIs increase the levels of asymmetrical dimethylarginine, a known risk factor for cardiovascular disease (CVD). Data from a select population of patients with CVD suggest that PPI use is associated with an increased risk of stroke, heart failure, and coronary heart disease. The impact of PPI use on incident CVD is largely unknown in the general population. Hypothesis: We hypothesized that PPI users have a higher risk of incident total CVD, coronary heart disease, stroke, and heart failure compared to nonusers. To demonstrate specificity of association, we additionally hypothesized that there is not an association between use of H 2 -blockers - another commonly used class of medications with similar indications as PPIs - and CVD. Methods: We used the Rochester Epidemiology Project’s medical records-linkage system to identify all residents of Olmsted County, MN on our baseline date of January 1, 2004 (N=140217). We excluded persons who did not grant permission for their records to be used for research, were <18 years old, had a history of CVD, had missing data for any variable included in our model, or had evidence of PPI use within the previous year.We followed our final cohort (N=58175) for up to 12 years. The administrative censoring date for CVD was 1/20/2014, for coronary heart disease was 8/3/2016, for stroke was 9/9/2016, and for heart failure was 1/20/2014. Time-varying PPI ever-use was ascertained using 1) natural language processing to capture unstructured text from the electronic health record, and 2) outpatient prescriptions. An incident CVD event was defined as the first occurrence of 1) validated heart failure, 2) validated coronary heart disease, or 3) stroke, defined using diagnostic codes only. As a secondary analysis, we calculated the association between time-varying H 2 -blocker ever-use and CVD among persons not using H 2 -blockers at baseline. Results: After adjustment for age, sex, race, education, hypertension, hyperlipidemia, diabetes, and body-mass-index, PPI use was associated with an approximately 50% higher risk of CVD (hazard ratio [95% CI]: 1.51 [1.37-1.67]; 2187 CVD events), stroke (hazard ratio [95% CI]: 1.49 [1.35-1.65]; 1928 stroke events), and heart failure (hazard ratio [95% CI]: 1.56 [1.23-1.97]; 353 heart failure events) compared to nonusers. Users of PPIs had a 35% greater risk of coronary heart disease than nonusers (95% CI: 1.13-1.61; 626 coronary heart disease events). Use of H 2 -blockers was also associated with a higher risk of CVD (adjusted hazard ratio [95% CI]: 1.23 [1.08-1.41]; 2331 CVD events). Conclusions: PPI use is associated with a higher risk of CVD, coronary heart disease, stroke and heart failure. Use of a drug with no known cardiac toxicity - H 2 -blockers - was also associated with a greater risk of CVD, warranting further study.

Introduction: Increased levels of hepatocyte growth factor (HGF), active in cell growth, motility, and morphogenesis, are associated with the presence of obesity, poor metabolic health, and cardiovascular disease. Hypothesis: We assessed the hypothesis that higher baseline levels of HGF will be associated with increased risk of diabetes. Methods: We examined the association between HGF and incident diabetes in MESA, including 5395 men and women 45-84 years of age at enrollment (2000-02). Fasting serum HGF was measured at baseline and on a subsample of participants at exam 2 (n = 1915). From 2000-11, incidence of diabetes was ascertained over 4 follow-up examinations, determined by new use of insulin or oral hypoglycemic medication or fasting glucose ≥ 126 mg/dL. Cox regression was used to estimate hazard ratios (HR) for incident diabetes according to 1 standard deviation unit (SDU) of HGF (1 SDU =256 pg/mL), before and after adjustment for age, sex, race/ethnicity, education, study center, smoking status, alcohol consumption, BMI, WC, fasting glucose and insulin, CRP, and IL-6 levels. Similarly, hazard ratios for incident diabetes were estimated according to change in HGF levels from exam 1 to exam 2 in the subsample. Results: At baseline, older age, male sex, current smoking, and higher body mass index (BMI), waist circumference (WC), fasting glucose and insulin, C-reactive protein (CRP) and interleukin-6 (IL-6) levels were all associated with higher levels of HGF, while greater education and physical activity were associated with lower serum HGF. Incidence of diabetes in this analytic sample was 12% (n cases = 670). Per 1 SDU increase in baseline HGF level, unadjusted risk for diabetes increased 1.46 fold (95% CI=1.37, 1.56). After adjustment, diabetes risk per 1 SDU increase in HGF was attenuated but remained significantly increased (HR=1.22; 95% CI=1.12, 1.32). No association was found between change in HGF level between exam 1 and exam 2 and incidence of diabetes. There was no evidence of effect modification by race/ethnicity for either analysis. Conclusion: In conclusion, in this ethnically diverse U.S. adult population, higher levels of serum HGF were independently associated with increased incidence of diabetes.

Background: Given the global burden of peripheral arterial disease (PAD) and the associated morbidity, continuing investigation of potential biomarkers as therapeutic targets for preventing PAD is warranted. The association of P-selectin, an endothelial cell adhesion molecule, with the ankle brachial index (ABI) and PAD is not well established. Thus, we examined the association of circulating P-selectin with prevalent and incident PAD, the ABI, and change in the ABI. Methods: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective population-based cohort including 6814 non-Hispanic white, African American, Hispanic and Chinese men and women aged 45-84 at baseline (2000-02). For this analysis, 5700 participants with both P-selectin at Exam 2 (2002-04) and the ABI at Exam 3 (2004-05) were available, with change in ABI from Exam 3 to Exam 5 (2010-12) available on 4276 participants. P-selectin was modeled per standard deviation (SD), while prevalent and incident PAD were defined as ABI ≤ 0.90 after excluding those with ABI>1.4. Linear regression was used for ABI, growth curve models for change in ABI, and logistic regression for prevalent and incident PAD. Results: In models adjusted for demographics, lifestyle factors, comorbidities, blood pressure, lipids, fasting glucose, c-reactive protein (CRP), interleukin-6 (IL-6), D-dimer, and fibrinogen, each SD (13 ng/mL) higher P-selectin was significantly associated with 0.007 lower ABI (95% CI ((-0.011, -0.004)), p<0.001), and an average change in the ABI of -0.006 ((-0.010, -0.003, p<0.001). P-selectin was also significantly associated with a 1.14-fold greater odds of prevalent PAD ((1.00, 1.28), p=0.04), and a 1.30-fold greater odds of incident PAD ((1.10, 1.55), p<0.001). There were no significant interactions of p-selectin by race/ethnicity or gender. Addition of P-selectin to models containing traditional PAD risk factors as well as CRP, IL-6, D-dimer and fibrinogen did not improve the c-statistic or net reclassification for incident PAD. Conclusions: P-selectin appears to be strongly associated with the development of PAD. However, further research is needed in population-based studies to confirm prospective associations of p-selectin with incident PAD and change in the ABI.