Person:

Agarwal, Isha

Background: Fibroblast growth factor–23 (FGF‐23) is a phosphaturic factor previously associated with left ventricular hypertrophy and systolic dysfunction among individuals with chronic kidney disease. Whether FGF‐23 acts directly to induce left ventricular hypertrophy, potentially independent of its klotho coreceptor, remains uncertain. We investigated associations of FGF‐23 with cardiac structural abnormalities among individuals with a broad range of kidney function and explored potential biological mechanisms using cardiac magnetic resonance imaging and histology in klotho‐null mice, an established model of constitutively elevated FGF‐23. Methods and Results: Among 887 participants with coronary artery disease in the Heart and Soul Study, FGF‐23 was modestly associated with worse left ventricular ejection fraction (−1.0% per standard deviation increase in lnFGF‐23; standard error, 0.4%), but was not associated with the overall prevalence of concentric hypertrophy (odds ratio, 1.5; CI, 0.9 to 2.4) or eccentric hypertrophy (odds ratio, 1.1; CI, 0.9 to 1.3). FGF‐23 was only associated with concentric hypertrophy among individuals with diminished kidney function (eGFR <60 mL/min per 1.73 m2; odds ratio, 2.3; CI, 1.0 to 5.3; P‐interaction=0.28). Comparing klotho‐null with wild‐type mice, null mice did not have greater left ventricular mass (P=0.37) or a lower ejection fraction (P=0.94). Conclusions: Together, our results suggest that FGF‐23 is unlikely to have major effects on cardiovascular structure and function among patients free of substantial chronic kidney disease, and these effects may not be independent of the klotho coreceptor.

We developed a general method to detect cellular small molecule-RNA conjugates that does not rely on the reactivity of the small molecule, revealing NAD-linked RNA in E. coli and S. venezuelae. Subsequent characterization shows NAD is a 5’ modification of RNA, cannot be installed in vitro through aberrant transcriptional initiation, is only found among smaller cellular RNAs, and is present at a surprisingly high abundance of ~3000 copies per cell.

Background: According to population-based cohort studies CT coronary calcium score (CTCS), carotid intima-media thickness (cIMT), high-sensitivity C- reactive protein (CRP), and ankle-brachial index (ABI) are promising novel risk markers for improving cardiovascular risk assessment. Their impact in the U.S. general population is however uncertain. Our aim was to estimate the predictive value of four novel cardiovascular risk markers for the U.S. general population. Methods and Findings: Risk profiles, CRP and ABI data of 3,736 asymptomatic subjects aged 40 or older from the National Health and Nutrition Examination Survey (NHANES) 2003–2004 exam were used along with predicted CTCS and cIMT values. For each subject, we calculated 10-year cardiovascular risks with and without each risk marker. Event rates adjusted for competing risks were obtained by microsimulation. We assessed the impact of updated 10-year risk scores by reclassification and C-statistics. In the study population (mean age 56±11 years, 48% male), 70% (80%) were at low (<10%), 19% (14%) at intermediate (≥10–<20%), and 11% (6%) at high (≥20%) 10-year CVD (CHD) risk. Net reclassification improvement was highest after updating 10-year CVD risk with CTCS: 0.10 (95%CI 0.02–0.19). The C-statistic for 10-year CVD risk increased from 0.82 by 0.02 (95%CI 0.01–0.03) with CTCS. Reclassification occurred most often in those at intermediate risk: with CTCS, 36% (38%) moved to low and 22% (30%) to high CVD (CHD) risk. Improvements with other novel risk markers were limited. Conclusions: Only CTCS appeared to have significant incremental predictive value in the U.S. general population, especially in those at intermediate risk. In future research, cost-effectiveness analyses should be considered for evaluating novel cardiovascular risk assessment strategies.