Background: Growth differentiation factor (GDF)-15, a stress responsive cytokine, is associated with the risk of CV events after an acute coronary syndrome (ACS). Unlike other established cardiac biomarkers, the level of GDF-15 remains elevated in sub-acute phase after ACS and gradually decreases over time. We evaluated the prognostic utility of GDF-15 in patients after ACS accounting for established markers and risk predictors. Methods: GDF-15 (R&D Systems) and other established cardiac biomarkers (BNP, hsCRP and hsTnI) were measured at baseline in a randomly selected cohort of 4,968 patients enrolled within 30 days of hospitalization with ACS (median=14d) in SOLID-TIMI 52. Previously defined cutpoints were applied for GDF-15 concentration: <1200 (n=3451), 1200-1800 (n=919), and > 1800 ng/L (n=598). Analyses were adjusted for established risk predictors, days from the ACS event and other markers. MACE was defined as CV death, MI or stroke. Median follow-up was 2.5 years. Results: Patients with higher GDF-15 tended to be older, more likely to have diabetes, hypertension, history of revascularization, and CKD at baseline. Higher baseline levels of GDF-15 identified patients with higher rates of MACE as well as each individual element (p-trend <0.001 for all endpoints, Fig). The rate of MI was ∼2-fold higher in those with GDF-15 concentration >1800ng/L compared to patients with GDF-15 concentration <1200 ng/L. After adjustment for clinical predictors and other markers, GDF-15 was independently associated with the risk of MACE (HR 1.4, 95% CI 1.1-1.7; HR 1.8, 95% CI 1.4-2.3 for GDF-15 1200-1800, >1800, respectively). Individuals with GDF-15 >1800 ng/L had an increased risk of MI (adj HR 1.4, 95% CI 1.1-2.0) and stroke (adj HR 2.3, 95% CI 1.3-3.9). Conclusion: In patients after ACS, GDF-15 concentration is associated with the risk of MACE including MI and stroke independent of traditional risk factors and risk markers.
Objective The myosin-binding protein C ( MYBPC3 ) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH−) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH− subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH− individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.
Clinical LC-MS/MS assays traditionally require that samples be run in batches with calibration curves in each batch. This approach is inefficient and presents a barrier to random access analysis. We developed an alternative approach called multipoint internal calibration (MPIC) that eliminated the need for batch-mode analysis.The new approach used 4 variants of 13C-labeled methotrexate (0.026-10.3 µM) as an internal calibration curve within each sample. One site carried out a comprehensive validation, which included an evaluation of interferences and matrix effects, lower limit of quantification (LLOQ), and 20-day precision. Three sites evaluated assay precision and linearity. MPIC was also compared with traditional LC-MS/MS and an immunoassay.Recovery of spiked analyte was 93%-102%. The LLOQ was validated to be 0.017 µM. Total variability, determined in a 20-day experiment, was 11.5%CV. In a 5-day variability study performed at each site, total imprecision was 3.4 to 16.8%CV. Linearity was validated throughout the calibrator range (r2 > 0.995, slopes = 0.996-1.01). In comparing 40 samples run in each laboratory, the median interlaboratory imprecision was 6.55%CV. MPIC quantification was comparable to both traditional LC-MS/MS and immunoassay (r2 = 0.96-0.98, slopes = 1.04-1.06). Bland-Altman analysis of all comparisons showed biases rarely exceeding 20% when MTX concentrations were >0.4 µM.The MPIC method for serum methotrexate quantification was validated in a multisite proof-of-concept study and represents a big step toward random-access LC-MS/MS analysis, which could change the paradigm of mass spectrometry in the clinical laboratory.
Background: “T50,” shortened transformation time from primary to secondary calciprotein particles may reflect deranged mineral metabolism predisposing to vascular calcification and cardiovascular disease (CVD). The glycoprotein fetuin-A is a major T50 determinant. Methods: The Folic Acid For Vascular Outcome Prevention In Transplantation (FAVORIT) cohort is a completed, large, multiethnic controlled clinical trial cohort of chronic, stable kidney transplant recipients (KTRs). We conducted a longitudinal case-cohort analysis using a randomly selected subcohort of patients, and all individual cases who developed CVD. Serum T50 and fetuin-A were determined in this total of n = 685 FAVORIT trial participants at randomization. Results: During a median surveillance of 2.18-years, 311 incident or recurrent CVD events occurred. Shorter T50 (minutes) or reduced fetuin-A concentrations (g/L) were associated with CVD after adjustment for treatment assignment, systolic blood pressure, age, sex, race, preexisting CVD and diabetes, smoking, body mass index, total cholesterol/HDL cholesterol, kidney allograft vintage and type, calcineurin inhibitor, or lipid-lowering drug use, estimated glomerular filtration rate, and urinary albumin/creatinine: tertile 1 (lowest) to tertile 3 (highest) comparisons, T50, (hazard ratio [HR] 1.86; 95% CI 1.20–2.89); fetuin-A, (HR 2.25; 95% CI 1.38–3.69). Elevated high sensitivity c-reactive protein (hsCRP) was an effect modifier of both these associations. Conclusions: Shortened T50, as well as reduced fetuin-A levels, ostensible promoters of vascular calcification, remained associated with greater risk for CVD outcomes, after adjustment for major CVD risk factors, measures of kidney function and damage, and KTR clinical characteristics and demographics, in a large, multiethnic cohort of long-term KTRs. Increased hsCRP was an effect modifier of these CVD risk associations.
Background: Some patients with heart failure (HF) are more prone to systemic congestion than others. The goal of this study was to identify clinical and humoral factors linked to congestion and its prognostic impact in HF patients. Methods: A total of 371 advanced HF patients underwent physical examination, echocardiography, right heart catheterization, blood samplings, and Minnesota Living with HF Questionnaire. Subjects were followed-up for adverse events (death, urgent transplantation, or assist device implantation without heart transplantation). Results: Thirty-one percent of patients were classified as prone to congestion. During a median follow-up of 1,093 days, 159 (43%) patients had an adverse event. In the Cox analysis, the congestion-prone (CP) status was associated with a 43% higher event risk. The CP status was strongly (p ˂ 0.001) associated with body weight loss, right ventricular dysfunction (RVD), dilated inferior vena cava (IVC), diuretics, and beta-blockers prescription and the majority of tested hormones in the univariate analysis. In the multivariate analysis, the only independent variables associated with the CP status were adiponectin, albumin, IVC diameter, and RVD. Adiponectin by itself was predictive of adverse events. In a multivariate model, CP status was no longer predictive of adverse events, in contrast to adiponectin. Conclusions: CP patients experienced more severe symptoms and had shorter survival. Potential role of adiponectin, a new independent predictor of CP status, should be further examined.
