Detectable Subclinical Myocardial Necrosis Is Associated With Cardiovascular Risk in Stable Patients With Diabetes

OBJECTIVE: To investigate the relationship between different degrees of subclinical myocardial necrosis, glycemic control, and long-term adverse clinical outcomes within a stable patient population with diabetes mellitus. RESEARCH DESIGN AND METHODS: We examined 1,275 stable patients with diabetes mellitus undergoing elective diagnostic coronary angiography with cardiac troponin I (cTnI) levels below the diagnostic cut-off for defining myocardial infarction (MI) (\u3c0.03 ng/mL). The relationship of subclinical myocardial necrosis (cTnI 0.009–0.029 ng/mL) with incident major adverse cardiovascular events (MACE; defined as any death, MI, or stroke) over 3 years of follow-up was examined. RESULTS: Subclinical myocardial necrosis was observed in 22% of patients. A strong association was observed between the magnitude of subclinical myocardial necrosis and risk of 3-year incident MACE (hazard ratio, 1.98; 95% confidence interval, 1.48–2.65; P \u3c 0.001) and remained statistically significant even after adjustment for traditional risk factors, high-sensitivity C-reactive protein, and creatinine clearance. Only a weak correlation was observed between the presence of subclinical myocardial necrosis and either glycemic control (r = 0.06; P = 0.044 for hemoglobin A1c versus cTnI) or insulin resistance (r = 0.04; P = 0.094 for glucose-to-insulin ratio versus cTnI). CONCLUSIONS: The presence of detectable subclinical myocardial necrosis in stable patients with diabetes mellitus is associated with heightened long-term risk for MACE, independent of traditional risk factors and glycemic control

Prognostic Value of Choline and Betaine Depends on Intestinal Microbiota-Generated Metabolite Trimethylamine-N-Oxide

Aims: Recent metabolomics and animal model studies show trimethylamine-N-oxide (TMAO), an intestinal microbiota-dependent metabolite formed from dietary trimethylamine-containing nutrients such as phosphatidylcholine (PC), choline, and carnitine, is linked to coronary artery disease pathogenesis. Our aim was to examine the prognostic value of systemic choline and betaine levels in stable cardiac patients. Methods and Results: We examined the relationship between fasting plasma choline and betaine levels and risk of major adverse cardiac events (MACE = death, myocardial infraction, stroke) in relation to TMAO over 3 years of follow-up in 3903 sequential stable subjects undergoing elective diagnostic coronary angiography. In our study cohort, median (IQR) TMAO, choline, and betaine levels were 3.7 (2.4–6.2)μM, 9.8 (7.9–12.2)μM, and 41.1 (32.5–52.1)μM, respectively. Modest but statistically significant correlations were noted between TMAO and choline (r = 0.33, P \u3c 0.001) and less between TMAO and betaine (r = 0.09, P \u3c 0.001). Higher plasma choline and betaine levels were associated with a 1.9-fold and 1.4-fold increased risk of MACE, respectively (Quartiles 4 vs. 1; P \u3c 0.01, each). Following adjustments for traditional cardiovascular risk factors and high-sensitivity C-reactive protein, elevated choline [1.34 (1.03–1.74), P \u3c 0.05], and betaine levels [1.33 (1.03–1.73), P \u3c 0.05] each predicted increased MACE risk. Neither choline nor betaine predicted MACE risk when TMAO was added to the adjustment model, and choline and betaine predicted future risk for MACE only when TMAO was elevated. Conclusion: Elevated plasma levels of choline and betaine are each associated with incident MACE risk independent of traditional risk factors. However, high choline and betaine levels are only associated with higher risk of future MACE with concomitant increase in TMAO

Gut Flora Metabolism of Phosphatidylcholine Promotes Cardiovascular Disease

Metabolomics studies hold promise for the discovery of pathways linked to disease processes. Cardiovascular disease (CVD) represents the leading cause of death and morbidity worldwide. Here we used a metabolomics approach to generate unbiased small-molecule metabolic profiles in plasma that predict risk for CVD. Three metabolites of the dietary lipid phosphatidylcholine—choline, trimethylamine N-oxide (TMAO) and betaine—were identified and then shown to predict risk for CVD in an independent large clinical cohort. Dietary supplementation of mice with choline, TMAO or betaine promoted upregulation of multiple macrophage scavenger receptors linked to atherosclerosis, and supplementation with choline or TMAO promoted atherosclerosis. Studies using germ-free mice confirmed a critical role for dietary choline and gut flora in TMAO production, augmented macrophage cholesterol accumulation and foam cell formation. Suppression of intestinal microflora in atherosclerosis-prone mice inhibited dietary-choline-enhanced atherosclerosis. Genetic variations controlling expression of flavin monooxygenases, an enzymatic source of TMAO, segregated with atherosclerosis in hyperlipidaemic mice. Discovery of a relationship between gut-flora-dependent metabolism of dietary phosphatidylcholine and CVD pathogenesis provides opportunities for the development of new diagnostic tests and therapeutic approaches for atherosclerotic heart disease

The human cytomegalovirus ul11 protein interacts with the receptor tyrosine phosphatase cd45, resulting in functional paralysis of t cells

Human cytomegalovirus (CMV) exerts diverse and complex effects on the immune system, not all of which have been attributed to viral genes. Acute CMV infection results in transient restrictions in T cell proliferative ability, which can impair the control of the virus and increase the risk of secondary infections in patients with weakened or immature immune systems. In a search for new immunomodulatory proteins, we investigated the UL11 protein, a member of the CMV RL11 family. This protein family is defined by the RL11 domain, which has homology to immunoglobulin domains and adenoviral immunomodulatory proteins. We show that pUL11 is expressed on the cell surface and induces intercellular interactions with leukocytes. This was demonstrated to be due to the interaction of pUL11 with the receptor tyrosine phosphatase CD45, identified by mass spectrometry analysis of pUL11-associated proteins. CD45 expression is sufficient to mediate the interaction with pUL11 and is required for pUL11 binding to T cells, indicating that pUL11 is a specific CD45 ligand. CD45 has a pivotal function regulating T cell signaling thresholds; in its absence, the Src family kinase Lck is inactive and signaling through the T cell receptor (TCR) is therefore shut off. In the presence of pUL11, several CD45-mediated functions were inhibited. The induction of tyrosine phosphorylation of multiple signaling proteins upon TCR stimulation was reduced and T cell proliferation was impaired. We therefore conclude that pUL11 has immunosuppressive properties, and that disruption of T cell function via inhibition of CD45 is a previously unknown immunomodulatory strategy of CMV

Elevated Cystatin C Predicts Long-Term Adverse Cardiac Events in Patients with Heart Failure Independent of Natriuretic Peptide Levels and Creatinine Clearance

Background: Cystatin C is a cysteine protease inhibitor that has been broadly accepted as a sensitive marker of glomerular filtration rate. The prognostic role of cystatin C has been described in both acute and chronic heart failure settings, but its ability to predict adverse long-term outcomes independent of B-type natriuretic peptide (BNP) has not been extensively explored. Methods: We evaluated cystatin C levels in a large cohort of stable patients with history of heart failure undergoing coronary angiography. Cystatin C and BNP levels were measured using the Abbott Architect ci8200 platform. Major adverse cardiac events (MACE 5 death, myocardial infarction, stroke) were followed prospectively over the course of 3 years. Results: In our study cohort (n5823, mean age 67611 years, 61% male, median BNP 300 pg/mL, 75% with preserved creatinine clearance [O60 mg/mL]), median cystatin C level was 1.11 mg/L (interquartile range 0.92-1.41 mg/L). There was modest correlation between cystatin C and BNP levels (Spearman’s r 5 0.34, p!0.001). In Cox proportional hazard analyses, cystatin C (per standard deviation increments) was predictive of future MACE at 3 years even after adjustments for BNP (Hazard ratio 1.20, 95% confidence interval 1.08-2.34, p!0.0009). This is particularly robust in the subset with preserved creatinine clearance Hazard ratio 1.68, 95% confidence interval 1.05-2.63, p50.03, n5615). Conclusion: Elevated cystatin C levels predict future adverse cardiac events independent of natriuretic peptide levels in stable patients with heart failure, particularly in those with underlying preserved renal function