Relative Predictive Value of Circulating Immune Markers in US Adults Without Cardiovascular Disease: Implications for Risk Reclassification.

OBJECTIVE: To investigate the relative predictive value of circulating immune cell markers for cardiovascular mortality in ambulatory adults without cardiovascular disease. METHODS: We analyzed data of participants enrolled in the National Health and Nutrition Examination Survey from January 1, 1999, to December 31, 2010, with the total leukocyte count within a normal range (4000-11,000 cells/µL [to convert to cells ×109/L, multiply by 0.001]) and without cardiovascular disease. The relative predictive value of circulating immune cell markers measured at enrollment-including total leukocyte count, absolute neutrophil count, absolute lymphocyte count, absolute monocyte count, monocyte-lymphocyte ratio (MLR), neutrophil-lymphocyte ratio, and C-reactive protein-for cardiovascular mortality was evaluated. The marker with the best predictive value was added to the 10-year atherosclerotic cardiovascular disease (ASCVD) risk score to estimate net risk reclassification indices for 10-year cardiovascular mortality. RESULTS: Among 21,599 participants eligible for this analysis, the median age was 47 years (interquartile range, 34-63 years); 10,651 (49.2%) participants were women, and 10,713 (49.5%) were self-reported non-Hispanic white. During a median follow-up of 9.6 years (interquartile range, 6.8-13.1 years), there were 627 cardiovascular deaths. MLR had the best predictive value for cardiovascular mortality. The addition of elevated MLR (≥0.3) to the 10-year ASCVD risk score improved the classification by 2.7%±1.4% (P=.04). Elevated MLR had better predictive value than C-reactive protein and several components of the 10-year ASCVD risk score. CONCLUSION: Among ambulatory US adults without preexisting cardiovascular disease, we found that MLR had the best predictive value for cardiovascular mortality among circulating immune markers. The addition of MLR to the 10-year risk score significantly improved the risk classification of participants.

Anemia, Mortality, and Hospitalizations in Heart Failure With a Preserved Ejection Fraction (from the TOPCAT Trial).

In this post-hoc analysis of the TOPCAT trial, we evaluated the prognostic role of anemia in adverse cardiovascular (CV) outcomes in heart failure with a preserved ejection fraction (HFpEF). Anemia was defined as hemoglobin of <12 g/dl in females and <13 g/dl in males. The primary outcome was a composite of CV mortality, aborted cardiac arrest (ACA), and heart failure (HF) hospitalization. Secondary outcomes were components of the primary outcome, all-cause, CV and non-CV mortality, cause-specific CV and non-CV mortality, all-cause and HF hospitalization, myocardial infarction, and stroke. Among 1,748 patients from TOPCAT-Americas, patients with anemia had a 52% higher risk of the primary outcome (hazard ratio [HR] 1.52, 95% confidence interval 1.27, 1.83, p<0.05) during a median follow up of 2.4 years. These patients were also at higher risk of all-cause and CV mortality with no difference in non-CV mortality. Among CV causes, patients with anemia had higher risk of sudden cardiac death (SCD)/ACA and presumed CV death with no difference in death due to pump failure. Among non-CV causes, patients with anemia had higher risk of death due to malignancy (HR 2.61, p<0.05). Patients with anemia had higher risk of all-cause and HF hospitalizations (HR 1.26 and 1.56, respectively, p<0.05 for both). There was no difference in the risk of myocardial infarction or stroke. In conclusion, patients with HFpEF and anemia are at higher risk of mortality and hospitalization. Anemia is a significant risk factor for SCD/ACA, death due to presumed CV causes and malignancy in HFpEF.

Effect of immunomodulation on cardiac remodelling and outcomes in heart failure: a quantitative synthesis of the literature.

AIMS: Immunomodulation in heart failure (HF) has been studied in several randomized controlled trials (RCTs) with variable effects on cardiac structure, function, and outcomes. We sought to determine the effect of immunomodulation on left ventricular ejection fraction (LVEF), LV end-diastolic dimension (LVEDD), and all-cause mortality in patients with HF with reduced ejection fraction (HFrEF) through meta-analyses and trial sequential analyses (TSAs) of RCTs. METHODS AND RESULTS: PubMed, Embase®, Cochrane CENTRAL, and ClinicalTrials.gov were systematically reviewed to identify RCTs that studied the effects of immunomodulation in patients with HFrEF. The primary endpoint in this analysis was change in LVEF. Secondary outcomes were changes in LVEDD and all-cause mortality. TSA was used to quantify the statistical reliability of data in the cumulative meta-analyses. Nineteen RCTs with 1341 HFrEF subjects were eligible for analyses. The aetiology of HF, specific immunomodulation strategy, and treatment duration were variable across trials. Immunomodulation led to a greater improvement in LVEF [mean difference: +5.7% 95% confidence interval (CI): 3.0-8.5%, P < 0.001] and reduction in LVEDD (mean difference: -3.7 mm, 95% CI: -7.0 to -0.4 mm, P = 0.028) than no immunomodulation in meta-analyses and TSAs. We observed a non-significant decrease in all-cause mortality among those on immumomodulation (risk ratio: 0.7, 95% CI: 0.4-1.3, P = 0.234), but the Z-curve for cumulative treatment effect of immunomodulation in the TSA did not cross the boundary of futility. CONCLUSIONS: Immunomodulation led to improved cardiac structure and function in patients with HFrEF. While these benefits did not translate into a significant improvement in mortality, our analysis suggests that larger studies of targeted immunomodulation are needed to understand the true benefits.