Specific Deficiency of Naïve CD4+ T Lymphocytes Characterizes Heart Failure and Heightens Mortality Risk in the HRS

Background: Heart failure (HF) is associated with inflammation, but its specific immunophenotypic characteristics and relevant prognostic relationships are poorly established. Methods: In the HRS (Health and Retirement Study; N=9566), we used multivariable logistic regression, linear regression, and Cox proportional hazard models to describe cross-sectional relationships between HF, plasma biomarkers, leukocyte levels, lymphocyte subsets enumerated by flow cytometry, and all-cause survival. We then analyzed real-world lymphocyte levels, incident HF, and death among outpatients within the US Veterans Affairs Health System (N=38 565). Results: HF was accompanied by elevated inflammatory cytokine levels as well as relative lymphopenia. This lymphopenia was due to marked reduction in the reservoir of naïve CD4+ T cells, whereas total CD8+ T-cell numbers were not reduced, and the CD4+ effector memory niche was expanded. Importantly, among those without HF, total lymphocytes and naïve CD4+ T cells were each inversely related to aminoterminal pro-B-type natriuretic peptide levels and signaled a higher mortality rate. Linkages between lymphocyte deficiency, HF, and survival were robust to adjustment for low physical activity and a variety of inflammatory biomarkers. In the Veterans Affairs system, real-world lymphopenia (absolute lymphocyte count <1.2: ≈11.5% of outpatient complete blood cell counts) is associated with incident HF (adjusted hazard ratio [aHR], 1.60 [95% CI, 1.38-1.86]; P<0.001) and also portends a poor subsequent prognosis (aHR, 1.43 [95% CI, 1.20-1.70]; P<0.001). Conclusions: HF is associated with total lymphopenia due to a specific deficiency of naïve CD4+ T lymphocytes. Crude lymphopenia among the general ambulatory population can herald incident HF and poor subsequent survival.