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

Heart failure (HF) is associated with inflammation, but its specific immunophenotypic characteristics and relevant prognostic relationships are poorly established.

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).

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).

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.