Leucocyte count predicts cardiovascular risk in heart failure with preserved ejection fraction: insights from TOPCAT Americas

Abstract

Aims: Prior evidence has implicated leucocyte expansion in several cardiovascular disorders, including heart failure (HF) with reduced ejection fraction (rEF). However, the prognostic importance of leucocyte count in HF with preserved EF (HFpEF) remains largely unexplored.

Methods and results: The Americas cohort of the treatment of preserved cardiac function heart failure with an aldosterone antagonist (TOPCAT-Americas) was used to evaluate the association between total leucocyte count and clinical outcomes in HFpEF. The primary outcome was a composite of aborted cardiac arrest, cardiovascular mortality, or hospitalization for HF. Secondary outcomes were hospitalization for HF, aborted cardiac arrest, stroke, non-fatal myocardial infarction (MI), cardiovascular mortality, non-cardiovascular mortality, and all-cause mortality. Survival models were used to identify the risk of the primary and secondary outcomes in those with leucocyte count above the median (7100 cells/μL), as compared to those with leucocyte count below the median, during the follow-up period. A total of 1746 (out of 1767; 99%) patients from TOPCAT-Americas were available for the analyses with a median follow up of 2.4 (25th to 75th percentile 1.4-3.9) years. Patients with leucocyte count >7100 cells/μL were 36% more likely to experience the primary endpoint compared to those with ≤7100 cells/μL (hazard ratio: 1.36, 95% confidence interval: 1.14-1.61). This association remained significant after extensive adjustment for potential confounders (hazard ratio: 1.27, 95% confidence interval: 1.06-1.52). We also observed a greater incidence of HF hospitalization and non-fatal MI in patients with higher leucocyte count. These associations remained robust on sensitivity analyses, suggesting a low probability of confounding. Exploratory analyses suggested that both higher leucocyte count (integrating the combined influence of both myeloid and lymphoid immune cells) and augmented platelet count (as a surrogate for myeloid immune cell expansion) in the same model were associated with the primary outcome (both P < 0.05).

Conclusions: Leucocyte count >7100 cells/μL was independently associated with adverse clinical outcomes in HFpEF patients from TOPCAT-Americas. These results were primarily driven by the HF hospitalization outcome but were also accompanied by an excess of non-fatal MI. Further research is needed to define the mechanisms underlying our findings and their prognostic implications.

Keywords: Cardiovascular outcomes; HFpEF; Inflammation; Leucocytes.

Figure 1

Flow diagram for subject selection. *TOPCAT‐Americas included patients from the United States, Canada, Argentina, and Brazil.

Figure 2

Cumulative proportion using Cox proportional hazard model (A) and cumulative incidence using competing risk regression (B) for primary end point stratified by median leucocyte count. Red represents patients with leucocyte count >7100 cells/μL, and blue represents patients with leucocyte count ≤7100 cells/μL. The primary endpoint was a composite of death from cardiovascular causes, aborted cardiac arrest, or hospitalization for heart failure. Non‐CV mortality and non‐HF hospitalizations were considered competing events in the competing risk model. The adjusted models for both analyses included age, gender, race, hypertension, diabetes, dyslipidaemia, coronary artery disease, estimated glomerular filtration rate, atrial fibrillation, body mass index, New York Heart Association class (III/IV vs. I/II), stroke, peripheral arterial disease, smoking, haematocrit, LVEF, and treatment with spironolactone. HR, hazard ratio; sHR, sub‐distributional hazard ratio.

Figure 3

Relationship between leucocyte count and the primary outcome, cardiovascular disease (CVD)‐related mortality, heart failure hospitalization, and aborted cardiac arrest in the TOPCAT‐Americas population. The adjusted Poisson regression models were controlled for age, gender, race, hypertension, diabetes, dyslipidaemia, coronary artery disease, estimated glomerular filtration rate, atrial fibrillation, body mass index, New York Heart Association class (III/IV vs. I/II), stroke, peripheral arterial disease, smoking, haematocrit, LVEF, and treatment with spironolactone. Restricted cubic spline Poisson regression models estimates (red) are presented with 95% confidence intervals (blue). IRR, incidence rate ratio for every 1000 cells/μL rise in leucocyte count.

Figure 4

Relationship between leucocyte count and all‐cause mortality, non‐cardiovascular disease (CVD)‐related mortality, non‐fatal myocardial infarction and stroke in the TOPCAT‐Americas population. The adjusted Poisson regression models were controlled for age, gender, race, hypertension, diabetes, dyslipidaemia, coronary artery disease, estimated glomerular filtration rate, atrial fibrillation, body mass index, New York Heart Association class (III/IV vs. I/II), stroke, peripheral arterial disease, smoking, haematocrit, LVEF, and treatment with spironolactone. Restricted cubic spline Poisson regression models are presented with 95% confidence intervals (blue). IRR, incidence rate ratio for every 1000 cells/μL rise in leucocyte count.