A new study suggests that higher levels of C-reactive protein (CRP) are independently associated with an increased long-term risk of incident heart failure (HF) in patients with established cardiovascular disease (CVD). Findings reveal that out of 810 incident HF cases identified during a median follow-up of 9.7 years (interquartile range [IQR]: 5.5-14.1 years), higher CRP was independently associated with an increased incident HF risk: hazard ratio [HR] per 1 mg/L: 1.10 (95% confidence interval [CI]: 1.07-1.13), and for last vs first CRP quartile: 2.22 (95% CI: 1.76-2.79). The prospective cohort study also deems the association significant for both HF with reduced ejection fraction (HR: 1.09; 95% CI: 1.04-1.14) and preserved ejection fraction (HR: 1.12; 95% CI:1.07-1.18), with no significant difference between the two levels of ejection fraction (P for difference=0.137). The study, reported by Pascal M. Burger, MD, of University Medical Center Utrecht, the Netherlands, and colleagues, also finds that additional adjustment for medication use, and interim myocardial infarction did not attenuate the association, which remained consistent beyond 15 years post-CRP measurement. “Regardless of the role of CRP in the pathogenesis of HF, this study shows that a single measurement of CRP is strongly associated with incident HF, even beyond 15 years after the initial measurement,” says the study, which was published Monday online. “This includes CRP concentrations >10 and >20 mg/L, which by clinicians are often assumed to be associated with a temporary inflammatory condition, and therefore often disregarded. The results of this study indicate all randomly measured CRP concentrations, including very high concentrations (>10/>20 mg/L), are clinically relevant indicators of HF risk that should be fully appreciated.” Reverse causality not possible In an accompanying editorial comment, Ishwarlal Jialal, MD, PhD, and Imo A. Ebong, MD, thought it “striking” that a single measurement of CRP in this study consistently predicted HF incidence over time, even extending to 15 years after the initial measurement. The editorialists added that the possibility of reverse causality was excluded by demonstrating persistence of the associations after excluding incident HF events that occurred within 1, 2, 5, 10 and 15 years of study initiation. “This is an important finding because HF also induces inflammation,” said Jialal and Ebong, who are both based at the University of California-Davis in Sacramento. “Patients with CVD are more likely to have chronic inflammation, and the CRP measurements reported in this study appeared stable across time. Among 24% of the cohort who had repeat CRP measurements, the median change was -0.10 mg/L over a median period of 10 years. This further underscores that CVD is a chronic inflammatory state.” CRP value for incident HF prediction While the editorialists commended the research team for demonstrating that CRP convincingly predicts incident HF in patients with CVD, they wanted to see evidence on the added value of CRP over natriuretic peptides and possibly troponin for incident HF prediction. “It is premature to recommend changes to clinical practice until these findings in patients with CVD have been replicated in prospective studies by other groups,” they said, “and there is evidence to show that pharmacotherapy directed at lowering CRP and inflammation have benefit for HF prevention and its sequalae. The role of SGLT2 [sodium-glucose cotransporter-2] inhibitor therapy, which is now commonly used to mitigate CVD risk including HF, could have been further discussed as one such therapy.” Study methodology Writing in the Aug. 1 issue of the Journal of the American College of Cardiology, the research team included data from patients enrolled on the Utrecht Cardiovascular Cohort-Second Manifestations of ARTerial disease (UCCSMART) study. All 8,089 subjects had established CVD but were without a history of hospitalization for HF at baseline. Baseline characteristics were described stratified by quartiles of CRP, where most patients were male, and hypertension and coronary artery disease (CAD) were reported in more than one-half of the cohort. Smoking was common, but only 15% to 20% had diabetes. High-sensitivity CRP was measured by immunonephelometry, with these levels later determined in heparin plasma using an AU5811 routine chemistry analyzer, thus providing comparable results. Patients enrolled on to the UCCSMART study, which remains ongoing, also had their systolic blood pressure (SBP), total cholesterol, high-density lipoprotein cholesterol (HDL-C), triglycerides, and creatinine measured from which non-HDL-C and estimated glomerular filtration rate could be calculated. The outcome of the study was incident HF, defined as a first hospitalization for HF and was further divided into heart failure with reduced ejection fraction (i.e., left ventricular ejection fraction [LVEF] ≤50%) and preserved ejection fraction (i.e., LVEF >50%) Patients were followed for all outcomes from the time of cohort entry until the predetermined end-of-study date of Jan. 1, 2019. The median follow-up was complete in 94.6% of patients. Sources: Burger PM, Koudstaal S, Mosterd A, et al. C-Reactive Protein and Risk of Incident Heart Failure in Patients With Cardiovascular Disease. J Am Coll Cardiol. 2023;82:414–426. Jialal I, Ebong IA. The Evolving Role of C-Reactive Protein in Heart Failure: Implications for Patients With Cardiovascular Disease. J Am Coll Cardiol. 2023;82:427–429. Image Credit: luchschenF – stock.adobe.com