Coronary Sinus Neuropeptide Y Levels and Adverse Outcomes in Patients With Stable Chronic Heart Failure

Abstract

Importance: Chronic heart failure (CHF) is associated with increased sympathetic drive and may increase expression of the cotransmitter neuropeptide Y (NPY) within sympathetic neurons.

Objective: To determine whether myocardial NPY levels are associated with outcomes in patients with stable CHF.

Design, setting, and participants: Prospective observational cohort study conducted at a single-center, tertiary care hospital. Stable patients with heart failure undergoing elective cardiac resynchronization therapy device implantation between 2013 and 2015.

Main outcomes and measures: Chronic heart failure hospitalization, death, orthotopic heart transplantation, and ventricular assist device placement.

Results: Coronary sinus (CS) blood samples were obtained during cardiac resynchronization therapy (CRT) device implantation in 105 patients (mean [SD] age 68 [12] years; 82 men [78%]; mean [SD] left ventricular ejection fraction [LVEF] 26% [7%]). Clinical, laboratory, and outcome data were collected prospectively. Stellate ganglia (SG) were collected from patients with CHF and control organ donors for molecular analysis. Mean (SD) CS NPY levels were 85.1 (31) pg/mL. On bivariate analyses, CS NPY levels were associated with estimated glomerular filtration rate (eGFR; rs = -0.36, P < .001); N-terminal-pro hormone brain natriuretic peptide (rs = 0.33; P = .004), and LV diastolic dimension (rs = -0.35; P < .001), but not age, LVEF, functional status, or CRT response. Adjusting for GFR, age, and LVEF, the hazard ratio for event-free (death, cardiac transplant, or left ventricular assist device) survival for CS NPY ≥ 130 pg/mL was 9.5 (95% CI, 2.92-30.5; P < .001). Immunohistochemistry demonstrated significantly reduced NPY protein (mean [SD], 13.7 [7.6] in the cardiomyopathy group vs 31.4 [3.7] in the control group; P < .001) in SG neurons from patients with CHF while quantitative polymerase chain reaction demonstrated similar mRNA levels compared with control individuals, suggesting increased release from SG neurons in patients with CHF.

Conclusions and relevance: The CS levels of NPY may be associated with outcomes in patients with stable CHF undergoing CRT irrespective of CRT response. Increased neuronal traffic and release may be the mechanism for elevated CS NPY levels in patients with CHF. Further studies are warranted to confirm these findings.

Trial registration: ClinicalTrials.gov identifier: NCT01949246.

Figure 1.. Association Between Coronary Sinus Neuropeptide Y (NPY) Level and Outcome Hazard Ratio (HR) in the Cohort

The hazard ratio (solid line) and the upper and lower 95% confidence limits (dashed lines) for major adverse cardiac events (MACE), outcome of death, ventricular assist device placement, and heart transplant and heart failure hospitalization are shown for patients in the cohort (n = 105) after adjusting for age, renal function (glomerular filtration rate), and ejection fraction (LVEF).

Figure 2.. Coronary Sinus Neuropeptide Y (NPY) Levels and Major Adverse Cardiac Events (MACE)

A and B, Kaplan-Meier survival analysis for MACE (death, heart transplantation [OHT], or ventricular assist device [VAD] placement) as a function of NPY before (A) and after (B) adjusting for age (hazard ratio [HR], 0.998; 95% CI, 0.95-1.05; P = .93), estimated glomerular filtration rate (eGFR) greater than 45 mL/min compared with less than 45 mL/min (HR, 0.325; 95% CI, 0.11-0.96; P = .04), and left ventricular ejection fraction (LVEF) per 1% increase (HR, 0.93; 95% CI, 0.86-1.01; P = .07), with subanalysis into groups with NPY levels 130 pg/mL or less and NPY levels greater than 130 pg/mL. C and D, Kaplan-Meier survival analysis for MACE (death, OHT, VAD placement, or heart failure hospitalization) as a function of NPY before (C) and after (D) adjusting for age (HR,  0.943; 95% CI, 0.91-0.98; P = .001), eGFR greater than 45 mL/min vs less than 45 mL/min (HR, 0.099; 95% CI, 0.038-0.258; P < .001), and LVEF per 1% increase (HR, 0.92; 95% CI, 0.88-0.97; P = .002), with subanalysis into groups, with NPY level of 130 pg/mL or less and NPY level greater than 130 pg/mL. HF indicates heart failure.

Figure 3.. Neuropeptide Y (NPY) Content in Human Stellate Ganglia

Immunohistochemical staining of NPY in stellate ganglia from control patients (organ donor) and patients with cardiomyopathy shows reduced NPY immunoreactivity (A) and an overall decrease in staining intensity, measured as optical density (B). This difference was not associated with tissue area compared (C) or number of cells (neurons and glia) per slide (D). Mean staining intensity was decreased in patients with cardiomyopathy (E). Quantitative polymerase chain reaction for NPY mRNA levels (normalized to glyceraldehyde 3-phosphate dehydrogenase) showed no change in NPY messenger RNA (mRNA) in patients with cardiomyopathy compared with controls (F). ^aP < .001. Scale bar: 50 μm.