Circulating Proneurotensin Concentrations and Cardiovascular Disease Events in the Community: The Framingham Heart Study

Arterioscler Thromb Vasc Biol. 2016 Aug;36(8):1692-7. doi: 10.1161/ATVBAHA.116.307847. Epub 2016 Jun 16.


Objective: Neurotensin is a peptide whose receptor (sortilin receptor 1) is linked to cardiovascular disease (CVD) development. We hypothesized concentrations of proneurotensin (stable profragment of neurotensin) would predict incident cardiovascular events in community-based subjects.

Approach and results: Blood samples from 3439 participants in the Framingham Heart Study (FHS) Offspring cohort (mean age 59.2 years, 47.1% male) were tested for proneurotensin. Primary outcome of interest was incident hard CVD (myocardial infarction, stroke, and cardiovascular death); interaction between proneurotensin concentration with sex, low-density lipoprotein concentrations, and sortilin receptor 1 single-nucleotide polymorphisms was sought. At baseline, those in the highest log-proneurotensin quartile were younger and heavier (P<0.001); across proneurotensin quartiles, more prevalent hard CVD (from 3% to 7%; P<0.001) and diabetes mellitus (from 6% to 14%; P<0.001) were present. In age- and sex-adjusted models, log-proneurotensin concentrations predicted incident hard CVD (hazard ratio [HR], 1.24 per SD change in log-proneurotensin; 95% confidence intervals [CIs], 1.11-1.39; P<0.001), a finding that remained on adjustment for standard CVD risk factors (HR, 1.13; 95% CI, 1.01-1.27; P=0.03). Elevated log-proneurotensin concentrations were associated with shorter time to first event (P=0.02). We found no effect modification by sex, low-density lipoprotein concentration, or sortilin receptor 1 single-nucleotide polymorphisms. Concentrations of proneurotensin were modestly associated with left ventricular mass and coronary artery calcium in these subjects.

Conclusions: Higher concentrations of proneurotensin are associated with a greater risk of incident cardiovascular events in the community. This association did not vary according to sex, baseline low-density lipoprotein, or sortilin receptor 1 genotype.

Keywords: diabetes mellitus; myocardial infarction; nucleotides; risk factors; stroke.

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Aged
  • Biomarkers / blood
  • Cardiovascular Diseases / blood*
  • Cardiovascular Diseases / diagnosis
  • Cardiovascular Diseases / epidemiology*
  • Cardiovascular Diseases / mortality
  • Cholesterol, LDL / blood
  • Cross-Sectional Studies
  • Female
  • Genetic Testing
  • Humans
  • Incidence
  • Kaplan-Meier Estimate
  • Linear Models
  • Male
  • Massachusetts / epidemiology
  • Middle Aged
  • Multivariate Analysis
  • Neurotensin / blood*
  • Polymorphism, Single Nucleotide
  • Prevalence
  • Prognosis
  • Proportional Hazards Models
  • Protein Precursors / blood*
  • Risk Assessment
  • Risk Factors
  • Sex Factors
  • Time Factors
  • Up-Regulation


  • Adaptor Proteins, Vesicular Transport
  • Biomarkers
  • Cholesterol, LDL
  • Protein Precursors
  • proneurotensin
  • Neurotensin
  • sortilin