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



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.



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.
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.). jjanuzzi@mgh.harvard.edu.
James L
JL
Januzzi
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Asya
A
Lyass
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Yuyin
Y
Liu
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Hanna
H
Gaggin
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
April
A
Trebnick
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Alan S
AS
Maisel
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Ralph B
RB
D'Agostino
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Thomas J
TJ
Wang
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Joseph
J
Massaro
From the Framingham Heart Study, MA (J.L.J., A.L., H.G., R.B.D.A., T.J.W., J.M., R.S.V.); Cardiology Division, Massachusetts General Hospital, Boston (J.L.J., H.G.); Departments of Cardiometabolic Trials (J.L.J, H.G., A.T.) and Biostatistics (A.L., Y.L., R.B.D., J.M.), Harvard Clinical Research Institute, Boston, MA; Department of Mathematics and Statistics, Boston University, MA (A.L., R.B.D.A.); Departments of Biostatistics (Y.L., J.M.) and Preventative Medicine (R.S.V.), Boston University Medical Center, MA; Heart Failure Section, Veterans Affairs Medical Center, San Diego, CA (A.S.M.); and Cardiology Division, Vanderbilt Medical Center, Nashville, TN (T.J.W.).
Ramachandran S
RS
Vasan
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics; D000368:Aged; D015415:Biomarkers / Q000097:blood; D002318:Cardiovascular Diseases / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology* / Q000401:mortality; D008078:Cholesterol, LDL / Q000097:blood; D003430:Cross-Sectional Studies; D005260:Female; D005820:Genetic Testing; D006801:Humans; D015994:Incidence; D053208:Kaplan-Meier Estimate; D016014:Linear Models; D008297:Male; D008404:Massachusetts / Q000453:epidemiology; D008875:Middle Aged; D015999:Multivariate Analysis; D009496:Neurotensin / Q000097:blood*; D020641:Polymorphism, Single Nucleotide; D015995:Prevalence; D011379:Prognosis; D016016:Proportional Hazards Models; D011498:Protein Precursors / Q000097:blood*; D018570:Risk Assessment; D012307:Risk Factors; D012737:Sex Factors; D013997:Time Factors; D015854:Up-Regulation; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D015415:Biomarkers; D008078:Cholesterol, LDL; D009496:Neurotensin; D011498:Protein Precursors; D000099183:Sortilin; C411471:proneurotensin
diabetes mellitus; myocardial infarction; nucleotides; risk factors; stroke