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Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels.

ABSTRACT: AIMS:Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch-induced circulating biomarkers for predicting hypertension-associated HF. METHODS AND RESULTS:Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch-activated gene expression changes in cultured neonatal rat ventricular myocytes (NRVMs) in response to 1-48 h of mechanical stretch. We also studied the association between protein levels and hypertension and HF incidence using respectively binary logistic and Cox regressions. Levels of 35 proteins were differentially expressed after Bonferroni correction in incident HF vs. control (P < 3.4E-4). Growth differentiation factor-15 (GDF-15), interleukin-6 (IL-6), IL-1 receptor type 1, and urokinase plasminogen activator surface receptor had corresponding mRNA levels up-regulated by stretch in NRVMs at all time points (P < 0.05). These four proteins were individually associated with increased risk of HF after age and sex adjustment [hazard ratio (HR) per standard deviation: 1.19 ? HR ? 1.49, P ? 4.90E-3]. GDF-15 and IL-6 were associated with HF independently of each other (1.22 ? HR ? 1.33, P ? 0.001). In subjects with hypertension, these associations remained significant after further adjustment for N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (1.23 ? HR ? 1.45, P ? 0.001). A higher fasting value of a GDF-15, IL-6 score aggregate was associated with increased risk of hypertensive HF after adjustment for all traditional risk factors for HF and NT-proBNP (HR = 1.31, P = 2.19E-4). CONCLUSIONS:Cardiomyocyte mRNA levels of GDF-15 and IL-6 are consistently up-regulated by stretch, and their circulating protein levels predict HF in hypertensive subjects independently of NT-proBNP during long-term follow-up. Our results encourage further studies on lower blood pressure goals in hypertensive subjects with high GDF-15 and IL-6, and interventions targeted at stretch-induced cardiomyocyte expressed biomarkers.

SUBMITTER: Fernandez C

PROVIDER: S-EPMC7373917 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels.

Fernandez Celine C Rysä Jaana J Ström Kristoffer K Nilsson Jan J Engström Gunnar G Orho-Melander Marju M Ruskoaho Heikki H Melander Olle O

ESC heart failure 20200514 4

<h4>Aims</h4>Hypertension is the leading cause for the development of heart failure (HF). Here, we aimed to identify cardiomyocyte stretch-induced circulating biomarkers for predicting hypertension-associated HF.<h4>Methods and results</h4>Circulating levels of 149 proteins were measured by proximity extension assay at baseline examination in 4742 individuals from the Malmö Diet and Cancer study. Protein levels were compared with stretch-activated gene expression changes in cultured neonatal rat ...[more]

PMID: 32410391

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Project description:BackgroundElevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) is associated with clinically overt heart failure (HF). However, whether it provides additive prognostic information for incident HF beyond traditional risk factors and left ventricular (LV) mass index among multi-ethnic asymptomatic individuals has not yet been determined. We studied the associations of plasma NT-proBNP and magnetic resonance imaging defined LV mass index with incident HF in an asymptomatic multi-ethnic population.Methods and resultsA total of 5597 multi-ethnic participants without clinically apparent cardiovascular disease underwent baseline measurement of NT-proBNP and were followed for 5.5±1.1 years. Among them, 4163 also underwent baseline cardiac magnetic resonance imaging. During follow-up, 111 participants experienced incident HF. Higher NT-proBNP was significantly associated with incident HF, independent of baseline age, sex, ethnicity, systolic blood pressure, diabetes mellitus, smoking, estimated glomerular filtration rate, medications (anti-hypertensive and statin), LV mass index, and interim myocardial infarction (hazard ratio: 1.95 per 1U log NT-proBNP increment, 95% CI 1.54-2.46, P<0.001). This relationship held among different ethnic groups, non-Hispanic whites, African-Americans, and Hispanics. Most importantly, NT-proBNP provided additive prognostic value beyond both traditional risk factors and LV mass index for predicting incident HF (integrated discrimination index=0.046, P<0.001; net reclassification index; 6-year risk probability categorized by <3%, 3-10%, >10% =0.175, P=0.019; category-less net reclassification index=0.561, P<0.001).ConclusionsPlasma NT-proBNP provides incremental prognostic information beyond traditional risk factors and the magnetic resonance imaging-determined LV mass index for incident symptomatic HF in an asymptomatic multi-ethnic population.Clinical trial registrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00005487.

Dataset Information

Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels.

Publications

Circulating protein biomarkers predict incident hypertensive heart failure independently of N-terminal pro-B-type natriuretic peptide levels.

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