Nirav Patel1, Griffin K Russell2, Kiran Musunuru3, Orlando M Gutierrez4,5, Ganesh Halade1, Vasundhara Kain1, Wenjian Lv6, Sumanth D Prabhu1,7, Kenneth B Margulies6, Thomas P Cappola6, Garima Arora1, Thomas J Wang8, Pankaj Arora1,7. 1. From the Division of Cardiovascular Disease (N.P., G.H., V.K., S.D.P., G.A., P.A.), University of Alabama at Birmingham. 2. School of Medicine (G.K.R.), University of Alabama at Birmingham. 3. Department of Medicine, Department of Genetics (K.M.), Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 4. Division of Nephrology, Department of Medicine (O.M.G.), University of Alabama at Birmingham. 5. Department of Epidemiology (O.M.G.), University of Alabama at Birmingham. 6. Division of Cardiovascular Medicine, Department of Medicine (W.L., K.B.M., T.P.C.), Cardiovascular Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia. 7. Section of Cardiology, Birmingham Veterans Affairs Medical Center, AL (S.D.P., PA.). 8. Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN (T.J.W.).
Abstract
RATIONALE: Lower NP (natriuretic peptide) levels may contribute to the development of cardiometabolic diseases. Blacks have lower NP levels than middle-aged and older white adults. A high-carbohydrate challenge causes an upregulation of a negative ANP regulator microRNA-425 (miR-425), which reduces ANP (atrial-NP) levels in whites. OBJECTIVES: We designed a prospective trial to study racial differences in (1) NP levels among young adults, (2) NP response to a high-carbohydrate challenge, and (3) explore underlying mechanisms for race-based differences. METHODS AND RESULTS: Healthy self-identified blacks and whites received 3 days of study diet followed by a high-carbohydrate challenge. Gene expression from whole blood RNA was assessed in the trial participants. Additionally, atrial and ventricular tissue samples from the Myocardial Applied Genomics Network repository were examined for NP system gene expression. Among 72 healthy participants, we found that B-type-NP, NT-proBNP (N-terminal-pro-B-type NP), and MRproANP (midregional-pro-ANP) levels were 30%, 47%, and 18% lower in blacks compared with whites (P≤0.01), respectively. The decrease in MRproANP levels in response to a high-carbohydrate challenge differed by race (blacks 23% [95% CI, 19%-27%] versus whites 34% [95% CI, 31%-38]; Pinteraction<0.001), with no change in NT-proBNP levels. We did not observe any racial differences in expression of genes encoding for NPs (NPPA/NPPB) or NP signaling (NPR1) in atrial and ventricular tissues. NP processing (corin), clearance (NPR3), and regulation (miR-425) genes were ≈3.5-, ≈2.5-, and ≈2-fold higher in blacks than whites in atrial tissues, respectively. We also found a 2-and 8-fold higher whole blood RNA expression of gene encoding for Neprilysin (MME) and miR-425 among blacks than whites. CONCLUSIONS: Racial differences in NP levels are evident in young, healthy adults suggesting a state of NP deficiency exists in blacks. Impaired NP processing and clearance may contribute to race-based NP differences. Higher miR-425 levels in blacks motivate additional studies to understand differences in NP downregulation after physiological perturbations. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT03072602. Unique identifier: NCT03072602.
RATIONALE: Lower NP (natriuretic peptide) levels may contribute to the development of cardiometabolic diseases. Blacks have lower NP levels than middle-aged and older white adults. A high-carbohydrate challenge causes an upregulation of a negative ANP regulator microRNA-425 (miR-425), which reduces ANP (atrial-NP) levels in whites. OBJECTIVES: We designed a prospective trial to study racial differences in (1) NP levels among young adults, (2) NP response to a high-carbohydrate challenge, and (3) explore underlying mechanisms for race-based differences. METHODS AND RESULTS: Healthy self-identified blacks and whites received 3 days of study diet followed by a high-carbohydrate challenge. Gene expression from whole blood RNA was assessed in the trial participants. Additionally, atrial and ventricular tissue samples from the Myocardial Applied Genomics Network repository were examined for NP system gene expression. Among 72 healthy participants, we found that B-type-NP, NT-proBNP (N-terminal-pro-B-type NP), and MRproANP (midregional-pro-ANP) levels were 30%, 47%, and 18% lower in blacks compared with whites (P≤0.01), respectively. The decrease in MRproANP levels in response to a high-carbohydrate challenge differed by race (blacks 23% [95% CI, 19%-27%] versus whites 34% [95% CI, 31%-38]; Pinteraction<0.001), with no change in NT-proBNP levels. We did not observe any racial differences in expression of genes encoding for NPs (NPPA/NPPB) or NP signaling (NPR1) in atrial and ventricular tissues. NP processing (corin), clearance (NPR3), and regulation (miR-425) genes were ≈3.5-, ≈2.5-, and ≈2-fold higher in blacks than whites in atrial tissues, respectively. We also found a 2-and 8-fold higher whole blood RNA expression of gene encoding for Neprilysin (MME) and miR-425 among blacks than whites. CONCLUSIONS: Racial differences in NP levels are evident in young, healthy adults suggesting a state of NP deficiency exists in blacks. Impaired NP processing and clearance may contribute to race-based NP differences. Higher miR-425 levels in blacks motivate additional studies to understand differences in NP downregulation after physiological perturbations. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov/ct2/show/NCT03072602. Unique identifier: NCT03072602.
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