Daniel Lee Dries MD, MPH

Associate Professor of Medicine (Cardiology); Medical Director, Yale Center for Advanced Heart Failure, Mechanical Circulatory Support and Cardiac Transplantation

Research Interests

Cardiomyopathy; Heart failure; Heart transplantation; Mechanical circulatory support; Genetics; Natriuretic peptide biology; Hypertrophy

Current Projects

RO1HL091663: "Genetics Determinants of Hypertesnive Heart Disease in Chronic Renal Insufficiency"

Research Summary

My clinical research is directed at the identification of clinical factors that are important in risk assessment in patients with advanced heart failure. In particular, we have an interest in the use of novel biomarkers as predictors of heart failure progression and the interaction between renal function of prognosis in heart failure.

My basic science research laboratory focuses on the natriuretic peptide system and how it functions as a compensatory system in regulating blood pressure, the cardiac response to elevated blood pressure and progression of heart failure once established. We also conduct genetic studies aimed at elucidating the genetic sdeterminants of heart failure.

Extensive Research Description

My human population research is aimed at elucidating the genetic factors that contribute to inter-individual differences in the cardiac response to hypertension, the progression to systolic or diastolic heart failure and the rate of progression of systolic heart failure once established. We have focused on both candidate gene and genome-wide approaches but are also utilizing admixture mapping. Our candidate gene approach has focused on genes related to nodal signaling pathways in natriuretic peptide biology and the matrix metalloproteinase pathways. Currently we are analyzing genetic variants in these systems using a tagging SNP approach within the Chronic Renal Insufficiency Cohort (CRIC). We previously identified a dysfunctional corin gene haplotype characterized by two missense mutations in the corin gene that is common in Blacks and associated with an increased risk for hypertension and cardiac hypertrophy.

Our basic laboratory is focused on the importance of the natriuretic peptide system and its autocrine/paracrine activities in the heart opposing pathological cardiac hypertrophy. The natriuretic peptide system regulates cardiac hypertrophy, interstitial fibrosis and neovascularization. Inadequate function of the NPS, therefore, results in impaired neovascularization, excessive fibrosis and exaggerated hypertrophy which we hypothesize increases the risk for the development of heart failure. Adequate autocrine/paracrine function of the NPS requires adequate pro-ANP/pro-BNP processing: atrial and brain natriuretic peptide are released as biologically inactive pro-hormones that must be processed into biologically active, carboxyl-terminal fragments. Impaired processing of natriuretic peptides is demonstrated in advanced heart failure and under chronic hypertension. The main focus of our basic laboratory is elucidating the molecular mechanisms regulating natriuretic peptide pro-hormone processing with a particular focus on the trans-membrane serine protease corin. We have a parallel interest in the contribution of excessive activation of the ER-stress response in heart failure and its interaction with natriuretic peptide processing and mRNA stability. In order to conduct this research we have developed novel conditional knockout murine models, knock-in murine models and we also have developed an intact heart (ex vivo) Langerdorf model that allows direct assessment of cardiac natriuretic peptide processing in our genetic strains under various conditions.

Selected Publications

  • Ky B, French B, McKloskey K, Rame JE, McIntosh E, Shahi P, Dries DL, Tang, WH, Wu AH, Fang JC, Boxer R, Sweitzer NK, Levy WC, Goldberg LR, Jessup M, Cappola TP. High-sensitivity ST2 for prediction of adverse outcomes in chronic heart failure. Circulation Heart Failure. 2011, 4(2): 180-187.
  • Dries DL, Ky, B, Rame E, Wu AH, Putt M, Cappola T.: Simultaneous assessment of unprocessed ProBNP 1-108 in addition to processed BNP32 improves risk stratification in ambulatory patients with heart failure. Circulation Heart Failure. 2010; 3(2): 220-227.
  • Dries DL. Genetic ancestry, population admixture and the genetic epidemiology of complex disease. Circulation Genetics 2009; 2(6): 540-3.
  • Rame JE, Tam W, McNamara D, Worcel M, Sabolinski M, Wu A, Dries DL. Dysfunctional corin I555(P568) allele is associated with impaired BNP processing and adverse outcomes in African-Americans with systolic heart failure: results from the genetic risk assessment in heart failure A-HeFT substudy Circulation Heart Failure. 2009, 2(6): 541-8.
  • Wang W, Liao X, Fukuda K, Knappe S, Wu F, Dries DL, Qin J, Wu Q. Corin variant associated with hypertension and cardiac hypertrophy exhibits impaired zymogen activation and natriuretic peptide processing activity. Circulation Research. 2008,103(5): 502-8.
  • Rame, JE, Drazner, MH, Post, W, Peshock, R, Lima, J, Cooper, RS, Dries, DL. Corin I555(P568) allele is associated with enhanced cardiac hypertrophic response to increased systemic afterload. Hypertension. 2007, 49(4): 857-864
  • Dries, DL, Victor, RG, Rame, JE, Cooper, RS, Wu, XD, Zhu, XF, Leonard, D, Ho, SI, Wu, QY, Post, W, Drazner, MH. Corin gene minor allele defined by 2 missense mutations is common in blacks and associated with high blood pressure and hypertension. Circulation. 2005,112(16): 2403-2410.
  • Drazner MH, Rame, JE, Stevenson, LW, Dries, DL. Prognostic importance of elevated jugular venous pressure and a third heart sound in patients with heart failure. New England Journal of Medicine. 2001, 345(8): 574-581.
  • Dries, DL, Exner, DV, Domanski, MJ, Greenberg, B, Stevenson, LW. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. Journal of the American College of Cardiology. 2000, 35(3): 681-689.
  • Dries, DL, Exner, DV, Gersh, BJ, Cooper, HA, Carson, PE, Domanski, MJ. Racial differences in the outcome of left ventricular dysfunction. New England Journal of Medicine. 1999, 340(8): 609-616.

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