Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage

Erik B Schelbert; Kayla M Piehler; Karolina M Zareba; James C Moon; Martin Ugander; Daniel R Messroghli; Uma S Valeti; Chung-Chou H Chang; Sanjeev G Shroff; Javier Diez; Christopher A Miller; Matthias Schmitt; Peter Kellman; Javed Butler; Mihai Gheorghiade; Timothy C Wong

doi:10.1161/JAHA.115.002613

Myocardial Fibrosis Quantified by Extracellular Volume Is Associated With Subsequent Hospitalization for Heart Failure, Death, or Both Across the Spectrum of Ejection Fraction and Heart Failure Stage

J Am Heart Assoc. 2015 Dec 18;4(12):e002613. doi: 10.1161/JAHA.115.002613.

Authors

Erik B Schelbert¹, Kayla M Piehler², Karolina M Zareba³, James C Moon⁴, Martin Ugander⁵, Daniel R Messroghli⁶, Uma S Valeti⁷, Chung-Chou H Chang⁸, Sanjeev G Shroff⁹, Javier Diez¹⁰, Christopher A Miller¹¹, Matthias Schmitt¹¹, Peter Kellman¹², Javed Butler¹³, Mihai Gheorghiade¹⁴, Timothy C Wong¹

Affiliations

¹ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.) Clinical and Translational Science Institute, University of Pittsburgh, PA (E.B.S., T.C.W.).
² UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.).
³ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) UPMC Cardiovascular Magnetic Resonance Center, Heart and Vascular Institute, Pittsburgh, PA (E.B.S., K.M.P., K.M.Z., T.C.W.) Department of Medicine, The Ohio State University, Columbus, OH (K.M.Z.).
⁴ Barts Heart Centre and University College London, London, UK (J.C.M.).
⁵ Department of Clinical Physiology, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden (M.U.).
⁶ Department of Congenital Heart Disease and Pediatric Cardiology, Deutsches Herzzentrum Berlin, Berlin, Germany (D.R.M.).
⁷ Cardiology Division, University of Minnesota, Minneapolis, MN (U.S.V.).
⁸ Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA (E.B.S., K.M.Z., C.C.H.C., T.C.W.) Department of Biostatistics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, PA (C.C.H.C.).
⁹ Department of Bioengineering, University of Pittsburgh, PA (S.G.S.).
¹⁰ Program of Cardiovascular Diseases, Center for Applied Medical Research and University Clinic of Navarra, Pamplona, Spain (J.D.).
¹¹ Centre for Imaging Sciences and Biomedical Imaging Institute, University of Manchester, UK (C.A.M., M.S.).
¹² National Heart, Lung, and Blood Institute, Bethesda, MD (P.K.).
¹³ Cardiology Division, Stony Brook University, Stony Brook, NY (J.B.).
¹⁴ Center for Cardiovascular Innovation, Northwestern University Feinberg School of Medicine, Chicago, IL (M.G.).

Abstract

Background: Myocardial fibrosis (MF) in noninfarcted myocardium may be an interstitial disease pathway that confers vulnerability to hospitalization for heart failure, death, or both across the spectrum of heart failure and ejection fraction. Hospitalization for heart failure is an epidemic that is difficult to predict and prevent and requires potential therapeutic targets associated with outcomes.

Method and results: We quantified MF with cardiovascular magnetic resonance extracellular volume fraction (ECV) measures in 1172 consecutive patients without amyloidosis or hypertrophic or stress cardiomyopathy and assessed associations with outcomes using Cox regression. ECV ranged from 16.6% to 47.8%. Over a median of 1.7 years, 111 patients experienced events after cardiovascular magnetic resonance, 55 had hospitalization for heart failure events, and there were 74 deaths. ECV was more strongly associated with outcomes than "nonischemic" MF observed with late gadolinium enhancement, thus ECV quantified MF in multivariable models. Adjusting for age, sex, renal function, myocardial infarction size, ejection fraction, hospitalization status, and heart failure stage, higher ECV was associated with hospitalization for heart failure (hazard ratio 1.77; 95% CI 1.32 to 2.36 for every 5% increase in ECV), death (hazard ratio 1.87 95% CI 1.45 to 2.40) or both (hazard ratio 1.85, 95% CI 1.50 to 2.27). ECV improved classification of persons at risk and improved model discrimination for outcomes (eg, hospitalization for heart failure: continuous net reclassification improvement 0.33, 95% CI 0.05 to 0.66; P=0.02; 0.16, 95% CI 0.01 to 0.33; P=0.02; integrated discrimination improvement 0.037, 95% CI 0.008 to 0.073; P<0.01).

Conclusion: MF measured by ECV is associated with hospitalization for heart failure, death, or both. MF may represent a principal phenotype of cardiac vulnerability that improves risk stratification. Because MF can be reversible, cells and enzymes regulating collagen could be potential therapeutic targets.

Keywords: T1 mapping; cardiovascular magnetic resonance; extracellular matrix; extracellular volume fraction; heart failure; myocardial fibrosis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Female
Fibrosis
Heart Failure / epidemiology*
Heart Failure / mortality
Heart Failure / pathology
Heart Failure / physiopathology
Hospitalization / statistics & numerical data
Humans
Male
Middle Aged
Myocardium / pathology*
Proportional Hazards Models
Risk Factors
Severity of Illness Index
Stroke Volume

Abstract

Publication types

MeSH terms

Grants and funding