Phenomapping for novel classification of heart failure with preserved ejection fraction.
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous clinical syndrome in need of improved phenotypic classification. We sought to evaluate whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct HFpEF categories.


RESULTS
We prospectively studied 397 patients with HFpEF and performed detailed clinical, laboratory, ECG, and echocardiographic phenotyping of the study participants. We used several statistical learning algorithms, including unbiased hierarchical cluster analysis of phenotypic data (67 continuous variables) and penalized model-based clustering, to define and characterize mutually exclusive groups making up a novel classification of HFpEF. All phenomapping analyses were performed by investigators blinded to clinical outcomes, and Cox regression was used to demonstrate the clinical validity of phenomapping. The mean age was 65±12 years; 62% were female; 39% were black; and comorbidities were common. Although all patients met published criteria for the diagnosis of HFpEF, phenomapping analysis classified study participants into 3 distinct groups that differed markedly in clinical characteristics, cardiac structure/function, invasive hemodynamics, and outcomes (eg, phenogroup 3 had an increased risk of HF hospitalization [hazard ratio, 4.2; 95% confidence interval, 2.0-9.1] even after adjustment for traditional risk factors [P<0.001]). The HFpEF phenogroup classification, including its ability to stratify risk, was successfully replicated in a prospective validation cohort (n=107).


CONCLUSIONS
Phenomapping results in a novel classification of HFpEF. Statistical learning algorithms applied to dense phenotypic data may allow improved classification of heterogeneous clinical syndromes, with the ultimate goal of defining therapeutically homogeneous patient subclasses.
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.). sanjiv.shah@northwestern.edu rahul.deo@ucsf.edu.
Sanjiv J
SJ
Shah
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Daniel H
DH
Katz
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Senthil
S
Selvaraj
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Michael A
MA
Burke
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Clyde W
CW
Yancy
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Mihai
M
Gheorghiade
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Robert O
RO
Bonow
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.).
Chiang-Ching
CC
Huang
From the Division of Cardiology, Department of Medicine (S.J.S., D.H.K., S.S., M.A.B., C.W.Y., M.G., R.O.B.), Feinberg Cardiovascular Research Institute (S.J.S.), and Center for Cardiovascular Innovation (M.G., R.O.B.), Northwestern University Feinberg School of Medicine, Chicago, IL; Zilber School of Public Health, University of Wisconsin, Milwaukee (C.-C.H.); and Division of Cardiology, Department of Medicine, Institute for Human Genetics, California Institute for Quantitative Biosciences, and Cardiovascular Research Institute, University of California, San Francisco (R.C.D.). sanjiv.shah@northwestern.edu rahul.deo@ucsf.edu.
Rahul C
RC
Deo
D000368:Aged; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006333:Heart Failure / Q000097:blood / Q000175:diagnosis* / Q000503:physiopathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies; D013318:Stroke Volume / Q000502:physiology*
cluster analysis; echocardiography; heart failure, diastolic; patient outcome assessment