TY - JOUR
T1 - Proteomics and Precise Exercise Phenotypes in Heart Failure With Preserved Ejection Fraction
T2 - A Pilot Study
AU - Shah, Ravi V.
AU - Hwang, Shih Jen
AU - Murthy, Venkatesh L.
AU - Zhao, Shilin
AU - Tanriverdi, Kahraman
AU - Gajjar, Priya
AU - Duarte, Kevin
AU - Schoenike, Mark
AU - Farrell, Robyn
AU - Brooks, Liana C.
AU - Gopal, Deepa M.
AU - Ho, Jennifer E.
AU - Girerd, Nicholas
AU - Vasan, Ramachandran S.
AU - Levy, Daniel
AU - Freedman, Jane E.
AU - Lewis, Gregory D.
AU - Nayor, Matthew
N1 - Publisher Copyright:
© 2023 The Authors.
PY - 2023/11
Y1 - 2023/11
N2 - BACKGROUND: While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets. METHODS AND RESULTS: We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we de-fined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O2 extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins), and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O2 extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50– 0.90] and 1.43 [95% CI, 1.11–1.85], respectively) with adjustment for clinical factors and B-type natriuretic peptides. CONCLUSIONS: The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.
AB - BACKGROUND: While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets. METHODS AND RESULTS: We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we de-fined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O2 extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins), and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O2 extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50– 0.90] and 1.43 [95% CI, 1.11–1.85], respectively) with adjustment for clinical factors and B-type natriuretic peptides. CONCLUSIONS: The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.
KW - HFpEF
KW - biomarkers
KW - exercise
KW - hemodynamics
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85176617078&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85176617078&partnerID=8YFLogxK
U2 - 10.1161/JAHA.122.029980
DO - 10.1161/JAHA.122.029980
M3 - Article
C2 - 37889181
AN - SCOPUS:85176617078
SN - 2047-9980
VL - 12
JO - Journal of the American Heart Association
JF - Journal of the American Heart Association
IS - 21
M1 - e029980
ER -