State-of-the-Art Paper and Commentary
A Novel Paradigm for Heart Failure With Preserved Ejection Fraction: Comorbidities Drive Myocardial Dysfunction and Remodeling Through Coronary Microvascular Endothelial Inflammation

https://doi.org/10.1016/j.jacc.2013.02.092Get rights and content
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Over the past decade, myocardial structure, cardiomyocyte function, and intramyocardial signaling were shown to be specifically altered in heart failure with preserved ejection fraction (HFPEF). A new paradigm for HFPEF development is therefore proposed, which identifies a systemic proinflammatory state induced by comorbidities as the cause of myocardial structural and functional alterations. The new paradigm presumes the following sequence of events in HFPEF: 1) a high prevalence of comorbidities such as overweight/obesity, diabetes mellitus, chronic obstructive pulmonary disease, and salt-sensitive hypertension induce a systemic proinflammatory state; 2) a systemic proinflammatory state causes coronary microvascular endothelial inflammation; 3) coronary microvascular endothelial inflammation reduces nitric oxide bioavailability, cyclic guanosine monophosphate content, and protein kinase G (PKG) activity in adjacent cardiomyocytes; 4) low PKG activity favors hypertrophy development and increases resting tension because of hypophosphorylation of titin; and 5) both stiff cardiomyocytes and interstitial fibrosis contribute to high diastolic left ventricular (LV) stiffness and heart failure development. The new HFPEF paradigm shifts emphasis from LV afterload excess to coronary microvascular inflammation. This shift is supported by a favorable Laplace relationship in concentric LV hypertrophy and by all cardiac chambers showing similar remodeling and dysfunction. Myocardial remodeling in HFPEF differs from heart failure with reduced ejection fraction, in which remodeling is driven by loss of cardiomyocytes. The new HFPEF paradigm proposes comorbidities, plasma markers of inflammation, or vascular hyperemic responses to be included in diagnostic algorithms and aims at restoring myocardial PKG activity.

Key Words

ejection fraction
endothelial dysfunction
heart failure
nitric oxide

Abbreviations and Acronyms

ACEI
angiotensin-converting enzyme inhibitor
ARB
angiotensin II receptor blocker
BNP
B-type natriuretic peptide
cGMP
cyclic guanosine monophosphate
DM
diabetes mellitus
HF
heart failure
HFPEF
heart failure with preserved ejection fraction
HFREF
heart failure with reduced ejection fraction
IL
interleukin
LV
left ventricular
PDE5
phosphodiesterase 5
PH-HFPEF
pulmonary hypertension secondary to heart failure with preserved ejection fraction
PKG
protein kinase G
ROS
reactive oxygen species
TGF
transforming growth factor
TNF
tumor necrosis factor
VCAM
vascular cell adhesion molecule

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Supported by a grant from the European Commission (FP7-Health-2010; MEDIA-261409). The authors have reported that they have no relationships relevant to the contents of this paper to disclose.