Microvascular Paradigm in Heart Failure With Preserved Ejection Fraction
A Quest for Proof of Concept
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Since its introduction in 2013, the microvascular paradigm for heart failure with preserved ejection fraction (HFpEF) gained widespread acceptance.1,2 In accordance to this paradigm, comorbidities and especially metabolic comorbidities trigger a systemic inflammatory state that results in coronary microvascular endothelial dysfunction, which alters paracrine signaling from endothelial cells to cardiomyocytes and microvascular permeability, allowing monocytes to infiltrate the myocardium. Altered paracrine signaling lowers myocardial nitric oxide availability and cyclic guanosine monophosphate content. This stiffens cardiomyocytes because of deficient phosphorylation of titin, the myofilamentary protein responsible for cardiomyocyte elasticity, and removes the brake on cardiomyocyte hypertrophy. Monocyte infiltration on its turn leads to activation of myofibroblasts and interstitial collagen deposition.
See Article by Gevaert et al
A vast amount of supportive clinical data for the new HFpEF paradigm has recently been acquired, the most important being a distinct inflammatory biomarker profile and evidence of impaired myocardial vascularization. Systemic inflammation was manifest from high plasma levels of soluble interleukin 1 receptor–like 1 and C-reactive protein, which exceeded levels observed in heart failure with reduced ejection fraction.3 Inflammatory biomarkers also better predicted outcome than NT-proBNP (N-terminal pro brain natriuretic peptide).4 Impaired myocardial vascularization was evident in left ventricular (LV) biopsies from microvascular expression of endothelial adhesion molecules5 and in LV autopsy material from microvascular rarefaction.6 Both microvascular inflammation and rarefaction explain the reduced coronary flow reserve on positron emission tomography.7
In search for mechanisms underlying clinical HFpEF, several animal models have been proposed over the last decennium. In this issue of Circulation: Heart Failure, a new model is comprehensively presented.8 In this model, HFpEF is observed in senescence-accelerated mice (SAM) after 24 weeks of a Western high-salt, high-fat diet (WD), and its development is attributed to the microvascular paradigm …