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Adhesion molecules in early adulthood predict heart failure with preserved ejection

fraction at older age

Brief/Cover Title: Adhesion Molecules and HFpEF

Walter J. Paulus, M.D., Ph.D.

Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands

Disclosures: None

Address for correspondence

Prof. Dr. Walter J. Paulus, M.D., Ph.D. Amsterdam Cardiovascular Sciences Amsterdam University Medical Centers O|2 building 10W13 De Boelelaan 1118, 1081 HV Amsterdam Tel.: 31 6 273 39 91 0 Fax: 31 204448255 E-mail: wj.paulus52@gmail.com Twitter: @Amsterdamumc Key Words: Adhesion Molecules, Heart Failure, Remodeling

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The natural history of heart failure with preserved ejection fraction (HFpEF) remains

largely unexplored (1). The few studies that addressed this issue were hindered by short

observation periods usually corresponding to the duration of trials and by focus on the late

transition from stage C (symptomatic HF) to stage D (refractory HF). In this issue of JACC, Patel

RB et al. overcame both obstacles as they present data from the CARDIA study with a

spectacular 15 to 23 years follow-up and focus on the early transition from Stage A (at risk for

HF) to Stage B (asymptomatic LV remodeling)(2). They showed circulating endothelial adhesion

molecules such as E-Selectin and intercellular adhesion molecule-1 (ICAM-1) determined in

early adulthood at ages varying from 18 to 30 years to predict a depressed left ventricular (LV)

global longitudinal strain (LGS) 15 to 23 years later(2). LVGLS is a sensitive speckle tracking

echocardiographic index of LV remodeling in HfpEF(3). These findings are important because

they support a personalized strategy of early risk assesment with determination of circulating

adhesion molecules to prevent later development of HFpEF, a condition for which an effective

therapy is unfortunately still lacking.

ADHESION MOLECULES AND HFPEF

Vascular biologists have a longstanding interest in adhesion molecules as markers of

inflammation-triggered endothelial activation. When nonhuman primates were fed a high fat

diet, endothelial inflammatory activation was the earliest event evident from expression of

carotid vascular cell adhesion molecule-1 (VCAM-1), that occurred coincident with the

development of insulin resistance and long before any measurable change in carotid intima-

media thickness(4). Because of the shift in our understanding of HFpEF from hypertension-

induced LV overload to obesity-induced myocardial inflammation(5,6), expression of

endothelial adhesion molecules was determined in LV biopsy samples of patients with HFpEF

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and compared to samples procured from patients with HF and reduced ejection fraction (HFrEF)

or aortic stenosis (AS)(7). ICAM-1 and E-Selectin expression was significantly higher in

myocardial biopsies of HFpEF than of HFrEF or AS patients. Only when HFrEF patients had

coexistent diabetes mellitus did the expression of endothelial activation molecules match the

levels observed in HFpEF. Because of microvascular endothelial expression of adhesion

molecules, there was myocardial infiltration of CD68 expressing macrophages(7). The latter are

known to secrete transforming growth factor β which turns fibroblasts into myofibroblasts that

produce collagen with a high tensile strength as observed in scar tissue. This evidently increased

myocardial stiffness and led to diastolic LV dysfunction. In HFpEF, infiltrating macrophages are

of a distinct phenotype as a result of metabolic activation that differs from classical endotoxic

activation(8). Expression of endothelial adhesion molecules is induced by proinflammatory

cytokines such as TNFα. In line with the study of Patel RB et al., an earlier report from the

Health ABC study showed an increased harzard for developing HFpEF over a 9.4 year time span

when baseline TNFα plasma level was elevated(9). Expression of endothelial adhesion

molecules is repressed by microRNA-223, which is transported in the circulation by high density

lipoproteins (HDL)(10). Obese HFpEF patients have low HDL plasma levels and therefore low

transfer of circulating microRNA-223. This favours endothelial expression of adhesion

molecules as also evident from the study of Patel RB et al. from the progressively lower HDL

plasma levels at higher quartiles of plasma E-selectin or ICAM-1.

BIOMARKERS AND HFPEF STAGES

The study by Patel RB et al. and previous investigations suggest elevations of different

biomarkers to start at distinct stages of the HFpEF timeline (Figure 1). The study by Patel RB et

al. indeed demonstrates E-Selectin and ICAM-1 to be already elevated in early adulthood in

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stage A HFpEF. This happened 15 to 23 years before stage B HFpEF became manifest from

depressed values of LVGLS, which were clearly lower than normal for the highest quartiles of

the E-Selectin and ICAM-1 distributions. In line with these findings, microalbuminuria, a direct

consequence of endothelial activation, has previously been demonstrated to predict HFpEF,

albeit incident clinical HFpEF, in a community-based, middle-aged cohort with 11 years follow-

up(11). In contrast to markers of endothelial activation, natriuretic peptides (NP) appear to be of

limited value in preclinical HFpEF as they are frequently low and even normal in clinical stage C

HFpEF(12). Despite these lower values of NP in HFpEF, a rise of NP implies poor prognosis and

suggests transition from stage C to advanced stage D HFpEF(13). Markers of myocardial fibrosis

show a similar relation to the HFpEF timeline as evident from galectin-3 levels in the Aldo-DHF

trial which predicted poor outcome and evolution from stage C to stage D HFpEF(14). Finally,

raised plasma troponin I levels also imply a poor prognosis and again track stages C and D(15).

Collectively, the study of Patel RB et al. and previous investigations suggest the natural history

of HFpEF to be reflected in successive elevations of distinct biomarkers with endothelial

adhesion molecules already raised in early subclinical HFpEF (Stages A and B) and NP,

galectin-3 and troponin I increased in clinical HFpEF (Stages C and D).

The present study by Patel RB et al. in this issue of the Journal paves the road for

personalized prevention of HFpEF. In a young patient with cardiovascular risks such as obesity,

diabetes mellitus or arterial hypertension, elevated circulating endothelial adhesion molecules

should prompt vigorous efforts to correct the risk factor profile in order to prevent HFpEF

development at older age. This strategy could similarly be of benefit for a condition closely

related to HFpEF namely atrial fibrillation because over a 20 year time span circulating VCAM-

1 has also been shown to be closely associated with incident atrial fibrillation(16).

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Figure Legend

Figure 1: Timing of biomarker elevations in relation to stages of HFpEF. Successive

elevations of biomarkers over the natural history of HFpEF with endothelial adhesion molecules

and microalbuminuria already raised in early preclinical stages (A and B) and natriuretic

peptides, markers of fibrosis (galectin-3) and troponin I raised in later clinical stages (C and D).

STAGE A• Risk Factors

STAGE B• LV Remodeling

• No Symptoms

STAGE C• LV Remodeling

• HF Symptoms

STAGE D• LV Remodeling

• Refractory HF

Symptoms

Endothelial Adhesion Molecules

Microalbuminuria

Natriuretic Peptides

Galectin-3

Troponin-I