Endothelial dysfunction and cellular repair in heart failure with preserved ejection fraction: response to a single maximal exercise bout

Abstract

Aims -Endothelial dysfunction contributes to exercise intolerance in heart failure with preserved ejection fraction (HFpEF). Endothelial progenitor cells (EPC) and angiogenic T lymphocytes (TA) participate in endothelial repair. Recruitment of EPC or TA with exercise might explain the vascular benefits of exercise training. We studied baseline endothelial function, EPC and TA numbers in HFpEF patients and the effects of a single exercise bout.Methods and Results -HFpEF patients (n=26) and age-and sex-matched healthy volunteers (HV, n=26) performed a maximal exercise test. Before and 10 minutes after exercise, EPC and TA were quantified by flow cytometry and endothelial function was assessed by reactive hyperaemia index.HFpEF patients had endothelial dysfunction at baseline (p=0.036). Worse endothelial function predicted worse diastolic function in a multiple linear regression (E/e' ratio: ß=-7.5 p=0.001). EPC and TA counts were lower in HFpEF in comparison with HV (p=0.025 and p=0.047 respectively). Lower TA levels predicted higher New York Heart Association functional class (ß=-1.1•10 -4 , p=0.042). Acute exercise did not further worsen endothelial function in HFpEF patients (p=1.0), in contrast with HV (p=0.003).TA increased with exercise in both groups (HV p=0.047, HFpEF p=0.047).Conclusions -We conclude that HFpEF patients have microvascular endothelial dysfunction.Lower EPC and TA suggest deficient endothelial repair in HFpEF. Exercise increases TA in HV, and this recruitment is intact in HFpEF patients. How repeated exercise impacts HFpEF pathophysiology through endothelial function and repair requires further study.

Heart Failure With Preserved Ejection Fraction: A Review of Cardiac and Noncardiac Pathophysiology

“…TAs secrete high amounts of pro-angiogenic factors (vascular endothelial growth factor, IL-8) and are thought to participate in endothelial repair through paracrine control of EPCs via CD184 (Walter et al., 2005). We have recently shown that numbers of circulating EPCs and TAs are reduced in HFpEF patients, indicating a deficient endothelial repair (Gevaert et al., 2019). Restoring endothelial regenerative capacity could be a future target in HFpEF research.…”

“…In short, vascular function in large and medium-size vessels seems relatively preserved in HFpEF patients. However, almost all studies comparing microvascular endothelial function between HFpEF patients and matched healthy volunteers show a microvascular endothelial dysfunction in HFpEF (Borlaug et al., 2010; Akiyama et al., 2012; Lee et al., 2016; Gevaert et al., 2019).…”

The impact of different forms of exercise on circulating endothelial progenitor cells in cardiovascular and metabolic disease

“…Fifteen clinical trials examined the acute effects to exercise (Adams et al 2004 ; Shaffer et al 2006 ; Van Craenenbroeck et al 2009 ; Van Craenenbroeck et al 2010a ; Sandri et al 2011 ; Van Craenenbroeck et al 2011 ; Rummens et al 2012 ; Scalone et al 2013 ; Kazmierski et al 2015 ; Rocha et al 2015 ; West et al 2015 ; Lutz et al 2016 ; Waclawovsky et al 2016 ; Gevaert et al 2019 ; Kourek et al 2020b ) (Table 1 ). Thirteen trials included independent groups before and after (Adams et al 2004 ; Shaffer et al 2006 ; Van Craenenbroeck et al 2009 ; Van Craenenbroeck et al 2010a ; Van Craenenbroeck et al 2011 ; Rummens et al 2012 ; Scalone et al 2013 ; Kazmierski et al 2015 ; Rocha et al 2015 ; West et al 2015 ; Lutz et al 2016 ; Gevaert et al 2019 ; Kourek et al 2020b ), one was a single arm trial (Sandri et al 2011 ) and another one a randomised cross over trial (Waclawovsky et al 2016 ). Across the 15 included trials (649 participants), 13 reported percentages of male and female distribution (Van Craenenbroeck et al 2009 ; Van Craenenbroeck et al 2010a ; Sandri et al 2011 ; Van Craenenbroeck et al 2011 ; Rummens et al 2012 ; Scalone et al 2013 ; Kazmierski et al 2015 ; Rocha et al 2015 ; West et al 2015 ; Lutz et al 2016 ; Waclawovsky et al 2016 ; Gevaert et al 2019 ; Kourek et al 2020b ).…”

“…Lastly, as a secondary outcome four trials measured the number and/ or function of cultured myeloid angiogenic cells (MACs) defined as double positive for acetylated Low-Density Lipoprotein labelled with 1,1′-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate and lectin (Di-acLDL + / lectin + cells) (Adams et al 2004;. Ten out of the 15 trials (Table 2) predominantly included two blood collection time points for circulating EPCs with the post-exercise time point varying between immediately post-exercise and 24 h post-exercise (Shaffer et al 2006;Van Craenenbroeck et al 2009;Van Craenenbroeck et al 2010a;Rummens et al 2012;Scalone et al 2013;Rocha et al 2015;Lutz et al 2016;Waclawovsky et al 2016;Gevaert et al 2019;Kourek et al 2020b). The most common time point adopted in the majority of trials was 10 min post-exercise.…”

Physical Exercise Protects Against Endothelial Dysfunction in Cardiovascular and Metabolic Diseases

“…The endothelium is a self-renew system; however, disruption of the injury and repair balance of endothelium will lead to the pathophysiology of vascular diseases. The endothelial injury can be repaired by endothelial cell proliferation, the differentiation of endothelial progenitor cells (EPCs) to endothelial cells, and other mechanisms [66,67]. There is a study in 1997 showing for the first time that human peripheral blood-derived EPC is one kind of stem cells which plays important role in endothelial repair and angiogenesis [68].…”