Enhanced external counterpulsation improves peripheral artery flow-mediated dilation in patients with chronic angina: a randomized sham-controlled study

Abstract

Background: Mechanisms responsible for anti-ischemic benefits of enhanced external counterpulsation (EECP) remain unknown. This was the first randomized sham-controlled study to investigate the extracardiac effects of EECP on peripheral artery flow-mediated dilation.

Methods and results: Forty-two symptomatic patients with coronary artery disease were randomized (2:1 ratio) to thirty-five 1-hour sessions of either EECP (n=28) or sham EECP (n=14). Flow-mediated dilation of the brachial and femoral arteries was performed with the use of ultrasound. Plasma levels of nitrate and nitrite, 6-keto-prostaglandin F(1α), endothelin-1, asymmetrical dimethylarginine, tumor necrosis factor-α, monocyte chemoattractant protein-1, soluble vascular cell adhesion molecule, high-sensitivity C-reactive protein, and 8-isoprostane were measured. EECP increased brachial (+51% versus +2%) and femoral (+30% versus +3%) artery flow-mediated dilation, the nitric oxide turnover/production markers nitrate and nitrite (+36% versus +2%), and 6-keto-prostaglandin F(1α) (+71% versus +1%), whereas it decreased endothelin-1 (-25% versus +5%) and the nitric oxide synthase inhibitor asymmetrical dimethylarginine (-28% versus +0.2%) in treatment versus sham groups, respectively (all P<0.05). EECP decreased the proinflammatory cytokines tumor necrosis factor-α (-16% versus +12%), monocyte chemoattractant protein-1 (-13% versus +0.2%), soluble vascular cell adhesion molecule-1 (-6% versus +1%), high-sensitivity C-reactive protein (-32% versus +5%), and the lipid peroxidation marker 8-isoprostane (-21% versus +1.3%) in treatment versus sham groups, respectively (all P<0.05). EECP reduced angina classification (-62% versus 0%; P<0.001) in treatment versus sham groups, respectively.

Conclusions: Our findings provide novel mechanistic evidence that EECP has a beneficial effect on peripheral artery flow-mediated dilation and endothelial-derived vasoactive agents in patients with symptomatic coronary artery disease.

Figure 1

Data are absolute values from within group repeated measures ANOVA and Tukey post hoc analysis of between group and between timepoint differences in absolute values. (A) Brachial artery FMD diameter (mm); (B) femoral artery FMD diameter (mm); (C) brachial artery FMD (Δ%); and (D) femoral artery FMD (Δ%); (E) brachial artery absolute diameter; and (F) femoral artery absolute diameter before (PRE) and after (POST) 35 sessions of EECP. **p < 0.01 versus pretreatment values; ‡p < 0.01 EECP versus SHAM. Data are expressed as mean ± SEM.

Figure 2

Statistically significant absolute values are represented as percent change from baseline. P values are from within group repeated measures ANOVA and Tukey post hoc analysis of between group and between timepoint differences in absolute values. Percentage (%) change in plasma (A) NOx; (B) ET-1; (C) NOx/ET-1 ratio; and (D) 6-keto-PGF_1α after 35 sessions of EECP. *p < 0.05 versus pretreatment values; **p < 0.01 versus pretreatment values; †p < 0.05 EECP versus SHAM. Data are expressed as mean ± SEM.

Figure 3

Statistically significant absolute values are represented as percent change from baseline. P values are from within group repeated measures ANOVA and Tukey post hoc analysis of between group and between timepoint differences in absolute values. Percentage (%) change in plasma (A) TNF-α; (B) hsCRP; (C) MCP-1; and (D) sVCAM after 35 sessions of EECP. *p < 0.05 versus pretreatment values; **p < 0.01 versus pretreatment values; †p < 0.05 EECP versus SHAM; ‡p < 0.01 EECP versus SHAM. Data are expressed as mean ± SEM.

Figure 4

Statistically significant absolute values are represented as percent change from baseline. P values are from within group repeated measures ANOVA and Tukey post hoc analysis of between group and between timepoint differences in absolute values. Percentage (%) change in plasma (A) 8-Iso PGF_2a; (B) ADMA; and (C) SOD after 35 sessions of EECP. **p < 0.01 versus pretreatment values; †p < 0.05 EECP versus SHAM; ‡p < 0.01 EECP versus SHAM. Data are expressed as mean ± SEM.