The impact of obesity on the regulation of muscle blood flow during exercise in patients with heart failure with a preserved ejection fraction

Abstract

Obesity is now considered a primary comorbidity in heart failure with preserved ejection fraction (HFpEF) pathophysiology, mediated largely by systemic inflammation. Although there is accumulating evidence for a disease-related dysregulation of blood flow during exercise in this patient group, the role of obesity in the hemodynamic response to exercise remains largely unknown. Small muscle mass handgrip (HG) exercise was used to evaluate exercising muscle blood flow in nonobese (BMI < 30 kg/m², n = 14) and obese (BMI > 30 kg/m², n = 40) patients with HFpEF. Heart rate (HR), stroke index (SI), cardiac index (CI), mean arterial pressure (MAP), forearm blood flow (FBF), and vascular conductance (FVC) were assessed during progressive intermittent HG exercise [15%-30%-45% maximal voluntary contraction (MVC)]. Blood biomarkers of inflammation [C-reactive protein (CRP) and interleukin-6 (IL-6)] were also determined. Exercising FBF was reduced in obese patients with HFpEF at all work rates (15%: 304 ± 42 vs. 229 ± 15 mL/min; 30%: 402 ± 46 vs. 300 ± 18 mL/min; 45%: 484 ± 55 vs. 380 ± 23 mL/min, nonobese vs. obese, P = 0.025), and was negatively correlated with BMI (R = -0.47, P < 0.01). In contrast, no differences in central hemodynamics (HR, SI, CI, and MAP) were found between groups. Proinflammatory biomarkers were markedly elevated in patients with obesity (CRP: 2,133 ± 418 vs. 4,630 ± 590 ng/mL, P = 0.02; IL-6: 2.9 ± 0.3 vs. 5.2 ± 0.7 pg/mL, nonobese vs. obese, P = 0.04), and both biomarkers were positively correlated with BMI (CRP: R = 0.40, P = 0.03; IL-6: R = 0.57, P < 0.01). Together, these findings demonstrate the presence of obesity and an accompanying milieu of systemic inflammation as important factors in the dysregulation of exercising muscle blood flow in patients with HFpEF.NEW & NOTEWORTHY Obesity is the primary comorbid condition in HFpEF pathophysiology, but the role of adiposity on the peripheral circulation is not well understood. The present study identified a 30%-40% reduction in forearm blood flow during handgrip exercise, accompanied by a marked elevation in proinflammatory plasma biomarkers, in obese patients with HFpEF compared with their nonobese counterparts. These findings suggest an exaggerated dysregulation in exercising muscle blood flow associated with the obese HFpEF phenotype.

Keywords: exercise hyperemia; heart failure; inflammation; preserved ejection fraction; vasodilation.

Graphical abstract

Figure 1.

Exercising muscle blood flow responses. Changes in brachial artery blood flow during handgrip exercise in nonobese and obese patients with HFpEF (A). When the relationship between the overall hyperemic response across all exercise intensities was viewed across the range of BMIs (18–61 kg/m²) among patients with and without obesity, a significant negative correlation was found between the slope of exercising muscle blood flow and BMI (B, Pearson correlation coefficient = −0.456, P < 0.001, n = 50). A 2 × 3 repeated-measures ANOVA (α < 0.05) (group, two levels: nonobese vs. obese HFpEF) (workload, three levels: 15%, 30%, and 45% of MVC) were performed to compare the hemodynamic responses in control and HFpEF during exercise. *Group effect, P < 0.05. Means ± SE. HFpEF, heart failure with preserved ejection fraction; MVC, maximal voluntary contraction.

Figure 2.

Circulating inflammatory biomarkers. Both plasma CRP (A) and IL-6 (C) were significantly elevated in obese patients with HFpEF compared with nonobese controls. When these inflammatory biomarkers of inflammation were viewed across the range of BMIs (18–61 kg/m²) among patients with and without obesity, a significant positive correlation was found between both CRP (Pearson correlation coefficient = 0.393, P < 0.001, n = 28; B) and IL-6 (Pearson correlation coefficient = 0.573, P < 0.001, n = 31; D) and BMI values. A Student’s t test was performed between groups (α < 0.05). *Group effect, P < 0.05. Means ± SE. CRP, C-reactive protein; HFpEF, heart failure with preserved ejection fraction; IL-6, interleukin-6.