Dapagliflozin Enhances Arterial and Venous Compliance During Exercise in Heart Failure With Preserved Ejection Fraction: Insights From the CAMEO-DAPA Trial

Abstract

Background: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF.

Methods: In this secondary analysis from the CAMEO-DAPA trial (Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial), 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model.

Results: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], -18.8 mm Hg [95% CI, -33.9 to -3.7] P=0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m² [95% CI, 0.003-0.11] P=0.039) and aortic root characteristic impedance (ETD, -2.6 mm Hg/mL*sec [95% CI: -5.1 to -0.03] P=0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, -292 mm Hg [95% CI, -530 to -53] P=0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, -7.3% [95% CI, -13.3 to -1.3] P=0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P=0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P<0.001).

Conclusions: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF.

Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04730947.

Keywords: Dapagliflozin; arterial compliance; exercise; heart failure, diastolic; hemodynamics; vascular stiffness; venous function.

Figure 1:. Key Parameters at Rest and During Exercise Prior to Treatment and Following 24 Weeks of Treatment with Placebo or Dapagliflozin

Systolic blood pressure (BP) (left panels), total arterial compliance assessed using the pulse pressure method from Windkessel modeling (TAC_WK) index (center panels), and estimated stressed blood volume (eSBV) (right panels) at rest and during exercise prior to treatment and following 24 weeks of treatment with placebo (up panels, blue) or dapagliflozin (lower panels, orange). Error bars in the panel reflect standard error. *p<0.05 versus baseline by paired t test; **p<0.01 versus by paired t test. BP, blood pressure; eSBV, estimated stressed blood volume; TAC_WK, total arterial compliance assessed using the pulse pressure method from Windkessel modeling.

Figure 2:. Changes in Key Parameters at Rest and Submaximal and Peak Exercise Compared to the Baseline Cardiac Catheterization in Patients Treated with Placebo or Dapagliflozin

Changes in systolic blood pressure (BP) (left up panels; Placebo [n=16] and Dapagliflozin [n=21]), pulse pressure (left bottom panels; Placebo [n=16] and Dapagliflozin [n=21]), total arterial compliance assessed using the pulse pressure method from Windkessel modeling (TAC_WK) index (right up panels; Placebo [n=13] and Dapagliflozin [n=18]), and estimated stressed blood volume (eSBV) (right bottom panels; Placebo [n=15] and Dapagliflozin [n=18]) at rest and submaximal and peak exercise compared to the baseline cardiac catheterization in patients treated with placebo (blue) or dapagliflozin (orange). Tukey box plots represent the median and interquartile ranges with whiskers representing minimum and maximum values, with individual patient data superimposed. BP, blood pressure; eSBV, estimated stressed blood volume; PP, pulse pressure; TAC_WK, total arterial compliance assessed using the pulse pressure method from Windkessel modeling.

Figure 3:. Correlations of Absolute Reductions during Peak Exercise in Key Parameters

Correlations of absolute reductions during peak exercise in estimated stressed blood volume (eSBV) and systolic blood pressure (BP) (r=0.40, p=0.019) (left panels); and in systolic BP and pulmonary capillary wedge pressure (PCWP) (r=0.56, p<0.001) (right panels). BP, blood pressure; eSBV, estimated stressed blood volume. PCWP, pulmonary capillary wedge pressure. Data points shown in blue are placebo whereas orange are for dapagliflozin.