Impact of Aortic Pulse Pressure Determinants on the Heart Rate-Aortic Pulse Pressure Relationship: An Intervention Study in Rats

Abstract

Heart rate-reducing agents such as β-blockers and ivabradine (IVB) are frequently used in the management of patients with cardiovascular disease (CVD). However, reductions in heart rate (HR) are associated with increases in central aortic pulse pressure (PPc), but not peripheral PP. The inverse HR-PPc relationship, and the mechanisms thereof, have been identified primarily in cross-sectional studies. Hence, intervention studies are required to establish causality and the primary mechanisms. The aim of this intervention study in rats, was to assess the effect of changes in HR on PPc, and the mechanisms involved. Male spontaneously hypertensive rats (SHR) (n=15) and Wistar Kyoto (WKY) (n=12), were studied. To induce changes in blood pressure (BP) and HR, phenylephrine (PE), followed by IVB was administered to anaesthetised rats. Aortic pressures and flow waves were coupled, and wave separation analysis was used to determine the determinants of PPc, including the forward wave pressure (Pf), backward wave pressure (Pb), reflected pressure, re-reflected pressure, aortic flow(Q), aortic characteristic impedance (Zc), and pressure generated by the product of flow and characteristic impedance (PQxZc). Heart rate was inversely associated with PPc (p<0.0001), backward wave pressure (Pb) (p<0.0001), forward wave pressure (Pf) (p<0.0001), reflected pressure (p<0.0001), and re- reflected pressure (p<0.0001). On the contrary, Q, Zc, and PQxZc were not related to heart rate. The slope of the relationship between HR and PPc was markedly diminished by adjustments for Pf, Pb, reflected pressure, or re-reflected pressure (p<0.05 to p<0.0001). In an intervention study in rats, we confirm the inverse relationship between HR and PPc and show that wave reflection and re-reflection are the primary mechanisms responsible for the HR-PPc relationship. These data suggest that wave reflection and re-reflection should be targeted in individuals who require HR-reducing agents, such as by intensive lowering of BP.