Background: Carotid-to-femoral pulse wave velocity (c-f PWV) is commonly used to assess large artery stiffness, particularly as a surrogate of aortic stiffness. Given that c-f PWV represents the average stiffness of all main arteries along the carotid-to-femoral arterial pathway, without specifically accounting for the stiffness of the proximal aorta, we hypothesized that c-f PWV may not represent stricto sensu the stiffness of the ascending aorta (AAO), which is the main contributor to total arterial compliance ( C _T ). Methods: To test our hypothesis, we recruited 45 healthy volunteers from different age groups. We evaluated the relation between c-f PWV and different indices of proximal aorta stiffness calculated from distensibility (AAO _dist PWV) and characteristic impedance (Zc) in frequency (AAO _Zc(f) PWV) and time domain (AAO _Zc(t) PWV) and compared their relationships with age and C _T . 2D phase contrast MRI was performed to measure AAO flow and cross-sectional area. Tonometry was used to obtain c-f PWV and pressure waveforms. Results: In healthy individuals, AAO PWV indices demonstrated a strong relationship with each other ( R ≥ 0.86), but c-f PWV did not show high correlations with AAO PWV indices ( R ≤ 0.50). All AAO PWV indices increased with age ( P ≤ 0.05); however, c-f PWV did not increase from young to middle-aged ( P = 0.13) and middle-aged to old age groups ( P = 0.28). AAO PWV indices correlated well with C _T ( R ² ≥ 0.60), whereas c-f PWV did not ( R ² = 0.23). Conclusion: The present study reveals that a complete understanding of large artery stiffness requires the direct assessment of proximal aortic stiffness rather than surrogate indices such as c-f PWV.

The transaortic valvular pressure gradient (TPG) plays a central role in decision-making for patients suffering from severe aortic stenosis. However, the flow-dependence nature of the TPG makes the diagnosis of aortic stenosis challenging since the markers of cardiac performance and afterload present high physiological interdependence and thus, isolated effects cannot be measured directly in vivo. We used a validated 1D mathematical model of the cardiovascular system, coupled with a model of aortic stenosis, to assess and quantify the independent effect of the main left ventricular performance parameters (end-systolic (E_es) and end-diastolic (E_ed) elastance) and principal afterload indices (total vascular resistance (TVR) and total arterial compliance (TAC)) on the TPG for different levels of aortic stenosis. In patients with critical aortic stenosis (aortic valve area (AVA) ≤ 0.6 cm²), a 10% increase of E_ed from the baseline value was associated with the most important effect on the TPG (−5.6 ± 0.5 mmHg, p < 0.001), followed by a similar increase of E_es (3.4 ± 0.1 mmHg, p < 0.001), in TAC (1.3 ±0.2 mmHg, p < 0.001) and TVR (−0.7 ± 0.04 mmHg, p < 0.001). The interdependence of the TPG left ventricular performance and afterload indices become stronger with increased aortic stenosis severity. Disregarding their effects may lead to an underestimation of stenosis severity and a potential delay in therapeutic intervention. Therefore, a comprehensive evaluation of left ventricular function and afterload should be performed, especially in cases of diagnostic challenge, since it may offer the pathophysiological mechanism that explains the mismatch between aortic severity and the TPG.