Left ventricular (LV) afterload is a major determinant of cardiac stress and a key factor for the development of hypertensive heart disease and load-induced ventricular dysfunction. Office brachial blood pressure (BP) is an established predictor of LV mass (with BP components in the following order: systolic > mean > pulse > diastolic),1 although the degree of correlation is rather weak and only slightly improved by the use of 24-h1 or central2,3 BP. Other markers of ventricular-vascular interaction may provide complementary information on the impact of the large vessels on LV structure and function. The present short review examines the impact of different markers of large-artery functional properties, including carotid-femoral pulse wave velocity (PWV) and the novel cardio-ankle vascular index (CAVI), on major prognostically adverse measures of LV involvement such as increased LV mass4 and systolic dysfunction.5
Carotid-femoral PWV, a direct measure of large-artery stiffness, is a strong independent predictor of cardiovascular morbidity and mortality in the general population, which improves model fit and reclassifies risk for future cardiovascular events in models that include standard risk factors.6 As such, the assessment of aortic PWV has been recommended by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) for cardiovascular risk stratification in hypertensive subjects.7
In several studies, carotid-femoral PWV, a direct measure of aortic stiffness, has shown a significant direct relationship with LV mass.8–10 However, PWV is intrinsically dependent on BP,11,12 and the above relationship between PWV and LV mass is generally no longer significant when the effects of BP are taken into account in appropriate multivariable analysis.8–10 Two recent large studies have strengthened the above view. In 2093, participants to the Multi-Ethnic Study of Atherosclerosis,13 aortic arch PWV measured with phase contrast cine magnetic resonance imaging was independently associated in multivariate analyses with LV remodelling and reduced LV function, but not with LV mass after appropriately adjusting for BP. In 5799, participants to the Framingham Heart Study, carotid-femoral PWV measured by arterial tonometry was not associated with LV geometry, mass or fractional shortening in models adjusted for mean arterial pressure as a measure of distending pressure.14
One of the reasons why the relationship of aortic PWV with LV mass is either weak or absent once the effects of BP is taken into account is due to its tight dependence on BP. As a matter of fact, arterial stiffness is intrinsically pressure-dependent due to the nonlinearity of the pressure-volume (or pressure-diameter) relationship in human arteries. As shown in Figure 1, pressure increases exponentially with increasing volume in human arteries (‘diastolic-to-systolic stiffening’). The exponential relationship between pressure and volume is equivalent to the linear increase in arterial stiffness with increasing pressure. The exponent of such a relationship is known as β, or stiffness constant, and is assumed to be constant at least over a certain pressure range. The slope of the relationship between pressure and volume at a given point of the curve expresses arterial stiffness at that specific pressure value. Despite its widely recognized clinical value, PWV only detects arterial stiffness at a very specific BP value, i.e. at diastolic BP, since it is usually determined at the foot of the pulse wave, and misses the potentially important changes in stiffness which occur during the cardiac cycle.
Diastolic-to-systolic carotid PWV variation and the heart
Previous studies have suggested that the increase in arterial stiffness which can be observed during physical exercise15 or throughout the cardiac cycle from diastolic to systolic BP levels16 may be more closely related to LV mass. By combining carotid artery ultrasound and tonometry, arterial stiffness, expressed in terms of PWV, has been shown to vary by about 0.7–4.0 m/s within individuals due to the cyclic diastolic-systolic BP variation. The above cyclic changes, or diastolic-to-systolic ‘stiffening’ of the carotid artery, are more strongly related with LV mass than diastolic stiffness.16 Of note, BP-dependent PWV velocity increase was larger in the older than in the younger subjects,17 thus indicating systolic stiffening as a very sensitive index of the effects of aging on the arterial wall. However, the complexity of the technique does not allow its widespread use in a preventive or clinical setting, and there is a need for simple, easy-to-use bedside markers of the pressure dependency of arterial stiffness.
CAVI and the heart
An accurate assessment of β in clinical practice has been hampered by the need for a simultaneous, instantaneous acquisition of high-fidelity pressure and volume at the same site, which can be only accurately obtained through relatively complex or invasive studies.
Cardio-Ankle Vascular Index (CAVI), a non-invasive indirect estimate of the arterial stiffness index (β) of the aorta and the iliac, femoral, and tibial arteries, is a surrogate measure of the increase in arterial stiffness occurring from end-diastole to end-systole (diastolic-to-systolic ‘stiffening’), and incorporates information on arterial properties during the entirety of systole. Briefly (Figure 1), CAVI can be described as an approximation of the arterial stiffness index β described by Hayashi et al.,18 with PWV replacing arterial distension according to the Bramwell-Hill equation. CAVI was determined by the following equation:
CAVI represents a simple, bedside, operator-independent estimate of the stiffness constant (β) of the aorta, iliac, femoral, and tibial arteries, which is less dependent on BP than PWV. CAVI has been widely applied to assess arterial stiffness both in subjects with clinically overt cardiovascular disease and in those at risk, including those with hypertension, diabetes, and the elderly, as well as in normal subjects.
The potential role of a high CAVI as a BP-independent measure of ventricular afterload has been recently assessed in a cross-sectional study performed in 133 subjects with either hypertension (n = 100) or high-normal BP (age 56±16 years, men 62%, average brachial BP 145/89±21/12 mmHg).21 We excluded subjects with poor-quality echocardiograms, heart failure, coronary heart disease, previous stroke, valvular defects or secondary causes of hypertension, atrial fibrillation, or important concomitant disease. CAVI was recorded using a VaSera VS-1500 vascular screening system (Fukuda Denshi, Tokyo, Japan), with the patient resting in a supine position. Carotid-femoral PWV was determined with the SphygmoCor system (SphygmoCor Vx, AtCor Medical, Sydney, Australia), which uses a high-fidelity applanation tonometer to measure the pressure pulse waveforms sequentially in two arterial sites, i.e. common carotid and femoral artery.22
LV structure and function were assessed by echocardiography.21 In particular, subclinical heart disease was defined as (1) inappropriately high LV mass, i.e. LV mass exceeding levels needed to compensate for hemodynamic load,23 and (2) LV systolic dysfunction, defined as a low afterload-corrected fractional shortening assessed at the midwall level according to a geometric model that takes into account the non-uniform systolic thickening of the LV wall.24–26
As expected, carotid-femoral PWV, but not CAVI, had a significant direct association with both systolic and diastolic BP. CAVI and carotid-femoral PWV were significantly related each other, although the strength of the correlation was only moderate (r = 0.46, P < 0.001).21
As shown in Figure 2 (left panel), the study participants with inappropriate LV mass (n = 44) had a significantly higher CAVI than those whose LV mass was appropriate for their cardiac workload (n = 89); however, the two groups did not differ in terms of carotid-femoral PWV. In a multivariate linear regression model, inappropriately high LV mass was independently predicted by CAVI (β = 0.40, P < 0.001) and body mass index (β = 0.19, P = 0.022).21
An inverse correlation was found between CAVI and LV midwall fractional shortening (r = −0.41, P <0.001), while carotid-femoral PWV had no significant relationship (r = –0.14, P = 0.14). Again, the study participants with low LV midwall systolic function (n = 24) had a significantly higher CAVI than the subjects with normal systolic function (n = 109), although the two groups did not differ in terms of carotid-femoral PWV (Figure 2, right panel). In multivariate linear regression, midwall fractional shortening was independently and inversely predicted by LV mass (β = –0.37, P < 0.001) and CAVI (β = –0.31, P < 0.001).21
The aging process is characterized by a progressive stiffening of the large arteries, which involves a number of profound structural and functional changes in the arterial wall. The above process is accelerated by the effect of cardiovascular risk factors and diseases such as hypertension, diabetes, and renal failure. Arterial stiffness, as a cause of premature return of reflected waves in systole, increases central pulse pressure and the load on the LV. The heart adapts to face the arterial stiffness-related increase in LV afterload by developing ventricular hypertrophy, which eventually leads to systolic dysfunction.
The data shown in this paper demonstrate that CAVI is higher in hypertensive patients with subclinical heart disease, defined as inappropriately high LV mass or LV systolic dysfunction. CAVI but not carotid-femoral PWV has BP-independent associations with important, prognostically adverse markers of LV structure and function such as inappropriately high LV mass and low LV midwall fractional shortening. The latter remark extends previous observations obtained in smaller populations27 and in patients with ischaemic heart disease or heart failure.28–30 This suggests that pressure-independent stiffness constant (β), a marker of systolic stiffening, may have an adverse impact on LV structure and function. These data might partly explain the adverse prognostic value of a high CAVI,31,32 and support the recent recommendation of the American Heart Association, stating that ‘the determination of CAVI is useful in cardiovascular outcome predictions in Asian populations, but longitudinal studies in the United States and Europe are lacking (Class I; Level of Evidence B)’.33
The reasons why CAVI may have a stronger impact on LV mass and function than carotid-femoral PWV could be three-fold. Firstly, CAVI is based on the pressure-independent stiffness constant (β), a marker of arterial diastolic-to-systolic stiffening, while PWV is a marker of diastolic arterial stiffness, given that it considers foot-to-foot transit time, which inherently involves measurements at diastolic BP. Of note, diastolic-to-systolic carotid stiffening, has been more closely related with LV mass than diastolic arterial stiffness.16 Secondly, CAVI and carotid-femoral PWV explore different arterial pathways. Specifically, at variance with carotid-femoral PWV, CAVI includes in its measurement the proximal ascending aortic segment, as well as the femoral, popliteal, and tibial arteries. There is evidence that proximal ascending aortic stiffness is a strong correlate of LV mass,34 and measures of regional stiffness which also included peripheral arteries were more strongly associated with electrocardiographic LV hypertrophy than carotid-femoral PWV.35,36 Thirdly, CAVI is fully operator-independent, and this may reduce the measurement bias which can be observed with partially operator-dependent measures such as carotid-femoral PWV.
Although aortic PWV is an established and prognostically relevant measure of diastolic arterial stiffness, it does not provide information on the cyclic ‘stiffening’ process which occurs from diastole to systole. The availability of non-invasive methods able to assess the functional properties of the large arteries during the cardiac cycle represents an exciting and growing opportunity to bring arterial function assessment into clinical practice and to refine cardiovascular risk stratification beyond PWV. Within this context, CAVI appears to be a particularly attractive parameter to be determined as a simple, non-invasive, repeatable, operator-independent, less BP-related measure of systolic arterial stiffening, and cardiovascular risk. Although aortic PWV remains an established tool for the functional evaluation of the large arteries, parameters such as CAVI that assess changes in arterial stiffness during the entire systole may give a more accurate picture of LV afterload and deserve a special consideration in cardiovascular risk assessment.
Conflict of interest: G.S. received research grants from AtCor Medical and public speaking grants from Fukuda-Denshi. The other authors have no conflicts of interest to declare.