Is Blood Pressure Independent Arterial Destiffening Possible?

Aging is associated with a stiffening of the large conduit arteries, which is accelerated by different cardiovascular risk factors, in particular by hypertension. Elevated aortic stiffness has therefore been included in the list of target organ damages to be screened for in hypertension by the European Society of Hypertension.1 Carotid-femoral pulse wave velocity (cfPWV) is the noninvasive “gold-standard” for the assessment of aortic stiffness2 and has been shown to be a powerful predictor of all-cause and cardiovascular mortality as well as cardiovascular events independent of classic cardiovascular risk factors.3 However, cfPWV has not yet fully qualified as surrogate endpoint,4 since its clinical use as therapeutic target still has to be demonstrated.5 Furthermore, a consensus on which strategy to pursue to selectively improve cfPWV is missing.6 In this context, the question if and how antihypertensive agents cause an arterial destiffening beyond the effect of blood pressure (BP) lowering alone has been receiving much attention.7–9 In this issue of the journal, Rodilla et al.10 present their results regarding the effect of antihypertensive treatment according to standard clinical practice on target organ damage with a special focus on arterial stiffness. In a population comprising 231 never-treated, mild hypertensives, and 125 controls, they measured BP, left ventricular mass index, urinary albumin excretion, and cfPWV at baseline and after 1 year to assess their changes with treatment. At follow up, BP levels were well-controlled and a significant reduction of left ventricular mass index and cfPWV could be observed. Age, gender, cfPWV at baseline, and change in BP were the main determinants of decrease in cfPWV. Rodilla et al. moreover found that all classes of antihypertensive drugs administered in the study, i.e., calcium channel blockers, angiotensin receptor blockers or angiotensin-converting enzyme inhibitors (ACEI), vasodilating betablockers, and diuretics resulted in a significant lowering of adjusted cfPWV. It should be noted that diuretics were used as add-on agent in all but 2 patients. However, control subjects showed a similar reduction as hypertensive patients in mean blood pressure-adjusted cfPWV after 1 year and an effect of the antihypertensive treatment beyond BP could therefore not be clearly established. The main strength of the work by Rodilla et al.10 is the observational nature of their study, reflecting clinical routine rather than experimental design and highly selected patients. They were able to demonstrate that the prevalence of elevated arterial stiffness could be markedly decreased within a year by standard care in this relatively large group of mild hypertensives. Moreover, the study was conducted in accordance with the latest guidelines for the assessment of the target organ damages considered, including a cut-off value of 10 m/s to define elevated stiffness and the use of 0.8 times the direct carotid-to-femoral distance for the computation of cfPWV as advised in the expert consensus document on the measurement of aortic stiffness.2 Unfortunately though, cfPWV was only linearly adjusted for mean blood pressure using a regression equation obtained at baseline, whereby the reported interaction with age11 was not taken into account. Because hypertensive patients were significantly older than controls, this might have led to an under- and over-adjustment of cfPWV respectively, making the results less comparable between the groups as well as between baseline and follow up in the treatment arm. A multiple regression approach including age as predictor, as chosen by Ong et al.12 or used by the reference values for arterial stiffness’ collaboration,11 might have been preferable to account for the strong association between BP, cfPWV, and age and might have eventually resulted in a more distinctly observable decrease in arterial stiffness with treatment. The stiffness of an artery represents a local, physical property of the vessel wall, and characterizes the relation between inner pressure and the induced distension of the vessel. This relation is nonlinear, meaning that arteries become stiffer as they dilate, which can be explained by the interplay between elastin and collagen fibers in the vessel media.6,13 Thus, higher BP results in a stiffer artery and, therefore, higher pulse wave velocity, yet without any change in the properties of the arterial wall itself. Arterial stiffening, in contrast, describes structural changes, which indeed affect the intrinsic properties of the vessel wall. For the same pressure level, a smaller distension and a higher pulse wave velocity will be observed in a stiffer artery compared to a more elastic one, implying that PWV is elevated beyond the effect of BP. For a given left ventricular ejection on the other side, elevated stiffness directly causes an increase in BP amplitude which is further indirectly augmented by the earlier return of the reflected waves due to the faster PWV, resulting in an increased cardiac afterload and a higher systolic and pulse pressure compared to normal stiffness. Besides the instantaneous relation between BP and arterial stiffness described above, both variables are mutually influencing the temporal progression of each other. Increased BP is supposed to accelerate vascular degradation (mechanical fatiguing) due to the increased cyclic stress exerted on the arterial wall,13 whereas elevated cfPWV was found to be associated to new onset hypertension and progressive rise of systolic BP in normotensive individuals.14 Hence, BP and arterial stiffness are highly interrelated and the improvement of one will also be beneficial for the other, suggesting that—although antihypertensive agents or treatment strategies inducing an additional reduction in aortic stiffness beyond BP might be favorable for the patient—this additional benefit is notoriously hard to demonstrate. The effects of antihypertensive medication on arterial stiffness reported in literature depend on the drug class used and the duration of treatment. In an individual meta-analysis performed by Ong et al.12 in previously untreated mild-to-moderate hypertensive patients, an (acute) lowering of cfPWV beyond BP was reported for ACEI compared to placebo in short-term (2 hours to 8 days) trials but not for calcium channel blockers. In long-term treatment (1–6 months), in contrast, cfPWV was significantly decreased independently of changes in BP for ACEI, calcium channel blockers, betablockers as well as diuretics, indicating that sustained BP-control and the unloading of the arterial wall over a longer timespan might induce reverse arterial remodeling. This is corroborated by results by Ait-Oufella et al.,15 who investigated the long-term changes (5.3 years) in cfPWV in patients treated for hypertension according to routine clinical practice. They found a progressive temporal reduction in cfPWV beyond BP. In their present work, Rodilla et al.10 could not definitely confirm a beneficial effect of standard BP lowering regimens on the reversal of arterial stiffness after 1 year. However, the duration of follow up was relatively short compared to the study by Ait-Oufella et al.15 and, in contrast to the interventional studies described before, the results obtained by different drug classes and combinations thereof were pooled for analysis. Even though a reduction of arterial stiffness could be found for all classes of antihypertensives, renin–angiotensin system inhibition by ACEI or angiotensin receptor blockers has been argued to be especially valuable for a destiffening of the arteries, because it is directly promoting the reverse remodeling of the large and small arteries.6,16 The favorable effect of a modulation of the renin–angiotensin system on arterial stiffness has been shown to be independent of BP in animal models.17 Ong et al.12 indeed found the (numerically) highest reduction of cfPWV after adjustment for BP when using ACEI in long-term treatment. However, the superiority of ACEI compared to other antihypertensive drug classes could not be confirmed in a recent meta-analysis including 9 trials and 378 patients, possibly due to the lack of power and quality of the randomized control studies included.18 Likewise, Rodilla et al.10 observed no significantly larger decrease in mean blood pressure-adjusted cfPWV in the 71% of the patients treated with ACEI or angiotensin receptor blockers compared to patients treated with other antihypertensive drugs. However, the study was not designed for the comparison of different drug classes. Therefore, further research is definitely needed to evaluate the favorable effects of a blockade of the renin–angiotensin system in monotherapy or in combination with other agents in a routine care setting. The authors declared no conflict of interest.