The theory behind the concept of arterial wave reflection is generally believed to be an uttermost complex story for a nonexpert reader. It is obvious that its implementation in current daily clinical practice will require more than goodwill of all parties involved as the concept is already a marriage of convenience between basic principles of physics and applied physiology. Accurate quantification of physical properties (e.g., forward (Pf) and backward (Pb) pressure wave, reflection magnitude (RM), and related parameters) expected to represent wave reflection has always been a cumbersome matter involving controversial methodological issues (See below) such as, without being exhaustive, preference of wave separation over waveform analyses or the intrinsic need for flow curves to end up with accurate measurements.1,2 Although nowadays still considered essentially a research tool, wave reflection parameters have drawn the attention of part of the medical community after the publication of several clinical outcome articles for some of these parameters, e.g., RM predicted all-cause mortality in the MESA cohort3 and higher Pf wave amplitude predicted increased risk of incident cardiovascular (CV) disease in the Framingham Heart Study.4 Moreover in the Framingham Offspring cohort the forward wave amplitude (FWA) predicted incident hypertension independent of classical risk factors.5 Studies of that kind further foster new research lines aiming at disentangling the underlying mechanisms. For instance, do and how do CV risk indicators such as diabetes mellitus (DM), uncontrolled hypertension, and target organ damage including impaired left ventricular function and mass or impaired renal function interact with arterial wave reflection (Pf, Pb, RM), arterial stiffness (gold standard: carotid-femoral pulse wave velocity, cf-PWV), and stiffness-related parameters (central pulse pressure: aortic or carotid pulse pressure (PP)). A group of investigators with a longstanding history of studies in the South West Township of Johannesburg, South Africa (SOWETO) was instrumental in the progress made in that field. In this issue of the Journal, this time they address the cross-sectional interplay between classical risk factors, DM, uncontrolled hypertension, cf-PWV, brachial and aortic PPs (by two methods: the SphygmoCor algorithm and the second systolic shoulder of the radial pulse) and wave reflection including Pf and Pb (by wave separation with the assumption of a triangular flow wave).6 Cf-PWV integrates risks and indeed cf-PWV was significantly associated in their multivariable analyses with age, sex, mean blood pressure, DM, body mass index, and alcohol intake but not with uncontrolled hypertension and smoking. DM and uncontrolled hypertension were independently associated with Pf but not independently of brachial and aortic PP. The authors concluded that neither brachial nor aortic PP adequately index CV risk factor-related changes in aortic stiffness and forward wave pressure. Some remarkable albeit unexpected findings deserve a more in-depth discussion. The absence of any meaningful association between respectively Pb, aortic and brachial PPs and either DM or uncontrolled hypertension is without any doubt striking. At first glance, it might look surprising if not in contradiction with earlier published material in the SOWETO cohort. Booysen et al.7 showed a far stronger relationship of Pb (than of Pf) with aortic PP in the same cohort and aortic pressure augmentation underestimated the contribution of aortic wave reflection to variations in aortic PP. In another SOWETO-related article, Sibiya et al.8 demonstrated that the reflected wave better accounted for the association between aortic PP and target organ damage. The authors themselves came up with reasonable but still unproven suggestions to explain the selective association between uncontrolled hypertension and Pf: disproportionally increased proximal aortic stiffness and aortic diameter changes deteriorating characteristic impedance. Such hypotheses, partially based on the FWA paradigm, have been questioned in literature. The principle of mismatch between aortic stiffness/geometry and peak aortic systolic flow needs some refining. Impedance mismatches also occur for backward traveling waves. As a consequence, the forward wave integrates primary waves and rectified wave reflections. Moreover, the FWA heavily depends on rectified reflections, a fact which limits the validity of the FWA paradigm to conditions showing minimal reflections.9 Thus, under real life conditions the contribution of the proximal aorta to an elevated FWA or PP might be somewhat overestimated. Of interest in the Belgian ASKLEPIOS population-based cohort characteristic impedance was not the single most important determinant of carotid PP. Time domain characteristic impedance and maximal aortic flow (important determinants of the magnitude of the Pf wave) accounted for 44% of the variance of the carotid artery PP and AIx for an additional 26%.10 Another strength of the article6 is that the authors took the opportunity to compare the results of the multiple regression analyses for two methodologies for the determination of the aortic PP: the inbuilt algorithm in the SphygmoCor device and a calculation derived directly from the second systolic shoulder of the radial pulse (P2) which the authors introduced in earlier research.11 For the same choice of covariates, the spectrum of significant associates of risk indicators with aortic PP was remarkable concurrent with only one notable albeit very important and striking exception. In sharp contrast to the SphygmoCor–derived aortic PP sex was highly significantly associated with the P2-derived aortic PP. Although an in-depth discussion on the validity of algorithms for the assessment of aortic PP and wave reflection parameters is out of the scope of this editorial commentary, the article by Motau et al.6 clearly illustrates that under selected conditions the investigators’ choice of methodology might not be an innocent bystander when addressing clinically relevant associations between traditional risk factors (e.g., sex) and hemodynamics- or arterial stiffness-related characteristics. Should results from the SOWETO cohort be extended to the population at large? There have been some (warranted?) claims that arterial stiffness and wave reflection would underlie elevated CV risk in diverse ethnic groups.12 Magnitudes of the published arterial stiffness- and wave reflection-related parameters in the SOWETO cohort might be at odds with those from other cohorts. Most of the evidence in ethnic (sub)-groups has been derived from cross-sectional associations between CV risks and AIx, a parameter integrating age, sex, blood pressure, body morphology, heart rate, contractility, and methodological aspects on the fiducial marker points. From a physiological point of view, AIx is neither an excellent surrogate of stiffness nor a genuine marker of wave reflection. Bearing in mind these constraints, black South Africans had higher AIx than other populations13 and AIx might have contributed in a sex-specific way to the indexed left ventricular mass in the SOWETO cohort.14 Is wave reflection in essence heritable? What proportion of the phenotypic variation can be accounted for by genotypic variation? In the SOWETO cohort, the still modest but significant multivariable adjusted heritability estimate for wave separation analysis-derived Pb largely exceeded heritability of Pf.15 Data on the effects of DM on central hemodynamics and reflection or reflection-like parameters are relatively scarce. Kario’s group, promoting radial AIx (PP2/rPP) as a longitudinal measure of stiffness, observed significantly lower radial AIx and central PP for comparable central systolic blood pressures in type 2 diabetics vs. non-diabetics in 1,787 participants from the J-HOP Study.16 Current thinking would link DM with increased wave reflections,17 however, population-based data are not univocally pointing into that direction. For instance, in the ASKLEPIOS Study,18 after adjustments for age, sex, and mean blood pressure type 2 DM was associated with higher cf-PWV but lower wave RM (wave separation analysis). The authors proposed aortic wall stiffness rather than muscular artery abnormalities or aortic root geometric remodeling or wave reflections as an underlying mechanism for the increased pulsatile load in type 2 DM. The higher aortic root characteristic impedance and elastance-thickness product and the higher aortic root PWV without an increase of the aortic diameter and the lower total arterial compliance are pleading for a more central role of arterial wall stiffness. Of note, although controversial, antihypertensive drugs may in their own right decrease wave reflections in type 2 DM whereas associated hypertension and nephropathy may have elicited opposite effects. In this issue of the Journal, Motau et al.6 addressed in the SOWETO cohort whether associations between CV risks such as DM and uncontrolled hypertension and respectively aortic stiffness and indices of pulse wave and wave separation analysis are indexed by an increased pulse pressure. Their exercise has proven “negative,” e.g., neither brachial nor aortic pulse pressure adequately indexed the relationships between those CV risks and the forward wave pressure. The article adds some relevant information to our knowledge of the contribution of central pulse pressure to central hemodynamics and arterial stiffness in patients at increased CV risk. However, after scrutinizing the existing literature it remains a matter of debate whether or not the exclusive significant association between the forward wave pressure (not for the backward wave pressure) and uncontrolled hypertension and DM and the poor performance of aortic pulse pressure should be considered SOWETO cohort-specific findings. More long-term follow-up studies are needed to better delineate the role and the prognostic value of the forward wave pressure and the central pulse pressure in South African and other subpopulations harboring a high burden of CV risks. DISCLOSURE The authors declared no conflict of interest. REFERENCES 1. Segers P , Rietzschel ER , De Buyzere ML , De Bacquer D , Van Bortel LM , De Backer G , Gillebert TC , Verdonck PR . Assessment of pressure wave reflection: getting the timing right ! Physiol Meas 2007 ; 28 : 1045 – 1056 . Google Scholar CrossRef Search ADS PubMed 2. Kips JG , Rietzschel ER , De Buyzere ML , Westerhof BE , Gillebert TC , Van Bortel LM , Segers P . Evaluation of noninvasive methods to assess wave reflection and pulse transit time from the pressure waveform alone . Hypertension 2009 ; 53 : 142 – 149 . Google Scholar CrossRef Search ADS PubMed 3. Zamani P , Jacobs DR Jr , Segers P , Duprez DA , Brumback L , Kronmal RA , Lilly SM , Townsend RR , Budoff M , Lima JA , Hannan P , Chirinos JA . Reflection magnitude as a predictor of mortality: the Multi-Ethnic Study of Atherosclerosis . Hypertension 2014 ; 64 : 958 – 964 . Google Scholar CrossRef Search ADS PubMed 4. 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American Journal of Hypertension – Oxford University Press
Published: Sep 1, 2018
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