Blood pressure (BP) measurements in the brachial artery have been essential to predict cardiovascular disease. Observational studies  and therapeutic intervention trials [2,3] have clearly shown the tight relationship between BP values and cardiovascular outcomes. Recently, the possibility of noninvasively determining central BP has aroused great interest, because it not only makes it possible to determine the values of BP where it originated, that is, aortic rather than brachial artery, but also because it appears to be a better predictor of future cardiovascular events and all-cause mortality than peripheral (brachial) pressures [3–8]. In turn, in different populations, a closer association with intermediate markers of end-organ damage, such as left ventricular hypertrophy [6,9], carotid [3,6,10] and coronary  atherosclerosis or decreased glomerular filtration rate , has also been observed. These findings have generated some expectations regarding the possibility of using the measurement of central BP (cBP), rather than peripheral BP (pBP), as a therapeutic target for antihypertensive treatment .
Insulin resistance, clinically identified by type 2 diabetes mellitus or by metabolic syndrome, is an increasingly prevalent disease. Both diabetes mellitus and metabolic syndrome confer a two-fold to four-fold higher cardiovascular risk to people suffering from these diseases in comparison with those free from them [12,13]. Therefore, cardiovascular diseases are responsible for most causes of death and morbidity in these patients . In addition, hypertension, which accounts for nearly 75% of these patients, is one of the main causes of the high cardiovascular morbidity and mortality in patients with insulin resistance, increasing the risk of macrovascular and microvascular complications .
Moreover, albuminuria, a recognized excellent marker of subclinical target organ damage [16,17], develops early in the natural history of patients with glucose metabolic disturbances  and predicts cardiovascular outcomes and mortality . Although albuminuria is highly dependent on BP in these patients , there is a surprising lack of information addressing the relationship between central BP and albuminuria. Only one study  reported a correlation between albuminuria and central augmentation pressure in type 2 diabetics. Thus, the present study aimed to determine the magnitude of the relationship between cBP and urinary albumin excretion (UAE), and to assess whether this relationship was better than that observed with pBP, in hypertensive patients with insulin resistance.
We enrolled 324 consecutively attended type 2 diabetic patients or patients with metabolic syndrome, who agreed to participate in this study. All patients were recruited from 70 specialized hypertension centers in Spain. All the participants were hypertensive and hypertension was a mandatory criterion to enter the study. Diabetes mellitus was diagnosed if patients had a minimum of two fasting plasma glucose determinations more than 7.0 mmol/l or when they were under antidiabetic treatment. Metabolic syndrome was diagnosed according to the most recent consensus document  when the subject had two or more of the following in addition to elevated BP: abdominal obesity, as defined by a waist circumference more than 102 cm in men or more than 88 cm in women, fasting serum glucose at least 5.6 mmol/l, high-density lipoprotein plasma cholesterol 1.0 mmol/l or less in men or 1.2 mmol/l or less in women, plasma triglycerides more than 1.7 mmol/l, or if the patient was under current treatment for any of them. This study was approved by the correspondent research ethic committee in accordance with the Declaration of Helsinki. All participants gave written informed consent.
Measurement of office blood pressure and central blood pressure
Office brachial BP was obtained by trained personnel as the average of triplicate measurements taken at intervals of 1 min after an initial 5 min of seated rest, using validated oscillometric devices. Regular or large adult cuffs were used according to arm circumference. After 10 min of rest in the supine position at a comfortable room temperature, cBP was measured using SphygmoCor device (AtCor Medical, Sydney, Australia). Mean arterial pressure was determined by mathematical integration of the radial pressure waveform obtained by applanation tonometry and calibrated using the oscillometric value of brachial SBP and DBP, as has been previously validated . cBP measurements were carried out at each investigation centre by either nurses or doctors who were specifically trained to perform this technique according to current standardized recommendations . They were closely monitored throughout the study to ensure accuracy in this BP measurement. After an initial training session, each participant center was checked within 1–2 months to confirm the adequate performance of cBP assessment and further rechecked whenever necessary. Moreover, it was a necessary requisite that the values of two consecutive valid (operator index higher than 80%) measurements at each visit were averaged. Intraobserver cBP measurement coefficients of variation were 7.8 and 8.9% for SBP and DBP, respectively. The interobserver cSBP and DBP coefficients of variation were 11.6 and 15.1%, respectively.
Pulse pressure (PP) amplification was calculated as the ratio between peripheral PP (pPP) and central PP (cPP) values, that is, pPP/cPP.
Urinary albumin excretion
UAE (measured by turbidimetry in local laboratories according to current recommended standards; maximum intra-assay and inter-assay variation coefficients being 1.3 and 4.2%, respectively) was determined as the average of urinary albumin/creatinine ratio from three first-morning-void urine samples obtained in separate days. Microalbuminuria was defined following the European Society of Hypertension Guidelines, as urinary albumin excretion at least 2.5 mg/mmol (men) and at least 3.5 mg/mmol (women) .
Continuous variables are summarized by mean ± SD or median [25th percentile (p. 25); 75th percentile (p. 75)]. Categorical variables are described as percentages for each category. Bivariate comparisons between patients with and without microalbuminuria were performed by unpaired t tests or ANOVA (age-adjusted and sex-adjusted) in continuous data, by Mann–Whitney test in asymmetrically distributed data, and by χ2 test in categorical data. Correlation between UAE and BP indices was assessed by means of partial correlation coefficients (age-adjusted and sex-adjusted). Differences in the strengths of association between cBP and pBP and UAE were compared by calculation of Z statistics for comparison of correlations within a single sample. The same analysis was used for comparing differences in means between cBP and pBP in patients with and without microalbuminuria.
A total of 324 hypertensive patients (61% men; mean age ± SD was 65 ± 10 years) were consecutively enrolled. Table 1 shows main clinical features of these patients. UAE (median [p. 25; p. 75]) was: 0.87 mg/mmol [0.40; 2.58]. The prevalence of microalbuminuria using the aforementioned criteria was 24.7%.
Clinical characteristics of patients with and without microalbuminuria are also shown in Table 1. Patients with microalbuminuria were more frequently men, exhibited higher levels of HbA1c and were more often treated with both renin–angiotensin system blockers and insulin. No differences regarding other clinical parameters (Table 1) or other antihypertensive drug class distribution (Table A of the online supplementary file, http://links.lww.com/HJH/A207) were found between patients with or without microalbuminuria. Comparisons of peripheral and cBP estimates between patients with and without microalbuminuria, after age-adjusted and sex-adjustment, are shown in Table 2. Both (central and peripheral) SBP and PP were significantly higher in patients with microalbuminuria, whereas no differences were found in peripheral and central DBP. In terms of other central hemodynamic parameters, no differences were found between patients with or without microalbuminuria in mean values of augmentation pressure, augmentation index, or PP amplification. The assessment of superiority/noninferiority of cBP vs. pBP (magnitude of differences between microalbuminuric and normoalbuminuric patients) revealed no significance among any of them (Z = 0.982, P = 0.327 for SBP comparison, Z = 0.771, P = 0.441 for DBP comparison and Z = 1.934, P = 0.054 for PP comparison).
Table 3 shows the partial correlation coefficients (age-adjusted and sex-adjusted) of cBP and pBP parameters with UAE. cSBP, central DBP and cPP were significantly correlated with UAE (P < 0.05 for all). As regards pBP, both SBP and DBP (P < 0.05), but not PP also showed a significant correlation with UAE. According to noninferiority analyses, there were no differences in the strength of the association of either cBP or pBP estimates with UAE (Z = 1.190; P = 0.265 for SBP comparison; Z = 0.672; P = 0.502 for DBP comparison and Z = 1.251; P = 0.212 for PP comparison).
Because of significant differences as regards plasma glycosylated hemoglobin levels between normoalbuminuric and albuminuric patients, we performed sensitivity analyses (see online supplementary file, Tables B, C and D, http://links.lww.com/HJH/A207) that confirmed these results when separately analyzing diabetics and nondiabetic patients.
We here report a significant correlation between cBP, as estimated by radial artery applanation tonometry, and UAE, a well characterized marker of subclinical target organ damage, in a cohort of hypertensive patients with insulin resistance (diabetics or patients with metabolic syndrome). Importantly, we also show that this association is not stronger than that observed with office pBP.
Since the advent of sphygmomanometry more than a century ago, brachial BP has allowed prediction of the risk of cardiovascular outcomes, mortality and subclinical organ damage [1,2,24]. However, it is well recognized that central BP is a more important determinant of myocardial perfusion and cardiac work than peripheral pressure. To support this assumption, a number of clinical outcome studies in different subpopulations, such as patients with coronary heart disease [7,25], end-stage renal disease , elderly , or in individuals belonging to certain ethnic groups [3,6], and a meta-analysis  have all shown an independent predictive value for cBP as regards major cardiovascular endpoints and mortality. Moreover, when considering intermediate markers of end-organ damage, several cross-sectional analyses have shown an independent relationship between some indices of central arterial pressure, mostly aortic SBP and PP, and left ventricular hypertrophy and altered geometry [6,9], carotid intima–media thickness [3,6,10], coronary atherosclerosis  and decreased glomerular filtration rate . However, to date information regarding relationship between cBP and albuminuria has been rather scarce.
We have found a significant correlation between UAE and cBP estimates, that is, SBP, DBP and PP. This is in agreement with a previous study  also reporting a significant correlation between both cSBP and cPP with UAE. Certainly, UAE has also been related to other central hemodynamic parameters, mainly pulse wave velocity (PWV). In this regard, most of the studies [28–30] have reported a significant association between UAE and PWV. However, it is important to note that, although a central hemodynamic derived parameter, PWV has shown to be independent from other central BP indices . In fact, it may be regarded mainly as a marker of arterial stiffness, and thus, of target organ damage. Consistent with this concept, in our study, like that aforementioned of Neisius et al. , PWV has been considered a marker of organ damage in the same category as UAE, and therefore we have not evaluated the relationship between UAE and PWV.
The second important finding in our study is that cBP was not superior to pBP in the strength of its association with microalbuminuria. With regard to the relationships of several intermediate markers of end-organ damage other than UAE, it is generally accepted that their association with cBP estimates is better than the association with their pBP counterparts [3,6,9], although an analysis of the Australian National Blood Pressure Study 2 showed that brachial BP measurement was superior to carotid arterial waveforms measurement in predicting cardiovascular outcomes in elderly female hypertensives . With respect to the relationship of cardiovascular outcomes and mortality with both cBP and pBP measurements. Vlachopoulos et al.  suggested that cBP estimates were not better predictors than the pBP ones, which agrees with our results in relation to UAE. Similar results were shown by Mitchell et al.  in the participants of the Framingham Heart Study in whom, after adjusting for pSBP, no central measurements of arterial stiffness but PWV were associated with increased risk for a first cardiovascular event.
Additionally, we have assessed the relationship between pulse pressure amplification (PPA) and UAE, exploring the possibility of a stronger association with this value than with cBP estimates per se. We have not found a significant correlation of PPA with UAE, neither did our study demonstrate significant differences in PPA between patients with or without microalbuminuria.
Another important aspect refers to the importance of night pressure as for the occurrence of microalbuminuria. It has recently been shown in resistant hypertensive patients  that night-time pressure is the BP parameter that associates the best with UAE. However, for now the standardized cBP measurement at night-time is not available. So, we cannot tell whether the relationship of night-time BP with UAE could be stronger than that observed with office cBP. Furthermore, to date, all studies reporting on cBP have been based on one-time office measurement. It would be interesting to see whether with multiple measurements taken in an out-of-office setting with both 24-h ambulatory pBP and 24-h cBP methodology, one might be able to show significant advantage of central monitoring of cBP over pBP in predicting UAE. Another limitation that needs to be mentioned is that the results cannot be extrapolated to other populations that are different from patients with insulin resistance. Moreover, most of the individuals were under an inhomogeneous antihypertensive therapeutic regime, because these hypertensive patients were treated in so many centers. Even though these drugs may influence both the determinations of central pressure and albuminuria, antihypertensive agents could not be withdrawn in these high-risk patients for ethical reasons, so we cannot disregard some different influence of the diverse antihypertensive drugs on albuminuria and either cBP or pBP. However, as shown in Table A (see online supplement file, http://links.lww.com/HJH/A207), antihypertensive drugs in both groups of patients, normoalbuminurics and microalbuminurics, did not significantly differ, except for renin–angiotensin blockers, but even here it should be noted that more than 90% of patients in each group were taking a drug in this class. A couple of very small-sized studies [35,36] (18 and 21 patients, respectively) have suggested that renin–angiotensin blockers could differently affect central and peripheral BP, but further studies are required to confirm this possible different effect. Taking these data together, it should not be expected that the lack of differences in the association between albuminuria and both central and peripheral BP could be due to the use of these drugs. Among the strengths of the present study, we must emphasize that our data on UAE are based on the measurement of urinary albumin/creatinine ratio obtained in three separate morning spot fresh urines, conferring a high accuracy to the results. This is in the line with the methodology used by all investigators on the measurement of both pBP and cBPs, since all of them attended a special training course to ensure technically homogeneous recordings and were then monitored for a proper BP measurement.
In conclusion, we have shown that, even though cBP is associated with UAE in hypertensive patients with insulin resistance, the strength of this association is not superior to that of pBP. This suggests that, until results from randomized controlled therapeutic trials become available, there is insufficient evidence to justify targeting cBP in place of the pBP estimation with regard to albuminuria.
The investigators: M.A., J. Agudo, B. Alvarez, AM. Arias-Salgado, M. Artigao, S. Artola, L. Barutell, L. Bousquets, R. Cabrera, RM. Cacharrón, J. Camacho, Lu. Carrión, M. Ceballos, ML. Comesaña, I. Chagoyen, ML. del Río, J. Díez, MI. Egocheaga, J. Espinosa, JM. Fernández, D. Ferrero, C. Fluixà, A. Fornos, A.Galgo, M. García, FJ. García-Norro, L. García-Ortiz, T. Gijón, M. Gil, MJ. Gomara, P. Gómez, MA. Gómez-Marcos, JA. Guzmán, A. Henríquez, Y. Hidalgo, A. Hortal, JP. Justel, A. Lara, MI. López, J. López, F. López, E. López de Coca, M. López, R. López, JL. López, MT. Marín, E. Márquez, N.M., JL. Martín, C. Martínez, M. Martínez, ML. Mellado, I. Morón, A.O., FJ. Palau, F. Parralejo, S. Pérez, MA. Prieto, L. Quiles, C. Rodríguez, AL. Ruiz, J.S., R. Serrano, C. Suárez, J. Suero, M. Tejero, J. Toril, F. Tornero, S. Vázquez, J. Velasco, L.V..
This study is partially funded by two Spanish research grants (ISCIII - FIS PI08/0896 and FIS PI10/01011). It is also partially supported by a Catalonian research grant from the MaratóTV3 Foundation (080431). This study has also received a partial unrestricted funding from Pfizer Laboratories, Spain.
Conflicts of interest
There are no conflicts of interest.
Reviewer's Summary Evaluation Reviewer 1
In this interesting study the authors report a correlation between albumin excretion and two different measures of blood pressure (central and peripheral), in a group of patients with insulin resistance. They conclude that, at present, there is insufficient evidence to justify targeting central instead of peripheral blood pressure. Although the study was carried out with sound methodology and results are well presented and commented upon, one must bear in mind a potential confounding factor due to the fact that a significant number of patients were taking antihypertensive drugs at the time of study. These may have influenced urine albumin excretion and, at least in theory, modified central and peripheral BP in different fashion.
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