Abstract
Objective: The role of risk factors on the progression of arterial stiffness has not yet been extensively evaluated. The aim of the current longitudinal study was to evaluate the determinants of the PWV progression over a 4 years follow-up period in hypertensive subjects.
Materials and Methods: We enrolled 333 consecutive hypertensive outpatients 18–80 aged, followed by the Hypertension Unit of St. Gerardo Hospital (Monza, Italy). At baseline anamnestic, clinical, BP, laboratory data and cfPWV were assessed. We performed a PWV follow-up examination with a median time amounting to 3.75 ± 0.53 years.
Results: At baseline the mean age was 54.5 ± 12.6 years, SBP and DBP were 141.3 ± 18.6 and 86.4 ± 10.4 mmHg and PWV was 8.56 ± 1.92 m/s. Despite an improvement in BP control (from 37 to 60%), at follow-up the population showed a PWV increase (ΔPWV 0.87 ± 3.05 m/s). PWV and ΔPWV gradually increased in age decades. In patients with uncontrolled BP values at follow-up ΔPWV showed a greater increase as compared to patients with controlled BP (1.46 ± 3.67 vs 0.62 ± 2.61 m/s, p < .05). The independent predictors of ΔPWV were age, baseline PWV, baseline SBP/MBP and ΔSBP/MBP.
Conclusions: the accelerated arterial aging in treated hypertensive subjects is in large measure explained by age and BP values. PWV changes over time would probably give important information that need further future research studies.
Introduction
Abnormal large artery function plays an important role in the pathogenesis of cardiovascular (CV) disease and there is a growing awareness that it participates at the “CV disease continuum” [Citation1]. Arterial stiffness, and consequently Pulse Wave Velocity (PWV), triggers an increase in the amplitudes of the forward and the backward pressure waves which is a major determinant of increased Systolic BP (SBP) and pulse pressure. Arterial stiffness of the large arteries can be investigated trough the development of readily available non invasive assessment techniques [Citation2–4]. Among different methods, carotid to femoral PWV (cfPWV) has emerged as the gold standard because of its relative simplicity and reliability and its association with all-cause and CV morbidity and mortality [Citation5–7].
Prior studies suggested that the principal determinants of arterial stiffening process in adulthood are age and BP [Citation4,Citation8–10] but also a number of CV risk factors, such as dyslipidemia [Citation11], diabetes [Citation12,Citation13], chronic kidney disease [Citation14–16], tobacco smoking [Citation17], high heart rate (HR) [Citation18] and inflammation [Citation19]. However, these observations were based on short-term pharmacological studies and on cross-sectional observational studies while the role of risk factors on the long-term progression of arterial stiffness has not yet been systematically evaluated [Citation20–23]. Furthermore the few studies evaluating PWV progression present some significant differences in final results and population characteristics that need further evaluation.
The aim of the current longitudinal study was to evaluate the determinants of the PWV progression over a 3.7 years follow-up in hypertensives subjects.
Materials and methods
Study population
From September 2006 to October 2008, we enrolled 333 consecutive 18–80 aged outpatients, followed by the Hypertension Unit of St. Gerardo Hospital (Monza, Italy) affected by essential hypertension. Those with atrial fibrillation, women who were pregnant, patients with acute cerebrovascular and cardiac events in the month before the study (defined as myocardial infarction, angina pectoris, heart failure, stroke, transient ischemic attacks and claudication) and with medical conditions that would modify the reliability of the study were excluded. Secondary hypertension was investigated by biochemical and instrumental assessment appropriated to the patients presentation and conditions and those patients were excluded.
Diabetes was defined as a fasting plasma glucose >7,0 momol (126 mg/dL) in two occasions or as the use of antidiabetic drugs.
From July 2010 to October 2011, we performed the second visit with a median follow-up time of 3.75 ± 0.53 years. Study protocol was approved by institutional ethics review committees of the institution involved and all participants provided informed written consent after being informed of its nature and purpose.
Protocol
At first visit (baseline) we collected a comprehensive medical history and perform a complete physical examination in all subjects. With the patient in the sitting position for at least 5 min and with the arm placed at heart level BP measurements were taken by a trained physician with a manual mercury sphygmomanometer (OMRON Helthcare Europe, Hoofddorp, The Netherlands). BP was measured two times and the mean of the two measurements was used for the calculation. Hypertension was defined as a SBP of at least 140 mmHg and/or a diastolic BP (DBP) of at least 90 mmHg or as the reported use of antihypertensive drugs.
We measured fasting serum glucose, serum total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL) cholesterol, serum triglycerides and creatinine levels. Height and weight were obtained to calculate the patient BMI and waist circumference was assessed halfway between the lower ribs and the iliac crest. Subjects were placed in the supine position and PWV was measured.
At follow-up patients medical history and physical examination was rechecked and BP was still measured two times. After BP, PWV was recorded trough the same techniques and using the same protocol.
Pulse wave velocity
Aortic stiffness was evaluated by PWV between the carotid and the femoral artery of the same side with the patient in the supine position. The pressure pulse waveforms were simultaneously obtained at the two arterial sites at the right side using an automatic device (Complior, Colson; Alam Medical, Paris, France) and their distance calculated by taking the distance between hip and neck via a rigid ruler. The values was corrected by a 0.8 factor accordingly to the PWV measurement methods consensus documents which states to use the subtraction methods instead of the direct one when assessing the distance between the two measurements points [Citation4]. Two measurements were obtained in each patient and the mean was used for the analysis.
A PWV higher than 10 m/s was considered suggestive of vascular organ damage referring to the guidelines ESH-ESC 2013 [Citation24].
In our laboratory the intra-session within- and between-operator variability of PWV amounts respectively to a coefficient of variation of the mean value of 2% and to 4%, the corresponding value for the inter-session between-operator variability being 4%.
Statistical analysis
Results were expressed as mean ± standard deviation (SD) for continuous variables and percentages for categorical data. We created a new variable (ΔPWV), which represented the difference between the measurement at follow-up and at baseline, so it’s positive value means an increase of PWV, while negative value indicated a decrease of PWV.
Between-group differences were assessed by paired Student t, Mann-Whitney test and χ2 tests (or Fisher exact test when needed) for normally distributed, non-normally distributed and categorical variables, respectively. The statistical significance of the differences in mean values between different age decades group was assessed by two-way analysis of variance (ANOVA). Pearson's Correlation analysis was used to examine associations between PWV and ΔPWV and other variables.
In order to investigate the possible predictors of changes in PWV and ΔPWV, multivariate model was made. The dependent variables were PWV and ΔPWV while the covariates were age, gender, HR, BMI, LDL cholesterol, glucose, microalbuminuria and creatinine. The models were repeated one time with SBP and another time with mean BP (MBP) since both of them can give important information regarding the relationship between PWV and BP values. Furthermore in the model with ΔPWV also ΔHR and ΔSBP or ΔMBP were used as covariates. Finally also anti-hypertensive therapies (both as the total number of drugs and the single classes) was added to all the models.
All data were analysed using SAS System (version 9.4; SAS Institute Inc., Cary, North Carolina, USA) and a p-value of less than 0.05 was taken as the minimal level of statistical significance.
Results
Population characteristics
shows baseline and follow-up data of our hypertensive treated population. At baseline the mean age was 54.5 ± 12.6 years, SBP was 141.3 ± 18.6 mmHg, while DBP was 86.4 ± 10.4 mmHg. Therefore 63% of patients had uncontrolled blood pressure defined as SBP ≥140mmHg and/or DBP ≥90 mmHg. The mean PWV was 8.56 ± 1.92 m/s, 22% of the individuals had a value of PWV up to 10 m/s. Regarding laboratory data mean serum creatinine was 76.1 ± 15.9 micromol/L, microalbuminuria 21.0 ± 73.7 mg/L, triglycerides 3.3 ± 1.9 mmol/L, total cholesterol 5.1 ± 0.8 mmol/L, LDL cholesterol 3.1 ± 0.8 mmol/L and HDL cholesterol 1.4 ± 0.3 mmol/L.
Table 1. Demographic, haemodinamic and clinical data of enrolled subject.
After an average time of 3.75 ± 0.53 years the population was reviewed, mean BP values change from 141.3/86.4 ± 18.6/10.4 to 131.6/78.6 ± 17.8/11.1 mmHg (p < .001 for SBP and DBP) while HR significantly increase (from 65.5 ± 10.6 to 75.4 ± 11.5 bpm, p < .001). Therefore we found a significant improvement in the blood pressure control (from 37 to 60%) with a greater proportion of patients taking antihypertensive drugs (from 82.2% to 94.2% at baseline and follow-up respectively). However, PWV increased significantly over that period (8.56 ± 1.92 m/sec at baseline vs. 9.36 ± 2.16 m/s at follow-up, p < .001) with an average PWV increase between baseline and follow-up of 0.87 ± 3.05 m/s.
The significant improvement in BP control has been determined by an increase in anti-hypertensive medication. As showed in median number of drugs increased from 2 to 3 and was mainly due to an increase in the prescription of Angiotensin-Receptor Blockers (ARB) and diuretics.
PWV progression, age and gender
The population was then divided into groups accordingly to age decades at baseline (30-40 years, 41–50 years, 51–60 years, 61–70 years; >71 years). The population under 30 years has not been included into this analysis due to the limited sample size (n = 9).
As shown in PWV and SBP gradually and significantly increase in the age-related groups while DBP progressively decrease. ΔPWV also showed a significant rising trend (p < .05; and ).
Figure 1. ΔPWV in age decades group.
Table 2. Blood Pressure and PWV data of enrolled subject when divided accordingly to age decades at baseline.
shows baseline and follow-up data of enrolled subjects divided in males and females. Both groups showed superimposable age, SBP and DBP at baseline and a significant decrease in SBP and DBP with a greater proportion of patients under antihypertensive drugs at follow-up. Females were less frequently smokers and showed a smaller BMI in comparison with male. Male subjects showed an increase in the diagnosis of diabetes mellitus not reported in the female group. Some differences exist regarding anti-hypertensive therapies: males got more frequently ARB and calcium antagonist and less frequently beta-blockers than females. Also the therapeutic changes during the follow-up were different: males received often an upgrade of therapies with ARB and ACE-Inhibitors administration, instead ARB, B-blockers and diuretics were given in the female patients. However, PWV PWV increased with a similar ΔPWV (0.75 ± 3.08 vs 1.02 ± 3.02; p = ns) at the follow-up evaluation in both male and female.
PWV progression and BP control
showed baseline characteristics of enrolled subject when divided accordingly to controlled or uncontrolled blood pressure values at follow-up evaluation. There were no significant differences in age, gender, percentage of patients on antihypertensive treatment and drug classes, number of smokers and laboratory data. Subjects with BP values uncontrolled at follow-up showed higher baseline SBP and DBP (SBP: 147.7 ± 17.9 vs 137.7 ± 16.9; DBP: 89.2 ± 10.6 vs 84.9 ± 10.1 mmHg; p < .001 for both comparison) but also higher BMI (27.8 ± 3.8 vs 26.7 ± 4.1 kg/m2; p .01) in comparison with subjects controlled on follow-up. Baseline PWV value was significantly higher in subjects uncontrolled at follow-up (9.04 ± 2.54 vs 8.32 ± 2.34 m/s, p = .03).
Table 3. Demographic, haemodinamic, clinical and laboratory data of enrolled subject when divided accordingly to controlled of uncontrolled blood pressure values at follow-up evaluation.
Despite the percentage of patients on antihypertensive therapy increase in both group a significantly different modification of BP values at follow-up was observed. Furthermore, as showed in , ΔPWV was also higher in subjects uncontrolled at follow-up (1.46 ± 3.67 vs 0.62 ± 2.61 m/s, p = .02) when compared with subjects with normal BP values at the follow-up.
Figure 2. ΔPWV of enrolled subject when divided accordingly to controlled or uncontrolled blood pressure values at follow-up evaluation.
Correlation and linear regression analysis
Baseline PWV correlated with age (r = 0.35, p < .001), SBP (r = 0.41, p < .001), DBP (r = 0.19, p < .001), glucose (r = 0.14, p = .01), creatinine (r = 0.20, p = < .001) and microalbuminuria (r = 0.16, p = .01), while gender and other classic CV risk factors didn't showed any correlation. The independent predictors of baseline PWV were age, gender, HR and SBP (age: β = 0.07 p < .001; gender: β = 0.75; p = .004; HR: β = 0.03; p = .002; SBP: β = 0.04, p < .001) at multivariate analysis, with a total R2 of 0.29. When the model was repeated with MBP similar results and total R2 were showed (age: β = 0.09 p < .001; gender: β = 0.73; p = .005; HR: β = 0.03; p = .005; MBP: β = 0.06, p < .001).
We found positive correlation between ΔPWV and age (r = 0.17, p = .001), BMI (r = 0.11 p = .04), ΔSBP (r = 0.29, p < .001; , panel A) and ΔDBP (r = 0.25, p < .001; , panel B). ΔPWV appeared to be inversely correlated with DBP (r = −0.15, p = .006) and PWV at baseline (r = −0.40, p < .0001). The independent predictors of the progression of ΔPWV were age, the baseline PWV and SBP values and ΔSBP (age: β = 0.08 p = .001; PWV: β = −0.73, p = .006; SBP: β = 0.04, p = .009; ΔSBP: β = 0.05, p = .008), at multivariate analysis, with a total R2 of 0.40. When the model was repeated with MBP and ΔMBP similar results and total R2 were showed (age: β = 0.08 p = .001; PWV: β = −0.70, p = .006; MBP: β = 0.05, p = .009; ΔMBP: β = 0.07, p < .001).
Figure 3. Correlation between ΔPWV and ΔSBP (panel A) and ΔMBP (panel B).
When anti-hypertensive therapies (both as the total number of drugs and the single classes) was added to the model no significant changes were observed.
Discussion
In our essential hypertensive patients antihypertensive treatment established a reduction in BP value with a better BP control after a median of 3.7 years of follow-up. Despite this, PWV continued to increase during the same follow-up period. This is one of the few longitudinal studies to evaluate the determinants of the progression of arterial stiffness over an extended period of time. Two factors were identified as being responsible for accelerated progression of PWV in our population after correction for baseline PWV and HR: age and BP values.
Firstly we would like to emphasize that no association between others major CV risk factors, starting from gender, and progression of aortic stiffness was found as it was for all the previous work on the same issue [Citation20–23]. The current longitudinal results confirm the close association between age and PWV and, even more, with ΔPWV as it is shown by correlation analysis and by the trend in age decades.
Following age, the second well recognized determinant of arterial stiffness is represented by BP. We confirm the strong association between baseline PWV and BP values and also between ΔPWV and BP values and even more its changes over time. Furthermore PWV progression was greater in patients with uncontrolled blood pressure at follow-up evaluation than those subjects which achieved a satisfactory blood pressure control at the second visit. The association between stiffness changes over time, age and BP might depend in the fact that both factors determine a longer or a stronger stretching of the elastic lamellae causing its fracture and progressive remodelling that finally leads to arterial stiffness [Citation25–28].
We would like to emphasize that in the current study, antihypertensive treatment was followed by hypertensive specialist without any specific recommendation, more than commonly used guidelines. Practitioners were not aware of PWV levels and therefore, the observed results reflect a “realistic” situation in treated hypertensive.
To our knowledge, only three previous studies focused on the determinants of PWV progression in hypertensive patients: two of them found an increase in PWV during the follow-up examination [Citation20,Citation21] and one a decrease in its values [Citation22]. At a first examination it could seem that when mean BP decrease also PWV decrease (mean decrease of 0.9 mmHg with a PWV decrease of 3.17 m/s) [Citation22] and when BP increase PWV increase (mean increase of 5.7 mmHg with a PWV increase of 0.83 m/s) [Citation20]. Our paper seems to be in the middle with a significant decrease of BP (9.7 mmHg) but with an increase in mean PWV values (0.87 m/s). All studies emphasize the important role of age and BP values (SBP or MBP depending on the paper) and control (uncontrolled BP at follow-up examination) but significant differences in the population can help understand the previous mentioned discrepancies in the results. Firstly patients present different age in the three population both as younger [Citation20] and older [Citation22]. But, in our opinion the most interesting difference, is in the blood pressure control: in our population only the 37% of the patients present BP values under 140/90 mmHg at baseline. Contrariwise the 35% [Citation22] and the 22% [Citation21] of the patients start from uncontrolled BP values in the other studies and this is also confirmed by the different baseline BP values (125.7/72.7 vs 141.3/86.4 mmHg in our study) [Citation21].
Considering all these factors together, we might speculate that relevance and/or duration of BP reduction should not have been enough to determine a relative changes in PWV. Even more, since patients were clinically followed independently on the PWV assessment, we don’t know when the BP reduction under 140/90 mmHg has been achieved.
Finally another potential factor that could allow to explain the increase in PWV values is the progressive aging during the follow-up. Since age is an important predictor of ΔPWV and a significant proportion of our patients (38%) was over sixthies, the further increase in age over the follow-up is also a possible cause increased PWV despite the SBP decrease observed.
A different hypothesis can be also advanced namely the possibility that drugs not so effective on the PWV regression have been used to reinforce the anti-hypertensive efficacy during the follow-up. In fact different BP drugs have been found to exert different effects on PWV modification [Citation29–33] but in our study a high proportion of patients used drug classes known to act on arterial stiffness, namely ACE-I, ARB and b-blockers (this last one of a lesser degree). Furthermore the prevalence of these drug classes increases over time excluding this hypothesis.
Our study has some limitations. Firstly, the data are based on ia relatively small sample size. Secondly, while serial measurements of PWV could be an element of high accuracy in dynamic assessment, it could determine logistic and economic difficulties in large population. Finally, no biochemical data were available at follow-up examination that could thus not provide a description of the relationship of alterations of PWV with their changes.
In conclusion, the current longitudinal study shows that accelerated arterial aging in treated hypertensive subjects is mainly explained by age and BP control. While one-single measurement of PWV provides important prognostic and stratification landmark, however its change over time (i.e. the difference of multiple sequential measurements) would probably provide different and more important information.
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References
- Dzau VJ, Antman AEM, Black HR, et al. The cardiovascular disease continuum validated: clinical evidence of improved patient outcomes: part I: pathophysiology and clinical trial evidence (risk factors through stable coronary artery disease). Circulation. 2006;114:2850–2870.
- Mackenzie IS, Wilkinson IB, Cockcroft JR. Assessment of arterial stiffness in clinical practice. Q J Med. 2002;95:67–74.
- Laurent S, Cockcroft J, Van Bortel L, et al. Expert consensus document on arterial stiffness: methodological issues and clinical applications. Eur Heart J. 2006;27:2588–2605.
- The Reference Values for Arterial Stiffness’ Collaboration. Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: ‘establishing normal and reference values’. Eur Heart J. 2010;31:2338–2350.
- Laurent S, Boutouyrie P, Asmar R, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension. 2001;37:1236–1241.
- Meaume S, Benetos A, Henry OF, et al. Aortic pulse wave velocity predicts cardiovascular mortality in subjects 70 years of age. Arterioscler Thromb Vasc Biol. 2001;21:2046–2050.
- Vlachopoulos C, Aznaouridis K, Stefanadis C, et al. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol. 2010;55:1318–1327.
- Lee HY, Oh BH. Aging and arterial stiffness. Circ J. 2010;74:2257–2262.
- Izzo JL Jr, Shykoff BE. Arterial stiffness: clinical relevance, measurement, and treatment. Rev Cardiovasc Med. 2001;2:29–34.
- Mitchell GF, Parise H, Benjamin EJ, et al. Changes in arterial stiffness and wave reflection with advancing age in healthy men and women: the framingham heart study. Hypertension. 2004;43:1239–1245.
- Lehmann E, Hopkins K, Parker J, et al. Hyperlipidaemia, hypertension, and coronary heart disease. Lancet. 1995;345:863–863.
- Giannattasio C, Failla M, Capra A, et al. Increased arterial stiffness in normoglycemic normotensive offspring of type 2 diabetic parents. Hypertension 2008;51:182–187.
- Chen Q, Chiheb S, Fysekidis M, et al. Arterial stiffness is elevated in normotensive type 2 diabetic patients with peripheral neuropathy. Nutr Metab Cardiovasc Dis. 2015;25:1041–1049.
- Pannier B, Guérin AP, Marchais SJ, et al. Stiffness of capacitive and conduit arteries: prognostic significance for end-stage renal disease patients. Hypertension. 2005;45:592–596.
- Blacher J, Safar ME, Guerin AP, et al. Aortic pulse wave velocity index and mortality in end-stage renal disease. Kidney Int. 2003;63:1852–1860.
- Blacher J, Guerin A, Pannier B, et al. Impact of aortic stiffness on survival in end-stage renal disease. Circulation. 1999;99:2434–2439.
- Sa Cunha R, Pannier B, Benetos A, et al. Association between high heart rate and high arterial rigidity in normotensive and hypertensive subjects. J Hypertens. 1997;15:1423–1430.
- Stefanadis C, Tsiamis E, Vlachopoulos C, et al. Unfavorable effect of smoking on the elastic properties of the human aorta. Circulation. 1997;95:31–38.
- Maloberti A, Meani P, Vallerio P, et al. Annexin A5 in treated hypertensive patients and its association with target organ damage. J Hypertens. 2017;35:154–161.
- Benetos A, Adamopoulos C, Bereau JM, et al. Determinants of accelerated progression of arterial stiffness in normotensive subjects and in treated hypertensive subjects over a 6-year period. Circulation. 2002;105:1202–1207.
- AlGhatrif M, Strait JB, Morrell CH, et al. Longitudinal trajectories of arterial stiffness and the role of blood pressure: the baltimore longitudinal study of aging. Hypertension. 2013;62:934–941.
- Ait-Oufella H, Collin C, Bozec E, et al. Long-term reduction in aortic stiffness: a 5.3-year follow-up in routine clinical practice. J Hypertens. 2010;28:2336–2341.
- Safar ME, Thomas F, Blacher J, et al. Metabolic syndrome and age-related progression of aortic stiffness. J Am Coll Cardiol. 2006;47:72–75.
- Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC Guidelines for themanagement of arterial hypertension. Thetask force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens. 2013;31:1281–1357.
- O’Rourke MF, Hashimoto J. Mechanical factors in arterial aging: a clinical perspective. J Am Coll Cardiol. 2007;50:1–13.
- Lakatta E, Wang M, Najjar SS, et al. Arterial aging and subclinical arterial disease are fundamentally intertwined at macro- scopic and molecular levels. Med Clin North Am. 2009;93:583–604.
- O’Rourke MF, Safar ME. Relationship between aortic stiff- ening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005;46:200–204.
- Nichols WW, O’Rourke MF. McDonald’s blood flow in arteries: theoretical, experimental and clinical principles. 5th ed. London (UK): Hodder Arnold; 2005.
- Ichihara A, Hayashi M, Koura Y, et al. Long-term effects of intensive blood pressure lowering on arterial wall stiffness in hypertensive patients. Am J Hypertens. 2003;16:959–965.
- Nakamura Y, Fujii S, Hoshino J, et al. Selective angiotensin receptor antagonisms with valsartan decreases arterial stiffness independently of blood pressure lowering in hypertensive patients. Hypertens Res. 2005;28:937–943.
- Ting CT, Chen CH, Chang MS, et al. Short- and long-term effects of antihypertensive drugs on arterial reflections, compliance, and impedance. Hypertension. 1995;26:524–530.
- Topouchian J, Asmar R, Sayegh F, et al. Changes in arterial structure and function under trandolapril-verapamil combination in hypertension. Stroke. 1999;30:1056–1064.
- Asmar RG, London GM, O’Rourke ME, et al. Improvement in blood pressure, arterial stiffness and wave reflections with a very-low-dose perindopril/indapamide combination in hypertensive patient: a comparison with atenolol. Hypertension. 2001;38:922–926.