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Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients
IJCA-18500; No of Pages 4 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients☆,☆☆ Pyung Chun Oh, Seung Hwan Han ⁎, Kwang Kon Koh, Kyounghoon Lee, Jong Goo Seo, Soon Yong Suh, Taehoon Ahn, In Suck Choi, Eak Kyun Shin Cardiology Division, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 June 2014 Accepted 27 July 2014 Available online xxxx Keywords: Statin Arterial stiffness Blood pressure Hypercholesterolemia
Evidences of a favorable effect of statin treatment on arterial stiffness are accumulating, but not all studies have shown a positive effect on arterial stiffness [1]. In addition, the precise mechanisms of statin on arterial stiffness are poorly understood. Therefore, we examined the effects of short term rosuvastatin treatment on arterial stiffness as assessed with brachial-ankle (ba) PWV and their mechanisms in patients with hypercholesterolemia who had no additional cardiovascular risk factors. A total of 56 hypercholesterolemic patients (total cholesterol ≥230 mg/dL; male, 35.7%; age, 50.3 ± 8.5 y) who had no history of diabetes mellitus, hypertension or other cardiovascular diseases were randomly (3:1 ratio, age and sex matched) assigned to rosuvastatin group (10 mg/day, n = 41) and lifestyle modification group (n = 15). The rosuvastatin group was assigned to conduct lifestyle modification and given rosuvastatin 10 mg daily for 2 months. The lifestyle modification group was assigned to conduct lifestyle modification and not to receive any medications including lipid lowering agents. Lifestyle modification in both groups was just limited to a general education of
☆ We presented our study in part as abstracts in the American College of Cardiology 2013, San Francisco, CA, USA, on March 10, 2013. ☆☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Division, Department of Internal Medicine, Gachon University Gil Hospitial, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, Republic of Korea. Tel.: +82 32 460 3054; fax: +82 32 469 1906. E-mail address: [email protected] (S.H. Han).
all subjects with educational materials and encouraging low fat diet and regular aerobic exercise at the baseline. The study protocol was approved by the local ethics committee and participants gave written informed consent. Patients underwent measurements for blood pressure (BP), heart rate, blood tests, and baPWV before and after treatment of 2 months. Quantitative Insulin-Sensitivity Check Index (QUICKI), a surrogate index of insulin sensitivity, was calculated as follows (insulin is expressed in μU/mL and glucose in mg/dL): QUICKI = 1 / [log(insulin) + log(glucose)] [2]. The baPWV and supine BP were measured by the automatic wave form analyzer (VP-2000, Nippon Colin Ltd., Komaki City, Japan) with simultaneous recordings of bilateral brachial and ankle BP, electrocardiogram and heart sound in a supine position after at least 5-min rest. Clinical and baseline laboratory characteristics did not differ significantly between both groups (Table 1). After rosuvastatin treatment for 2 months, total cholesterol, low density lipoprotein cholesterol (LDLC) and triglycerides (TG) were significantly reduced by 34.6 ± 11.8% (P b 0.001), 45.6 ± 17.7% (P b 0.001) and 12.8 ± 28.4% (P = 0.001), respectively, as compared with those at baseline. In the lifestyle modification group, total cholesterol and LDL-C were significantly reduced by 12.8 ± 13.1% (P = 0.002) and 11.8 ± 23.3% (P = 0.045), respectively, as compared with those at baseline. However, the percent changes of total cholesterol and LDL-C in the rosuvastatin group were significantly greater than those in the lifestyle modification group (P b 0.001 for both). With regard to metabolic parameters, insulin, fasting glucose, glycated hemoglobin, and QUICKI were not significantly changed after 2 months of the intervention in both groups, as compared with those at baseline. However, rosuvastatin treatment significantly decreased the level of high sensitivity C-reactive protein (hsCRP) after 2 months (0.60 mg/L [0.30–1.55] to 0.60 mg/L [0.30–1.05], P = 0.032) although the median values of hsCRP level were not changed, but life style modification didn't decrease the level of hsCRP. Rosuvastatin significantly decreased systolic and diastolic BP measured at the office (125.7 ± 14.0 mm Hg to 122.1 ± 12.4 mm Hg, P = 0.024 and 77.3 ± 8.1 mm Hg to 74.0 ± 7.7 mm Hg, P = 0.003, respectively) and supine systolic and diastolic BP (122.4 ± 11.5 mm Hg to 118.4 ± 9.9 mm Hg, P b 0.001 and 77.5 ± 8.6 mm Hg to 74.1 ± 7.8 mm Hg, P b 0.001, respectively) relative to baseline measurements. However, the lifestyle modification group did not change. The baPWV was significantly reduced by 3.1 ± 6.9% in the rosuvastatin group in comparison with that at baseline (1389.9 ± 185.3 cm/s to 1342.0 ± 164.4 cm/s, P = 0.006), but not in the life style modification (1380.4 ±
http://dx.doi.org/10.1016/j.ijcard.2014.07.181 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Oh PC, et al, Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.181
2
P.C. Oh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Baseline characteristics of study subjects and changes following treatments. Variables
Age, years Male, % Smoking history, % Body mass index, kg/m2 Waist circumference, cm Office systolic BP, mm Hg Office diastolic BP, mm Hg Office mean BP, mm Hg Office heart rate, beats/min Supine systolic BP, mm Hg Supine diastolic BP, mm Hg Supine mean BP, mm Hg Supine heart rate, beats/min Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL Insulin, μU/mL Glucose, mg/dL HgA1c, % QUICKI hsCRP, mg/L baPWV, cm/s
Rosuvastatin group (n = 41)
Life style modification group (n = 15)
Baseline
Treatment
P
Baseline
Treatment
P
50.3 ± 8.8 39.0 39.0 25.00 ± 3.47 87.39 ± 9.5 125.7 ± 14.0 77.3 ± 8.1 93.4 ± 9.7 80.0 ± 12.4 122.4 ± 11.5 77.5 ± 8.6 92.4 ± 9.0 70.6 ± 11.4 260.1 ± 21.5 171.4 ± 27.0 55.7 ± 14.2 133.0 (95.5–184.5) 8.550 ± 5.269 102.0 ± 13.0 5.88 ± 0.43 0.353 ± 0.035 0.60 (0.30–1.55) 1389.9 ± 185.3
– – – 24.92 ± 3.41 89.22 ± 7.9 122.1 ± 12.4 74.0 ± 7.7 90.0 ± 8.8 78.2 ± 12.5 118.4 ± 9.9 74.1 ± 7.8 88.9 ± 7.8 68.1 ± 10.7 166.6 ± 27.6 90.6 ± 26.7 52.1 ± 11.0 109.0 (88.5–144.5) 8.602 ± 4.352 101.2 ± 14.9 5.91 ± 0.43 0.350 ± 0.033 0.60 (0.30–1.05) 1342.0 ± 164.4
– – – 0.404 0.250 0.024 0.003 0.003 0.270 0.016 0.001 0.002 0.091 b0.001 b0.001 0.006 0.001
50.4 ± 7.8 26.7 30.4 25.16 ± 3.40 88.65 ± 7.2 132.9 ± 15.3 84.4 ± 9.6 100.6 ± 10.7 83.8 ± 10.4 123.0 ± 20.9 75.5 ± 11.6 91.4 ± 14.3 73.9 ± 11.9 251.4 ± 16.3 156.7 ± 20.3 60.1 ± 10.4 130.0 (108.0–142.0) 8.186 ± 6.330 97.1 ± 12.7 5.76 ± 0.28 0.361 ± 0.039 0.60 (0.30–1.60) 1380.4 ± 176.5
– – – 25.13 ± 3.32 88.71 ± 9.3 131.5 ± 10.8 83.2 ± 9.6 99.3 ± 9.4 81.6 ± 11.5 121.2 ± 16.4 75.4 ± 14.8 90.7 ± 15.0 68.7 ± 8.6 219.2 ± 35.9 135.7 ± 28.6 54.1 ± 8.6 113.0 (85.0–88.5) 6.766 ± 3.816 93.4 ± 12.8 5.62 ± 0.31 0.372 ± 0.043 0.70 (0.30–2.20) 1365.8 ± 200.1
– – – 0.841 0.107 0.644 0.566 0.532 0.499 0.739 0.967 0.858 0.034 0.002 0.045 0.036 0.379
0.842 0.679 0.705 0.341 0.032 0.006
0.315 0.072 0.061 0.207 0.349 0.698
Data are expressed as mean ± standard deviation or median (interquartile range). At baseline, no significant differences existed in variables between the two groups (P N 0.05 for all). The P values are presented for the effects of treatment within each group. BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HgA1c, hemoglobin A1c; QUICKI, quantitative insulin-sensitivity check index; hsCRP, highsensitivity C-reactive protein; baPWV, brachial-ankle pulse wave velocity.
176.5 cm/s to 1365.8 ± 200.1 cm/s, P = 0.698) (Fig. 1). The percent changes of systolic BP, diastolic BP, and baPWV following rosuvastatin treatment did not differ significantly than that in the lifestyle modification group (all P = NS). In the rosuvastatin group, the percent change of baPWV was positively correlated with the percent change of supine systolic and diastolic BP (r = 0.50, P b 0.001; r = 0.54, P b 0.001, respectively), but not with those of lipid profiles, hsCRP, or metabolic parameters except fasting insulin (r = −0.33, P = 0.04). The multivariate linear regression analysis showed that the percent change of supine systolic BP was an independent factor for the percent change of baPWV following rosuvastatin treatment (Table 2). In this study, we evaluated the effects of short term moderate intensity rosuvastatin treatment on arterial stiffness in patients with hypercholesterolemia who had no additional cardiovascular risk factors (except smoking history). Our results demonstrate that short term (2 months) rosuvastatin treatment significantly reduced arterial stiffness with lowering BP in healthy hypercholesterolemic patients, independent of lipid-lowering, metabolic and anti-inflammatory effects. In addition, the change of supine systolic BP was an independent factor for the change of arterial stiffness by multivariate analysis. Regarding the effects of statin on arterial stiffness, some conflicting results have been reported. Some studies have shown improvement of arterial stiffness with statin therapy which was not associated with BP [3–9]. Two studies revealed that improvement of arterial stiffness was related with BP [10,11]. The others have shown no beneficial effects of statin on arterial stiffness [12–14]. Taken together, there are still controversies for the effects of statin on arterial stiffness and its related mechanisms. These discrepancies could be due to the different patient populations, the duration of treatment, the types or doses of statin, or different protocols or different arteries of PWV measurement. To resolve this problem, in our study, we tested whether short term moderate intensity rosuvastatin (10 mg/day) treatment can reduce arterial stiffness in hypercholesterolemic patients who had no additional cardiovascular risk factors because hypercholesterolemic patients without additional
cardiovascular risk factors are the most reliable patient group to assess the effects of statin on arterial stiffness. In addition, we sought the related factors for the changes of arterial stiffness after rosuvastatin treatment. With regard to the effects of statin on BP, although data have been still controversial [15–20], recent meta-analysis revealed small but statistically significant BP lowering effects of statins [20,21]. For this topic, our current study demonstrates that short term moderate intensity rosuvastatin treatment can produce significant modest BP-lowering effect and it is related with improved aortic stiffness in hypercholesterolemic patients without hypertension. The mechanisms mediating the improvement of arterial stiffness by statin treatment remain unclear. Arterial stiffness, which alters arterial pressure, may relate to structural alterations of the arterial wall or extracellular matrix, changes in vascular smooth muscle tone or content, changes in neuroendocrine signaling, and endothelial dysfunction [22]. Favorable alterations in any of these mechanisms may result in improvement of arterial stiffness. However, any short term intervention, such as in the present study, is unlikely to lead to favorable structural alterations in arterial wall. Thus, more plausible mechanisms might be based on the beneficial effects of statin on endothelial function and smooth muscle tone. It is possible that the reduction in arterial stiffness during statin treatment may be attributable to the improvement in endothelial function and consequent vasodilation, which may reduce arterial pressure. In addition, we previously suggested a cross-talk between statins and renin–angiotensin system [23,24]. Briefly, hypercholesterolemia enhanced vascular expression of angiotensin II type I receptors that mediate increased activity of angiotensin II [25]. Statins can downregulate the density of angiotensin II type 1 receptor, which may induce BP reduction by inhibition of the renin–angiotensin system [16,23,24]. Therefore, we suggest that the improvement of arterial stiffness by short term rosuvastatin treatment might be attributed to the improvement of endothelial function, vascular tone and cross-talk with the renin–angiotensin system which induce BP lowering effects.
Please cite this article as: Oh PC, et al, Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.181
P.C. Oh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 2 Multivariate linear regression analysis for the percent change of arterial stiffness following rosuvastatin treatment. B
95% CI
Model 1 Age Sex Body mass index hsCRP Supine systolic BP
P
−0.037 −0.023 0.184 0.051 0.480
−0.290, 0.232 −4.772, 4.141 −0.441, 1.599 −0.015, 0.021 0.158, 0.685
0.823 0.887 0.257 0.726 0.003
Model 2 Age Sex LDL cholesterol HDL cholesterol Supine systolic BP
0.020 −0.016 −0.062 0.185 0.467
−0.230, 0.262 −4.875, 4.423 −0.153, 0.103 −0.075, 0.267 0.134, 0.686
0.897 0.922 0.697 0.261 0.005
Model 2 Age Sex Glucose Insulin Supine systolic BP
−0.040 −0.012 0.051 −0.447 0.567
−0.230, 0.173 −3.981, 3.657 −0.143, 0.212 −0.087, −0.022 0.242, 0.678
0.773 0.932 0.697 0.002 b0.001
CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
have changed. Further long-term follow-up and larger studies are warranted to resolve these issues. In conclusion, short term moderate intensity rosuvastatin treatment in healthy hypercholesterolemic patients significantly reduced arterial stiffness with lowering BP, independent of lipid lowering, metabolic and anti-inflammatory effects. In addition, the change of supine systolic BP was an independent factor for the change of arterial stiffness. Our results support the concept that the preventive effect of statins on cardiovascular events may be attributed to not only reduction of the cholesterol level, but also arterial destiffening effects with lowering BP. Conflict of interest None. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References
Fig. 1. The effects of rosuvastatin group (a) and lifestyle modification group (b) on baPWV. Data are presented as mean ± standard deviation. baPWV, brachial ankle pulse wave velocity.
Our study presents some limitations. First, there were no significant differences of percent changes of systolic BP, diastolic BP and baPWV between the rosuvastatin and lifestyle modification groups. It may be caused by the small number of subjects or subjects at low risk. Second, this study was open-labeled and single-center study, although an examiner measuring BP and baPWV was blinded to subject group. Third, we could not interpret the cause and effect relationships between arterial stiffness and BP by this study. Fourth, lifestyle modification was only performed through diet and exercise education and subject's selfcontrol. So if patients were forced to intensive diet and exercise guided by supervisors, the results of aortic stiffness and BP in both groups might
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Please cite this article as: Oh PC, et al, Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.181
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients☆,☆☆ Pyung Chun Oh, Seung Hwan Han ⁎, Kwang Kon Koh, Kyounghoon Lee, Jong Goo Seo, Soon Yong Suh, Taehoon Ahn, In Suck Choi, Eak Kyun Shin Cardiology Division, Department of Internal Medicine, Gachon University Gil Hospital, Incheon, Republic of Korea
a r t i c l e
i n f o
Article history: Received 16 June 2014 Accepted 27 July 2014 Available online xxxx Keywords: Statin Arterial stiffness Blood pressure Hypercholesterolemia
Evidences of a favorable effect of statin treatment on arterial stiffness are accumulating, but not all studies have shown a positive effect on arterial stiffness [1]. In addition, the precise mechanisms of statin on arterial stiffness are poorly understood. Therefore, we examined the effects of short term rosuvastatin treatment on arterial stiffness as assessed with brachial-ankle (ba) PWV and their mechanisms in patients with hypercholesterolemia who had no additional cardiovascular risk factors. A total of 56 hypercholesterolemic patients (total cholesterol ≥230 mg/dL; male, 35.7%; age, 50.3 ± 8.5 y) who had no history of diabetes mellitus, hypertension or other cardiovascular diseases were randomly (3:1 ratio, age and sex matched) assigned to rosuvastatin group (10 mg/day, n = 41) and lifestyle modification group (n = 15). The rosuvastatin group was assigned to conduct lifestyle modification and given rosuvastatin 10 mg daily for 2 months. The lifestyle modification group was assigned to conduct lifestyle modification and not to receive any medications including lipid lowering agents. Lifestyle modification in both groups was just limited to a general education of
☆ We presented our study in part as abstracts in the American College of Cardiology 2013, San Francisco, CA, USA, on March 10, 2013. ☆☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Cardiology Division, Department of Internal Medicine, Gachon University Gil Hospitial, 1198 Guwol-dong, Namdong-gu, Incheon 405-760, Republic of Korea. Tel.: +82 32 460 3054; fax: +82 32 469 1906. E-mail address: [email protected] (S.H. Han).
all subjects with educational materials and encouraging low fat diet and regular aerobic exercise at the baseline. The study protocol was approved by the local ethics committee and participants gave written informed consent. Patients underwent measurements for blood pressure (BP), heart rate, blood tests, and baPWV before and after treatment of 2 months. Quantitative Insulin-Sensitivity Check Index (QUICKI), a surrogate index of insulin sensitivity, was calculated as follows (insulin is expressed in μU/mL and glucose in mg/dL): QUICKI = 1 / [log(insulin) + log(glucose)] [2]. The baPWV and supine BP were measured by the automatic wave form analyzer (VP-2000, Nippon Colin Ltd., Komaki City, Japan) with simultaneous recordings of bilateral brachial and ankle BP, electrocardiogram and heart sound in a supine position after at least 5-min rest. Clinical and baseline laboratory characteristics did not differ significantly between both groups (Table 1). After rosuvastatin treatment for 2 months, total cholesterol, low density lipoprotein cholesterol (LDLC) and triglycerides (TG) were significantly reduced by 34.6 ± 11.8% (P b 0.001), 45.6 ± 17.7% (P b 0.001) and 12.8 ± 28.4% (P = 0.001), respectively, as compared with those at baseline. In the lifestyle modification group, total cholesterol and LDL-C were significantly reduced by 12.8 ± 13.1% (P = 0.002) and 11.8 ± 23.3% (P = 0.045), respectively, as compared with those at baseline. However, the percent changes of total cholesterol and LDL-C in the rosuvastatin group were significantly greater than those in the lifestyle modification group (P b 0.001 for both). With regard to metabolic parameters, insulin, fasting glucose, glycated hemoglobin, and QUICKI were not significantly changed after 2 months of the intervention in both groups, as compared with those at baseline. However, rosuvastatin treatment significantly decreased the level of high sensitivity C-reactive protein (hsCRP) after 2 months (0.60 mg/L [0.30–1.55] to 0.60 mg/L [0.30–1.05], P = 0.032) although the median values of hsCRP level were not changed, but life style modification didn't decrease the level of hsCRP. Rosuvastatin significantly decreased systolic and diastolic BP measured at the office (125.7 ± 14.0 mm Hg to 122.1 ± 12.4 mm Hg, P = 0.024 and 77.3 ± 8.1 mm Hg to 74.0 ± 7.7 mm Hg, P = 0.003, respectively) and supine systolic and diastolic BP (122.4 ± 11.5 mm Hg to 118.4 ± 9.9 mm Hg, P b 0.001 and 77.5 ± 8.6 mm Hg to 74.1 ± 7.8 mm Hg, P b 0.001, respectively) relative to baseline measurements. However, the lifestyle modification group did not change. The baPWV was significantly reduced by 3.1 ± 6.9% in the rosuvastatin group in comparison with that at baseline (1389.9 ± 185.3 cm/s to 1342.0 ± 164.4 cm/s, P = 0.006), but not in the life style modification (1380.4 ±
http://dx.doi.org/10.1016/j.ijcard.2014.07.181 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Oh PC, et al, Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.181
2
P.C. Oh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
Table 1 Baseline characteristics of study subjects and changes following treatments. Variables
Age, years Male, % Smoking history, % Body mass index, kg/m2 Waist circumference, cm Office systolic BP, mm Hg Office diastolic BP, mm Hg Office mean BP, mm Hg Office heart rate, beats/min Supine systolic BP, mm Hg Supine diastolic BP, mm Hg Supine mean BP, mm Hg Supine heart rate, beats/min Total cholesterol, mg/dL LDL cholesterol, mg/dL HDL cholesterol, mg/dL Triglycerides, mg/dL Insulin, μU/mL Glucose, mg/dL HgA1c, % QUICKI hsCRP, mg/L baPWV, cm/s
Rosuvastatin group (n = 41)
Life style modification group (n = 15)
Baseline
Treatment
P
Baseline
Treatment
P
50.3 ± 8.8 39.0 39.0 25.00 ± 3.47 87.39 ± 9.5 125.7 ± 14.0 77.3 ± 8.1 93.4 ± 9.7 80.0 ± 12.4 122.4 ± 11.5 77.5 ± 8.6 92.4 ± 9.0 70.6 ± 11.4 260.1 ± 21.5 171.4 ± 27.0 55.7 ± 14.2 133.0 (95.5–184.5) 8.550 ± 5.269 102.0 ± 13.0 5.88 ± 0.43 0.353 ± 0.035 0.60 (0.30–1.55) 1389.9 ± 185.3
– – – 24.92 ± 3.41 89.22 ± 7.9 122.1 ± 12.4 74.0 ± 7.7 90.0 ± 8.8 78.2 ± 12.5 118.4 ± 9.9 74.1 ± 7.8 88.9 ± 7.8 68.1 ± 10.7 166.6 ± 27.6 90.6 ± 26.7 52.1 ± 11.0 109.0 (88.5–144.5) 8.602 ± 4.352 101.2 ± 14.9 5.91 ± 0.43 0.350 ± 0.033 0.60 (0.30–1.05) 1342.0 ± 164.4
– – – 0.404 0.250 0.024 0.003 0.003 0.270 0.016 0.001 0.002 0.091 b0.001 b0.001 0.006 0.001
50.4 ± 7.8 26.7 30.4 25.16 ± 3.40 88.65 ± 7.2 132.9 ± 15.3 84.4 ± 9.6 100.6 ± 10.7 83.8 ± 10.4 123.0 ± 20.9 75.5 ± 11.6 91.4 ± 14.3 73.9 ± 11.9 251.4 ± 16.3 156.7 ± 20.3 60.1 ± 10.4 130.0 (108.0–142.0) 8.186 ± 6.330 97.1 ± 12.7 5.76 ± 0.28 0.361 ± 0.039 0.60 (0.30–1.60) 1380.4 ± 176.5
– – – 25.13 ± 3.32 88.71 ± 9.3 131.5 ± 10.8 83.2 ± 9.6 99.3 ± 9.4 81.6 ± 11.5 121.2 ± 16.4 75.4 ± 14.8 90.7 ± 15.0 68.7 ± 8.6 219.2 ± 35.9 135.7 ± 28.6 54.1 ± 8.6 113.0 (85.0–88.5) 6.766 ± 3.816 93.4 ± 12.8 5.62 ± 0.31 0.372 ± 0.043 0.70 (0.30–2.20) 1365.8 ± 200.1
– – – 0.841 0.107 0.644 0.566 0.532 0.499 0.739 0.967 0.858 0.034 0.002 0.045 0.036 0.379
0.842 0.679 0.705 0.341 0.032 0.006
0.315 0.072 0.061 0.207 0.349 0.698
Data are expressed as mean ± standard deviation or median (interquartile range). At baseline, no significant differences existed in variables between the two groups (P N 0.05 for all). The P values are presented for the effects of treatment within each group. BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein; HgA1c, hemoglobin A1c; QUICKI, quantitative insulin-sensitivity check index; hsCRP, highsensitivity C-reactive protein; baPWV, brachial-ankle pulse wave velocity.
176.5 cm/s to 1365.8 ± 200.1 cm/s, P = 0.698) (Fig. 1). The percent changes of systolic BP, diastolic BP, and baPWV following rosuvastatin treatment did not differ significantly than that in the lifestyle modification group (all P = NS). In the rosuvastatin group, the percent change of baPWV was positively correlated with the percent change of supine systolic and diastolic BP (r = 0.50, P b 0.001; r = 0.54, P b 0.001, respectively), but not with those of lipid profiles, hsCRP, or metabolic parameters except fasting insulin (r = −0.33, P = 0.04). The multivariate linear regression analysis showed that the percent change of supine systolic BP was an independent factor for the percent change of baPWV following rosuvastatin treatment (Table 2). In this study, we evaluated the effects of short term moderate intensity rosuvastatin treatment on arterial stiffness in patients with hypercholesterolemia who had no additional cardiovascular risk factors (except smoking history). Our results demonstrate that short term (2 months) rosuvastatin treatment significantly reduced arterial stiffness with lowering BP in healthy hypercholesterolemic patients, independent of lipid-lowering, metabolic and anti-inflammatory effects. In addition, the change of supine systolic BP was an independent factor for the change of arterial stiffness by multivariate analysis. Regarding the effects of statin on arterial stiffness, some conflicting results have been reported. Some studies have shown improvement of arterial stiffness with statin therapy which was not associated with BP [3–9]. Two studies revealed that improvement of arterial stiffness was related with BP [10,11]. The others have shown no beneficial effects of statin on arterial stiffness [12–14]. Taken together, there are still controversies for the effects of statin on arterial stiffness and its related mechanisms. These discrepancies could be due to the different patient populations, the duration of treatment, the types or doses of statin, or different protocols or different arteries of PWV measurement. To resolve this problem, in our study, we tested whether short term moderate intensity rosuvastatin (10 mg/day) treatment can reduce arterial stiffness in hypercholesterolemic patients who had no additional cardiovascular risk factors because hypercholesterolemic patients without additional
cardiovascular risk factors are the most reliable patient group to assess the effects of statin on arterial stiffness. In addition, we sought the related factors for the changes of arterial stiffness after rosuvastatin treatment. With regard to the effects of statin on BP, although data have been still controversial [15–20], recent meta-analysis revealed small but statistically significant BP lowering effects of statins [20,21]. For this topic, our current study demonstrates that short term moderate intensity rosuvastatin treatment can produce significant modest BP-lowering effect and it is related with improved aortic stiffness in hypercholesterolemic patients without hypertension. The mechanisms mediating the improvement of arterial stiffness by statin treatment remain unclear. Arterial stiffness, which alters arterial pressure, may relate to structural alterations of the arterial wall or extracellular matrix, changes in vascular smooth muscle tone or content, changes in neuroendocrine signaling, and endothelial dysfunction [22]. Favorable alterations in any of these mechanisms may result in improvement of arterial stiffness. However, any short term intervention, such as in the present study, is unlikely to lead to favorable structural alterations in arterial wall. Thus, more plausible mechanisms might be based on the beneficial effects of statin on endothelial function and smooth muscle tone. It is possible that the reduction in arterial stiffness during statin treatment may be attributable to the improvement in endothelial function and consequent vasodilation, which may reduce arterial pressure. In addition, we previously suggested a cross-talk between statins and renin–angiotensin system [23,24]. Briefly, hypercholesterolemia enhanced vascular expression of angiotensin II type I receptors that mediate increased activity of angiotensin II [25]. Statins can downregulate the density of angiotensin II type 1 receptor, which may induce BP reduction by inhibition of the renin–angiotensin system [16,23,24]. Therefore, we suggest that the improvement of arterial stiffness by short term rosuvastatin treatment might be attributed to the improvement of endothelial function, vascular tone and cross-talk with the renin–angiotensin system which induce BP lowering effects.
Please cite this article as: Oh PC, et al, Rosuvastatin treatment improves arterial stiffness with lowering blood pressure in healthy hypercholesterolemic patients, Int J Cardiol (2014), http://dx.doi.org/10.1016/j.ijcard.2014.07.181
P.C. Oh et al. / International Journal of Cardiology xxx (2014) xxx–xxx
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Table 2 Multivariate linear regression analysis for the percent change of arterial stiffness following rosuvastatin treatment. B
95% CI
Model 1 Age Sex Body mass index hsCRP Supine systolic BP
P
−0.037 −0.023 0.184 0.051 0.480
−0.290, 0.232 −4.772, 4.141 −0.441, 1.599 −0.015, 0.021 0.158, 0.685
0.823 0.887 0.257 0.726 0.003
Model 2 Age Sex LDL cholesterol HDL cholesterol Supine systolic BP
0.020 −0.016 −0.062 0.185 0.467
−0.230, 0.262 −4.875, 4.423 −0.153, 0.103 −0.075, 0.267 0.134, 0.686
0.897 0.922 0.697 0.261 0.005
Model 2 Age Sex Glucose Insulin Supine systolic BP
−0.040 −0.012 0.051 −0.447 0.567
−0.230, 0.173 −3.981, 3.657 −0.143, 0.212 −0.087, −0.022 0.242, 0.678
0.773 0.932 0.697 0.002 b0.001
CI, confidence interval; hsCRP, high-sensitivity C-reactive protein; BP, blood pressure; LDL, low-density lipoprotein; HDL, high-density lipoprotein.
have changed. Further long-term follow-up and larger studies are warranted to resolve these issues. In conclusion, short term moderate intensity rosuvastatin treatment in healthy hypercholesterolemic patients significantly reduced arterial stiffness with lowering BP, independent of lipid lowering, metabolic and anti-inflammatory effects. In addition, the change of supine systolic BP was an independent factor for the change of arterial stiffness. Our results support the concept that the preventive effect of statins on cardiovascular events may be attributed to not only reduction of the cholesterol level, but also arterial destiffening effects with lowering BP. Conflict of interest None. Acknowledgments The authors of this manuscript have certified that they comply with the Principles of Ethical Publishing in the International Journal of Cardiology. References
Fig. 1. The effects of rosuvastatin group (a) and lifestyle modification group (b) on baPWV. Data are presented as mean ± standard deviation. baPWV, brachial ankle pulse wave velocity.
Our study presents some limitations. First, there were no significant differences of percent changes of systolic BP, diastolic BP and baPWV between the rosuvastatin and lifestyle modification groups. It may be caused by the small number of subjects or subjects at low risk. Second, this study was open-labeled and single-center study, although an examiner measuring BP and baPWV was blinded to subject group. Third, we could not interpret the cause and effect relationships between arterial stiffness and BP by this study. Fourth, lifestyle modification was only performed through diet and exercise education and subject's selfcontrol. So if patients were forced to intensive diet and exercise guided by supervisors, the results of aortic stiffness and BP in both groups might
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