High plasma cholesterol levels have been frequently reported in patients with arterial hypertension (1-3), where they can contribute to significantly increase the individual risk for cardiovascular events. Indeed, according to the epidemiologic approach (1), the probability of developing a major cardiovascular event in patients with hypertension is progressively increased when high blood pressure occurs with other cardiovascular risk factors. In particular, the results of the MRFIT study have clearly demonstrated that the cardiovascular mortality associated with a progressive increase in blood pressure values is significantly greater in the group of patients characterized by high plasma cholesterol levels (4). A significant increase in plasma cholesterol levels has been also described in hypertension-prone subjects (5,6) in comparison with the normotensive population, as well as in patients showing an exaggerated blood pressure response to stress (7), thus suggesting that plasma cholesterol levels can be directly involved in blood pressure control.
The exact mechanism responsible for the relation between hypercholesterolemia and blood pressure control is still under investigation. Experimental and clinical studies have demonstrated a significant correlation between high plasma cholesterol levels and impaired endothelium-dependent vascular relaxation (8-10). Furthermore, a reduction in plasma cholesterol levels is associated with an improvement of the endothelium-dependent vasodilating capacity (2,11,12). In experimental animal models, the presence of hypercholesterolemia has been associated with an overexpression of the gene coding for angiotensin II receptors (13), whereas increased levels of chymase activity forming angiotensin II have been found in the aorta of monkeys fed a high-cholesterol diet (14). These data strongly suggest that the modulation of plasma cholesterol levels could be directly involved in the control of vascular tone and reactivity and could contribute to the development of systemic hypertension.
Whether the cholesterol reduction can exert some of its cardiovascular benefit by improving blood pressure control and whether this mechanism can have clinical relevance for event reduction remain, however, an open question. The reduction in plasma cholesterol levels by the use of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitors (statins) has been demonstrated to prevent the occurrence of coronary and cerebrovascular events in patients with hypercholesterolemia with or without prior clinical manifestations of coronary artery disease (15-18). Unfortunately, no information is currently available from those studies about the blood pressure control achieved in the population of patients undergoing statin treatment. Nevertheless, in a large primary prevention trial (18), the use of pravastatin has decreased the risk of cardiovascular diseases early after randomization and in comparison to placebo, thus suggesting that in addition to the long-term prevention of atherosclerosis, other more immediate mechanisms might account for the clinical benefit of statins. The aim of our study was to investigate the hypothesis that blood pressure control can be improved by the use of statins in hypertensive hypercholesterolemic patients receiving antihypertensive treatment.
One hundred thirty-five hypertensive patients aged 39-79 years were selected among the population followed up at the Hypertension Clinic of the Department of Internal Medicine of the University of Bologna. All the patients were actively treated with antihypertensive drugs, whereas hypercholesterolemia (total cholesterol, >240 mg/dl) was present in 90 patients, and the plasma cholesterol levels were normal (≤240 mg/dl) in 45 after a 3-month period of intervention with the phase I diet of the National Cholesterol Education Program of the American Heart Association (19). Patients with a diagnosis of diabetes, liver diseases, kidney diseases, chronic pancreatitis, cancer, major cardiovascular complication (myocardial infarction or unstable angina within 6 months, congestive heart failure), severe dyslipidemia (total cholesterol, >350 mg/dl), using corticosteroids or hormone replacement therapies and having any other diseases with poor prognosis were excluded. Secondary forms of hypertension were excluded according to standard routine clinical and laboratory examination.
Eligible patients were enrolled into a 4-week run-in period to stabilize blood pressure and plasma cholesterol levels. During this phase, the patients were taking their usual antihypertensive treatment and were assigned a daily diet containing 120 mmol sodium and 2,000 Kcal, 30% of which was represented by saturated fatty acids. The patients were then instructed to maintain the same diet throughout the study. On completion of the run-in phase, 45 patients with high plasma cholesterol were randomly assigned in an open-label fashion to a 3-month treatment with different statins (either pravastatin, 10-40 mg/day, or simvastatin, 10-40 mg/day). A dietary treatment alone was maintained in the 45 remaining hypercholesterolemic patients and in the 45 normocholesterolemic controls. Different antihypertensive drugs and statins were used to exclude specific synergistic effects between the different compounds not related to the lipid-lowering effect.
During the 3-month period of observation, the antihypertensive treatment was modified as appropriate to achieve an adequate blood pressure control (SBP/DBP, <140/90 mm Hg). The initial dose of statins (10 mg/day), either pravastatin or simvastatin, was doubled every 4 weeks, with a target of total cholesterol reduction of 20% or more.
Systolic, diastolic, and pulse pressure were blindly measured at trough between 8 and 10 a.m., with the patient in sitting position by the same well-trained operator, unaware of the cholesterol levels and treatment allocation. Four consecutive measurements were taken over 10 min using a mercury sphygmomanometer, and the average of the last three measurements was used. Pulse pressure was calculated by subtracting diastolic from systolic blood pressure.
Fasting blood samples were drawn by venipuncture between 8 and 10 a.m. Plasma total and HDL-cholesterol and triglycerides serum glucose and serum creatinine, glutamic pyruvic transaminase, and glutamic oxaloacetic transaminase and 24-h urinary sodium excretion were measured every 4 weeks by the same laboratory with standard methods. In particular, the commercial enzymatic method was used for the determination of total cholesterol (CHOD-PAP; Boehringer-Mannheim, Mannheim, Germany). The Friedewald formula was used to calculate the LDL cholesterol level.
The sample-size calculation has been carried out by estimating that ≥40 patients should be included in any group to detect a difference of 5 mm Hg in diastolic blood pressure or a 10 mm Hg in systolic blood pressure, given a dropout rate of 10%, a power of 90%, and an α error of 0.05.
The results are expressed as mean ± SD. Statistical analysis was carried out using an SPSS statistical package (version 6.1). Two-way analysis of variance has been used to compare the differences between the three groups of patients. The Pearson product-moment correlation test was used to correlate cholesterol and blood pressure variations. The χ2 test was used to compare the categorical variables among the different groups.
The study protocol was revised by the Ethical Committee of the University of Bologna, and written informed consent was obtained by each participant.
A total of 130 patients completed the 3-month follow-up period of observation. In the population of patients with high cholesterol levels, four patients in the statin group and one in the diet group dropped out of the study because of poor compliance (two), increase in serum transaminase (one), and poor blood pressure control (two). Blood pressure and cholesterol measurements were obtained in all participants, whereas additional biochemical measures were available at follow-up in only 127 of them. The baseline characteristics of the study population measured at the end of the run-in period are summarized in Table 1. No significant differences have been observed among the three groups of patients in term of demographic variables, blood pressure profile, and nonlipid biochemical variables (data not shown). Twenty-one patients have been allocated to the treatment with pravastatin and 20 to simvastatin. No significant differences have been observed in the number of drugs and in the distribution of the different antihypertensive drugs between the three groups both at the end of the run-in period and after 3 months of follow-up (Table 2). The effects of the different treatment regimens on blood pressure and lipid profile are summarized in Table 3. Systolic and diastolic blood pressure values were significantly reduced during the 3 months of follow-up in all the groups of patients, even whether the decrease was greater in patients treated with statins, and the same differences were observed for pulse pressure. As expected, total plasma cholesterol levels were greatly reduced in patients treated with statins (Table 3), who also showed the greater increase in plasma levels of HDL-C with no significant changes in plasma triglycerides (data not shown). In terms of percentage decrease from baseline, the changes in systolic and diastolic blood pressure values were enhanced in high-cholesterol patients treated with statins (Fig. 1) that showed a greater decrease in plasma cholesterol levels as well. In the group of patients undergoing statin treatment, a slight but significant linear relation was found between the percentage changes in diastolic blood pressure and those in plasma total cholesterol (R = 0.37, p = 0.043), whereas no relation was found with systolic blood pressure changes (R = 0.11; p = 0.35). In the group of patients allocated to statins, the percentage reduction of systolic blood pressure and total serum cholesterol level was largely comparable in subjects treated with simvastatin or pravastatin, respectively (SBP, −11.4 ± 2 vs. −11.1 ± 2 %; p = 0.53; T-cholesterol, −20.4 ± 4 vs. − 20.7 ± 3 %; p = 0.67), whereas the DBP reduction was slightly enhanced in patients treated with pravastatin (−12.7 ± 2 vs. −8.5%; p = 0.048), and this difference achieved a borderline statistical significance. For the interaction between the treatment with statins and the different antihypertensive drugs, a separate stratified analysis has been carried out on blood pressure and total cholesterol changes in the subgroups of patients whose treatment regimen included (alone or in combination): angiotensin-converting enzyme (ACE) inhibitors (26), calcium channel blockers (20), or any other drugs (13), not including the two former classes. This post hoc analysis showed a greater antihypertensive effect in patients to whom statins were given in combination with ACE inhibitors or calcium channel blockers (Fig. 2), whereas in the remaining population, the blood pressure decrease was comparable to that observed in subjects with high cholesterol treated with the combination of antihypertensive treatment and dietary regimen alone.
Among the widely accepted issues in the field of cardiovascular risk, there is the relation between high cholesterol levels and hypertension. It has been reported in the general population (1-5), as well as in the young hypertension-prone subjects where the incidence of stable hypertension over time has been reported to be significantly increased in the presence of serum cholesterol levels above the cut-off value of 200 mg/dl (6). Moreover, a retrospective review of this issue has demonstrated that the reduction in plasma cholesterol in patients with hyperlipemia is associated with a reduction in blood pressure that is clinically significant (from 3 to 5 mm Hg reduction in diastolic blood pressure), directly related to the decrease of serum cholesterol, and larger in patients treated with statins (20). Our study demonstrates that in patients with hypertension and high plasma cholesterol levels, the use of an HMG-CoA reductase inhibitor (statin) not only improves the lipid profile but may significantly improve blood pressure control as well. This effect seems to be partially independent from the reduction in plasma cholesterol levels and could largely contribute to improve the risk profile of patients with abnormalities of blood pressure and lipid profile. These results can be minimally affected by the open-label design of the study for two main reasons. All the patients received the same level of standard medical care, irrespective of treatment allocation, and the evaluation of the primary objective, the blood pressure response, was carried out by the same investigator, who was completely unaware of plasma cholesterol levels or treatment allocation.
Earlier preliminary studies have found that the combination between statins and antihypertensive drugs can result in a better blood pressure control in patients with hypertension (21,22). In particular, Sposito et al. (21) have recently reported that the antihypertensive of effect of enalapril or lisinopril in patients with hypertension and hypercholesterolemia can be significantly enhanced by the concomitant administration of pravastatin or lovastatin. Our study has confirmed such findings in a larger population and has extended the benefit to patients treated with calcium channel blockers as well. These observations suggest the possibility of a positive "synergistic" interaction between statins and drugs involved in blood pressure control. The rationale for such clinical synergism is basically threefold and could involve a pharmacologic interaction between statins and antihypertensive drugs, a direct blood pressure-lowering effect of statins, and/or the capacity of statins to improve the sensitivity of the vessel wall to the vasodilating effect of antihypertensive drugs. In addition, the cholesterol reduction associated with the use of statins could improve the peripheral arterial compliance, thus improving both systolic blood pressure and pulse pressure control. All these effects of statins could enhance the blood pressure decrease induced by antihypertensive drugs and could provide a suitable explanation for the better pressor control achieved in our study in hypercholesterolemic hypertensive patients treated with statins.
As for the possibility of a pharmacokinetic interaction between statins and the drugs used to treat hypertension, this could result in an increased bioavailability of the antihypertensive drugs, leading to a greater blood pressure reduction. However, although many drug-to-drug interactions have been reported for statins (i.e., competition for the cytochrome P-450) (23), none of them has been described for the drugs used in our study for the treatment of hypertension. For these reasons, we suggest that any explanation of data based on drug interactions could be reasonably ruled out.
Earlier studies have found a blood pressure-lowering effect of statins. In two experimental studies, both pravastatin and lovastatin significantly decreased the mean arterial pressure in hypertensive rats after a few weeks of treatment (24,25). In two additional open-label studies carried out in 49 and 23 hypertensive patients with high plasma cholesterol levels, a 12-week treatment with fluvastatin significantly decreased both systolic and diastolic blood pressure (26,27). Conversely, other studies that included either normotensive individuals (28,29) or well-controlled hypertensive patients (30,31) were unable to demonstrate a blood pressure-lowering effect of statins. These findings suggest that statins may decrease elevated but not normal blood pressure values. The results of a large Italian survey, the Brisighella Heart Study, support this hypothesis, showing that in the hypercholesterolemic population, any additional effect of statins and antihypertensive drugs on blood pressure can be selectively observed in patients with blood pressure values outside the normal range (32). The effect of statins on blood pressure could be fairly explained by the vasodilatory effect that follows their capacity to improve endothelium-dependent vasorelaxation. Additional mechanisms could involve the upregulation of NO synthase (33,34), the blockade of calcium influx (35), and/or the reduction in plasma levels of aldosterone (36) that have been described in experimental conditions as potential effects of statins. An impairment in peripheral arterial compliance has been described in patients with high serum cholesterol levels (29) and could contribute to increase blood pressure. The treatment with statins, by reducing serum cholesterol levels, can increase arterial compliance (23), thereby improving the vasodilator capacity of the large arteries. This could contribute to the overall blood pressure-lowering effect observed in our study and, particularly, could explain the greater reduction of pulse pressure values observed in patients treated with the combination of antihypertensive drugs and statins. However, despite these promising data that support the capacity of statins to reduce elevated blood pressure values, further data are awaited on this issue for the future.
Apart from any direct influence on blood pressure, the observed hemodynamic effect of the combination between statins and antihypertensive drugs may be more strictly related to their pharmacodynamic interaction at the level of the vascular wall. A reduced diastolic blood pressure response to vascular agonists such as angiotensin II and norephinephrine has been reported after a 3-month treatment with pravastatin in patients with mild hypertension (37). Furthermore, cholesterol reduction with statins improves endothelium-dependent vascular function and may cause a significant vasodilatation (11,12). This could result in a significant increase in the sensitivity of the vessel wall to the vasodilating effect of the antihypertensive drugs. In our study, a greater blood pressure decrease has been observed in the patients treated with the combination of statins and ACE inhibitors or calcium channel blockers. Because both classes of drugs have been reported to reduce blood pressure by improving the endothelium-mediated vasodilatation (38) and by reducing the peripheral vascular tone, we speculate that their interaction with the vasorelaxant effect of statin could provide a reliable explanation for the better blood pressure control observed in our study in patients undergoing the combination of lipid-lowering and antihypertensive treatment.
Despite the demonstration that peripheral vascular tone improves by reducing serum cholesterol levels, the blood pressure decrease observed in our study was only partially correlated with the changes in serum cholesterol. A weak positive linear relation has been found only between the changes in total plasma cholesterol and those in diastolic blood pressure, whereas this has not been confirmed for systolic blood pressure. Again, these finding are largely in keeping with the observations of Sposito et al. (21) and suggest that other additional mechanisms, apart from cholesterol reduction, could contribute to the better blood pressure control achieved with the combination of antihypertensive drugs and statins (39). These would include a direct modulation of the endothelial function (34,40), as well as an interaction with the activity of the renin-angiotensin-aldosterone system (41). In particular, even in the absence of a cholesterol-lowering effect, statins may increase the expression of the activity of NO synthase (34), and this could contribute to a decrease in vascular tone. On the other hand, the results of the Brisighella Heart Study (32) have clearly demonstrated that the blood pressure reduction observed with the combination of statins and blood pressure-lowering drugs can not be achieved in matched patients treated with fibrates, suggesting the primary importance of the type of drug over the cholesterol-lowering effect.
In terms of comparison between the different statins, the article of Sposito et al. (21) reported that the extent of blood pressure reduction was independent of the type of statin used, either lovastatin or pravastatin, even whether the two drugs have been given at different daily dosages (pravastatin, 25.9 ± 12 mg/day vs. lovastatin, 38.8 ± 14 mg/day). In our experience, based on the administration of the same average daily dose for both statins, we achieved a greater diastolic blood pressure decrease in patients treated with pravastatin (Fig. 2). Whether this observation reflects a true difference in the capacity of statins to contribute to blood pressure control is still matter for speculation and should be assessed by an appropriate trial design.
In conclusion, the results of our study demonstrate that the use of statins in combination with antihypertensive drugs can improve blood pressure control in patients with uncontrolled hypertension and high serum cholesterol levels. The additional blood pressure reduction observed in patients treated with statins is clinically relevant and only partially related to the lipid-lowering effect of such drugs. The better blood pressure control showed by this study in hypertensive hypercholesterolemic patients could significantly contribute to reducing their individual cardiovascular risk and to improving the overall preventive impact of antihypertensive and lipid-lowering treatment.
Acknowledgment: We are indebted to Dr. Ada Dormi for her invaluable contribution in providing data from the Brisighella Heart Study database. We also are grateful to Dr. Stefano Collatina from Bristol-Myers Squibb, Princeton, NJ, U.S.A., for his continuous support of the research.
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