Vascular Protection of Dual Therapy (Atorvastatin-Amlodipine) in Hypertensive Patients
José Luis Martín-Ventura*,
José Tuñon,
Mari Carmen Duran,
Luis Miguel Blanco-Colio*,
Fernando Vivanco and
Jesús Egido*
* Renal and Vascular Research Lab and Cardiology Department, Fundacion Jimenez Diaz, Autonoma University, and Proteomics Unit, Complutense University, Madrid, Spain
Address correspondence to: Prof. Jesús Egido, Renal and Vascular Research Lab, Division of Nephrology and Hypertension, Fundación Jiménez Díaz, Avenida Reyes Católicos 2, 28040, Madrid, Spain. Phone: +34-91-5504800, ext. 3362; Fax: +34-91-5494764; E-mail:jegido{at}fjd.es
Hypertension frequently coexists with other cardiovascular riskfactors, such as hypercholesterolemia, and their combinationis associated with a greater rate of cardiovascular events.Recent clinical data support that treatment of hypertensivepatients with a combination of antihypertensive and lipid-loweringtherapies leads to a higher reduction in the incidence of cardiovascularevents. In the Anglo-Scandinavian Cardiac Outcomes Trial–BloodPressure Lowering Arm (ASCOT-BPLA), an optimal prevention ofcardiovascular events was reached in patients who were randomlyassigned to atorvastatin and the amlodipine treatment. However,the potential underlying mechanisms of these vascular protectiveeffects are not fully elucidated. Because experimental studieshave shown that statins and calcium channel blockers have antiatheroscleroticeffects, the effect of atorvastatin alone or in combinationwith amlodipine was analyzed in the protein secretion profileof atherosclerotic plaques that were cultured ex vivo. In thisrespect, the addition of atorvastatin and amlodipine to atheroscleroticplaques normalized the levels of the different released proteinsto that obtained from healthy arteries. This review highlightsrecent clinical and experimental studies that support that acombined treatment of hypertensive patients with both statinsand calcium channel blockers could promote a higher reductionin their global cardiovascular risk profile and associated mortality.As an example, the application of a proteomic approach to assessthe modulation by atorvastatin alone or in combination withamlodipine on the proteins that are released by atheroscleroticplaques has allowed the identification of novel therapeutictargets by which these drugs could promote their additive/synergiceffects.
Nephrologists traditionally have been involved in the care ofpatients with hypertension, because this disorder is both causeand consequence of kidney disease. However, hypertension frequentlycoexists with other cardiovascular risk factors, such as hypercholesterolemia,and their combination is associated with a greater rate of cardiovascularevents (1). Clinical and experimental studies that were performedin the past few years suggested that when treating hypertensivepatients, all of these factors should be considered to achievea higher reduction in cardiovascular morbidity and mortalityon these patients.
Combined Antihypertensive and Lipid-Lowering Therapies in the Clinical Practice
A large number of clinical trials have demonstrated that treatmentof either hypercholesterolemia or hypertension leads to a reductionin the incidence of cardiovascular events. Moreover, subgroupanalyses that were performed in the Heart Outcomes PreventionEvaluation (HOPE) study showed the benefits of angiotensin-convertingenzyme inhibitors in patients who received concomitant statintherapy (2). Similarly, in the Heart Protection Study (HPS),simvastatin diminished cardiovascular events in patients whoused angiotensin-converting enzyme inhibitors (3).
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) studieshave shed new light on this matter. The ASCOT Blood PressureLowering Arm (ASCOT-BPLA) analyzed 19,257 patients who had hypertensionand at least three other cardiovascular risk factors and wererandomly assigned to therapy with the calcium channel blockeramlodipine, adding perindopril when necessary, or to a blocker,atenolol, using bendroflumethiazide as a second drug (4). Bythe end of the trial, 78% of patients were taking the secondantihypertensive drug, and the amlodipine/perindopril regimenwas superior to atenolol atenolol/bendroflumethiazide in reducingall-cause mortality, stroke, total cardiovascular events, andnew-onset diabetes. When several variables of the ASCOT-BPLAwere analyzed, BP reduction was not the only contributor tothe amlodipine/perindopril reduction in cardiovascular events(5). It is interesting that although BP was the most importantvariable associated with the incidence of stroke, differencesin HDL cholesterol were more important for coronary events.Furthermore, full adjustment for these variables as well asfor body weight, glucose, triglycerides, creatinine, and potassiumserum levels explained only 50 and 40% of the differences incoronary and stroke events, respectively, leaving the remainingpercentages to be explained potentially by other variables thatwere not considered in this analysis. These data suggest thatBP reduction is not the only mediator in the beneficial effectof antihypertensive drugs. Accordingly, several vasculoprotectivemechanisms have been demonstrated for antihypertensive drugs(6).
The ASCOT Lipid Lowering Arm (ASCOT-LLA), published in 2003,showed data of further interest (7). A total of 10,305 patientswho were from the ASCOT-BPLA study and had total cholesterolconcentrations of 6.5 mmol/L were randomly assigned to 10 mg/datorvastatin or placebo. Treatment with the statin reduced theincidence of nonfatal myocardial infarction or fatal coronaryheart disease and that of stroke, cardiovascular, and coronaryevents. The results of the ASCOT-LLA trial proved to be independentof the degree of BP reduction associated with lipid lowering,as both the atorvastatin and the placebo group showed a similarlygood BP control. The emerging new concept that the ASCOT-LLAstudy addresses is that the concomitant use of statins improvedthe clinical evolution of hypertensive patients with moderatelyincreased or even normal total cholesterol levels but at riskfor cardiovascular events because of other accompanying riskfactors. In this respect, statins have been claimed to exerta part of their beneficial actions by cholesterol-independentmechanisms (8). Remarkably, in the ASCOT-BPLA, an optimal preventionof cardiovascular events was reached in patients who were randomlyassigned to atorvastatin and the amlodipine/perindopril treatment,with a reduction of 48% in the risk for fatal myocardial infarctionand nonfatal coronary heart disease and 44% in the incidenceof stroke. However, the underlying mechanisms of these beneficialeffects have not been elucidated.
Protective Role of Dual Therapy (Atorvastatin-Amlodipine) in Atherosclerosis
Calcium channel blockers (CCB) have been used for decades totreat hypertension, but it also has been suggested that theyinterfere with the progression of atherosclerotic disease (9–11).Although the initial results for dihydropyridines in this areawere weak, the appearance of amlodipine changed this view (11).In the Prospective Randomized Evaluation of the Vascular Effectsof Norvasc Trial (PREVENT), this drug reduced carotid intima-mediathickness progression and the incidence of unstable angina andrevascularization in patients with coronary artery disease (12).These effects could be due to the special profile of amlodipine,which includes antioxidant, antiproliferative, and anti-inflammatoryproperties, among others (13–15) (Figure 1).
Figure 1. Known antiatherosclerotic mechanisms of action of statins and calcium channel blockers (CCB). The scheme represents the described similar mechanisms that potentially are involved in the vascular protection that is afforded by statins and CCB. SMC, smooth muscle cells; NO, nitric oxide; MMP, matrix metalloproteinases.
Statins, in addition to lowering lipid levels, decrease theincidence of vascular thrombotic events (2,16). Specifically,atorvastatin has demonstrated a powerful effect on clinicalevents and even stopped or reversed the progression of atherosclerosis(17–19). Given that statins and CCB have different mechanismsof action, it is conceivable that they may have an additiveor synergic effect, not only on new plaque formation but alsoon inhibiting the progression of established lesions (20). Indeed,this synergic effect of lipid-lowering therapy and CCB on humancoronary atherosclerosis was reported in the Regression GrowthEvaluation Statin Study (REGRESS) (21). Moreover, various studiesin hypertensive hyperlipidemic patients have shown that thecombination of atorvastatin and amlodipine has additive effectsin the improvement of arterial compliance and in the fibrinolyticbalance, early markers of vascular damage and atherosclerosis(22,23). Collectively, these studies support the clinical antiatheroscleroticadvantages of the combination of both CCB and statins and, inparticular, of atorvastatin with amlodipine beyond their establishedantihyperlipidemic and antihypertensive modes of action.
Effect of Dual Therapy on Protein Profile of Atherosclerotic Plaques
The beneficial effect of combining CCB with statins has beenreplicated in transgenic atherosclerotic mice, in which treatmentwith amlodipine and atorvastatin produced an additional reductionof atherosclerosis compared with that observed with either amlodipineor atorvastatin alone (24). Given that previous papers haveshown that statins and amlodipine have antiatherosclerotic effects(6,8,14,24–26), it is conceivable that the synergisticeffect of both drugs may be extended to these actions previouslyknown (Figure 1). Considering this, we decided to analyze theeffect of atorvastatin alone or in combination with amlodipinein the protein secretion profile of atherosclerotic plaquesby following the same proteomic approach that we previouslyapplied to characterize the atherosclerotic process (27). Inthis previous report, we showed that atherosclerotic plaquesare able to release proteins to the conditioned medium. Moreover,a differential protein profile was detected when the secretomesof human atherosclerotic plaques that were incubated ex vivoand the one from healthy arterial segments were compared byusing two-dimensional electrophoresis and mass spectrometry.These tools have become popular in protein research becausethey allow the separation, detection, and identification ofthousands of proteins in a single experiment and promote thecharacterization of new, unforeseen proteins.
In this work, significant improvements, mainly related to samplepreparation protocols, that have allowed us to identify a highernumber of proteins that are differentially released by atheroscleroticplaques in culture in comparison with control arterial segmentshave been made. In this respect, from an average of 620 spotsper gel detected, we focused on the analysis of 260 proteins.According to the analysis that was done using the PD-Quest Software(BIO-RAD Laboratories, Veenendaal, The Netherlands), 217 proteinspots were present at higher levels in the conditioned mediaof atherosclerotic plaques than in those of the control region,whereas 43 protein spots were decreased or remained unchanged.From a total of 83 proteins that were identified by mass spectrometry,34 showed higher levels in atheroma plaque secretome, whereasanother 31 proteins presented lower levels compared with thecontrol-conditioned media. Examples of these proteins includeleucine-rich -2-glycoprotein, transferrin, apolipoprotein A-I,fibrinogen, -1-antitrypsin, complex-forming glycoprotein HC,serum amyloid P component, heat-shock protein 27, and enolase1. Some of these identified proteins were detected in more thanone spot on the gels, suggesting the presence of posttranslationalmodifications and affecting to their isoelectric point and/ormolecular weight. Experiments to understand the potential pathophysiologicrole of these posttranslational modifications are in progress.
We hypothesized that the addition of atorvastatin alone or incombination with amlodipine to complicated atherosclerotic plaquescould modulate some of the novel identified proteins that werereleased by the plaques ex vivo. For that purpose, atheroscleroticplaques were incubated in the presence/absence of atorvastatin(10 µmol/L) alone or in combination with amlodipine (1µmol/L, dual), and the released proteins were analyzedand compared by two-dimensional electrophoresis. The modulationby atorvastatin or dual treatment of the identified proteinsis represented in a hierarchical cluster, where differencesamong all experimental conditions can be observed (Figure 2).The addition of drugs to the complicated atherosclerotic segmentspromoted different effects in protein levels of tissue-conditionedmedia, but in the majority of the cases, treatment with atorvastatinalone or in combination with amlodipine normalized the levelsof the different released proteins. Furthermore, in some cases,dual treatment was superior to that observed with atorvastatinalone. In this respect, treatment with the combination of atorvastatinand amlodipine but not with atorvastatin alone was able to upregulatethe decreased levels that were observed for the protein -galactosidesoluble lectin in the conditioned media of atherosclerotic plaquesin culture, reaching control values. It is interesting thatthe member of the family of -galactoside soluble lectins galectin-1was shown to inhibit leukocyte rolling and extravasation inexperimental inflammation (28), a main mechanism involved inatherogenesis. Other examples are retinol-binding protein, proteindisulfide isomerase, and the antioxidant protein thioredoxinperoxidase B2, probably related to the antioxidant propertiesthat are associated to amlodipine treatment.
Figure 2. Novel potential therapeutic targets for atorvastatin or dual therapy in atherosclerosis. The hierarchical cluster reflects the modulation of the protein secretion profile detected by proteomic analysis for complicated atherosclerotic plaques (atheroma) that were cultured ex vivo in the presence of atorvastatin alone or in combination with amlodipine (DUAL). Following the color scale, the lower secretion levels of proteins are in the green scale, and the ones with higher secretion are red.
Clinical and experimental studies support that a combined treatmentof hypertensive patients with both atorvastatin and amlodipinecould promote a higher reduction in their global cardiovascularrisk profile and associated mortality. In this respect, theapplication of a proteomic approach to assess the modulationby atorvastatin alone or in combination with amlodipine of theproteins that are released by complicated atherosclerotic plaqueshas allowed us to identify novel therapeutic targets by whichthese drugs could promote their additive/synergic effects. However,the underlying mechanisms of these beneficial effects deservefurther research.
Acknowledgments
This research was supported by Pfizer-Spain, SAF 2004/0619,Mutua Madrileña Automovilista.
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Abstract
Introduction
blocker, atenolol, using bendroflumethiazide as a second drug (4). By the end of the trial, 78% of patients were taking the second antihypertensive drug, and the amlodipine/perindopril regimen was superior to atenolol atenolol/bendroflumethiazide in reducing all-cause mortality, stroke, total cardiovascular events, and new-onset diabetes. When several variables of the ASCOT-BPLA were analyzed, BP reduction was not the only contributor to the amlodipine/perindopril reduction in cardiovascular events (5). It is interesting that although BP was the most important variable associated with the incidence of stroke, differences in HDL cholesterol were more important for coronary events. Furthermore, full adjustment for these variables as well as for body weight, glucose, triglycerides, creatinine, and potassium serum levels explained only 50 and 40% of the differences in coronary and stroke events, respectively, leaving the remaining percentages to be explained potentially by other variables that were not considered in this analysis. These data suggest that BP reduction is not the only mediator in the beneficial effect of antihypertensive drugs. Accordingly, several vasculoprotective mechanisms have been demonstrated for antihypertensive drugs (6). 
6.5 mmol/L were randomly assigned to 10 mg/d atorvastatin or placebo. Treatment with the statin reduced the incidence of nonfatal myocardial infarction or fatal coronary heart disease and that of stroke, cardiovascular, and coronary events. The results of the ASCOT-LLA trial proved to be independent of the degree of BP reduction associated with lipid lowering, as both the atorvastatin and the placebo group showed a similarly good BP control. The emerging new concept that the ASCOT-LLA study addresses is that the concomitant use of statins improved the clinical evolution of hypertensive patients with moderately increased or even normal total cholesterol levels but at risk for cardiovascular events because of other accompanying risk factors. In this respect, statins have been claimed to exert a part of their beneficial actions by cholesterol-independent mechanisms (8). Remarkably, in the ASCOT-BPLA, an optimal prevention of cardiovascular events was reached in patients who were randomly assigned to atorvastatin and the amlodipine/perindopril treatment, with a reduction of 48% in the risk for fatal myocardial infarction and nonfatal coronary heart disease and 44% in the incidence of stroke. However, the underlying mechanisms of these beneficial effects have not been elucidated. 
-2-glycoprotein, transferrin, apolipoprotein A-I, fibrinogen, 
