Hypertension and hypercholesterolemia represent the most important risk factors responsible for the high prevalence and incidence of cardiovascular disease (CVD) Citation[1]. Both hypertension and hypercholesterolemia are often present in subjects with CVD; in particular, hypercholesterolemia determines a significant increase of cardiovascular complications in subjects with CVD Citation[2,3].
During the last few years, many studies have provided important evidence, confirming that hypercholesterolemia contributes to the development of hypertension and that the reduction of low-density lipoprotein-cholesterol (LDL-C) values improves the control of blood pressure Citation[4].
Hypertension and hypercholesterolemia characterize another important type of peripheral vascular system damage – specifically affecting the common carotid arteries (CCAs), which represent the expression of atherosclerotic vascular damage characterized by intima-media thickness (IMT) of arterial walls. IMT is an early phase of the atherosclerotic process, secondary to hyperplasia/hypertrophy of muscular smooth cells with hyperproduction of collagen and plaque formation Citation[5]. These lesions are more frequent in patients with hypertension and dyslipidemia and can determine ischemic stroke leading to both cerebral microembolization and stenosis, or occlusion of carotid arteries Citation[6].
Targets of antihypertensive treatment
The treatment of hypertension is aimed not at simple reduction of blood pressure values but at the prevention of cardiovascular complications that are known to accompany the high pressure. Large randomized controlled trials have provided strong evidence regarding the reduction of cardiovascular mortality and morbidity from stroke and myocardial infarction.
In the past, most physicians assumed that the effects of a reduction of blood pressure on cardiovascular risk would fit a decreasing straight line, justifying the opinion ‘the lower, the better’. The analysis of data derived from randomized controlled trials, in particular the Hypertension Optimal Treatment (HOT) trial, have shown that the optimal goal of antihypertensive therapy, in most patients with combined systolic and diastolic hypertension who were not at high risk, is a blood pressure of less than 140/90 mmHg. The greatest benefit is probably derived from lowering the diastolic pressure to 80–85 mmHg. Not only is there no proven benefit with more intensive control but added cost and probable increased side effects are also associated with more aggressive antihypertensive therapy Citation[7].
Some drug classes of antihypertensives can be used because they have the characteristic to not only act on pressure values, but also to interact with both endothelium and other molecules involved in the pathogenesis of hypertension. In particular, calcium-channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) can be considered in the treatment of hypertension administered to control several aspects of disease.
CCBs are the most popular class of agents used in the treatment of hypertension. They reduce the likelihood of a stroke more than other therapies but are not as effective at reducing the risk of a myocardial infarction, while having similar effects on overall mortality. They work well and are usually well tolerated across the entire spectrum of hypertensives.
In patients with primary hypertension, ACEIs provide antihypertensive effects that are equal to those with other classes and provide significant protection against CVD and death when compared with placebo and offer comparable, if not better, protection than other classes of drugs Citation[8]. ACEIs have been impressively effective in the treatment of hypertensives with coronary disease, congestive heart failure and chronic renal disease (whether diabetic or nondiabetic).
These drugs provide special advantages in patients with heart failure, coronary ischemia or nephropathy. In particular, the evidence from the Heart Outcomes Prevention Evaluation (HOPE) trial has led to the recommendation that an ACEI be given to all patients at high risk for coronary disease, whether hypertensive or not Citation[7].
ARBs have comparable antihypertensive effects, with respect to other drug classes, and reduce the progression of nondiabetic nephropathy and in patients with Type 2 diabetes complicated with nephropathy. As reflected in the rapidly increasing usage of ARBs, these drugs are probably being prescribed for many more patients than the 10% or so who are intolerant of an ACEI. Additional outcome data are required in order to judge whether they are as effective as the proven ACEIs. Many outcome trials now in progress should provide proof of their value beyond that found in Type 2 diabetic nephropathy.
Diabetic patients with hypertension need special attention since, in these patients, an important cardiovascular risk coexists. In these patients, the treatment of hypertension should be aggressive and intensive in concert with the management of dyslipidemia that commonly accompanies hypertension and diabetes. The benefits of such intensive management were clearly documented in a 7.8-year follow-up of 160 patients with Type 2 diabetes and hypertension with microalbuminuria Citation[9]. In particular, the drugs used should have the following important characteristics: effectiveness, metabolic neutrality, good tolerance and compliance, vasoselectively and important scientific research evidence. For these reasons, ACEIs and ARBs represent the two antihypertensive drug classes with important pleiotropic effects, in particular on endothelium and other molecules involved in hypertension.
Recent data have shown that hypercholesterolemia is associated with an enhancing cellular expression of the (angiotensin) AT1 receptor Citation[4,10]. In particular, candesartan has been demonstrated in subjects with hypertension and hypercholesterolemia as an important vasodilatatory response endothelium-mediated drug with respect to subjects treated with felodipine. This small study demonstrates the important role that the renin–aldosterone–angiotensin system and AT1 receptor drugs have in the treatment of hypertension in subjects with hypercholesterolemia Citation[11].
Targets of hypercholesterolemia treatment
The importance of LDL-C reduction in the development of atherosclerosis has long been documented and actually remains the primary target for the prevention of coronary heart disease. In particular, increasing research attention has been devoted to the heterogeneity of LDL-C particles and the atherogenicity of lipids and lipoproteins.
The treatment of hypercholesterolemia with statins has demonstrated the importantance of effective prevention of cardiovascular events (coronary disease and cerebrovascular attack) proportional to the reduction of LDL-C and total cholesterol values Citation[12]. The most benefit is correlated to the presence of hypertension. In fact, the correction of both hypertension and hypercholesterolemia in subjects with two risk factors determine an important clinical benefit: a reduction in the number of cardiovascular events that is significantly higher than the reduction obtained with treatment by a single risk factor Citation[10]. In this study, the omission or insufficient treatment of both hypertension and dyslipidemia compromised the correction of associated risk factors.
Statins are an effective treatment for dyslipidemia. In particular, high-intensive therapy with rosuvastatin (ROS) (40 mg/day) has recently demonstrated an average LDL-C reduction, an increased high-density lipoprotein-cholesterol (HDL-C) and a reduction of atherosclerotic plaque mass evaluated via intravascular ultrasound (IVUS) Citation[4].
Two important trials with statins have demonstrated that aggressive treatment to reduce LDL-C is associated with an important reduction of atherosclerotic plaque formation and progression.
In a recent REVERSal of Atherosclerosis with aggressive Lipid lowering therapy (REVERSAL) trial in 210 patients, researchers obtained a remodeling of the arterial wall and plaque stabilization after therapy with atorvastatin (80 mg/day for 18 weeks) Citation[13]. This study has shown a slowing down of atheroma formation. However, the scientific dilemma regarding the regression of atherosclerotic plaque has not yet been solved. Subsequently, A Study To Evaluate the effect of Rosuvastatin On Intravascular ultrasound-Derived coronary atheroma burden (ASTEROID) trial has revolutionized the pathophysiology and therapeutic approach to atherosclerosis and has provided an answer to the dilemma. In this trial, intensive treatment with ROS (40 mg/day) significantly reduced both the coronary atherosclerosis assessed by serial IVUS (median reduction 9.1%) and the LDL-C (mean level reduction 53.2%), with an increase of HDL-C (mean increase 14.7%) Citation[14].
Carotid arteries mirror the cardiovascular system
The measurement of CCA IMT is an important marker of atherosclerosis that correlates with established coronary artery disease Citation[15]. The most frequently involved extracranial vessels in the atherosclerotic process are the carotid bifurcation, including the origins of internal carotid arteries (ICAs) and external carotid arteries (ECAs) (90%), the origins of the vertebral arteries and the aortic arch with its proximal branches.
The IMT represents a step of carotid plaque progression and formation. In particular, these two steps are associated with expansive remodeling of the arterial wall. In fact, the remodeling response during plaque-stabilizing therapy and its relationship to markers of lipid metabolism and inflammation are not completely understood currently.
Changes in IMT measured by B-mode high-resolution carotid ultrasonography (CUS) are one of most recent markers to evaluate the progression of the atherosclerotic process. The ability of CUS to provide visualization of IMT offers significant advantages, such as noninvasiveness, good safety and repeatability.
Since IMT correlates with coronary artery disease and represents a precursor of plaque formation, it is important to start a systemic antihypertensive and hypolipidic treatment aimed at reducing the IMT present in carotid and coronary arteries.
Many antihypertensive drugs, such as CCAs (isradipin, amldipin nifedipin, lacidipin and verapamil) and ACEIs (e.g., ramipril), can prevent the development or induce a regression of carotid atherosclerotic lesions in patients with essential hypertension. Only two statins, atorvastatin and ROS, have published data regarding the stabilization/regression of atherosclerotic plaque in carotid and coronary arteries.
New perspectives: ‘drug cocktail’
Hypertension, hypercholesterolemia and carotid atherosclerosis have not only epidemiological links but common pathophysiologic mechanisms. For this reason, it is implicit and correct to hypothesize a treatment aimed not only at correction of simple causal effects but at other important targets of cardiovascular risk, such as endothelial dysfunction, inflammation, vascular oxidative stress and many morphological features of atherosclerosis.
Although several major risk factors have been identified in the development of atherosclerotic CVD, abnormalities in the plasma lipids and lipoproteins, hypertension and diabetes are clearly central to this problem. All these risk factors support the atherosclerotic process, which now could probably be stopped or even regressed. The way to procede is not the aggressive attack with a drug for single risk factors but with a ‘drug cocktail’ to modify the numerous factors involved in the atherosclerotic process.
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