Current Vascular Pharmacology - Volume 8, Issue 6, 2010

Reappraisal of the guidelines of the European Society of Hypertension (ESH) was published online on October 15, 2009 [1]. It was an important update which paid attention to the fact that many aspects needed to be explained [1]. The guidelines have been competently summarized in the paper by Mancia and Grassi in this issue [2]. For this special issue of Current Vascular Pharmacology (CVP), we invited very experienced hypertensiologists in order to continue the discussion on these controversial aspects. Therefore the issue was titled: “Controversies in Hypertension Treatment”. Bielecka-Dabrowa et al. [3] present the most current knowledge on the role of beta-blockers in the treatment of hypertension, where despite many available meta-analyses and new trials (favorable for beta-blockers) [4, 5], some authors still have doubts on their role in hypertension therapy [6]. Bielecka-Dabrowa et al. suggest that beta-blockers are one of the major classes of antihypertensive drugs, but they should not be preferred in individuals in whom there is a high risk of incident diabetes [3]. On the other hand, they remain drugs of crucial importance in many other clinical pictures frequently associated with hypertension, such as: atrial fibrillation, angina pectoris, post-myocardial infarction and congestive heart failure [1,3]. Older betablockers, such as atenolol and propranolol, may not be preferred as antihypertensive drugs, and newer beta-blockers, especially with vasodilatory properties, such as carvedilol and nebivolol, should be considered in hypertensive patients [3]. However, the authors emphasize that we still need large, prospective randomized hypertension trials to evaluate primary prevention of cardiovascular outcomes, using these newer beta-blockers as preferred therapy for hypertension [3, 7]. Another important problem has been addressed in the paper by Verdecchia and colleagues [8], who try to answer the question of whether we have enough data to consider hypertension therapy with the application of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) together, and if so, in which group of patients [8]. They suggest that on the basis of existing evidence, ACEIs and ARBs should not be considered as a preferred antihypertensive combination [8]. On the other hand, patients with resistant hypertension, particularly with proteinuria, may essentially benefit from dual blockade of the renin-angiotensin system (RAS) in terms of further blood pressure (BP) reduction and control of proteinuria [8, 9]. This combination, however, dictates the need for careful monitoring for adverse events including hyperkalemia and worsening kidney function [8]. The problem of hypertension therapy in elderly patients was presented in this issue by Aronow [10]. He agrees with the current recommendation of ESH [1] and confirms that on the basis of numerous double-blind, randomized, placebo-controlled trials, antihypertensive drug therapy significantly reduces the number of cardiovascular events in elderly persons, even including octogenarians [1, 10]. The therapy of hypertension is inseparably connected to compliance and therapeutic inertia [11]. This important problem was presented in detail in the review by Chrostowska and Narkiewicz [12]. The authors emphasized that hypertension remains an area of medicine where major improvements must be made, since goal blood pressure levels are achieved too rarely [12]. They suggest that patients must become better informed, doctors must prescribe more aggressive hypotensive treatment and the healthcare systems must be more supportive [12]. They have no doubts that these efforts might translate into a further worldwide reduction of hypertension-related cardiovascular morbidity and mortality [12]....

Hypertension represents the most common cardiovascular risk factor, affecting more than 25% of the adult population in developed societies. Although beta-blockers have been previously shown to effectively reduce blood pressure and have been used for hypertension treatment for over 40 years, their effect on cardiovascular morbidity and mortality in hypertensive patients remains controversial and their use in uncomplicated hypertension is currently still under debate. According to the previous recommendations beta-blockers should not be preferred as first-line therapy in hypertension patients. This review summarizes the current knowledge on application of beta-blockers in patients with hypertension and discusses the most recent guidelines of the European Society of Hypertension (2009) on beta-blockers applications.

The combined use of angiotensin converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) poses a dilemma to clinicians. On the one hand, indirect evidence from compelling, but still surrogate outcome measures such as blood pressure and proteinuria suggest some merits of this combination. On the other hand, the outcome benefits of the ACEIs+ARBs combination in morbidity/mortality trials remain confined to patients with severe congestive heart failure (CHF) and reduced ejection fraction. Incidentally, most of the benefit offered by the ACEIs+ARBs combination in these patients was not driven by mortality, but by fewer rehospitalizations for CHF. Even in patients with renal disease and proteinuria, the combined use of ACEIs and ARBs, although highly effective in reducing urinary protein excretion, has not yet been proven to significantly delay end-stage renal disease and the need for dialysis. In the Ongoing Telmisartan Alone and In Combination With Ramipril Global Endpoint Trial (ONTARGET), the dual blockade of the renin angiotensin system did not produce additional outcome benefit over that afforded by ACE inhibition alone. Notably, however, patients with BP >160/100 mmHg at entry were excluded from ONTARGET, thus limiting the applicability of these results to the treatment of hypertension. The European Society of Hypertension guidelines do not suggest large-scale use of the ACEIs+ARBs combination in patients with hypertension. However, patients with resistant hypertension, particularly if proteinuria coexists, could benefit from this combination, which however requires close monitoring for adverse events,including hyperkalemia and worsening renal function.

Central arterial systolic blood pressure is a very important factor in the pathophysiology of cardiovascular diseases. Central arterial pressure is a better predictor of cardiovascular risk than peripheral brachial blood pressure. Measurement of central blood pressure is useful for a diagnosis of spurious systolic hypertension in young people. Antihypertensive drugs have a different impact on central blood pressure, for example angiotensin converting enzyme inhibitors, antagonists of angiotensin II receptors, calcium channel blockers more effectively lower central blood pressure than betablockers, despite all of those drugs (including beta-blockers) having a similar impact on peripheral pressure. This mechanism may be responsible for the beneficial effect of some antihypertensive drugs on cardiovascular end points observed in clinical trials, despite a low peripheral hypotensive effect. However, further clinical trials are required to provide more evidence for the prognostic and therapeutic implications of the measurement of central blood pressure before adopting its routine application in clinical practice.

The prevalence of secondary hypertension is lower than that of primary (essential) hypertension, but it is likely that it has been underestimated because appropriate tests were not generally performed. Hence, before embarking on a search for secondary hypertension physicians are generally advised to select populations of patients with a high pre-test probability of secondary forms of hypertension in order to maximize the positive predictive value and the gain in “ruling in” of the diagnostic tests. Based on updated information on prevalence and pathophysiology we herein critically review the general diagnostic strategy and the management of the main forms of secondary hypertension. In particular, strategies for identifying primary aldosteronism, the most frequent form of endocrine secondary hypertension, and for determining its unilateral or bilateral causes are discussed in details, because of the differences of treatment that requires adrenalectomy in the unilateral forms and mineralocorticoid receptor blockade in the bilateral forms. The tests available for the diagnosing pheochromocytoma, which is much rarer but extremely important to identify, as it can be fatal if unrecognized are also discussed, with emphasis on the recent developments in genetic testing. Renovascular hypertension is also a common curable form of hypertension, which should be identified as early as possible to avoid the onset of cardiovascular target organ damage and events, is also discussed.

Atrial fibrillation is the most common clinically significant cardiac arrhythmia and is associated with markedly increased risks of cardiovascular diseases. Atrial fibrillation and hypertension often coexist and are both responsible for considerable morbidity and mortality. Aggressive treatment of hypertension, especially with a blocker of the reninangiotensin system, may postpone or prevent development of atrial fibrillation and reduce thromboembolic complications. Awareness of the risk of developing atrial fibrillation in hypertensives may be of great importance and focus on prevention of atrial fibrillation development with optimal antihypertensive treatment may reduce morbidity, mortality and health care expenditures.

Malignant hypertension (MHT) is the most severe form of hypertension which is clinically defined as the presence of high blood pressure in association with bilateral retinal haemorrhages and/or exudates, with or without papilloedema. The aim of this review article is to discuss whether MHT is a problem which is truly becoming a rarity, or is it simply a problem with underdiagnosis. Despite the improvements in the general management of hypertension, we have no strong evidence of a declining incidence of MHT. In contrast, this disorder may appear to become even more common worldwide taking into account the growing hypertensive population in the developing countries. Although the diagnostic criteria of MHT appear to be simple and straightforward, the prompt diagnose of MHT may be difficult in substantial proportion of patients who often present with clinical symptoms only at a late stage of irreversible target organ changes. Furthermore, MHT and the accompanying ocular changes may gradually resolve making retrospective diagnosis problematic, whilst persistent target organ damage can drive the development of complications and have a negative prognosis in these patients. Clearly, MHT should not yet be forgotten nor ignored by clinicians.

Double-blind, randomized, placebo-controlled studies have documented that antihypertensive drug therapy decreases cardiovascular events in older persons. In the Hypertension in the Very Elderly Trial, patients aged 80 years and older treated with antihypertensive drug therapy had at 1.8-year follow-up, a 30% insignificant decrease in fatal or nonfatal stroke, a 39% significant decrease in fatal stroke, a 21% significant decrease in all-cause mortality, a 23% insignificant decrease in death from cardiovascular causes, and a 64% significant decrease in heart failure. The goal of treatment of hypertension in older persons is to decrease the blood pressure to <140/90 mm Hg and to <130/80 mm Hg in older persons with diabetes or chronic renal disease. Elderly persons with diastolic hypertension should have their diastolic blood pressure reduced to 80 to 85 mm Hg. There are no randomized controlled clinical trials supporting a target blood pressure of less than 130/80 mm Hg in elderly persons. The optimum diastolic blood pressure goal in elderly persons is unclear. Diuretics should be used as initial therapy in persons with no associated medical conditions. The selection of antihypertensive drug therapy in persons with associated medical conditions depends on their medical conditions. If the blood pressure is > 20/10 mm Hg above the goal blood pressure, drug therapy should be initiated with 2 antihypertensive drugs. Other coronary risk factors must be treated.

In 2009, the European Society of Hypertension (ESH) has developed a document updating the recommendations for the diagnosis and treatment of hypertension issued in 2007. The main elements of novelty refer to the assessment of organ damage, the blood pressure thresholds for treatment initiation as well as the blood pressure goals, the use of drug combination treatment and the therapeutic intervention in specific clinical conditions. This paper will review the novelties of the ESH update document and the implications of the “new guidelines” for current clinical practice.

Antihypertensive agents exert different effects on insulin sensitivity, lipids and haemostasis. However, most studies assessing these effects were small and short-term yielding conflicting results. Moreover, it has not been established whether the impact of antihypertensive drugs on insulin sensitivity, lipids, thrombosis and fibrinolysis adds to or attenuates vascular risk reduction. On the other hand, new onset type 2 diabetes mellitus (T2DM) appears to be more frequent in patients treated with β-blockers and diuretics, whereas angiotensin converting enzyme inhibitors and angiotensin receptor blockers might reduce the risk for T2DM and calcium channel blockers have a neutral effect. Therefore, the risk of developing T2DM should be considered when selecting an antihypertensive agent. This review discusses the differential effects of antihypertensive drugs on insulin sensitivity, lipids and haemostasis and considers their association with vascular risk.

Hypertension, the leading cause of mortality and the third largest cause of disability, is poorly controlled worldwide. The failure to control hypertension takes an unacceptable toll on patients and their families. In addition to the personal cost, to the individual patient, uncontrolled hypertension creates huge, avoidable economic burdens when viewed in terms of the general population. Almost one-half of patients drop out entirely from treatment within 1 year. This review summarizes key challenges related to hypertension management with special focus on patient compliance. Firstly, we will present consequences of poor blood pressure control. Secondly, methods of patient compliance assessment will be reviewed. Thirdly, we will present recent studies assessing adherence with hypertension treatment. Finally, we will review potential solutions to improve patient compliance and blood pressure control which are of crucial importance for reduction of hypertension-related morbidity and mortality.

Abdominal Aortic Aneurysm (AAA) is a common, progressive, and potentially lethal vascular disease. A major obstacle in AAA research, as well as patient care, is the lack of technology that enables non-invasive acquisition of molecular/ cellular information in the developing AAA. In this review we will briefly summarize the current techniques (e.g. ultrasound, computed tomography, and magnetic resonance imaging) for anatomical imaging of AAA. We also discuss the various functional imaging techniques that have been explored for AAA imaging. In many cases, these anatomical and functional imaging techniques are not sufficient for providing surgeons/clinicians enough information about each individual AAA (e.g. rupture risk) to optimize patient management. Recently, molecular imaging techniques (e.g. optical and radionuclide- based) have been employed to visualize the molecular alterations associated with AAA, which are discussed in this review. Lastly, we try to provide a glance into the future and point out the challenges for AAA imaging. We believe that the future of AAA imaging lies in the combination of anatomical and molecular imaging techniques, which are largely complementary rather than competitive. Ultimately, with the right molecular imaging probe, clinicians will be able to monitor AAA growth and evaluate the risk of rupture accurately, so that the life-saving surgery can be provided to the right patients at the right time. Equally important, the right imaging probe will also allow scientists/clinicians to acquire critical data during AAA development and to more accurately evaluate the efficacy of potential treatments.

Small, dense low density lipoprotein (sdLDL) particles are considered an emerging cardiovascular risk factor. Obese patients with mixed dyslipidaemia frequently have elevated sdLDL cholesterol (sdLDL-C) levels. Therefore, agents that favourably modulate the LDL phenotype may be of clinical value in these patients. We review the efficacy of anti-obesity and lipid lowering drugs other than statins on LDL subfractions in patients with mixed dyslipidaemia primarily focusing on those who are overweight/obese. The literature search was based on PubMed listings up to 26 November 2009. In most studies ezetimibe decreases the large and medium LDL subclasses and, to a lesser extent, the sdLDL particles, while it does not substantially influence LDL size. Fibrates and niacin reduce sdLDL particles and shift LDL size towards large, buoyant LDL particles. More studies are needed to elucidate the effects of fish oils and resins on LDL phenotype. Orlistat and rimonabant have been associated with reductions in sdLDL-C levels along with an increase in LDL particle size. We did not find any literature describing the effect of sibutramine on sdLDL profile. Treatment with fibrates and niacin seems to be beneficial in patients with mixed dyslipidaemia. The addition of orlistat may further improve LDL phenotype in overweight/obese patients.

The 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors (statins) are a class of drug used to lower low-density lipoprotein (LDL) levels. However, in recent years, statins have been shown to possess a pleiotropic effect beyond its cholesterol lowering ability, including attenuating the effect of ischaemia reperfusion injury. This review considers the biomolecular processes that may lead to this beneficial effect.

Adiponectin has been implicated in the pathogenesis of coronary heart disease. We review the literature describing the effect of lipid-lowering agents on adiponectin bioavailability. Statins exert variable effects that can be influenced by patient-dependent characteristics (i.e. diabetes or insulin resistance). Fibrates and especially niacin can raise adiponectin levels. The impact of plant sterols, ezetimibe and ω-3 fish oils on adiponectin in humans remains to be defined.There was no literature on whether resins can alter adiponectin levels As far as mechanisms are concerned, statins enhance peroxisome proliferator-activator receptor (PPAR)-γ activation and have antioxidant or anti-inflammatory potential. Niacin, ω-3 fatty acids, plant sterols and bezafibrate primarily act by increasing PPAR-γ activity and possibly by reducing oxidative stress or inflammation. Both fibrates and ω-3 fish oils act as synthetic ligands for PPAR-γ. Hypolipidaemic drugs can affect adiponectin bioavailability, although the impact depends on the individual drug administered and patient characteristics. However, with the exception of niacin, the results observed are not conclusive.

Diabetic nephropathy is the leading cause of end-stage renal failure in the Western World and accounts for significant morbidity and mortality in patients with diabetes. Although hyperglycaemia and hypertension are established key determinants in the development of the complication, recent studies suggest that a low-grade inflammatory response may also play a role. Monocyte Chemoattractant Protein 1 (MCP-1), a potent chemokine produced by renal cells, has emerged as a very important player in this process. Specifically, it has been shown that MCP-1 is overexpressed in the kidneys from diabetic animals. Furthermore, there is amelioration of both functional and structural abnormalities in MCP-1- knockout mice in the setting of concomitant diabetes. Over recent years the cellular mechanisms linking MCP-1 to kidney injury have been increasingly delineated and, in particular, it has become evident that MCP-1 contributes to the kidney damage not only by inducing mononuclear cell recruitment, but also by direct activation of resident renal cells. The present review focuses on the most significant advances in understanding the role of MCP-1 in diabetic kidney disease and future potential therapeutic implications.

Introduction: Chlamydia pneumoniae was the first pathogen linked with carotid atherosclerotic changes and plaque rupture. Currently, other common pathogens are also under investigation as potential contributors. Methods: A systematic review of PubMed and Scopus databases was performed. Studies evaluating the infectious burden between symptomatic and asymptomatic patients with carotid plaque disease (CPD) were included. Furthermore, trials referring to common infectious agents (other than C. pneumoniae) incriminated for contribution in CPD were analyzed separately. Results: Forty four studies were identified; 6 investigated the connection of infection with the plaque destabilization, 3 of which reported a significant association between infection and symptoms. Studies retrieved for the investigation of agents other than C. pneumoniae were: 18 about viruses, 16 about other bacteria and 4 examining both. Significant association or high detection rates of agents’ genome or specific antibodies with CPD characteristics (intima media thickness values > 1mm or symptoms) were found in a number of studies: 3 for HCV, 2 for CMV and 1 for enterovirus, EBV, HBV, and HIV. Moreover 4 studies about dental pathogens (i.e. Porpyromonas gingivalis), 5 about H. Pylori strains and 1 about Borrelia burgdorferi were identified supporting a positive association. Conclusion: There is considerable evidence supporting the contribution of other commonly encountered pathogens in the pathogenesis and rupture of the carotid plaque. Research in this direction should not be abandoned and further studies are necessary to elucidate the exact role of common infections in the pathogenesis and development of CPD and how this can be translated into novel pharmacological approaches for prevention and treatment.