Current Vascular Pharmacology - Volume 10, Issue 6, 2012

Carotid stenosis is frequent in the general population, especially in elderly people and is associated with a high risk of stroke and vascular events. In patients with asymptomatic carotid stenosis the overall annual risk of ipsilateral stroke has dramatically decreased over the past decades, due to improvement in medical management. Asymptomatic carotid stenosis is probably a better indicator of generalized atherosclerotic disease than of stroke risk, with an average risk of nonstroke death (mainly due to ischemic heart disease) generally higher than the risk of ipsilateral stroke. Management of risk factors, antiplatelet therapy, and statins are highly beneficial in these patients. Carotid surgery in patients with asymptomatic carotid stenosis is associated with a small absolute benefit compared to medical treatment. The prognosis of patients with symptomatic carotid stenosis is dramatically different from that of patients with asymptomatic carotid stenosis because the risk of stroke on medical treatment alone is very high and highest during the first few days and weeks. In these patients, endarterectomy is highly beneficial and the absolute benefit of is increased in patients with 70- 99% stenosis, men, patients over 75 years, and in those treated within 2 weeks after the last event. The meta-analysis of the 3 major European trials comparing endarterectomy to stenting in symptomatic stenosis has shown an increased risk of perioperative risk of any stroke or death in the stenting group (74% increase in risk in patients treated with stenting). However, the risk of stroke or death after stenting and surgery were equivalent below the age of 70 whereas there was a two-fold increase in risk of stenting over endarterectomy above this age. Thus, surgery remains the first line method in most cases but stenting is potentially an alternative in young patients.

High blood pressure (BP) along with smoking habit and lipid disorders are the most important and modifiable risk factors for cardiovascular diseases. However, the prevalence of high BP has grown progressively over time with a progressive increase not only in the absolute number of patients but in the proportion of those showing BP values out of control. The increasing world-wide prevalence of hypertension and the related increase in burden of the disease due to diagnosis, treatment and management of the complications mandates both Health Authorities and research institutions to find out new strategies to improve the BP control. So, one of the main questions is which are the possible perspectives for the future of high BP management, and in particular how can we face the problem of hypertension in the near future? Four main points will be shortly discussed: the genetic contribution to hypertension development and control, the availability of effective preventive strategies, the improvement of disease management, and the role of extensive control of concomitant risk factors. It is relatively easy to suppose that the integration of the best available knowledge with the more recent diagnostic and therapeutic achievements will improve the management of hypertension through a more effective detection of subjects at risk who will undergo an earlier diagnosis leading to a more tailored, tolerated and effective treatment of the hypertensive disease. This means that the future direction of the hypertension management is the simpler: the patient instead of the disease.

The lecture covered the role of lipids in the pathogenesis and treatment of non-cardiac vascular disease. The following conditions were considered: abdominal aortic aneurysms (AAAs), peripheral arterial disease (PAD), carotid artery disease and atherosclerotic renal artery stenosis (ARAS).

In this issue of Curr Vasc Pharmacol, Pfeiffer et al. [1] and Glorioso et al. [2] report the efficacy and tolerability of aliskiren/amlodipine single-pill combinations (SPCs) in patients with inadequate blood pressure (BP) response to amlodipine or aliskiren monotherapy, respectively.

Many patients with hypertension will require multiple antihypertensive drugs to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combinations (SPCs) in patients with mild-to-moderate hypertension who were non-responsive to aliskiren monotherapy. After a 4-week run-in with aliskiren 300 mg, patients with mean sitting diastolic BP (msDBP) ≥ 90 and <110 mmHg were randomized to oncedaily aliskiren/ amlodipine 300/10 mg or 300/5 mg, or aliskiren 300 mg for 8 weeks. Aliskiren/amlodipine SPCs provided significantly greater mean reductions in mean sitting systolic BP/msDBP (300/10 mg, 18.0/13.1 mmHg; 300/5 mg, 14.4/10.5 mmHg) than aliskiren 300 mg (6.4/5.8 mmHg) at week 8 endpoint. This represents additional mean reductions of 11.6/7.2 mmHg (300/10 mg) and 8.0/4.7 mmHg (300/5 mg) over aliskiren alone (both p<0.0001). Significantly more patients achieved BP control (<140/90 mmHg) with aliskiren/amlodipine 300/10 mg (65.5%) and 300/5 mg (56.6%) than with aliskiren (31.5% both p<0.0001). Aliskiren, alone and in combination with amlodipine, was well tolerated, with a slightly higher incidence of adverse events with SPCs (29.0-30.1%) than with monotherapy (22.7%). In conclusion, aliskiren/amlodipine SPCs offer an effective next step for patients who have an inadequate BP response to aliskiren alone.

Intravascular hemolysis is a major component of anemia in sickle cell disease (SCD). Plasma extracellular hemoglobin (ECHb) liberated by intravascular hemolysis has deleterious effects on the vasculature. ECHb scavenges nitric oxide (NO) and promotes the pathogenesis of several clinical events including pulmonary hypertension, priapism and non-hemorrhagic strokes. ECHb reduces the bioavailability of NO which down-regulates platelet activation, leading to platelet aggregation and vascular clot formation. Recently we have identified an additional mechanism whereby increased hemolysis can lead to a prothrombotic state in SCD by increasing the activity of von Willebrand factor (VWF), a multimeric plasma glycoprotein secreted by the endothelium. Our studies show that ECHb binds to the A2-domain on VWF at the proteolytic site of the metalloprotease, ADAMTS13, and blocks VWF cleavage in vitro. Elevated ECHb is associated with high levels of ultralarge and hyperactive VWF multimers in SCD patients' plasma. A sub-population of VWF multimers, bound to ECHb is hyperactive, and exists in greater quantity in SCD patients' plasma compared to normal controls. These results suggest a possible role for plasma ECHb in the accumulation of hyperactive VWF multimers in vivo that may mediate thrombotic and vasoocclusive complications in SCD patients.

Resting endothelial cells lining the inner surface of blood vessels have anti-thrombotic and anti-inflammatory actions, critical for maintaining normal vascular homeostasis. Upon localized or systemic stimulation, endothelial cells are activated to secrete bioactive molecules; among them is von Willebrand factor (VWF). Freshly secreted VWF is enriched in ultra-large (UL) forms that are anchored to endothelial cells to form long string-like structures, to which platelets tether and aggregate. This prothrombotic event is normally prevented by proteolytic cleavage of ULVWF multimers by ADAMTS-13 at a single peptide bond of Tyr1605-Met1606 in the A2 domain. The cleavage reduces the size and adhesion activity of (UL)VWF multimers. Lacking this cleaving activity due to mutations in the ADAMTS13 gene or autoantibodies against the metalloprotease is associated with systemic microvascular thrombosis found in patients with thrombotic thrombocytopenic purpura (TTP). Recombinant ADAMTS-13 has the potential to be a therapeutic agent to reduce prothrombotic activity of ULVWF multimers. Alternatively, blocking an interaction between ULVWF and its platelet receptor could achieve the same therapeutic goal. This review discusses potentials of using recombinant ADAMTS-13 and VWF-blocking agents as therapeutics for TTP and other acquired ADAMTS-13 deficiencies.

Portal hypertension is a hemodynamic abnormality that involves a high risk of disability as well as a reduced life expectancy in patients with cirrhosis. Progress in the knowledge of pathophysiology of portal hypertension has opened a new perspective for different pharmacological approaches. In this context, the pleiotropic actions of statins on endothelial cell function have emerged as new options to reduce portal pressure levels by targeting multiple molecular pathways involved in hepatic vascular homeostasis. We highlight how statins may target some molecular pathways involved in the pathophysiology of portal hypertension and how these drugs may correct impaired hepatic vascular tone.

Most patients with hypertension will require treatment with at least two antihypertensive agents to achieve blood pressure (BP) control. This double-blind study evaluated the efficacy and safety of aliskiren/amlodipine single-pill combination (SPC) therapy in patients with mild-to-moderate hypertension who are inadequately responsive to amlodipine monotherapy. Patients with mean sitting diastolic BP (msDBP) ≥ 90 and < 110 mmHg after 4 weeks' treatment with amlodipine 10 mg were randomized to once-daily aliskiren/amlodipine 300/10 mg (n = 279) or 150/10 mg (n = 285) or amlodipine 10 mg monotherapy (n = 283) for 8 weeks. Aliskiren/amlodipine 300/10 and 150/10 mg SPCs provided significantly greater reductions in mean sitting systolic BP/msDBP (14.4/11.0 and 11.0/9.0 mmHg, respectively) than amlodipine 10 mg (8.2/7.2 mmHg) at week 8 endpoint. This represents additional mean reductions of 6.2/3.8 mmHg (300/10 mg) and 2.8/1.7 mmHg (150/10 mg) over amlodipine alone (all P < 0.01). Significantly more patients achieved BP control (< 140/90 mmHg) with aliskiren/amlodipine 300/10 mg (58.8%) than amlodipine 10 mg (38.4%; P < 0.0001). Aliskiren/amlodipine SPCs were generally well tolerated. In conclusion, aliskiren/amlodipine SPCs offers an effective option for management of patients who have an inadequate BP response to amlodipine alone.

Energy homeostasis in mammalians is a teleological process regulated by the interplay between caloric intake and energy expenditure. Incretins are a significant component of the complex homeostatic network regulating the metabolic state in humans. This narrative review will focus on the basic concepts regarding incretins physiology and their regulatory feedback mechanisms affecting energy homeostasis. In this context, glucagon-like peptide 1 (GLP-1) promotes satiety and weight loss through centrally and peripherally mediated pathways. On the other hand, gastric inhibitory peptide (GIP) is implicated in energy storage by its actions on adipose tissue. Understanding this biological model requires a holistic approach, since it is dually manifested by promoting weight reduction, in the case of GLP-1, or favoring lipid accumulation, in the case of GIP. The complete spectrum of incretin actions related to energy homeostasis is yet to be fully elucidated. Currently, new drugs based on incretin physiology are available for treatment of type 2 diabetes mellitus, whereas the implication of similar drugs in the treatment of obesity is under investigation. These agents exert several beneficial effects that minimize cardiovascular risk.