Autoren-und Stichwortsuche HMG-CoA-Reductase Inhibitors / Statins : An Improval for Patients suffering from Peripheral Vascular Disease

In the past, numerous studies have investigated the benefit of statin use in patients suffering from coronary arterial disease and the adjacent diseases for cardiac tissue. Up to now, more than 31,000 patients participated in these trials and we can say without any doubt that for all of those under statin therapy it became an enormous advance in reducing their cardiovascular morbidity. Nevertheless, atherosclerosis and cardiovascular morbidity is not only limited to specific areas and so peripheral vascular disease became a major clinical problem, especially for elder patients. Unfortunately, statin use in patients with peripheral vascular disease is not as well investigated as it is in patients with coronary arterial and associated heart diseases. Recent published data showed the possible power of statin therapy in patients with peripheral arterial disease. The results and possible benefits seem to warrant a more detailed view upon the published papers. Thus, this review strikes the current trials and studies concerning statins in their effect, use and benefit in patients suffering from peripheral vascular disease in order to elucidate specific functions and their associated results in a cohort of such patients. Kurzfassung: HMG-CoA-Reduktase-Inhibitoren/ Statine: Verbesserung des kardiovaskulären Krankheitsbildes bei Patienten mit peripherer arterieller Verschlußkrankheit. In der Vergangenheit haben verschiedene Studien den positiven Nutzen der Einnahme von Statinen, besonders bei Patienten mit koronarer Herzkrankheit und damit assoziierten Erkrankungen des kardialen Gewebes, gezeigt. Bisher nahmen mehr als 31.000 Patienten an diesen Studien teil, so daß wir heute ohne jeden Zweifel behaupten können, daß diejenigen, denen Statine verabreicht wurden, eine enorme Verbesserung ihres kardiovaskulären Krankheitsbildes erfuhren. Nichtsdestotrotz bleiben kardiovaskuläre Morbidität und Atherosklerose nicht auf bestimmte Gefäßregionen begrenzt, so daß die periphere arterielle Verschlußkrankheit (PAVK) besonders für ältere Patienten ein großes klinisches Problem darstellt. Leider ist der Nutzen der Statintherapie bei Patienten mit PAVK nicht so gut erforscht wie bei Patienten mit koronarer Herzkrankheit. Kürzlich veröffentlichte Daten zeigten dabei das mögliche positive Potential der Statintherapie bei Patienten mit PAVK. Diese Resultate und der mögliche positive Nutzen initiierten daher eine genauere Betrachtung des Sachverhalts der bisher publizierten Artikel. Daher soll sich dieser Review mit den aktuellen Studien und Versuchen, die den Effekt, Gebrauch und Nutzen der Statintherapie bei Patienten mit peripherer arterieller Verschlußkrankheit behandeln, auseinandersetzen, um den genauen Gebrauch und die daraus folgenden Resultate in einer Patientenkohorte ins genauere Betrachtungslicht zu rücken. J Kardiol 2004; 11: 84–9. For personal use only. Not to be reproduced without permission of Krause & Pachernegg GmbH. 86 J KARDIOL 2004; 11 (3) Statins in PAVK coagulation, vessel wall contraction and relaxation, so that endothelial dysfunction maintained the investigative field for vascular disease [9]. Indeed, there is now evidence that statins improve endothelial function in a number of ways, increasing production of nitric oxide, promoting blood flow, dampening inflammation, antagonizing thrombogenicity, and reducing endothelial vasoresponses [10]. In patients with hypercholesterolaemia, endotheliumdependent vasodilator function is impaired in coronary and systemic arteries [11, 12]. The proposed mechanism for such dysfunctional vasomotion involves an enhanced inactivation and decreased production of NO by endothelial cells [13, 14]. Vasomotor dysfunction is extended to conduit and small resistance vessels and can be ameliorated after some weeks of statin treatment or immediately after LDL apheresis [15–18]. In addition, statins might influence vascular tone by modulating the expression of endothelial vasoactive factors, such as endothelin-1, or by their direct effects on calcium inflow response in vascular myocytes [19, 20]. Reendothelialization is a limiting step in the improvement of arterial function and perfusion after plaque disruption. Llevadot et al. [21] and Dimmeler et al. [22] demonstrated that inhibitors of HMGCoA reductase also promote vasculogenesis, which is also in ischaemic limbs of normo-cholesterolaemic rabbits possible [23]. Endothelial cell progenitors have been shown to leave the bone marrow in response to cytokines or ischaemic injury, and they are recruited to the periphery to promote compensatory new blood vessel formation. In male persons, statin therapy is associated with a significant increase in the number of circulating endothelial progenitor cells (EPCs) after 1 week of treatment [24]. Thus, given the established role of circulating EPCs in endothelial repair, the differentiation and mobilization of EPCs after short-term statin treatment may contribute potentially to the rapid amelioration of endothelial function. Secondly, Akt activation has emerged as an indispensable signalling gateway at the crossroads between angiogenesis and endothelial stem cell recruitment and differentiation. Walter et al. [25] observed that statin treatment accelerates the reendothelialization of balloon injured arterial segments in rats by mechanisms related to the phosphatidylinositol 3-kinase/ Akt pathway. The Akt protein kinase is a multifunctional regulator involved in cell growth, survival, and glycogen synthesis [26]. Statins rapidly induce phosphorylation of Akt at serine residue 473, which increases its protein kinase activity. In consequence of this mechanism, statins increase EPC proliferation, survival, and mobilization to sites of endothelial denudation [22, 25]. Statin-Mediated Effects on Inflammation Statins reduce the residence time of LDL particles in the circulation and so the substrate available for generation of oxidized LDL, the prerequisite for reducing the inflammatory stimulus. A large number of trials observed that statin treatment can result in local inflammatory modification. In a rabbit model of diet-induced atherosclerosis, lipid lowering by diet or statin treatment reduced the content and activation of macrophages in atherosclerotic plaques [27–29]. In the same model, lipid lowering equally promoted the accumulation of mature smooth muscle cells and collagen in the atherosclerotic intima, thereby increasing tensile strength within the plaque [30, 31]. The inflammatory activity measured by systemic inflammatory markers decreased after statin treatment. Clinical trials involving pravastatin, cerivastatin, lovastatin, simvastatin, and atorvastatin treatments in dyslipidaemic patients have consistently demonstrated a decrement in plasma CRP levels, which is a marker of overall systemic inflammation unrelated to their effects on LDLor HDL-cholesterol levels [32–35]. In the Cholesterol and Recurrent Events (CARE) trial, patients showed progressive reduction of CRP levels (up to 37.8 %) during the 5-year follow-up period under pravastatin treatment. This might have been an indication that the anti-inflammatory effect is progressive and maintained over a prolonged period [35]. The effect of statins on systemic inflammatory markers may result from lipid-lowering-dependent and -independent actions [36]. Arterial wall macrophages, stimulated by oxidized LDL, secrete proinflammatory cytokines, such as interleukin-6, which, in turn stimulate hepatic production of CRP and other acute-phase reactants [36]. According to this, Rezaie-Majd et al. investigated the potential effects of simvastatin decreasing proinflammatory cytokines [37]. They demonstrated in a cohort of 107 hypercholesterolaemic patients, who have been treated with either 20 or 40 mg simvastatin daily, caused a significant reduction in serum level of IL-6, IL-8 and monocyte chemoattractant protein-1. They discussed that this reduction might contribute to attenuation of the systemic inflammatory marker, CRP in patients with hypercholesterolaemia. The authors showed in the same patients cohort, that simvastatin reduced the expresTable 2: Effects of statins potentially contributing to protection and treatment in PAD • Cholesterol lowering • Amelioration of endothelial cell dysfunction by increase of endothelial NO • Anti-inflammatory effects – Decrease of serum level of CRP – Decrease of serum level of proinflammatory cytokines – Decrease of membran bound and soluble adhesion molecules • Inhibition of platelet activation and enhancement of fibrinolysis – Decrease of thromboxane A2, vWf, PAI-1 – Increase of tPa • Increase of circulating endothelial progenitor cells – Akt activation inducing angiogenesis Table 1: Comparison of statins Atorvastatin Cerivastatin Fluvastatin Lovastatin Pravastatin Rosuvastatin Simvastatin Solubility Lipophilic Hydrophilic Hydrophilic Lipophilic Hydrophilic Hydrophilic Lipophilic Protein binding > 98 % > 99 % > 99 % > 95 % 50 % 90 % 98 % Active metabolites Yes Yes No Yes Yes Minor Yes Half-life 14 h 2–3 h 0.7 h 3 h 2.8 h 19 h 2–3 h Metabolism by 3A4 3A4 2C9 3A4 None Limited cyp450 3A4 cytochrome isoform 2C8 Renal excretion < 5 % 30 % 6 % 10 % 60 % 10 % 13 %