Saturday, December 01, 2007
Statins en AF en ACE-remmers
Statin Therapy
Statins are well-known for their lipid-lowering ability and consequently their cardioprotective effects. The reduction of cholesterol via activity at the 3-hydroxymethylglutaryl-coenzyme A (HMG-CoA) is well-established, and its effect on reducing cardiovascular events has been well documented. It is now thought that their cardioprotective effects can at least partially be explained by their so called "pleiotropic effect" ( Table 3 ). In a study by Nissen et al.,[34] CRP levels were dramatically reduced from baseline in the 80-mg atorvastatin group compared with 40-mg pravastatin group (36.4% vs. 5.2%, p < 0.001), suggesting that statins might possess some anti-inflammatory properties.
The exact mechanism of how statins exert their pleiotropic effects is not well understood and is the current focus of much research.[35] In vitro studies have suggested that stabilization of endothelial cells offer a partial explanation for its nonlipid-lowering effects. Leukocyte adhesion to the endothelium occurs early on in atherosclerosis and is mediated by the release of cytokines. Statins have been found to selectively inhibit leukocyte-function antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, paramount for the process of adhesion of inflammatory cells to the endothelium.[36] Other studies have shown that statins can also diminish migration and proliferation of leukocytes to endothelial membrane and even induce apoptosis in smooth muscle cells, endothelial cells, and macrophages, while reducing inflammation through suppression of CRP and IL-6.[35-38]
Whereas statins primary role is to reduce cholesterol formation by suppressing the formation of mevalonate, it is through the inhibition of mevalonate that the other pleiotropic effects of statins are observed. Inhibition of mevalonate diminishes the production of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are integral in the prenylation process of signal transducers, such as G-proteins, Rho, and Ras. Thus, protein-protein interactions needed for initiation of inflammatory-mediated pathways are interrupted.[35-38]
Animal Studies. Initial studies in dogs have found that atorvastatin prevents AF by inhibiting inflammation in a canine sterile pericarditis model.[39] The CRP levels were decreased, atrial effective refractory period (AERP) was increased, atrial conduction time decreased, and AF duration was diminished in the atorvastatin arm on post-operative day 2. In another similar study in a canine model of inducing AF by rapid atrial pacing, simvastatin-treated dogs had longer AERP and consequently shorter duration of AF.[40]
Clinical Trials. Very few studies of statin therapy in patients with AF have been published ( Table 4 ). One of the first studies to report a beneficial effect of chronic statin use on AF was a retrospective analysis of the recurrence rate of persistent lone AF in 62 patients receiving statin therapy undergoing direct current cardioversion (DCCV). Patients receiving chronic statin therapy had a lower recurrence rate after DCCV (40% vs. 84%, p = 0.007) at an average follow-up of 44 months, with the benefit of statin therapy reaching clinical and statistical significance after 3 to 4 months of therapy ( Table 4 ). Not all patients in this trial had evidence of structural heart disease.[41] These results could not be duplicated in 114 patients undergoing DCCV on pravastatin therapy.[42] The different outcomes between these 2 studies might be explained by the limited duration and dosage of statin therapy before and after DCCV and by the greater percentage of patients that had structural heart disease in the latter study. Another possibility is the innate difference in the ability of different statins to attenuate inflammation.
Another study by Young-Xu et al.[43] examined 449 patients with coronary artery disease in sinus rhythm and followed them prospectively for up to 5 years to assess the incidence of AF while receiving a statin of any brand. Eight percent of regular-statin users (p = 0.01), 10% of intermittent-statin users (p = 0.11), and 15% of nonstatin users developed AF over the course of 5 years. These results were independent of the lipid-lowering effects of statin, suggesting that the pleiotropic effect of statins might have contributed to the reduction in AF.
In a more recent study, Dernellis and Panaretou[44] examined the effects of atorvastatin in patients with PAF. Eighty patients were randomized into 40 mg of either atorvastatin or placebo. In the atorvastatin arm, CRP levels were lower (decreased by 2.4 from baseline, p = 0.01) and resolution of PAF was seen in 26 of 40 patients (p < 0.01) at 6-month follow-up. This study further supports the notion that CRP can be considered as an independent risk factor for AF.
The overall results of these trials support the idea that statin therapy might affect the natural history of AF by ameliorating the inflammatory process.
Glucocorticoids
Most of the initial studies involving glucocorticoid therapy in AF were done in patients undergoing cardiovascular surgery, and the results were equivocal. Early studies by Chaney et al.[45] did not find any significant benefit to steroid administration to patients undergoing CABG; however, Yared et al.[46] in a study of 216 patients undergoing cardiothoracic surgery found that dexamethasone administration perioperatively decreased the incidence of post-operative AF in the first few days after surgery. Inflammatory markers (i.e., CRP, IL-6, and so forth) were not measured in this study. More recently, Yared et al.[47] reported on the outcome of 78 patients undergoing combined CABG and valve surgery, who were randomized to receive either dexamethasone or placebo before surgery. In this study, dexamethasone did not affect the incidence of perioperative AF. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes. Most recently, another group from Finland showed in a prospective, randomized, double-blind study that the use of 100 mg cortisone, given intravenously immediately before cardiac surgery and continued for 3 consecutive days, significantly decreases the incidence of AF after cardiac surgery by 15%.[48]
One major prospective trial examined the effects of adding methylprednisolone to propafenone in AF patients undergoing pharmacological cardioversion to assess the recurrence rate. The methylprednisolone-treated group experienced an 80% decrease in CRP levels (p < 0.001) within the first month, which was maintained throughout the duration of the study. This corresponded to a reduction of AF recurrence from 50% in the placebo group to 9.6% in the methylprednisolone group (p < 0.001).[22]
Angiotensin-converting Enzyme Inhibitors (ACE-Is)
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) are 2 classes of drugs that act on the renin-angiotensin system (RAS). The RAS is intimately involved in the pathophysiology of various cardiovascular diseases such as hypertension, congestive heart failure, and ischemic heart disease. Studies have now linked the RAS gene polymorphisms to the development of AF.[49] These results might indicate that angiotensin II might be involved in atrial structural and electrical remodeling in patients with AF.[50]
The inhibition of the RAS and consequently of angiotensin II might have protective effect on remodeling.[51,52] It is known that angiotensin II is a potent promoter of atrial fibrosis by stimulating mitogen-activated protein kinases and extracellular signal-related kinase, which contributes to fibrosis formation and AF duration via expression of TGF-ß.[53] Furthermore, angiotensin II also increases atrial pressure, leading to greater atrial stretch, which reduces AERP and increases intra-atrial conduction time—all of which are factors in the initiation and maintenance of AF. Furthermore, it is now postulated that ACE-Is/ARBs can modulate potassium and calcium ion channels, ameliorating the deleterious effects of both atrial structural and electrical remodeling.[50,51]
Animal Studies. Much of our current understanding of ACE-Is and their effect on AF originates from research on canine models with either rapid atrial or ventricular pacing[51,54,55] to induce AF and/or heart failure, respectively. The ACE-I-treated dogs consistently had longer AERP, shorter AF duration, diminished atrial apoptosis, and less atrial remodeling. Similar effects were not seen in dogs treated with hydralazine and isosorbide mononitrate, suggesting that the inhibition of the RAS (via ACE-I) might be responsible for the attenuated atrial electrical and structural remodeling.[52]
Human Studies. There are only a few prospective human trials that correlate whether ACE-Is/ARBs can modulate the duration or onset of AF[56] ( Table 5 ). However, post hoc analysis of large, randomized ACE-I trials provided an opportunity to study their effects on development of AF.
Clinical Trials in Patients With Normal Ejection Fraction. In 1 particular retrospective study, hypertensive patients with PAF were treated with ACE-I and followed for up to 8 years ( Table 5 ). The ACE-Is were found to prevent the progression of PAF to chronic AF.[57] Two other prospective trials found benefit in ACE-I use on incidence of AF. One study found that the addition of enalapril to amiodarone in patients undergoing DCCV had lower recurrence of AF (4.3% in amiodarone with ACE-I vs. 14.7% in amiodarone alone, p = 0.067) and maintained longer duration of sinus rhythm.[58] In another study, the total number of cardioversion attempts for AF were lower (24 in ACE-I vs. 34 in calcium channel blockers, p < 0.001) and the number of hospital stays for AF were fewer (p = 0.02) in the ACE-I group.[59] In another retrospective analysis by L'Allier et al.[60] on 10,926 patients treated with either ACE-I or calcium channel blockers for AF, those in the ACE-I arm had lower incidence of new-onset AF, longer time to onset of AF, and fewer hospital stays as a consequence of AF.
Clinical Trials in Patients With Left Ventricular Dysfunction. Retrospective analysis of large scale randomized trials suggest that ACE-I might have some benefit in reducing incidence of AF in patients with depressed ejection fraction (T able 4 ). In the TRACE (Trandolapril Cardiac Evaluation) trial,[61] 2.8% of patients in the trandolapril arm developed AF versus 5.3% (p < 0.05) in the placebo arm; similarly, patients randomized to enalapril in SOLVD (Studies Of Left Ventricular Dysfunction)[62] had a 78% relative risk reduction in developing AF (p < 0.0001).
ARBs
There are a few studies linking reduction in AF with an administration of an ARB ( Table 5 ). In 1 prospective study, addition of irbesartan to amiodarone resulted in lower recurrence of AF after DCCV in patients with normal ejection fraction (79.52% vs. 55.91%, p = 0.007).[63] Subset analysis of Val-Heft (the Valsartan Heart Failure Trial)[64] and CHARM (Candesartan in Heart Failure)[65] showed a reduction in the incidence of AF in patients receiving ARBs compared with placebo ( Table 5 ). In the Val-Heft trial, valsartan-treated patients had a 5.1% incidence of AF versus 7.9% in the placebo arm (p = 0.002). The average ejection fraction in this study was approximately 27%. Similarly in the CHARM trial, patients with both normal and depressed ejection fraction were enrolled, and AF was reduced both in patients with depressed left ventricular function and in those with normal left ventricular function.
Statins are well-known for their lipid-lowering ability and consequently their cardioprotective effects. The reduction of cholesterol via activity at the 3-hydroxymethylglutaryl-coenzyme A (HMG-CoA) is well-established, and its effect on reducing cardiovascular events has been well documented. It is now thought that their cardioprotective effects can at least partially be explained by their so called "pleiotropic effect" ( Table 3 ). In a study by Nissen et al.,[34] CRP levels were dramatically reduced from baseline in the 80-mg atorvastatin group compared with 40-mg pravastatin group (36.4% vs. 5.2%, p < 0.001), suggesting that statins might possess some anti-inflammatory properties.
The exact mechanism of how statins exert their pleiotropic effects is not well understood and is the current focus of much research.[35] In vitro studies have suggested that stabilization of endothelial cells offer a partial explanation for its nonlipid-lowering effects. Leukocyte adhesion to the endothelium occurs early on in atherosclerosis and is mediated by the release of cytokines. Statins have been found to selectively inhibit leukocyte-function antigen (LFA)-1 and intercellular adhesion molecule (ICAM)-1, paramount for the process of adhesion of inflammatory cells to the endothelium.[36] Other studies have shown that statins can also diminish migration and proliferation of leukocytes to endothelial membrane and even induce apoptosis in smooth muscle cells, endothelial cells, and macrophages, while reducing inflammation through suppression of CRP and IL-6.[35-38]
Whereas statins primary role is to reduce cholesterol formation by suppressing the formation of mevalonate, it is through the inhibition of mevalonate that the other pleiotropic effects of statins are observed. Inhibition of mevalonate diminishes the production of isoprenoids such as farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate (GGPP), which are integral in the prenylation process of signal transducers, such as G-proteins, Rho, and Ras. Thus, protein-protein interactions needed for initiation of inflammatory-mediated pathways are interrupted.[35-38]
Animal Studies. Initial studies in dogs have found that atorvastatin prevents AF by inhibiting inflammation in a canine sterile pericarditis model.[39] The CRP levels were decreased, atrial effective refractory period (AERP) was increased, atrial conduction time decreased, and AF duration was diminished in the atorvastatin arm on post-operative day 2. In another similar study in a canine model of inducing AF by rapid atrial pacing, simvastatin-treated dogs had longer AERP and consequently shorter duration of AF.[40]
Clinical Trials. Very few studies of statin therapy in patients with AF have been published ( Table 4 ). One of the first studies to report a beneficial effect of chronic statin use on AF was a retrospective analysis of the recurrence rate of persistent lone AF in 62 patients receiving statin therapy undergoing direct current cardioversion (DCCV). Patients receiving chronic statin therapy had a lower recurrence rate after DCCV (40% vs. 84%, p = 0.007) at an average follow-up of 44 months, with the benefit of statin therapy reaching clinical and statistical significance after 3 to 4 months of therapy ( Table 4 ). Not all patients in this trial had evidence of structural heart disease.[41] These results could not be duplicated in 114 patients undergoing DCCV on pravastatin therapy.[42] The different outcomes between these 2 studies might be explained by the limited duration and dosage of statin therapy before and after DCCV and by the greater percentage of patients that had structural heart disease in the latter study. Another possibility is the innate difference in the ability of different statins to attenuate inflammation.
Another study by Young-Xu et al.[43] examined 449 patients with coronary artery disease in sinus rhythm and followed them prospectively for up to 5 years to assess the incidence of AF while receiving a statin of any brand. Eight percent of regular-statin users (p = 0.01), 10% of intermittent-statin users (p = 0.11), and 15% of nonstatin users developed AF over the course of 5 years. These results were independent of the lipid-lowering effects of statin, suggesting that the pleiotropic effect of statins might have contributed to the reduction in AF.
In a more recent study, Dernellis and Panaretou[44] examined the effects of atorvastatin in patients with PAF. Eighty patients were randomized into 40 mg of either atorvastatin or placebo. In the atorvastatin arm, CRP levels were lower (decreased by 2.4 from baseline, p = 0.01) and resolution of PAF was seen in 26 of 40 patients (p < 0.01) at 6-month follow-up. This study further supports the notion that CRP can be considered as an independent risk factor for AF.
The overall results of these trials support the idea that statin therapy might affect the natural history of AF by ameliorating the inflammatory process.
Glucocorticoids
Most of the initial studies involving glucocorticoid therapy in AF were done in patients undergoing cardiovascular surgery, and the results were equivocal. Early studies by Chaney et al.[45] did not find any significant benefit to steroid administration to patients undergoing CABG; however, Yared et al.[46] in a study of 216 patients undergoing cardiothoracic surgery found that dexamethasone administration perioperatively decreased the incidence of post-operative AF in the first few days after surgery. Inflammatory markers (i.e., CRP, IL-6, and so forth) were not measured in this study. More recently, Yared et al.[47] reported on the outcome of 78 patients undergoing combined CABG and valve surgery, who were randomized to receive either dexamethasone or placebo before surgery. In this study, dexamethasone did not affect the incidence of perioperative AF. However, it did modulate the release of several inflammatory and acute-phase response mediators that are associated with adverse outcomes. Most recently, another group from Finland showed in a prospective, randomized, double-blind study that the use of 100 mg cortisone, given intravenously immediately before cardiac surgery and continued for 3 consecutive days, significantly decreases the incidence of AF after cardiac surgery by 15%.[48]
One major prospective trial examined the effects of adding methylprednisolone to propafenone in AF patients undergoing pharmacological cardioversion to assess the recurrence rate. The methylprednisolone-treated group experienced an 80% decrease in CRP levels (p < 0.001) within the first month, which was maintained throughout the duration of the study. This corresponded to a reduction of AF recurrence from 50% in the placebo group to 9.6% in the methylprednisolone group (p < 0.001).[22]
Angiotensin-converting Enzyme Inhibitors (ACE-Is)
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ARBs) are 2 classes of drugs that act on the renin-angiotensin system (RAS). The RAS is intimately involved in the pathophysiology of various cardiovascular diseases such as hypertension, congestive heart failure, and ischemic heart disease. Studies have now linked the RAS gene polymorphisms to the development of AF.[49] These results might indicate that angiotensin II might be involved in atrial structural and electrical remodeling in patients with AF.[50]
The inhibition of the RAS and consequently of angiotensin II might have protective effect on remodeling.[51,52] It is known that angiotensin II is a potent promoter of atrial fibrosis by stimulating mitogen-activated protein kinases and extracellular signal-related kinase, which contributes to fibrosis formation and AF duration via expression of TGF-ß.[53] Furthermore, angiotensin II also increases atrial pressure, leading to greater atrial stretch, which reduces AERP and increases intra-atrial conduction time—all of which are factors in the initiation and maintenance of AF. Furthermore, it is now postulated that ACE-Is/ARBs can modulate potassium and calcium ion channels, ameliorating the deleterious effects of both atrial structural and electrical remodeling.[50,51]
Animal Studies. Much of our current understanding of ACE-Is and their effect on AF originates from research on canine models with either rapid atrial or ventricular pacing[51,54,55] to induce AF and/or heart failure, respectively. The ACE-I-treated dogs consistently had longer AERP, shorter AF duration, diminished atrial apoptosis, and less atrial remodeling. Similar effects were not seen in dogs treated with hydralazine and isosorbide mononitrate, suggesting that the inhibition of the RAS (via ACE-I) might be responsible for the attenuated atrial electrical and structural remodeling.[52]
Human Studies. There are only a few prospective human trials that correlate whether ACE-Is/ARBs can modulate the duration or onset of AF[56] ( Table 5 ). However, post hoc analysis of large, randomized ACE-I trials provided an opportunity to study their effects on development of AF.
Clinical Trials in Patients With Normal Ejection Fraction. In 1 particular retrospective study, hypertensive patients with PAF were treated with ACE-I and followed for up to 8 years ( Table 5 ). The ACE-Is were found to prevent the progression of PAF to chronic AF.[57] Two other prospective trials found benefit in ACE-I use on incidence of AF. One study found that the addition of enalapril to amiodarone in patients undergoing DCCV had lower recurrence of AF (4.3% in amiodarone with ACE-I vs. 14.7% in amiodarone alone, p = 0.067) and maintained longer duration of sinus rhythm.[58] In another study, the total number of cardioversion attempts for AF were lower (24 in ACE-I vs. 34 in calcium channel blockers, p < 0.001) and the number of hospital stays for AF were fewer (p = 0.02) in the ACE-I group.[59] In another retrospective analysis by L'Allier et al.[60] on 10,926 patients treated with either ACE-I or calcium channel blockers for AF, those in the ACE-I arm had lower incidence of new-onset AF, longer time to onset of AF, and fewer hospital stays as a consequence of AF.
Clinical Trials in Patients With Left Ventricular Dysfunction. Retrospective analysis of large scale randomized trials suggest that ACE-I might have some benefit in reducing incidence of AF in patients with depressed ejection fraction (T able 4 ). In the TRACE (Trandolapril Cardiac Evaluation) trial,[61] 2.8% of patients in the trandolapril arm developed AF versus 5.3% (p < 0.05) in the placebo arm; similarly, patients randomized to enalapril in SOLVD (Studies Of Left Ventricular Dysfunction)[62] had a 78% relative risk reduction in developing AF (p < 0.0001).
ARBs
There are a few studies linking reduction in AF with an administration of an ARB ( Table 5 ). In 1 prospective study, addition of irbesartan to amiodarone resulted in lower recurrence of AF after DCCV in patients with normal ejection fraction (79.52% vs. 55.91%, p = 0.007).[63] Subset analysis of Val-Heft (the Valsartan Heart Failure Trial)[64] and CHARM (Candesartan in Heart Failure)[65] showed a reduction in the incidence of AF in patients receiving ARBs compared with placebo ( Table 5 ). In the Val-Heft trial, valsartan-treated patients had a 5.1% incidence of AF versus 7.9% in the placebo arm (p = 0.002). The average ejection fraction in this study was approximately 27%. Similarly in the CHARM trial, patients with both normal and depressed ejection fraction were enrolled, and AF was reduced both in patients with depressed left ventricular function and in those with normal left ventricular function.
# posted by roodbont @ 7:55 AM 
