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Effects of statin and lipoprotein metabolism in heart failure
Journal of Cardiology (2010) 55, 287—290
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
Review
Effects of statin and lipoprotein metabolism in heart failure Shin-ichiro Miura (MD, PhD, FJCC), Keijiro Saku (MD, PhD, FJCC) ∗ Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka 814-0180, Japan Received 30 January 2010; accepted 3 February 2010 Available online 15 March 2010
KEYWORDS Statin; Heart failure; Lipids; Lipoprotein
Summary Statins decrease serum levels of low-density lipoprotein (LDL) cholesterol and have pleiotropic effects. Statin therapy may have beneficial effects on the clinical outcome in patients with heart failure (HF). HF is associated with lipoprotein components. A recent study suggested that lower levels of high-density lipoprotein (HDL) cholesterol were the strongest predictor of worsening HF. In addition, serum total cholesterol (TC) is a prognostic factor for patients with HF. Although the levels of HDL cholesterol, apolipoprotein (Apo) A-I, triglyceride, TC, and LDL cholesterol may be associated with the onset of HF and/or an adverse prognosis in patients with HF, it is not yet clear which lipoprotein plays the most important role in this context. Among these lipoproteins, HDL protects against cardiovascular events by mediating the enhancement of reverse cholesterol transport. Moreover, HDL also has pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties. An increase in HDL cholesterol or ApoA-I, the principal Apo of HDL, may be a therapeutic target in HF. Therefore, we discuss here the usefulness of statins and lipoprotein metabolism for preventing HF. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents Introduction.............................................................................................................. Statin therapy in HF...................................................................................................... Association between lipid profile and HF ................................................................................. ApoA-I as a therapeutic target for the prevention of HF .................................................................. Conclusions .............................................................................................................. References ...............................................................................................................
287 288 288 289 289 290
Introduction ∗ Corresponding author. Tel.: +81 92 801 1011; fax: +81 91 865 2692. E-mail address: [email protected] (K. Saku).
Statins, which are potent inhibitors of 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (HMG-CoA), inhibit cholesterol biosynthesis and decrease serum levels of
0914-5087/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2010.02.003
288 Table 1
S.-i. Miura, K. Saku Pleiotropic effects of statins.
Effects
Ref. no.
Blocking cardiac hypertrophy Vasodilatation and improvement of endothelial function Preventing myocardial ischemia and vascular remodeling Decreasing plasma levels of tumor necrosis factor, interleukin-6, and C-reactive protein Inhibition of matrix metalloproteinase activation Decreasing plasma norepinephrine levels and reduce renal sympathetic nerve activity
[7] [8] [8] [9]
[10] [11]
low-density lipoprotein (LDL) cholesterol. In addition to their main effects, statins also have pleiotropic effects, such as anti-inflammatory and anti-oxidant effects, and improve endothelial function and angiogenesis [1,2]. Statins have primary and secondary effects that help to prevent against the development of coronary artery disease (CAD) [3]. Heart failure (HF) is one of the most common diseases in the industrial world because any heart disease can ultimately lead to HF. Although HF is induced by CAD and the treatment of CAD patients with statins results in a significant decrease in mortality [4—6], the potential benefits of statins in HF remain unclear. In addition, serum total cholesterol (TC) is a novel prognostic factor for patients with HF. Although the levels of high-density lipoprotein (HDL) cholesterol, apolipoprotein (Apo) A-I, triglyceride (TG), TC, and LDL cholesterol are associated with the onset of HF and/or an adverse prognosis in patients with HF, it is not yet clear which lipoprotein plays the most important role in this context. HDL protects against cardiovascular events through the enhancement of reverse cholesterol transport. Moreover, HDL also has pleiotropic effects, such as anti-oxidant, antiinflammatory, and anti-thrombotic properties. An increase in HDL cholesterol or ApoA-I, the principal Apo of HDL, may be a therapeutic target in HF. This review addresses the clinical benefits of statins in patients with HF and the role of lipoprotein metabolism in the prevention of HF.
Statin therapy in HF Statins have pleiotropic effects (Table 1). They have been shown to block the development of cardiac hypertrophy through the inhibition of Rho and Ras pathways [7]. In addition, they induce vasodilatation and improve endothelial function through an increase in nitric oxide production [8] and rescue myocardial ischemia and vascular remodeling. Although HF is associated with the activation of pro-inflammatory cytokines, statins decrease plasma levels of tumor necrosis factor-␣, interleukin-6, and C-reactive protein in patients with nonischemic HF [9]. Statins inhibit the activation of matrix metalloproteinase, fibrosis, and myocardial apoptosis in experimental myocardial infarction [10]. Statins also decrease plasma norepinephrine levels and reduce renal sympathetic nerve activity after experimental
HF [11]. Based on this basic research, statin therapy should improve the mortality in HF independent of its lipid-lowering effect. Statin therapy is beneficial in reducing major cardiovascular events associated with CAD [12,13]. Although statins have not been administered routinely to HF patients, clinical trials have shown that statin therapy is effective in the prognosis of HF. In the Kaiser Permanente Chronic Heart Failure cohort, statin therapy was associated with a lower relative risk of death and hospitalization for HF [4]. Statin therapy was associated with improvements in mortality in older patients with HF [5]. In addition, simvastatin reduces the occurrence of HF in patients with CAD without previous evidence of HF regardless of the TC level or CAD status in long-term prevention [6]. After these cohort and retrospective trials, randomized clinical trials were required to determine the role of statins in improving outcomes in the large and growing population of patients with HF. Recently, important randomized large-scale clinical trials have been reported [14—16]. In the controlled rosuvastatin multinational study in heart failure (CORONA), rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic HF (New York Heart Association (NYHA) Class II—IV, ischemic, systolic HF), although it did reduce the number of HF hospitalizations [14]. The Gruppo Italiano per lo Studio della Sopravvivenza Nell’Insufficienza Cardiaca Heart Failure (GISSI-HF) trial also indicated that rosuvastatin did not affect clinical outcomes in patients with chronic HF with any cause [15]. In addition, rosuvastatin lowered LDL cholesterol levels, but had no significant effect on death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with end-stage renal disease [A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA)] [16]. These trials used rosuvastatin, in contrast to previous trials that used more lipophilic statins, and the CORONA study enrolled older patients with more advanced HF. Possible explanations for the negative findings may include the choice of statins, differences in dosage, and the patient background. On the other hand, the results of a small-scale trial suggested that atorvastatin may benefit patients with HF and diabetes mellitus by improving ventricular electrical stability and decelerating the deterioration of renal function [17]. In addition, a meta-analysis was performed using 13 studies, of which 11 were retrospective analyses and 2 were prospective trials (Fig. 1) [1]. Statin use in HF patients was associated with a significant 26% decrease in the relative risk of mortality [hazard ratio (HR) = 0.74; 95% confidence interval (CI) = 0.68—0.8]. HRs for HF of ischemic and nonischemic etiology were 0.73 (95% CI = 0.65—0.82) and 0.73 (95% CI = 0.61—0.87), respectively (8 of the 13 studies). Although a meta-analysis has several limitations, the results show a significant reduction in mortality with statin use in patients with HF.
Association between lipid profile and HF Cardiac and renal dysfunctions frequently coexist. This is referred to as the cardio-renal syndrome. In patients with
Effects of statin and lipoprotein metabolism in heart failure
289 HDL cholesterol levels are associated with a worse prognosis in patients with HF, since HF patients may require more energy for protecting against inflammation and activating the immune system. In fact, higher baseline levels of LDL cholesterol, HDL cholesterol, ApoA-I, ApoB, and TG were associated with a better prognosis in HF patients [22]. Since HDL has pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties, and since lower serum HDL cholesterol levels are associated with a worse prognosis in patients with HF, an increase in HDL or improvement in HDL function should decrease the mortality in HF patients depending on and/or independent of its main function of enhancing reverse cholesterol transport.
ApoA-I as a therapeutic target for the prevention of HF
Figure 1 Mortality among patients with heart failure (total 13 studies, 8 ischemic and 8 nonischemic studies).
renal failure (RF), the lipid profile shows higher serum TG, very low-density lipoprotein (VLDL) and intermittentdensity lipoprotein (IDL) levels, and lower LDL cholesterol and HDL cholesterol levels according to the disturbance of the catabolism of VLDL and IDL. The lipid profile in HF is similar to that in RF. There have been several reports on the association between serum cholesterol levels and HF in humans (Table 2). Horwich et al. reported that serum TC is a novel prognostic factor for patients with advanced HF [18]. Lower TC levels independently predict increased in-hospital mortality risk [19]. Although a reduced left ventricular (LV) ejection fraction, a high NYHA class, and increased LV end-diastolic diameter were strong risk factors associated with the endpoint [20], decreased TC and HDL cholesterol levels were also identified as weak predictors of risk. In addition, data regarding lipid profiles, including serum TC, TG, HDL cholesterol, and LDL cholesterol were obtained after the improvement of HF and discharge from the hospital [21], and 21 patients died during the follow-up period (2.3 ± 0.9 years). In this report, there was a significant difference between survivors and nonsurvivors with regard to HDL cholesterol (53 ± 15 and 43 ± 15 mg/dl, respectively, p < 0.01), but no differences were observed in other variables. These trials indicated that lower serum LDL and/or
Table 2
Lipid profile and prognosis in HF patients.
Lipid profile
Prognosis
Ref. no.
TC level Lower TC
Prognostic factor Increasing in-hospital mortality risk Risk predictors
[18] [19]
Survivors > nonsurvivors
[21]
Decreased TC and HDL cholesterol HDL cholesterol
[20]
HDL, high-density lipoprotein; HF, heart failure; TC, total cholesterol.
ApoA-I is one of the most important components of apolipoprotein in HDL. Lipoprotein components have usually not been recognized as risk factors for the development of HF. However, low levels of ApoA-I are independently associated with an adverse prognosis in patients with nonischemic HF [23]. Ingelsson et al. reported that the ApoB/ApoA-Iratio (HR = 1.27, 95% CI = 1.09—1.48) was associated with an increased risk of the development of HF [24]. Lorgelly et al. studied the biomarkers in prognostic models in HF, and found that ApoA-I more strongly predicted a range of clinical outcomes than LDL cholesterol or HDL cholesterol (or the LDL/HDL ratio) [22]. In addition, HF is associated with lipoprotein components in statin-treated patients with CAD. Variables related to LDL cholesterol less strongly predicted new-onset congestive HF than those related to HDL cholesterol, and ApoA-I was the single variable that was most strongly associated with HF [25]. Why would ApoA-I be the most strongly predictive lipidemic factor? In an experimental study, ApoA-I gene transfer reduced the development of streptozotocin-induced diabetic cardiomyopathy. This ApoA-I gene transfer-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and the glycogen synthase kinase ratio, respectively, and gene transfer reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold [26]. Moreover, we have been studying the use of reconstituted (r) HDL therapy for preventing the progression of coronary atherosclerosis [27—29]. rHDL (containing ApoA-I)promoted cell survival has beneficial morphological effects that help to prevent LV remodeling and improve function after myocardial infarction, and may prevent the arrest of cell growth through an extracellular-regulated kinase pathway in myocytes [28]. Therefore, ApoA-I may be a target lipidemic factor for preventing HF.
Conclusions Statin therapy has primary and secondary effects that help protect against the development of CAD. Although HF is mainly induced by CAD and CAD patients treated with statins show a significant decrease in mortality, we cannot confirm that cholesterol levels need to be lower in patients with HF at this stage. Actually, a cohort study indicated that about
290 20% of HF patients received statins at discharge, and a lower percentage was seen in Japan [30]. Therefore, we should not use statins in every patient with HF until more useful data are available.
S.-i. Miura, K. Saku
[17]
References [18] [1] Ramasubbu K, Estep J, White DL, Deswal A, Mann DL. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy. J Am Coll Cardiol 2008;51:415—26. [2] Takemoto M, Laio JK. Pleiotropic effects of 3-hydroxy-3methyl-glutaryl-coenzyme A reductase inhibitor. Arterioscler Thromb Vasc Biol 2001;21:1712—9. [3] Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996;335:1001—9. [4] Go AS, Lee WY, Yang J, Lo JC, Gurwitz JH. Statin therapy and risks for death and hospitalization in chronic heart failure. JAMA 2006;296:2105—11. [5] Foody JM, Shah R, Galusha D, Masoudi FA, Havranek EP, Krumholz HM. Statins and mortality among elderly patients hospitalized with heart failure. Circulation 2006;113:1086—92. [6] Kjekshus J, Pedersen TR, Olsson AG, Faergeman O, Pyörälä K. The effects of simvastatin on the incidence of heart failure in patients with coronary heart disease. J Card Fail 1997;3:249—54. [7] Laufs U, Liao JK. Isoprenoid metabolism and the pleiotropic effects of statins. Curr Atheroscler Rep 2003;5:372—8. [8] Laufs U, Liao JK. Post-transcriptional regulation of endothelial nitric oxide synthase mRNA stability by Rho GTPase. J Biol Chem 1998;273:24266—71. [9] Sola S, Mir MQ, Lerakis S, Tandon N, Khan BV. Atorvastatin improves left ventricular systolic function and serum markers of inflammation in nonischemic heart failure. J Am Coll Cardiol 2006;47:332—7. [10] Hayashidani S, Tsutsui H, Shiomi T, Suematsu N, Kinugawa S, Ide T, Wen J, Takeshita A. Fluvastatin, a 3-hydroxy-3methylglutaryl coenzyme A reductase inhibitor, attenuates left ventricular remodeling and failure after experimental myocardial infarction. Circulation 2002;105:868—73. [11] Pliquett RU, Cornish KG, Peuler JD, Zucker IH. Simvastatin normalizes autonomic neural control in experimental heart failure. Circulation 2003;107:2493—8. [12] Teshima Y, Yufu K, Akioka H, Iwao T, Anan F, Nakagawa M, Yonemochi H, Takahashi N, Hara M, Saikawa T. Early atorvastatin therapy improves cardiac function in patients with acute myocardial infarction. J Cardiol 2009;53:58—64. [13] Kadota S, Matsuda M, Izuhara M, Baba O, Moriwaki S, Shioji K, Takeuchi Y, Uegaito T. Long-term effects of early statin therapy for patients with acute myocardial infarction treated with stent implantation. J Cardiol 2008;51:171—8. [14] Kjekshus J, Apetrei E, Barrios V, Böhm M, Cleland JG, Cornel JH, Dunselman P, Fonseca C, Goudev A, Grande P, Gullestad L, Hjalmarson A, Hradec J, Jánosi A, Kamensk´ y G, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248—61. [15] GISSI-HF InvestigatorsTavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, Lucci D, Nicolosi GL, Porcu M, Tognoni G. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a randomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231—9. [16] Fellström BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, Chae DW, Chevaile A, Cobbe SM, Grönhagen-Riska
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C, De Lima JJ, Lins R, Mayer G, McMahon AW, Parving HH, et al. Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med 2009;360:1395—407. Kishi T, Yamada A, Okamatsu S, Sunagawa K. Atorvastatin might improve ventricular electrostability and decelerate the deterioration of renal function in patients with heart failure and diabetes mellitus. J Cardiol 2009;53:341—8. Horwich TB, Hamilton MA, Maclellan WR, Fonarow GC. Low serum total cholesterol is associated with marked increase in mortality in advanced heart failure. J Card Fail 2002;8:216—24. Horwich TB, Hernandez AF, Dai D, Yancy CW, Fonarow GC. Cholesterol levels and in-hospital mortality in patients with acute decompensated heart failure. Am Heart J 2008;156:1170—6. Christ M, Klima T, Grimm W, Mueller HH, Maisch B. Prognostic significance of serum cholesterol levels in patients with idiopathic dilated cardiomyopathy. Eur Heart J 2006;27: 691—9. Sakatani T, Shirayama T, Suzaki Y, Yamamoto T, Mani H, Kawasaki T, Sugihara H, Matsubara H. The association between cholesterol and mortality in heart failure. Comparison between patients with and without coronary artery disease. Int Heart J 2005;46:619—29. Lorgelly PK, Briggs AH, Wedel H, Dunselman P, Hjalmarson A, Kjekshus J, Waagstein F, Wikstrand J, Jánosi A, van Veldhuisen DJ, Barrios V, Fonseca C, McMurray JJ, CORONA Study Group. Predictors of fatal and non-fatal outcomes in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): incremental value of apolipoprotein A-I, high-sensitivity C-reactive peptide and N-terminal pro B-type natriuretic peptide. Eur J Heart Fail 2009;11:281—91. Iwaoka M, Obata JE, Abe M, Nakamura T, Kitta Y, Kodama Y, Kawabata K, Takano H, Fujioka D, Saito Y, Kobayashi T, Hasebe H, Kugiyama K. Association of low serum levels of apolipoprotein A-I with adverse outcomes in patients with nonischemic heart failure. J Card Fail 2007;13:247—53. Ingelsson E, Arnlöv J, Sundström J, Zethelius B, Vessby B, Lind L. Novel metabolic risk factors for heart failure. J Am Coll Cardiol 2005;46:2054—60. Holme I, Fellstrom B, Jardine A, Holdaas H. Congestive heart failure is associated with lipoprotein components in statintreated patients with coronary heart disease Insights from the Incremental Decrease in End points Through Aggressive Lipid Lowering Trial (IDEAL). Atherosclerosis 2009;205:522—7. Van Linthout S, Spillmann F, Riad A, Trimpert C, Lievens J, Meloni M, Escher F, Filenberg E, Demir O, Li J, Shakibaei M, Schimke I, Staudt A, Felix SB, Schultheiss HP, et al. Human apolipoprotein A-I gene transfer reduces the development of experimental diabetic cardiomyopathy. Circulation 2008;117:1563—73. Sumi M, Sata M, Miura S, Rye KA, Toya N, Kanaoka Y, Yanaga K, Ohki T, Saku K, Nagai R. Reconstituted high-density lipoprotein stimulates differentiation of endothelial progenitor cells and enhances ischemia-induced angiogenesis. Arterioscler Thromb Vasc Biol 2007;27:813—8. Imaizumi S, Miura S, Nakamura K, Kiya Y, Uehara Y, Zhang B, Matsuo Y, Urata H, Ideishi M, Rye KA, Sata M, Saku K. Antiarrhythmogenic effect of reconstituted high-density lipoprotein against ischemia/reperfusion in rats. J Am Coll Cardiol 2008;51:1604—12. Kiya Y, Miura S, Imaizumi S, Uehara Y, Matsuo Y, Abe S, Jimi S, Urata H, Rye KA, Saku K. Reconstituted high-density lipoprotein attenuates postinfarction left ventricular remodeling in rats. Atherosclerosis 2009;203:137—44. Tsutsui H, Tsuchihashi-Makaya M, Kinugawa S. Clinical characteristics and outcomes of heart failure with preserved ejection fraction: lessons from epidemiological studies. J Cardiol 2010;55:13—22.
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
Review
Effects of statin and lipoprotein metabolism in heart failure Shin-ichiro Miura (MD, PhD, FJCC), Keijiro Saku (MD, PhD, FJCC) ∗ Department of Cardiology, Fukuoka University School of Medicine, 7-45-1 Nanakuma, Jonan-Ku, Fukuoka 814-0180, Japan Received 30 January 2010; accepted 3 February 2010 Available online 15 March 2010
KEYWORDS Statin; Heart failure; Lipids; Lipoprotein
Summary Statins decrease serum levels of low-density lipoprotein (LDL) cholesterol and have pleiotropic effects. Statin therapy may have beneficial effects on the clinical outcome in patients with heart failure (HF). HF is associated with lipoprotein components. A recent study suggested that lower levels of high-density lipoprotein (HDL) cholesterol were the strongest predictor of worsening HF. In addition, serum total cholesterol (TC) is a prognostic factor for patients with HF. Although the levels of HDL cholesterol, apolipoprotein (Apo) A-I, triglyceride, TC, and LDL cholesterol may be associated with the onset of HF and/or an adverse prognosis in patients with HF, it is not yet clear which lipoprotein plays the most important role in this context. Among these lipoproteins, HDL protects against cardiovascular events by mediating the enhancement of reverse cholesterol transport. Moreover, HDL also has pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties. An increase in HDL cholesterol or ApoA-I, the principal Apo of HDL, may be a therapeutic target in HF. Therefore, we discuss here the usefulness of statins and lipoprotein metabolism for preventing HF. © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved.
Contents Introduction.............................................................................................................. Statin therapy in HF...................................................................................................... Association between lipid profile and HF ................................................................................. ApoA-I as a therapeutic target for the prevention of HF .................................................................. Conclusions .............................................................................................................. References ...............................................................................................................
287 288 288 289 289 290
Introduction ∗ Corresponding author. Tel.: +81 92 801 1011; fax: +81 91 865 2692. E-mail address: [email protected] (K. Saku).
Statins, which are potent inhibitors of 3-hydroxy-3methyl-glutaryl-coenzyme A reductase (HMG-CoA), inhibit cholesterol biosynthesis and decrease serum levels of
0914-5087/$ — see front matter © 2010 Japanese College of Cardiology. Published by Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.jjcc.2010.02.003
288 Table 1
S.-i. Miura, K. Saku Pleiotropic effects of statins.
Effects
Ref. no.
Blocking cardiac hypertrophy Vasodilatation and improvement of endothelial function Preventing myocardial ischemia and vascular remodeling Decreasing plasma levels of tumor necrosis factor, interleukin-6, and C-reactive protein Inhibition of matrix metalloproteinase activation Decreasing plasma norepinephrine levels and reduce renal sympathetic nerve activity
[7] [8] [8] [9]
[10] [11]
low-density lipoprotein (LDL) cholesterol. In addition to their main effects, statins also have pleiotropic effects, such as anti-inflammatory and anti-oxidant effects, and improve endothelial function and angiogenesis [1,2]. Statins have primary and secondary effects that help to prevent against the development of coronary artery disease (CAD) [3]. Heart failure (HF) is one of the most common diseases in the industrial world because any heart disease can ultimately lead to HF. Although HF is induced by CAD and the treatment of CAD patients with statins results in a significant decrease in mortality [4—6], the potential benefits of statins in HF remain unclear. In addition, serum total cholesterol (TC) is a novel prognostic factor for patients with HF. Although the levels of high-density lipoprotein (HDL) cholesterol, apolipoprotein (Apo) A-I, triglyceride (TG), TC, and LDL cholesterol are associated with the onset of HF and/or an adverse prognosis in patients with HF, it is not yet clear which lipoprotein plays the most important role in this context. HDL protects against cardiovascular events through the enhancement of reverse cholesterol transport. Moreover, HDL also has pleiotropic effects, such as anti-oxidant, antiinflammatory, and anti-thrombotic properties. An increase in HDL cholesterol or ApoA-I, the principal Apo of HDL, may be a therapeutic target in HF. This review addresses the clinical benefits of statins in patients with HF and the role of lipoprotein metabolism in the prevention of HF.
Statin therapy in HF Statins have pleiotropic effects (Table 1). They have been shown to block the development of cardiac hypertrophy through the inhibition of Rho and Ras pathways [7]. In addition, they induce vasodilatation and improve endothelial function through an increase in nitric oxide production [8] and rescue myocardial ischemia and vascular remodeling. Although HF is associated with the activation of pro-inflammatory cytokines, statins decrease plasma levels of tumor necrosis factor-␣, interleukin-6, and C-reactive protein in patients with nonischemic HF [9]. Statins inhibit the activation of matrix metalloproteinase, fibrosis, and myocardial apoptosis in experimental myocardial infarction [10]. Statins also decrease plasma norepinephrine levels and reduce renal sympathetic nerve activity after experimental
HF [11]. Based on this basic research, statin therapy should improve the mortality in HF independent of its lipid-lowering effect. Statin therapy is beneficial in reducing major cardiovascular events associated with CAD [12,13]. Although statins have not been administered routinely to HF patients, clinical trials have shown that statin therapy is effective in the prognosis of HF. In the Kaiser Permanente Chronic Heart Failure cohort, statin therapy was associated with a lower relative risk of death and hospitalization for HF [4]. Statin therapy was associated with improvements in mortality in older patients with HF [5]. In addition, simvastatin reduces the occurrence of HF in patients with CAD without previous evidence of HF regardless of the TC level or CAD status in long-term prevention [6]. After these cohort and retrospective trials, randomized clinical trials were required to determine the role of statins in improving outcomes in the large and growing population of patients with HF. Recently, important randomized large-scale clinical trials have been reported [14—16]. In the controlled rosuvastatin multinational study in heart failure (CORONA), rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic HF (New York Heart Association (NYHA) Class II—IV, ischemic, systolic HF), although it did reduce the number of HF hospitalizations [14]. The Gruppo Italiano per lo Studio della Sopravvivenza Nell’Insufficienza Cardiaca Heart Failure (GISSI-HF) trial also indicated that rosuvastatin did not affect clinical outcomes in patients with chronic HF with any cause [15]. In addition, rosuvastatin lowered LDL cholesterol levels, but had no significant effect on death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke in patients with end-stage renal disease [A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA)] [16]. These trials used rosuvastatin, in contrast to previous trials that used more lipophilic statins, and the CORONA study enrolled older patients with more advanced HF. Possible explanations for the negative findings may include the choice of statins, differences in dosage, and the patient background. On the other hand, the results of a small-scale trial suggested that atorvastatin may benefit patients with HF and diabetes mellitus by improving ventricular electrical stability and decelerating the deterioration of renal function [17]. In addition, a meta-analysis was performed using 13 studies, of which 11 were retrospective analyses and 2 were prospective trials (Fig. 1) [1]. Statin use in HF patients was associated with a significant 26% decrease in the relative risk of mortality [hazard ratio (HR) = 0.74; 95% confidence interval (CI) = 0.68—0.8]. HRs for HF of ischemic and nonischemic etiology were 0.73 (95% CI = 0.65—0.82) and 0.73 (95% CI = 0.61—0.87), respectively (8 of the 13 studies). Although a meta-analysis has several limitations, the results show a significant reduction in mortality with statin use in patients with HF.
Association between lipid profile and HF Cardiac and renal dysfunctions frequently coexist. This is referred to as the cardio-renal syndrome. In patients with
Effects of statin and lipoprotein metabolism in heart failure
289 HDL cholesterol levels are associated with a worse prognosis in patients with HF, since HF patients may require more energy for protecting against inflammation and activating the immune system. In fact, higher baseline levels of LDL cholesterol, HDL cholesterol, ApoA-I, ApoB, and TG were associated with a better prognosis in HF patients [22]. Since HDL has pleiotropic effects, such as anti-oxidant, anti-inflammatory, and anti-thrombotic properties, and since lower serum HDL cholesterol levels are associated with a worse prognosis in patients with HF, an increase in HDL or improvement in HDL function should decrease the mortality in HF patients depending on and/or independent of its main function of enhancing reverse cholesterol transport.
ApoA-I as a therapeutic target for the prevention of HF
Figure 1 Mortality among patients with heart failure (total 13 studies, 8 ischemic and 8 nonischemic studies).
renal failure (RF), the lipid profile shows higher serum TG, very low-density lipoprotein (VLDL) and intermittentdensity lipoprotein (IDL) levels, and lower LDL cholesterol and HDL cholesterol levels according to the disturbance of the catabolism of VLDL and IDL. The lipid profile in HF is similar to that in RF. There have been several reports on the association between serum cholesterol levels and HF in humans (Table 2). Horwich et al. reported that serum TC is a novel prognostic factor for patients with advanced HF [18]. Lower TC levels independently predict increased in-hospital mortality risk [19]. Although a reduced left ventricular (LV) ejection fraction, a high NYHA class, and increased LV end-diastolic diameter were strong risk factors associated with the endpoint [20], decreased TC and HDL cholesterol levels were also identified as weak predictors of risk. In addition, data regarding lipid profiles, including serum TC, TG, HDL cholesterol, and LDL cholesterol were obtained after the improvement of HF and discharge from the hospital [21], and 21 patients died during the follow-up period (2.3 ± 0.9 years). In this report, there was a significant difference between survivors and nonsurvivors with regard to HDL cholesterol (53 ± 15 and 43 ± 15 mg/dl, respectively, p < 0.01), but no differences were observed in other variables. These trials indicated that lower serum LDL and/or
Table 2
Lipid profile and prognosis in HF patients.
Lipid profile
Prognosis
Ref. no.
TC level Lower TC
Prognostic factor Increasing in-hospital mortality risk Risk predictors
[18] [19]
Survivors > nonsurvivors
[21]
Decreased TC and HDL cholesterol HDL cholesterol
[20]
HDL, high-density lipoprotein; HF, heart failure; TC, total cholesterol.
ApoA-I is one of the most important components of apolipoprotein in HDL. Lipoprotein components have usually not been recognized as risk factors for the development of HF. However, low levels of ApoA-I are independently associated with an adverse prognosis in patients with nonischemic HF [23]. Ingelsson et al. reported that the ApoB/ApoA-Iratio (HR = 1.27, 95% CI = 1.09—1.48) was associated with an increased risk of the development of HF [24]. Lorgelly et al. studied the biomarkers in prognostic models in HF, and found that ApoA-I more strongly predicted a range of clinical outcomes than LDL cholesterol or HDL cholesterol (or the LDL/HDL ratio) [22]. In addition, HF is associated with lipoprotein components in statin-treated patients with CAD. Variables related to LDL cholesterol less strongly predicted new-onset congestive HF than those related to HDL cholesterol, and ApoA-I was the single variable that was most strongly associated with HF [25]. Why would ApoA-I be the most strongly predictive lipidemic factor? In an experimental study, ApoA-I gene transfer reduced the development of streptozotocin-induced diabetic cardiomyopathy. This ApoA-I gene transfer-mediated protection was associated with a 1.6-, 1.6-, and 2.4-fold induction of diabetes-downregulated phospho to Akt, endothelial nitric oxide synthase, and the glycogen synthase kinase ratio, respectively, and gene transfer reduced hyperglycemia-induced cardiomyocyte apoptosis by 3.4-fold [26]. Moreover, we have been studying the use of reconstituted (r) HDL therapy for preventing the progression of coronary atherosclerosis [27—29]. rHDL (containing ApoA-I)promoted cell survival has beneficial morphological effects that help to prevent LV remodeling and improve function after myocardial infarction, and may prevent the arrest of cell growth through an extracellular-regulated kinase pathway in myocytes [28]. Therefore, ApoA-I may be a target lipidemic factor for preventing HF.
Conclusions Statin therapy has primary and secondary effects that help protect against the development of CAD. Although HF is mainly induced by CAD and CAD patients treated with statins show a significant decrease in mortality, we cannot confirm that cholesterol levels need to be lower in patients with HF at this stage. Actually, a cohort study indicated that about
290 20% of HF patients received statins at discharge, and a lower percentage was seen in Japan [30]. Therefore, we should not use statins in every patient with HF until more useful data are available.
S.-i. Miura, K. Saku
[17]
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