Use of Statins in Patients With Ischemic and Nonischemic Cardiomyopathy
Use of Statins in Patients With Ischemic and Nonischemic Cardiomyopathy
Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non-lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.
Statins lower plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that is responsible for cholesterol synthesis. As illustrated in Figure 1, important intermediate products in the mevalonate pathway include the isoprenoids, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. These intermediate products lead to activation of various downstream intracellular signaling molecules by prenylation of the guanosine triphosphate-binding proteins Rho, Ras, and Rac. The Rho signal transduction pathway is involved in the activation of inflammatory cytokines and chemokines. It also plays an important role in the formation and maintenance of the actin cytoskeleton and thereby affects intracellular transport, messenger ribonucleic acid (mRNA) stability, and gene transcription. The Ras proteins are responsible for cell proliferation and hypertrophy, and the Rac proteins are involved in the production of reactive oxygen species. Thus, inhibition of HMG-CoA reductase leads to a decrease in farnesylated and geranylgeranylated proteins and a subsequent dose-dependent reduction in the downstream signaling pathways mediated by Rho, Ras, and Rac.
(Enlarge Image)
Cholesterol Biosynthesis and the Beneficial and Adverse Downstream Effects of Statin Treatment
Beneficial (gray background) and adverse (checkered background) downstream effects of statin treatment. eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NFκB = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid.
Over the past 2 decades our understanding of the pathologic mechanisms that lead to heart failure (HF) has evolved from simplistic hemodynamic models to more complex models that have implicated neurohormonal activation and adverse cardiac remodeling as important mechanisms of disease progression. 3-Hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) have become a standard part of the armamentarium in the prevention and treatment of coronary artery disease. Apart from their lipid-lowering capabilities, statins seem to have non-lipid-lowering effects that impact neurohormonal activation and cardiac remodeling. This review will examine the potential benefits of statins in HF patients with ischemic and nonischemic cardiomyopathy as well as potential concerns regarding the use of statins in these patients.
Statins lower plasma cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the mevalonate pathway that is responsible for cholesterol synthesis. As illustrated in Figure 1, important intermediate products in the mevalonate pathway include the isoprenoids, farnesyl pyrophosphate, and geranylgeranyl pyrophosphate. These intermediate products lead to activation of various downstream intracellular signaling molecules by prenylation of the guanosine triphosphate-binding proteins Rho, Ras, and Rac. The Rho signal transduction pathway is involved in the activation of inflammatory cytokines and chemokines. It also plays an important role in the formation and maintenance of the actin cytoskeleton and thereby affects intracellular transport, messenger ribonucleic acid (mRNA) stability, and gene transcription. The Ras proteins are responsible for cell proliferation and hypertrophy, and the Rac proteins are involved in the production of reactive oxygen species. Thus, inhibition of HMG-CoA reductase leads to a decrease in farnesylated and geranylgeranylated proteins and a subsequent dose-dependent reduction in the downstream signaling pathways mediated by Rho, Ras, and Rac.
(Enlarge Image)
Cholesterol Biosynthesis and the Beneficial and Adverse Downstream Effects of Statin Treatment
Beneficial (gray background) and adverse (checkered background) downstream effects of statin treatment. eNOS = endothelial nitric oxide synthase; HMG-CoA = 3-hydroxy-3-methylglutaryl coenzyme A; LPS = lipopolysaccharide; NAD(P)H = nicotinamide adenine dinucleotide phosphate; NFκB = nuclear factor kappa B; PI3 = phosphatidylinositol-3; PP = pyrophosphate; tRNA = transfer ribonucleic acid.
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