Targeting Cholesterol in Non-ischemic Heart Failure: A Role for LDLR Gene Therapy?
Authors: Alberico Luigi Catapano, Angela Pirillo, Giuseppe Danilo Norata
Journal: Molecular Therapy (2017)

The relationship between plasma cholesterol levels and non-ischemic heart failure has been controversial. In this issue of Molecular Therapy, Muthuramu et al. 1Muthuramu I. Amin R. Postnov A. Mishra M. Aboumsallem J.P. Dresselaers T. Himmelreich U. Van Veldhoven P.P. Gheysens O. Jacobs F. De Geest B. Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice.Mol. Ther. 2017; 25 (this issue): 2513-2525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar address this issue by modulating plasma lipid levels by gene transfer of low-density lipoprotein receptor using an AAV8 vector (AAV8-LDLr) in a mouse model of cardiac pressure overload induced by transverse aortic constriction (TAC). AAV8-LDLr gene transfer induced a strong reduction of plasma cholesterol and lipoprotein levels, which then resulted in the attenuation of cardiac hypertrophy and decreased lung congestion as well as mortality after TAC1Muthuramu I. Amin R. Postnov A. Mishra M. Aboumsallem J.P. Dresselaers T. Himmelreich U. Van Veldhoven P.P. Gheysens O. Jacobs F. De Geest B. Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice.Mol. Ther. 2017; 25 (this issue): 2513-2525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar (Figure 1). The reduced plasma cholesterol achieved through this approach improved cardiac function and reduced interstitial and perivascular fibrosis. At the molecular level, AAV8-LDLr gene transfer dampened oxidative stress and myocardial apoptosis, perhaps through the improvement of cellular metabolic adaptations induced in the heart by pressure overload. Ischemic heart disease represents the most common cause of heart failure, but non-ischemic cardiomyopathies may result in heart failure as well. There is conflicting evidence for a relationship between plasma cholesterol levels and heart failure, as several studies have reported different patterns of plasma cholesterol in patients with ischemic and non-ischemic disease. Low levels of total cholesterol appear to be associated with an improved outcome in ischemic heart failure, but in patients with non-ischemic disease, they appear to predict a worse prognosis (referred to as “reverse epidemiology”)2Afsarmanesh N. Horwich T.B. Fonarow G.C. Total cholesterol levels and mortality risk in nonischemic systolic heart failure.Am. Heart J. 2006; 152: 1077-1083Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 3Sakatani 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: 619-629Crossref PubMed Scopus (47) Google Scholar, 4Fröhlich H. Raman N. Täger T. Schellberg D. Goode K.M. Kazmi S. Grundtvig M. Hole T. Cleland J.G.F. Katus H.A. et al.Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.Int. J. Cardiol. 2017; 238: 97-104Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar (Figure 1). In the Framingham study, plasma total cholesterol was not significantly related to the occurrence of congestive heart failure, whereas an increased total cholesterol to high-density lipoprotein (HDL) ratio predicted disease incidence.5Horwich T. Low-density lipoprotein in the setting of congestive heart failure: is lower really better?.Curr. Atheroscler. Rep. 2009; 11: 343-349Crossref PubMed Scopus (10) Google Scholar Despite the inconsistent data on the relationship between cholesterol and heart failure incidence, statin-induced cholesterol lowering has been shown to reduce the risk of new-onset heart failure in patients with coronary artery disease (CAD).5Horwich T. Low-density lipoprotein in the setting of congestive heart failure: is lower really better?.Curr. Atheroscler. Rep. 2009; 11: 343-349Crossref PubMed Scopus (10) Google Scholar Initially, two large trials failed to show an increased survival in chronic heart failure patients treated with statins.5Horwich T. Low-density lipoprotein in the setting of congestive heart failure: is lower really better?.Curr. Atheroscler. Rep. 2009; 11: 343-349Crossref PubMed Scopus (10) Google Scholar A retrospective analysis of the CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) study later demonstrated that rosuvastatin treatment significantly decreased the risk of hospitalization.6Rogers J.K. Jhund P.S. Perez A.C. Böhm M. Cleland J.G. Gullestad L. Kjekshus J. van Veldhuisen D.J. Wikstrand J. Wedel H. et al.Effect of rosuvastatin on repeat heart failure hospitalizations: the CORONA Trial (Controlled Rosuvastatin Multinational Trial in Heart Failure).JACC Heart Fail. 2014; 2: 289-297Crossref PubMed Scopus (95) Google Scholar Similar findings were observed following post hoc analysis of the 4S study with simvastatin7Pedersen T.R. Coronary artery disease: the Scandinavian Simvastatin Survival Study experience.Am. J. Cardiol. 1998; 82: 53T-56TAbstract Full Text Full Text PDF PubMed Scopus (34) Google Scholar and the PROVE IT-TIMI 22 study with atorvastatin.8Scirica B.M. Morrow D.A. Cannon C.P. Ray K.K. Sabatine M.S. Jarolim P. Shui A. McCabe C.H. Braunwald E. PROVE IT-TIMI 22 InvestigatorsIntensive statin therapy and the risk of hospitalization for heart failure after an acute coronary syndrome in the PROVE IT-TIMI 22 study.J. Am. Coll. Cardiol. 2006; 47: 2326-2331Crossref PubMed Scopus (140) Google Scholar Large meta-analyses further demonstrated that statins persistently decreased the incidence of rehospitalization for heart failure in chronic patients9Wang J.Q. Wu G.R. Wang Z. Dai X.P. Li X.R. Long-term clinical outcomes of statin use for chronic heart failure: a meta-analysis of 15 prospective studies.Heart Lung Circ. 2014; 23: 105-113Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar and patients with non-ischemic disease.10Deo S.V. Rababa’h A. Altarabsheh S.E. Lim J.Y. Cho Y.H. Park S.J. Statin therapy improves long-term survival in non-ischaemic cardiomyopathy: a pooled analysis of 4500 patients.Heart Lung Circ. 2014; 23: 985-987Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar Importantly, this beneficial effect was confirmed in national registry studies in patients with or without preserved ejection fraction (EF),11Alehagen U. Benson L. Edner M. Dahlström U. Lund L.H. Association Between Use of Statins and Mortality in Patients With Heart Failure and Ejection Fraction of ≥50.Circ Heart Fail. 2015; 8: 862-870Crossref PubMed Scopus (65) Google Scholar, 12Alehagen U. Benson L. Edner M. Dahlström U. Lund L.H. Association between use of statins and outcomes in heart failure with reduced ejection fraction: prospective propensity score matched cohort study of 21 864 patients in the Swedish Heart Failure Registry.Circ Heart Fail. 2015; 8: 252-260Crossref PubMed Scopus (28) Google Scholar and statins were shown to attenuate the strength of the inverse association between total cholesterol levels and survival.4Fröhlich H. Raman N. Täger T. Schellberg D. Goode K.M. Kazmi S. Grundtvig M. Hole T. Cleland J.G.F. Katus H.A. et al.Statins attenuate but do not eliminate the reverse epidemiology of total serum cholesterol in patients with non-ischemic chronic heart failure.Int. J. Cardiol. 2017; 238: 97-104Abstract Full Text Full Text PDF PubMed Scopus (4) Google Scholar Based on these observations, the beneficial effects of statins have been attributed to their anti-inflammatory properties, counter-regulatory action on the renin-angiotensin-aldosterone and sympathetic systems, or positive effects on cardiac hypertrophy and fibrosis rather than to their lipid-lowering activity13Ramasubbu K. Estep J. White D.L. Deswal A. Mann D.L. Experimental and clinical basis for the use of statins in patients with ischemic and nonischemic cardiomyopathy.J. Am. Coll. Cardiol. 2008; 51: 415-426Crossref PubMed Scopus (146) Google Scholar (Figure 1). Beyond the mechanism, it is reasonable to speculate that statins exert their protective effect before heart failure develops by reducing the risk of ischemic heart disease, whereas they may be neutral when disease is already manifest. The study by Muthuramu et al., however, demonstrates in animal models that lipid lowering, other than that achieved with statins, is beneficial on non-ischemic heart failure development. These observations nevertheless leave some key questions unsolved. Could cholesterol reduction be the common driver of this effect? Statins lack a robust lipid lowering activity in animal models, suggesting that, at least in animal models, their protective effect on heart failure14Saka M. Obata K. Ichihara S. Cheng X.W. Kimata H. Nishizawa T. Noda A. Izawa H. Nagata K. Murohara T. Yokota M. Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure.J. Cardiovasc. Pharmacol. 2006; 47: 770-779Crossref PubMed Scopus (45) Google Scholar, 15Gómez-Garre D. González-Rubio M.L. Muñoz-Pacheco P. Caro-Vadillo A. Aragoncillo P. Fernández-Cruz A. Rosuvastatin added to standard heart failure therapy improves cardiac remodelling in heart failure rats with preserved ejection fraction.Eur. J. Heart Fail. 2010; 12: 903-912Crossref PubMed Scopus (34) Google Scholar might occur through mechanisms other than those observed following AVV8 gene therapy. Do increased plasma lipoprotein levels foster cardiac cell proliferation and in turn hypertrophy? Muthuramu et al.1Muthuramu I. Amin R. Postnov A. Mishra M. Aboumsallem J.P. Dresselaers T. Himmelreich U. Van Veldhoven P.P. Gheysens O. Jacobs F. De Geest B. Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice.Mol. Ther. 2017; 25 (this issue): 2513-2525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar do not show whether LDLR knockout (KO) mice with TAC develop cardiac hypertrophy to an extent greater than C57BL6 TAC mice or whether LDLR KO mice fed a normal or lipid-enriched diet present a similar degree of hypertrophy. It must be acknowledged, however, that the mouse presents some diversity in plasma lipid and lipoprotein distribution, with HDL being the main class of lipoprotein that transports cholesterol compared to humans, where low density lipoproteins dominate. Muthuramu et al.1Muthuramu I. Amin R. Postnov A. Mishra M. Aboumsallem J.P. Dresselaers T. Himmelreich U. Van Veldhoven P.P. Gheysens O. Jacobs F. De Geest B. Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice.Mol. Ther. 2017; 25 (this issue): 2513-2525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar used mice lacking the LDLR which, when fed a hyperlipidic diet, present a lipid and lipoprotein profile that is closer to that of humans. Nevertheless, testing AAV8-LDLr gene transfer in more humanized animal models for hypercholesterolemia, such as the LDLR-KO Apob100/100 Tg mouse or the ApoE*3Leiden/CETP Tg mouse, might have further supported a role for plasma cholesterol reduction in non-ischemic heart failure with a clinical perspective. Could the beneficial effect be peculiar to the animal model used? TAC is a procedure commonly used in the mouse for pressure overload-induced cardiac hypertrophy and heart failure. While heart hypertrophy initially develops to compensate the overload, the chronic hemodynamic changes become maladaptive, resulting in cardiac dilatation and heart failure. This is a robust model that mimics the human pathology and provides a more reproducible model of heart failure development compared to complete occlusion of the left anterior descending (LAD) coronary artery, thus enforcing the findings of the present work. Is the AAV8-LDLr gene transfer ready for translation in patients with heart failure? Not yet. In fact, whereas AAV8-LDLr gene therapy is already under investigation in patients with familial hypercholesterolemia, with the aim of restoring LDLR activity (NCT02651675) and thus limiting atherosclerosis and the risk of premature death for myocardial infarction, expansion of the indication of AAV8-LDLr gene therapy to heart failure is far from ready for clinical testing. If induction of the LDLR in the liver and the consequent lowering of plasma cholesterol are key, as it appears in this study, then statins should work as well. Despite these aspects, the work by Muthuramu et al.1Muthuramu I. Amin R. Postnov A. Mishra M. Aboumsallem J.P. Dresselaers T. Himmelreich U. Van Veldhoven P.P. Gheysens O. Jacobs F. De Geest B. Cholesterol-lowering gene therapy counteracts the development of non-ischemic cardiomyopathy in mice.Mol. Ther. 2017; 25 (this issue): 2513-2525Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar paves the way for addressing the role of lipid-lowering approaches that increase LDLR expression/function in improving non-ischemic heart failure. In an era where many pharmacological approaches for the treatment of dyslipidemia are emerging, further analyses of the data from the trials with ezetimibe, PCSK9, or CETP inhibitors on non-ischemic heart failure incidence/progression are warranted to support a beneficial effect in patients that might be related to the lipid lowering activity. Cholesterol-Lowering Gene Therapy Counteracts the Development of Non-ischemic Cardiomyopathy in MiceMuthuramu et al.Molecular TherapyJuly 31, 2017In BriefA causal role of hypercholesterolemia in non-ischemic heart failure has never been demonstrated. In this issue of Molecular Therapy, Muthuramu et al. demonstrate that AAV8-mediated cholesterol-lowering gene therapy potently counteracts structural and metabolic remodeling, and enhances cardiac function in mice with pressure overload induced by transverse aortic constriction. Full-Text PDF Open Access