Statin therapy: striking a balance between prevention and disease control for the heart Michele Emdin Giuseppe Vergaro, Gianluca Mirizzi, Luigi Emilio Pastormerlo Fondazione G. Monasterio, Scuola Superiore Sant’Anna, Pisa, Italy Heart Failure & Co. Thirteenth International Symposium, My Sweet Heart: Manage with Care. Naples, April

shear stress LDL accumulation oxidation – glication inflammation vasoconstriction rupture -thrombosis vascular remodeling …….. atherogenesis preclinical ATS preATS risk From healthy to diseased vessels GENETICS COMORBIDITY > Chol. HABIT GENDER plaque instabilization infarction death ischemic syndrome LV remodeling Overt HF DIABETES Art.HT AGE

CV risk: Diabetes as CVD/CHD equivalent..

Statin Secondary Prevention Trials CHD Event Reduction in Patients With Diabetes

The good: statins & diabetes Early clinical trials: statins benefit CHD patients with type 2 diabetes Pre-specified analyses (diabetes with/without CHD, ASCOT-LLA, HPS, LIPID) have shown significant benefits of statins in reducing CV events including stroke CARDS—the first prospective statin trial in patients with diabetes— terminated 2 years earlier than anticipated due to a highly significant reduction in major CV events compared with placebo High-dose statin therapy in patients with CHD and diabetes (TNT) has shown a significant reduction in CV events compared with lower-dose statin therapy These trials have contributed to changes in guidelines focusing on intensive LDL-C management in patients with diabetes

The bad: when compliance is a problem.. High dose, elderly, women, kidney failure…

The ugly: Best treatment may be not enough…

From risky conditions, through acute damage and ventricular silent dysfunction, up to overt HF: a role for statins in HF? GENETICS -COMORBIDITY

Potential pleiotropic mechanisms of benefit of statins in HF

GISSI-HF Tavazzi L et al, 2008 CORONA Kjekshus J. et al, 2007 Statin therapy in HF: still arguments for a debate?

Clinical studies pointing out the benefits of statin therapy…. Both CORONA (systolic ischemic HF) and GISSI- HF were well designed trials, but they did not confirm previous findings from observational studies... Tang WH et al, 2010

Both CORONA and GISSI-HF studied the effects of rosuvastatin, a recently approved (2003) lipid-lowering drug, which is hydrophilic, (atorvastatin and simvastatin are lipophilic), thus likely less effective in penetrating cell membrane Tang WH et al, 2010 Mc Taggart F et al, 2001

Effects of atorvastatin (top) and rosuvastatin (bottom) on LVEF in HF patients

Tsutamoto T et al, 2011 NT-proBNP (pg/ml) LVEF (%) atorvastatinrosuvastatin atorvastatin 6-month treatment with atorvastatin (n=32), but not rosuvastatin (n=31), improves NT-proBNP and LVEF in non-diabetic patients with dilated cardiomyopathy

Atorvastatin but not rosuvastatin restores ANS balance in non-ischemic DCM Comparison of cardia c123I- MIBG scintigraphic parameters before and after 6 months of treatment H/M, heart to mediastinum; WR washout rate Tsutamoto T et al., 2011

Statins in advanced HF: contra Observational studies have suggested that low plasma cholesterol and lipoprotein levels are independent predictors of poor outcome in CHF. It is suggested that lipoproteins rich in cholesterol and TG can bind and detoxify endotoxins (bacterial lipopolysaccharides), whose production is increased in HF. Endotoxins stimulate release of proinflammatory cytokines, which are associated with progression of the disease. There may be a level below which it is unsafe to reduce cholesterol levels, at least in symptomatic HF. Plasma levels of ubiquinone (coenzyme Q10) are reduced during treatment with statins. Ubiquinone is a coenzyme in mitochondrial respiration, and depletion could in theory adversely affect the cardiac muscle. Mabuchi H et al, 2005 Rauchhaus M et al, 2003 Lyons KS et al, 2010

Statins in HF: perspectives Mostly observational and retrospective data suggest statins are associated with better outcomes in patients with HF with both ischemic and non-ischemic etiologies. Patients at an early stage of disease (stage A/B HF, stage C- early LV remodeling) may benefit more from statin therapy While cholesterol reduction and plaque stabilisation likely play a role in reducing cardiovascular events in ischemic HF patients, the mechanisms underlying the benefit in non- ischaemic HF patients are less clear, possibly due to the pleiotropic effects of statin therapy. Further study, including randomised trials on lipophilic statins, is needed to confirm these benefits and to determine the mechanisms underlying the statin protection in non-ischemic HF patients.

Artwork by Ursula ferrara Michele Emdin,