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Statin therapy: striking a balance betweenprevention and disease control for the heart
Michele EmdinGiuseppe 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 12 2013
shear stressLDL accumulation
oxidation – glicationinflammation
vasoconstrictionrupture -thrombosis vascular remodeling
……..
atherogenesis
preclinical
ATS
preATS
risk
From healthy to diseased vessels
GENETICS COMORBIDITY
> Chol. HABITGENDER
plaque instabilization
infarction
death
ischemic
syndrome
LV remodeling
Overt HF
DIABETES Art.HTAGE
CV risk: Diabetes as CVD/CHD equivalent..
Statin Secondary Prevention TrialsCHD 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 treatmentmay be notenough…
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, 2010Mc 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 rosuvastatin 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 treatmentH/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, 2005Rauchhaus 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.
