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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 12 2013
From healthy to diseased vessels
> Chol.
DIABETES
shear stress
LDL accumulation
oxidation – glication
inflammation
vasoconstriction
rupture -thrombosis
vascular remodeling
……..
preATS
risk
preclinical
ATS
ischemic
syndrome
LV remodeling
Overt HF
infarction
death
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
Statin therapy in HF: still arguments for a debate?
CORONA
GISSI-HF
Tavazzi L et al, 2008
Kjekshus J. et al,
2007
Clinical studies pointing out the benefits of statin therapy….
Both CORONA (systolic
ischemic HF) and GISSIHF 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
LVEF (%)
NT-proBNP (pg/ml)
rosuvastatin
atorvastatin
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
Tsutamoto T et al, 2011
Atorvastatin but not rosuvastatin restores ANS balance in
non-ischemic DCM
Comparison of
cardia c123IMIBG
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.
Lyons KS et al, 2010
Rauchhaus M et al, 2003
Mabuchi H et al, 2005
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 Cearly 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 nonischaemic 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, [email protected]