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[Are all HMG-CoA reductase inhibitors protective against ischemic heart disease?]
K Ichihara1, K Satoh, A Yamamoto
1Department of Pharmacology, Hokkaido College of Pharmacy, Otaru, Japan.
Insights
Lipophilic statins worsened heart function recovery after ischemia by reducing ATP levels. Hydrophilic statins like pravastatin showed no adverse effects on myocardial contractile function.
Area of Science:
- Cardiology
- Biochemistry
- Pharmacology
Background:
- Myocardial stunning is a post-ischemic contractile dysfunction.
- Statins are HMG-CoA reductase inhibitors used to lower cholesterol.
- Understanding statin effects on cardiac function during ischemia-reperfusion is crucial.
Purpose of the Study:
- To investigate the differential effects of lipophilic and hydrophilic statins on myocardial recovery post-ischemia.
- To determine the impact of specific statins on myocardial ATP levels during reperfusion.
Main Methods:
- Dogs were pretreated with various statins (pravastatin, simvastatin, atorvastatin, fluvastatin, cerivastatin) for three weeks.
- Myocardial contractile function was assessed during reperfusion following brief ischemia.
- Myocardial ATP levels were measured to correlate with functional recovery.
Main Results:
- Lipophilic statins (simvastatin, atorvastatin, fluvastatin, cerivastatin) impaired recovery of myocardial contraction and reduced ATP levels.
- Hydrophilic pravastatin did not adversely affect myocardial contractile function or ATP levels.
- Reduced ATP levels in lipophilic statin-treated groups suggest mitochondrial dysfunction.
Conclusions:
- Lipophilic statins may worsen myocardial stunning by inhibiting mitochondrial ATP generation.
- Hydrophilic statins appear to be safer regarding ischemia-reperfusion injury in the myocardium.
- The mechanism involves potential intracellular entry of lipophilic statins, affecting ubiquinone biosynthesis and ATP production.
Abstract:
Effects of pravastatin, simvastatin, atorvastatin, fluvastatin and cerivastatin on myocardial contractile dysfunction during reperfusion after brief ischemia were examined in dogs. Pretreatment of the dog with lipophilic HMG-CoA reductase inhibitors for 3 weeks, simvastatin (2 mg/kg/day), atorvastatin (2 mg/kg/day), fluvastatin (4 mg/kg/day), and cerivastatin (40 micrograms/kg/day) worsened recovery of myocardial contraction during reperfusion after brief ischemia in association with reduced myocardial ATP level. A hydrophilic HMG-CoA reductase inhibitor, pravastatin (2 and 4 mg/kg/day), did not affect the recovery of myocardial contractile function and ATP level during reperfusion following ischemia. The lipophilic inhibitors may enter the myocardial cell, inhibit ubiquinone biosynthesis, and depress ATP generation in mitochondria, leading to worsening of the myocardial stunning after reperfusion subsequent to ischemia.