Statins and the Reduction of Sudden Cardiac Death: Antiarrhythmic or Anti-Ischemic Effect?

Abhimanyu Beri; Tahmeed Contractor; Atul Khasnis; Ranjan Thakur

Disclosures

Am J Cardiovasc Drugs. 2010;10(3):155-164. 

In This Article

3. Statins and Sudden Cardiac Death Prevention: Mechanisms

Several mechanisms have been proposed to explain the reduction of ventricular arrhythmias/sudden cardiac death by statins.[32] These mechanisms can be classified as described in sections 3.1 to 3.4.

3.1 Prevention of Ischemia

Plaque erosion, rupture, and intraluminal thrombus formation are known precipitating factors for acute myocardial ischemia. Statins, through their anti-inflammatory, anti-proliferative, plaque stabilization, and regression properties contribute to ischemia prevention.[33] The risk reduction in sudden cardiac death with statins has been shown to be independent of lipid lowering and may be explained by these pleiotropic effects.[34]

Occlusive mural platelet microthrombi may predispose to microischemia and sudden cardiac death, and have been demonstrated more frequently in the coronary microvasculature of patients with sudden death related to cardiac causes compared with other etiologies.[35–37] These microthrombi are more common in the intramyocardial vessels distal to epicardial arterial thrombi,[37,38] suggesting downstream embolization. In situ microthrombus formation secondary to ischemic endothelial injury and a generalized increase in platelet aggregability is another proposed mechanism.[14] These microischemic episodes, while often clinically inapparent, could be the underlying cause for VT/VF. Through their effects on the coagulation cascade,[39,40] platelet aggregability,[41] and endothelial integrity,[42] statins can reduce thrombogenicity. This may in turn reduce these microischemic episodes and explain an indirect antiarrhythmic effect of statins.

3.2 Modulation of the Autonomic Nervous System

Statins have shown varied effects on heart rate variability. In patients with established coronary artery disease[43,44] and hyperlipidemia,[45,46] statins have demonstrated an increased heart rate variability that may protect against sudden cardiac death. This finding, however, could not be confirmed in a randomized crossover study of 80 patients with coronary artery disease treated with atorvastatin over 6 weeks.[47] In nondyslipidemic patients without underlying coronary artery disease, statins failed to demonstrate any change in heart rate variability.[48] Thus, the observed protective increase in heart rate variability may represent yet another anti-ischemic effect rather than a direct effect of statins on the autonomic nervous system.

3.3 Primary Antiarrhythmic Effect

The incidence of ventricular arrhythmias, appropriate implantable cardioverter defibrillator (ICD) therapies, and sudden cardiac death have a circadian variation with early morning preponderance.[49,50] In hypercholesterolemic individuals, statins attenuate the circadian variation in QTc dispersion, resulting in a flat 24-hour QTc dispersion curve.[51] This phenomenon, like the effect of statins on platelet aggregability (see section 3.1) [which also peaks in the morning],[52] could be responsible for their benefit in sudden cardiac death.

Ventricular late potentials are low amplitude waveforms that correspond to fragmented activation of diseased ventricular tissue and may serve as an anatomical substrate for repeated VT/VF. Early statin administration following an acute myocardial infarction has been shown to significantly decrease the incidence of these late potentials, accompanied by a reduction in the incidence of VT/VF.[53–55]

Similarly, statins have demonstrated a reduced occurrence of exercise-induced premature ventricular contractions,[56] which is a known risk factor for cardiovascular mortality.[57] This effect was independent of clinical predisposition or markers for coronary artery disease, suggesting a mechanism other than ischemia prevention.

It has been hypothesized that statins alter lipid portions of the membrane through which transmembrane segments of ion channels penetrate. This possibly occurs by statin-induced modification of lipid rafts, which are cellular microdomains containing signaling molecules and ion channel regulatory proteins.[58] Thus, by favorably altering conductance of ion channels, statins may directly reduce arrhythmias.[13] In animal models, statins have been found to reduce hypercholesterolemia and ischemia-reperfusion-induced electrophysiological remodeling.[59,60]

3.4 Anti-inflammatory Effect

Atherogenic dyslipidemias induce a systemic pro-inflammatory, pro-thrombotic state through oxidized lipids such as platelet-activating factor receptor-modulating phospholipids, leukotrienes, and oxysterols. Subendothelial deposition of these molecules occurs during atherosclerosis; this may represent yet another molecular mechanism of arrhythmogenesis.[61] Statins inhibit this systemic pro-inflammatory, prothrombotic state and may directly reduce the risk of fatal arrhythmias.

Certain normolipidemic individuals may also have a proinflammatory state as suggested by elevated C-reactive protein (CRP) levels (particularly high-sensitivity CRP or hs-CRP).[62–64] In healthy persons without hyperlipidemia but with elevated hs-CRP levels, rosuvastatin significantly reduced the incidence of major cardiovascular events.[65] Statins have been shown to reduce elevated CRP levels,[66] which have been found to be a risk factor for sudden cardiac death.[67] Thus, irrespective of lipid levels, the anti-inflammatory effect of statins may cause a reduction in sudden cardiac death.

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