A significant minority, estimated at 10 percent, of individuals undergoing statin therapy for cholesterol management report experiencing unexplained muscular discomfort, a phenomenon that frequently leads to the cessation of these vital medications.
Recent investigations conducted by teams from Columbia University and the University of Rochester in the United States have elucidated the underlying cause of statin-associated muscle symptoms (SAMS), characterized by sensations like aching and fatigue. This condition is attributed to an excessive influx of calcium ions into muscle cells, precipitating tissue damage and potentially grave health consequences.
The pharmacological action of statins involves the inhibition of a specific enzyme critical to the liver’s synthesis of cholesterol. Consequently, circulating levels of low-density lipoprotein (LDL), often referred to as ‘bad’ cholesterol, are diminished, thereby mitigating the risk of cardiovascular ailments such as atherosclerosis, a condition marked by the accumulation of lipid deposits within arterial walls – a leading cause of mortality in the United States.
However, statins exhibit effects on ancillary molecular targets, including a protein known as ryanodine receptor 1 (RyR1). This protein, structurally resembling a mushroom, functions as a channel or gate situated on the sarcoplasmic reticulum, an intricate sarcoplasmic network enveloping muscular fibers.
RyR1 functions akin to security personnel, regulating the passage of calcium ions into muscle tissue, a process indispensable for orchestrating muscular contractions.
Employing murine models, the research fraternity meticulously documented the precise interaction between statins and RyR1, utilizing an advanced imaging methodology termed cryo-electron microscopy (cryo-EM).
Cryo-EM procedures entail rapidly freezing biological specimens, followed by exposure to electron beams. The resultant scattering patterns of these electrons reveal minute structural details, enabling the reconstruction of high-resolution three-dimensional visualizations of complex biological entities like proteins and their constituent molecular components.
Paradoxically, cholesterol-lowering agents such as simvastatin can sustain the open state of these ion channels, facilitating the leakage of calcium ions into muscle cells. This intracellular calcium excess can directly inflict damage upon muscle tissue or activate enzymatic pathways responsible for its degradation.
Consequently, individuals on statin regimens may experience persistent discomfort, diminished strength, tenderness, and spasms. This predicament is particularly pronounced in those with RyR1 genetic predispositions, who might also encounter episodes of malignant hyperthermia – a severe, medication-induced hyperpyrexia – or diaphragmatic weakness leading to impaired respiratory function and attendant pulmonary disorders.
In infrequent but potentially life-threatening scenarios, statin-induced complications can manifest as rhabdomyolysis. This severe syndrome is characterized by the disintegration of muscle tissue, leading to the release of myoglobin into the bloodstream, ultimately culminating in renal failure.
Similarly, though rarely observed, autoimmune-mediated necrotizing myositis, a condition where the immune system erroneously targets and destroys muscle tissue, can also arise.
While the calcium channel dysfunction hypothesis might not encompass every instance of SAMS, this newly established mechanistic understanding offers a potential pathway for identifying individuals susceptible to statin intolerance. In the United States alone, approximately 40 million adults are prescribed statins, with a notable 10 percent experiencing SAMS.
“I have encountered patients who, upon being prescribed statins, opted against their use due to the adverse effects,” states lead author Andrew Marks, a cardiologist affiliated with Columbia University Vagelos College of Physicians and Surgeons.
“This is the most prevalent justification for patients discontinuing statin therapy, and it represents a genuine challenge necessitating a resolution.”
The investigative team has put forth two promising avenues for resolution. The primary approach involves the molecular redesign of statins to prevent their interaction with RyR1 while preserving their efficacy in reducing hepatic cholesterol synthesis.
Alternatively, in experiments where statin-intolerant murine subjects were administered Rycal, an investigational therapeutic class employed for rare muscular pathologies, researchers successfully induced closure of aberrant RyR1 calcium channels, thereby averting simvastatin-induced muscular debility.
This groundbreaking research is published in the Journal of Clinical Investigation.
