Summary: Researchers report statins could potentially reduce cardiovascular risks in people with Friedreich’s ataxia.
Source: University of Pennsylvania.
In preclinical studies using cell models that mimicked liver cells of patients with the rare disease Friedreich’s ataxia (FA), a widely used cholesterol-lowering drug increased a precursor of HDL (high-density lipoprotein), the “good cholesterol,” according to new research published in PLOS ONE from the Perelman School of Medicine at the University of Pennsylvania.
Decreased HDL and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of death from cardiomyopathy and heart failure. “We found the FA patients had serum ApoA-I levels that were lower than healthy control subjects,” said senior author Ian Blair, PhD, a professor of Systems Pharmacology and Translational Therapeutics. The next step of the research, conducted in collaboration with David Lynch, MD, PhD, a professor of Neurology at Children’s Hospital of Philadelphia (CHOP), showed that statins may be able to help Friedreich’s ataxia patients increase their naturally low ApoA-I levels and so increase their HDL levels, which might help prevent heart disease.
Friedreich’s ataxia (FA) is a rare condition diagnosed in about in 50,000 people worldwide. It is the most common form of inherited ataxia, a condition characterized by a progressive loss of coordinated movement and balance. Onset of symptoms usually occurs in childhood, and most patients are confined to a wheelchair by their mid-to-late twenties. Most FA patients die from the thickening of their heart walls (hypertrophic cardiomyopathy) rather than from neurological issues.
In FA, the protein frataxin is made in insufficient amounts for mitochondria to function properly. This happens because of a mutation in the FXN gene, which results in reduced expression of frataxin protein. Frataxin is normally found in the mitochondria of cells and is involved in biochemical reactions that produce energy.
Using a highly specific and sensitive assay, the researchers found a 22 percent decrease in ApoA-I in the blood of FA patients compared with blood samples from non-affected healthy individuals. Using an experimental FA cell line, they also found that cells without frataxin produced lower levels of ApoA-I compared to controls. However, the cholesterol-lowering drug simvastatin increased the ApoA-I levels by 20 percent in these cells.
“I think that our findings provide compelling evidence for a trial of statins in FA patients to potentially reduce their cardiovascular risk,” Blair said. One issue is that higher doses of statins are associated with myositis (muscle inflammation) and rhabdomyolysis (destruction of skeletal muscle) so it would be essential to carefully monitor these side effects, he noted. In addition, co-administration of coenzyme Q10 supplement could help reduce the risk of muscle-related side effects.
Overall, Blair maintains that the potential benefits to FA patients with low ApoA-I levels taking low doses of statins outweigh the potential risks.
Funding: This research was funded by the Penn Medicine/CHOP Friedreich’s Ataxia Center of Excellence, in partnership with the Hamilton and Finneran families.
Source: Karen Kreeger – University of Pennsylvania
Publisher: Organized by NeuroscienceNews.com.
Image Source: NeuroscienceNews.com image is in the public domain.
Original Research: Open access research for “Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy” by QingQing Wang, Lili Guo, Cassandra J. Strawser, Lauren A. Hauser, Wei-Ting Hwang, Nathaniel W. Snyder, David R. Lynch, Clementina Mesaros, and Ian A. Blair in PLOS ONE. Published February 15 2018.
[cbtabs][cbtab title=”MLA”]University of Pennsylvania “Could Statins Ease Deadly Heart Condition in Friedreich’s Ataxia?.” NeuroscienceNews. NeuroscienceNews, 17 April 2018.
<https://neurosciencenews.com/statins-friedreichs-ataxia-8827/>.[/cbtab][cbtab title=”APA”]University of Pennsylvania (2018, April 17). Could Statins Ease Deadly Heart Condition in Friedreich’s Ataxia?. NeuroscienceNews. Retrieved April 17, 2018 from https://neurosciencenews.com/statins-friedreichs-ataxia-8827/[/cbtab][cbtab title=”Chicago”]University of Pennsylvania “Could Statins Ease Deadly Heart Condition in Friedreich’s Ataxia?.” https://neurosciencenews.com/statins-friedreichs-ataxia-8827/ (accessed April 17, 2018).[/cbtab][/cbtabs]
Low apolipoprotein A-I levels in Friedreich’s ataxia and in frataxin-deficient cells: Implications for therapy
Friedreich’s ataxia (FA) is an autosomal recessive neurodegenerative disorder, which results primarily from reduced expression of the mitochondrial protein frataxin. FA has an estimated prevalence of one in 50,000 in the population, making it the most common hereditary ataxia. Paradoxically, mortality arises most frequently from cardiomyopathy and cardiac failure rather than from neurological effects. Decreased high-density lipoprotein (HDL) and apolipoprotein A-I (ApoA-l) levels in the general population are associated with an increased risk of mortality from cardiomyopathy and heart failure. However, the pathophysiology of heart disease in FA is non-vascular and there are conflicting data on HDL-cholesterol in FA. Two studies have shown a decrease in HDL-cholesterol compared with controls and two have shown there was no difference between FA and controls. One also showed that there was no difference in serum Apo-A-I levels in FA when compared with controls. Using a highly specific stable isotope dilution mass spectrometry-based assay, we demonstrated a 21.6% decrease in serum ApoA-I in FA patients (134.8 mg/dL, n = 95) compared with non-affected controls (172.1 mg/dL, n = 95). This is similar to the difference in serum ApoA-I levels between non-smokers and tobacco smokers. Knockdown of frataxin by > 70% in human hepatoma HepG2 cells caused a 20% reduction in secreted ApoA-I. Simvastatin, a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor caused a 200% increase in HMG-CoA in the control HepG2 cells with a similar increase in the frataxin knockdown HepG2 cells, back to levels found in the control cells. There was a concomitant 20% increase in secreted ApoA-I to levels found in the control cells that were treated with simvastatin. This study provides compelling evidence that ApoA-I levels are reduced in FA patients compared with controls and suggest that statin treatment would normalize the ApoA-I levels.