Molecular Signatures of Statins on Human Cardiomyocytes
By Amanda Chase, PhD
April 7, 2020
Statins are widely prescribed to lower cholesterol and prevent cardiovascular disease in at-risk patients. In combination with lifestyle modifications, statins can reduce the risk of heart attack, stroke, and death in at-risk patients by 25-35%. Although statins have established benefits in reducing the risk of cardiovascular diseases, indiviudal patient response to statin treatment is highly variable. In addition to lowering cholesterol levels, statins have been shown to exert cholesterol-independent effects, or pleiotropic effects (i.e., having multiple effects), on different organs (e.g., brain, heart, muscle, liver, and others). This suggests that statins may have different drug-specific responses depending on the specific cell types, such as cardiomyocytes, that could explain their pleiotropic effects.
Given the benefits of statins on heart disease, a group of researchers at the Stanford Cardiovascular Institute, led by co-first authors Lei Tian, PhD, and Angelos Oikonomopoulos, PhD, and senior author Joseph C. Wu, MD, PhD, sought to investigate the drug- and individual-specific effects of clinically relevant concentrations of statins on human cardiomyocytes. Because testing the direct effect of statins on human cardiomyocytes is difficult due to the relative lack of access to these cells, the Stanford team instead used human induced pluripotent stem cells (iPSCs) that can be readily differentiated into iPSC-derived cardiomyocytes (iPSC-CMs). This iPSC-CM platform is ideal for individualized disease modeling, drug screening, and drug testing to understand the effects of statins and other drug targets in a cell-type specific way.
In their recently published letter in Circulation, the authors looked at the effects of four different statins (atorvastatin, lovastatin, simvastatin, and fluvastatin) on iPSC-CMs from healthy patients. Specifically, they looked at transcriptional effects, or differences in gene expression, of the different statins. Gene expression can vary under different conditions such as drug treatments, with certain genes being active at different levels, analogous to using a dimmer switch for a light. They were able to identify previously unknown effects on human cardiomyocytes primarily related to statins’ pleiotropic effects, independent of their primary action on cholesterol lowering. These effects were mainly related to fatty acid metabolism (energy production), anti-hypertrophic response (preventing abnormal heart muscle thickening), and pro-survival response (preventing cell death during stress). In addition to identifying a core set of commonly regulated genes that correlated with the clinical effects of statins, they also found that each statin had a different, specific response on cardiomyocytes. Together, these findings provide a framework for future research to test how the use of statins may benefit the heart directly and to better understand the variable responses observed among patients.
Other authors include Chun Liu, Tomoya Kitani, Rajani Shrestha, Christopher Chen, Sang-Ging Ong, Mark Smeets, Ioannis Karakikes, and Nazish Sayed. Funding was provided by the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad, the Dutch Heart Association and the Michaël Fonds, AHA 16POST30960020 and 17SDG33660794, and NIH R00 HL130416, K01 HL135455, R01 HL123968, R01 HL126527, R01 HL145676, R01 HL146690, R01 HL130020, and P01 HL141084.