Cardiovascular diseases (CVD) include coronary heart disease, stroke, myocardial infarction and heart failure. They are the leading cause of mortality globally, with CVD accounting for 31% of deaths worldwide in 2015 . Within the UK alone 27.4% of male deaths and 25.2% of female deaths in 2015 were due to CVD. Despite the similar mortality rate between the sexes, the risk of CVD in women is often under-estimated. Researchers are turning to iPSC-derived cardiomyocytes from male and female donors to increase our understanding of gender-based differences and the role that these play in the development and progression of CVD.

    Why is the risk of CVD in women often under-estimated?

    CVD typically develops 7-10 years later in women than in men, a phenomenon which has caused a misconception that women are protected against CVD. In turn this has resulted in the under-recognition of CVD in women, less aggressive treatment strategies and a lower representation of women than men in clinical trials .

    Classic risk factors for CVD include high cholesterol, high blood pressure, smoking, being overweight and having type II diabetes. These are shared by men and women alike, however the weighting and significance varies between the sexes. For instance, the loss of endogenous estrogen production following menopause is typically accompanied by increases in blood pressure, which are significantly steeper in post-menopausal women than in age-matched men .

    How can iPSC-derived cardiomyocytes enhance cardiovascular disease research?

    Substantial progress has been made in recent years concerning our knowledge of gender-related CVD risk factors. Researchers have employed models of atherosclerosis, vascular injury, aortic aneurysm formation, myocardial injury, pressure overload and volume overload, as well as utilizing transgenic and knockout mouse models to better understand female susceptibility to CVD . While these models have provided a wealth of valuable information, many have relied on the use of animals.

    Animal studies are expensive to perform, do not always translate to humans, and are associated with ethical issues. The use of iPSC-derived cardiomyocytes therefore represents an efficient and biologically relevant system that reduces the need for animal studies and offers substantial cost-savings.

    As just one example of the changing landscape of CVD research, we can consider the way in which methods of studying ion composition have evolved. This has been the focus of many research groups since modulating ion composition has been implicated both as an anti-arrhythmic target and as a means of protection from myocardial injury.

    In 2005, a study by Brown et al generated infarcts (areas of dead tissue resulting from a loss of blood supply) via induction of ischemia-reperfusion injury in male and female rats. Expression of the sarcolemmal ATP-sensitive potassium (K ATP ) channel was then quantified alongside measurement of infarct size. Protein expression was highest in female rats and corresponded with smaller infarcts, leading the authors to suggest a potential protective role for this ion channel in females.

    In a more recent study, published in 2017, Papp et al used human iPSC-derived ventricular cardiomyocytes to study the effects of estrogen on two key calcium channels. The aim of this research was to compare the results obtained in rabbit hearts with equivalent human samples, during which the iPSC-derived cardiomyocytes fulfilled the role of healthy human heart tissue. In females, both channels were up-regulated by estrogen, whereas a similar effect was not observed in males. The authors hypothesized that estrogen binding to its receptor may increase channel expression and promote Ca 2+ overload, contributing to a higher risk of lethal arrhythmias in women. The latter study allowed a direct comparison of human and animal samples within the same set of experiments.

    iPSC-derived male and female cardiomyocytes: applications and benefits

    iPSC-derived cardiomyocytes allow researchers to build their findings on human cellular models, considerably reducing reliance on animal systems. These cells are ideal for use in cardiotoxicity testing, drug screening and drug validation, as well as within metabolism studies and electrophysiology applications.

    Other potential applications include their use for studying the effects of menopausal hormone therapy on cardiovascular health, and as a tool in understanding how medical conditions, such as growth hormone deficiency, can impact cardiac function.

     
     

    Watch how Axol's human iPSC-derived Ventricular Cardiomyocytes begin to beat following thawing.

    Axol’s ventricular cardiomyocytes are derived from male and female donors of multiple genetic backgrounds, offering an effective method of studying gender-based differences with regards to CVD. Our cells have been rigorously characterized by marker expression and have also been functionally validated. To complement them, we supply expertly optimized growth media for their successful culture and propagation, along with unrivalled technical support.

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