The study of Jacqueline Bliley en Mathilde Vermeer et al., published in Science Translational Medicine, shows that dynamic loading of human-derived engineered heart tissues increases the contractility compared to isometric loading. More importantly, is dynamic loading also shown to drive a disease phenotype in tissues derived from a patient with arrhythmogenic cardiomyopathy. This study is part of an ongoing Trans-Atlantic collaboration between the group of Peter van der Meer and Adam W. Feinberg, principle investigator at Carnegie Mellon University in Pittsburgh.
Isometric versus eccentric and concentric contraction
The heart displays 3 different types of contractions. During diastole, the left ventricle fills with blood causing the ventricle wall to dilate (muscle elongation= eccentric contraction). When the ventricle is fully filled with blood, tension rises further into the ventricle wall, momentarily without any muscle shortening or elongation (= isometric contraction). When the pressure is high enough to overcome the pressure in the aorta, the aortic valves open. During this systolic phase, the ventricle wall contracts (muscle shortening=concentric contraction) to pump the blood into the circulation. The human heart is in fact able to contract 30% of its maximum muscle length and the higher this percentage, the better the ejection fraction.
Currently, it is impossible to investigate cardiac myocytes, derived from hearts of living patients. However, with the invention of induced pluripotent stem cells, any somatic cell can be transformed into a stem cell. This allows us to differentiate these stem cells to cardiac myocytes, in order to investigate patient-specific heart cells in an indirect way.
Most important findings
Until now, scientists have mostly investigated isometric loading of human engineered heart tissues, which allows only a few percentages of contractile shortening. Our study shows that dynamic loading (eccentric and concentric contraction) is needed to reach a more optimal contractile power. Using a bendable strip that applies pressure to the tissue, tissues can unlimitedly shorten and elongate (>20%), like in the human heart. The applied pressure is dictated by the thickness of the strip, which in turn determines the contractile power that is generated by the tissue. Contrasting, when tissues have a mutation in the gene DSP (desmoplakin), one of the genetic causes of arrhythmogenic cardiomyopathy, dynamic loading causes diseased tissues to become more dilated with lower contractile power than healthy tissues. This phenotype closely resembles the clinical characteristics of patients with arrhythmogenic cardiomyopathy. The advantage of this finding is that scientists are now able to more physiologically investigate how a clinical phenotype arises and progresses, without burdening the patient any further. This could lead to a better understanding of disease, which is much needed for future therapeutic interventions.
