Differences in the Kinetics and Spatial Distribution of Actin in the Left and Right Ventricles of Human Hearts
Fudala, Rafal PhD
gryczynski, ignacy PhD
borejdo, julian PhD
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The left and right ventricles (LV, RV) are morphologically and physiologically different because they are play vastly different roles in the human circulatory system: the RV pumps blood into the pulmonary system and LV into the systemic systems, both of which offer different resistances to contracting ventricles. It is therefore not surprising that large differences are seen when ventricles are examined on a macroscopic level. This does not mean, however, that the ventricles are different on a molecular level, i.e. that the contractile proteins that are responsible for the ventricular contraction are different in the LV and RV. If this is true it should be possible to develop drugs affecting only one, not both, ventricles. Such drugs are currently not available, and would be of clinical importance because there exist a[J1] number of heart diseases caused by dysfunction of one ventricle only. For example, pulmonary hypertension is mainly due to RV dysfunction. Systolic or diastolic heart failure is mainly due to LV dysfunction. Because of these macroscopic differences, experiments can’t be carried out on the whole organs. Moreover, the whole ventricles (or papillary muscles) contain a large number of contractile molecules (1011-1013). Measurements which originate from such a large assembly yield the average values and all the kinetic information about molecular action is absent from macroscopic data. Similarly, all the details of the steady-state measurements are lost. Therefore, the experiments need to be carried out on a few molecules of contractile proteins: we observed the A-band of a sarcomere - a volume where a force producing interaction between actin and myosin molecules takes place. We measured kinetics and distribution of ~16 actin molecules of isometrically contracting A-bands. Experiments were done ex-vivo – in the A-bands of myofibrils isolated from human non-failing and failing ventricles. We show that the kinetics and the steady-state distribution of actin were different in contracting left and right ventricle of the non-failing human heart. In contrast, these parameters obtained from failing hearts were the same. These results suggest that there exists genuine differences in the way actin interacts with myosin cross-bridges in both ventricles of non-failing hearts, and suggests how the absence of such differences in failing ventricles can be offset.