Cardiovascular
Permanent URI for this collectionhttps://hdl.handle.net/20.500.12503/21705
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Browsing Cardiovascular by Author "Campbell, Kenneth"
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Item Contractile Differences In Left And Right Ventricles Of Healthy Human Hearts(2016-03-23) Nagwekar, Janhavi; Raut, Sangram; Rich, Ryan; Das, Hriday; Gryczysnki, Ignacy; Fudala, Rafal; Gryczysnki, Zygmunt; Blair, Cheavar; Campbell, Kenneth; Borejdo, Julian; Guglin, Maya; Duggal, DivyaLeft ventricle (LV) and right ventricle (RV) differ in embryology, structure and function. Left ventricle originates from the primary heart field while right ventricle originates from the secondary heart field. The two heart fields express different sets of transcription factors and signaling molecules. At the molecular level, the gene expression in response to the pressure loading and failure is different in both ventricles. They also exhibit differences in response to adrenergic stimulation. Adrenergic agonist increase LV contractility but RV contractility may be reduced. Although numerous studies have been performed at macroscopic (whole organ) level previously, none (to my knowledge) address the differences at a mesoscopic level, where only a few molecules are investigated. This becomes important, as in macroscopic studies there may be differences due to basic fiber structures, differences in orientation of fibers as well as molecular crowding. These differences were investigated at the level of few molecules by sparsely labeling the myosin lever arm with SeTau 647 Maleimide. The kinetics and steady-state distribution of cross-bridges were examined in ex-vivo myofibrils isolated from the ventricles of human non-failing and failing hearts and differences were compared in LV and RV. We show that the kinetics and the steady-state distribution of orientations of myosin were different in contracting LV and RV of the non-failing human heart. In contrast, kinetics and the steady-state distribution of myosin in the failing hearts were the same. These results suggest that there is a difference in the way actin interacts with myosin cross-bridges in ventricles of non-failing hearts. We compare the clinical parameters of the failing heart with the kinetics and the distribution of the non-failing heart, and suggest molecular effectors of the function of myosin.Item Differences in the Kinetics and Spatial Distribution of Actin in the Left and Right Ventricles of Human Hearts(2016-03-23) Duggal, Divya; Rich, Ryan; Fudala, Rafal; Gryczynski, Ignacy ; Raut, Sangram; Borejdo, Julian; Guglin, Maya; Campbell, Kenneth; Nagwekar, JanhaviThe 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.