Phosphorylation-dependent relief of Rad inhibition of cardiac Caᵥ1.2 channels underlies β-adrenergic increase in heart contraction essential for the fight-or-flight response. Prevailing evidence outline 4 steps involved in PKA-dependent relief of Caᵥ1.2 inhibition by Rad: basally, Rad inhibits Caᵥ1.2 by binding Caᵥβ and the plasma membrane using the G-domain and C-terminus, respectively (step 0), PKA-dependent phosphorylation of Ser residues in Rad C-terminus disengages Rad from the plasma membrane (step 1) and decreases affinity for Caᵥβ (step 2), potentially leading to Rad loss from Caᵥ1.2 nanodomain (step 3). It is unclear which steps and Rad structural determinants are necessary and sufficient for PKA regulation of CaV channels and the mechanism linking steps 1 and 2 is not entirely understood. Moreover, there is an apparent Rad-concentration-dependence to Caᵥ1.2 regulation wherein PKA activation is unable to overcome over-expressed Rad inhibition of the channel. The basis of this effect is unknown and constitutes a significant gap in our complete understanding of convergent regulation of Caᵥ channels, by Rad and PKA. We developed a systematic protein engineering-based approach to dissect the distinct steps and determinants involved in PKA modulation of Rad-inhibited Caᵥ channels. Fusing Rad C-terminus to Caᵥβ₃ generated β3-CT which was tethered to the plasma membrane when expressed alone in HEK293 cells and yielded constitutively inhibited channels when co-expressed with CaV2.2. Unexpectedly, PKA activation with forskolin further deepened inhibition of Caᵥ2.2 currents despite being sufficient to release β₃-CT from the plasma membrane. Phosphomimetic mutations in β₃-CT 6SD yielded deeply inhibited Caᵥ2.2 currents that were not further affected by forskolin. Two CaVβ-binding nanobodies fused to Rad C-terminus, F3-CT and B11-CT, were membrane-targeted yet yielded Caᵥ2.2 currents that were not basally inhibited and decreased by forskolin. Over-expressing wildtype Rad C-terminus (WTCT) by itself with Caᵥ1.2 produced basally inhibited channels that were further reduced by forskolin and co-expression of Caᵥ1.2 with a phosphomimetic Rad C-terminus (CTD) also produced constitutively inhibited channels. Truncated Rad lacking the C-terminus (Rad[1-276]) displayed low affinity to Caᵥβ, discounting a direct role for phosphorylated Rad C-terminus in linking steps 1 and 2. Fusing the protein kinase C C1 domain to Rad[1-276] yielded Rad₂₇₆-C1 which was cytosolic and displayed low affinity to Caᵥβ. Exposure to PdBu recruited Rad₂₇₆-C1 to the plasma membrane, increased affinity for Caᵥβ, and concomitantly inhibited Caᵥ1.2 currents. These results reveal that all 4 steps are necessary for PKA regulation of Caᵥ channels, membrane association regulates Rad affinity for CaVβ, and the Rad G-domain and C-terminus are replaceable with modular units that mimic their function. Our findings deepen understanding of PKA modulation of Caᵥ channels and provide new insights for developing chemo-genetic Caᵥ channel regulators.

Tyrimo objektas. Vidutinių ir ilgų nuotolių bėgikų aerobinis pajėgumas ir kvėpavimo sistemos rodiklių sąryšis. Tyrime dalyvavo 19 vidutinio bei didelio meistriškumo vidutinių (pagrindinis varžybinis nuotolis – nuo 600 m iki 2 km, n =9) ir ilgųjų (3 km arba daugiau, n =10) nuotolių bėgikai. Tiriamiesiems buvo atliktas kvėpavimo sistemos funkcinės būklės nustatymas ramybėje ir aerobinio pajėgumo nustatymas atliekant nepertraukiamą nuosekliai didėjantį krūvį. Tikslas - nustatyti vidutinių ir ilgų nuotolių bėgikų aerobinio pajėgumo ir kvėpavimo sistemos funkcijos ypatumus. Darbo uždaviniai: 1. Palyginti vidutinių ir ligų nuotolių bėgikų aerobinį pajėgumą. 2. Palyginti vidutinių ir ligų nuotolių bėgikų kvėpavimo sistemos funkcinius rodiklius. 3. Įvertinti sąryšį tarp bėgikų aerobinio pajėgumo ir kvėpavimo sistemos funkcijos rodiklių. Išsikėlėme hipotezę, kad kvėpavimo funkcinės galimybės dėl skirtingo intensyvumo treniruotės ir varžybinių krūvių turėtų būti didesnės tarp vidutinių nuotolių bėgikų, o aerobinės ištvermės rodikliai turėtų būti didesni tarp ilgų nuotolių bėgikų. Išvados 1. Absoliutus maksimalus deguonies suvartojimas lyginant vidutinių ir ilgų nuotolių bėgikus nesiskiria, o santykinės šio rodiklio reikšmės reikšmingai didesnės ilgų nuotolių bėgikų grupėje. 2. Ilgų nuotolių bėgikų pirmasis ventiliacinis slenkstis ir jį atitinkantis ŠSD didesni ilgų nuotolių bėgikų grupėje, nors maksimalios ŠSD reikšmės nuosekliai didinamo krūvio metu nesiskiria. 3. Bėgimo... [toliau žr. visą tekstą] / Object of research. Middle distance and long distance runners aerobic capacity and the connection of respiratory system indicators. We researched 19 superior level middle distance (main competition distance from 600m to 2 km, n = 9) and long distance (3 km or more, n = 10) runners. Researched sportsman have undergone respiratory system functional condition test in tranquility state and aerobic capacity test during consecutively heavier physical load. Goal of research. To determine the functional features of middle distance and long distance runners aerobic capacity and respiratory system. Tasks: 1. To compare aerobic capacity between middle distance and long distance runners. 2. To compare respiratory system functional indicators between middle distance and long distance runners. 3. Analyze and connection between runners aerobic capacity and respiratory system indicators. Hypothesis. Because of different training intensiveness and competition loads, functional capacities of respiration system are greater of the middle distance runners, and aerobic capacity indicators are greater of the long distance runners. Conclusion. 1. Absolute maximum oxygen consumption is almost the same of both middle distance and long distance runners, while relative indicators are significantly greater in the long distance runners group 2. Long distance runners first ventilator threshold and its corresponding heart contraction rate is greater in the long distance runners group, while maximum heart... [to full text]

This study investigated whether acute myocardial ischemia of the anterior left ventricular wall induced an increase in cardiac sympathetic efferent nerve activity and thereby affected regional myocardial blood flow and contractile function.

Thesis (M. Tech.) -- Central University of Technology, Free State, 2010 / This main aim of this study was to assess patients in a general cardiology practice in order to determine the systolic and diastolic profiles of these patients. The aim was also to determine what effect life style and risk factors may have on the echocardiographic variables measured during such an examination. The specific aim of this study was the importance of not only examining the systolic function but the necessity to also examine the diastolic profile of patients. Life-style plays an important role, with the main culprit being obesity. Obesity was the single most important factor that affected the diastolic profile of patients seen in this study. With obesity a combination of other risk factors related to obesity was observed. Most abnormalities found due to these risk factors were associated with diastolic changes in the left ventricle. Echocardiography is routinely used in daily practice, but the diagnostic value of this tool can be enhanced if proper analyses of the systolic as well as the diastolic profiles are determined. Many cardiologists only measure the systolic function of the heart as an indication of the well- being of the left ventricle, although in this study it was proven that systolic function did not alter with ageing or with changes in the risk profile. Hundred-and-twelve patients, divided into three age groups, were evaluated in this study. Both systolic and diastolic variables were measured and analysed for abnormalities. None of these patients had systolic function abnormalities, although they had detectable anatomic changes due to ageing, obesity and hypertension. Several abnormalities were found on the diastolic profile of these patients. Muscle thickness increased due to obesity and hypertension and even with ageing, but with no significant abnormalities in the systolic function of the heart. There was a slight increase in the circumferential shortening of the left ventricle and that both the septal and longitudinal functions decreased with ageing. It is noteworthy that even where the systolic function remained normal in ageing subjects, their diastolic profiles changed significantly. Assessment of left ventricular function required a meticulous and systematic approach. In this study forty- one percent of patients visiting this general practice had abnormalities of their diastolic function although their systolic function was normal. It was found that with ageing, especially in the older age group, important abnormalities occur in their diastolic profile. The most common changes were that the E- peak velocity decreased and that the Apeak velocity of the trans-mitral flow increased. It seemed that passive filling decreased with ageing but that active filling increased simultaneously, causing the cardiac output to remain constant in older subjects. This is important to know because diseases affecting the atrium may have a profound effect on the cardiac output of older patients, even if they have normal systolic function, (due to the decreased passive filling they need their active filling or atrial contraction to support a normal cardiac output). An important marker will be to look at the ratio of the E/A- velocities in older patients to determine the ratio of active against passive filling. Other than that, a relatively new tool in echocardiography called tissue Doppler was used to determine what happened to the muscle with ageing. Here it was demonstrated that the different layers of the left ventricle acted differently with ageing. Results showed that the longitudinal fibres weakened with ageing although the circumferential fibres remained unchanged or even strengthened with ageing. It was apparent in this study that the traditional use of only systolic function may not be adequate when evaluating relative asymptomatic patients presenting at a general cardiology practice. It is important to also evaluate the diastolic profiles of these patients in order to scientifically quantify their heart health, even in asymptomatic patients. It is important to routinely evaluate the diastolic profile of patients so that early detection of these diastolic variables can be detected and timely consideration for its treatment can be given by their cardiologist. It is also important to take note of the significance of the obesity problem and the effect it has on the heart’s health. In conclusion, this study emphasizes the importance of the echocardiographic evaluation of diastolic cardiac function in addition to routine systolic evaluation in asymptomatic patients. This will enable the clinician to detect abnormalities early and tailor therapy accordingly. Lifestyle related risk factors, especially obesity, also have significant effects on diastolic cardiac function.

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Synchronous contraction and relaxation of the myocardium is required to optimize cardiac function. Regional timing of contraction and relaxation is dyssynchronous in many patients with heart failure. Cardiac resynchronization therapy (CRT) is a highly successful treatment for dyssynchronous heart failure. Patients are currently selected for CRT using surface electrocardiogram QRS duration as a measure of dyssynchrony. However, up to 30% of patients selected for CRT show no improvement. This poor response rate may in part be explained by the poor correlation between mechanical dyssynchrony and QRS duration. Thus, better methods to quantify mechanical dyssynchrony in the heart may improve the poor CRT response rate. The overall goal of this project was to develop better methods to diagnose dyssynchrony in the left ventricle (LV). We developed two new methods with different approaches. The first method improved upon existing tissue-Doppler based echocardiographic diagnosis of dyssynchrony by utilizing a cross-correlation (XC) function to quantify dyssynchrony during post-processing as opposed to the quantitatively simplistic time-to-peak analysis that is currently utilized. The second method utilized standard cine cardiac magnetic resonance (CMR) images to quantify the dyssynchrony in the flow of blood within the LV, which may represent a more direct, physiologically relevant measure of dyssynchrony. Specific aim 1 demonstrated that the new XC delay parameters can be quantified accurately with a stationary region of interest and therefore require significantly less post-processing time to calculate compared to the time-to-peak dyssynchrony parameters. Specific aim 2 showed that XC delays are superior to existing time-to-peak dyssynchrony parameters at discriminating patients with LV dyssynchrony from those with normal function. The time-to-peak parameters showed dyssynchrony in approximately half of the normal, healthy volunteers while the XC delay parameters had nearly perfect diagnostic accuracy. The results of specific aim 3 showed that XC delays could diagnose acute, pacing-induced dyssynchrony in young, healthy children with 79% accuracy while the time-to-peak parameters showed accuracies of 71%, 57% and 57%. Specific aim 4 showed that CMR-based quantification of LV internal flow can be used to discriminate patients with dyssynchronous heart failure from normal controls with 95% accuracy.