Cardiac function and ischemia-reperfusion injury in chronic kidney disease
Uloženo v:
| Vydáno v: | ProQuest Dissertations and Theses (2013) |
|---|---|
| Hlavní autor: | |
| Vydáno: |
ProQuest Dissertations & Theses
|
| Témata: | |
| On-line přístup: | Citation/Abstract Full Text - PDF |
| Tagy: |
Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!
|
| Abstrakt: | Cardiovascular disease (CVD) is the leading cause of death in the chronic kidney disease (CKD) patient population. At the heart, CVD presents, in part, as cardiac dysfunction that increases in a monotonic fashion with disease progression. Cardiac dysfunction is considered an important risk factor for not only the development of congestive heart failure but also ischemic heart disease and mortality. Therefore, the goal of the present study was to assess cardiac function in the 5/6 ablation-infarction (AI) rodent model of CKD. In doing so, the relationship between cardiac function and ischemia-reperfusion (IR) injury was evaluated. In addition, we sought to investigate the role of oxidative stress in kidney disease-related cardiac pathology, and the effect of increased physical activity on cardiac dysfunction was determined. The global study hypothesis was that poor outcomes following ischemic cardiac events in CKD may be due to impaired baseline cardiac performance and augmented IR injury as mediated, in part, by elevated levels of oxidative stress. As such, physical activity would be an effective therapeutic strategy to attenuate the effects of oxidative stress and improve cardiac function in CKD. AI animals in our first set of studies presented with impaired baseline cardiac function and heterogeneous responses to 15 minutes of global no-flow ischemia. For those AI animals able to withstand this ischemic perturbation, no differences in percent recovery of cardiac output (CO) and cardiac work were observed compared to sham controls. However, approximately 36% of isolated AI hearts did not recover enough to achieve aortic overflow, and absolute measures of cardiac function indicated persistent functional impairments with IR insult. Impaired cardiac function and ischemic intolerance in AI were associated with increased oxidative stress and reduced nitric oxide (NO) production. Specifically, the non-phagocytic NADPH-oxidase (Nox)-4 isoform was increased in the uremic myocardium in conjunction with increased H2O2 and altered antioxidant defense. Conversely, left ventricular nitric oxide synthase (NOS)-3 and stable NO metabolites (NO2- + NO3 -; NOx) were decreased in these animals. Taken together, these findings suggest that myocardial stunning is not augmented in AI, but impaired cardiac function may result in poor outcomes following short duration ischemia. Further, cardiac dysfunction and ischemic intolerance may be due to increased oxidative stress via NO dependent and -independent mechanisms. In the second part our investigation, we demonstrated improvements in cardiac function following a short 4-week voluntary wheel running intervention in AI. AI animals presented with significantly impaired cardiac performance at baseline as well as in response to alterations in atrial filling pressure and aortic pressure. Conversely, different measures of cardiac function in isolated perfused hearts from AI wheel running rats that only ran an average of ~0.48km/day were not different from sham. Improved cardiac performance following 4-weeks of voluntary wheel running was associated with increased expression of left ventricular (LV) NOx and the constitutive NOS-3 isoform as well as reduced inducible NOS-2. In addition, LV 2O2 was lower in AI-WR as associated with increased expression of superoxide oxide dismutase-2 & glutathione peroxidase-1/2. These findings suggest that a short period of increased physical activity is sufficient enough to modestly improve cardiac function in renal diseased rats, as related to improved redox homeostasis and increased NO production and/or bioavailability. In summary, a rodent of model of CKD demonstrated cardiac dysfunction and poor tolerance to ischemic insult similarly to that observed in CKD patients. Impaired cardiac function was demonstrated in the presence of increased ROS production, altered antioxidant homeostasis, and decreased NO production. A short period of increased physical activity was sufficient enough to improve cardiac function as well as related underlying mechanisms. Therefore, habitual physical activity represents a promising adjunct therapy to improve cardiac function in CKD and potentially ischemic prognosis as well as poor patient outcomes. |
|---|---|
| ISBN: | 9781303751141 |
| Zdroj: | ProQuest Dissertations & Theses Global |