The Role of the Carotid Body Chemoreflex in the Development of Renal Dysfunction in Chronic Heart Failure

Des Moines Univ Osteopathic Medical Ctr, Des Moines IA

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Abstract

Cardio-renal syndrome (CRS) is associated with increased morbidity and mortality in patients with chronic heart failure (CHF). Previous work shows that increases in carotid body chemoreflex (CBC) sensitivity contributes to increased renal sympathetic nerve activity (RSNA) and decreased renal blood flow (RBF) in CHF, but it is not known if this CBC sensitization contributes to tissue hypoxia, oxidative stress, or inflammation associated with the development of CRS. It is also unknown whether sleep apnea (SA) aggravates CBC sensitization and therefore contributes to development of CRS in CHF. The compound effects of SA and CHF on CB function would be expected to lead to further increases in RSNA, decreases in RBF, and deterioration of renal function. Thus the overall objective of this proposal is to clearly delineate the role of CBC in the etiology of CRS in CHF. The proposed studies will determine whether tonic CBC activation of RSNA mediates decreases in RBF, renal tissue oxygenation (RTO2), and glomerular filtration rate (GFR), and contributes to development of renal inflammation, oxidative stress, and fibrosis in CHF. The second aim will determine whether chronic intermittent hypoxia (CIH), a model of SA, during CHF exacerbates CBC-mediated increases in RSNA and decreases in RBF, and if this has a downstream effect on RTO2, GFR, renal inflammation, oxidative stress, and fibrosis. To address these aims, RSNA, RBF, RTO2, and GFR will be measured via implanted telemetry, ultrasound, or fluorescent tracer methods. In addition, acute RSNA and ventilatory responses to hypoxia will be measured as an index of chemoreflex sensitivity, and left ventricular function will be quantified via echocardiography. Renal cortical tissue will be assessed for superoxide levels, as well as expression of anti-oxidant enzymes, pro-inflammatory cytokines, and pro-fibrotic genes. Kidney slices will be stained for detection of collagen content as an index of fibrosis. In order to determine the role of the CB chemoreflex on these effects, CBC will be surgically denervated during CHF. These measures will allow for identification of chemoreflex sensitization, sympathetic activation, renal hypoperfusion, renal dysfunction, inflammation, oxidative stress, and fibrosis as CHF progresses and clarify the importance of CBC input to this phenomenon. Secondly, these studies will determine whether exposure to CIH exacerbates any of the derangements hypothesized to occur with CHF. For this aim methodology will be as described above, however exposure to CIH will be incorporated after CAL surgery, during the development of CHF. These studies will determine if CIH hastens the progression and degree of renal dysfunction during development of CHF and will document the role of CBC in this process. Finally, the studies outlined in this proposal will have a positive impact on the institutional research environment at Des Moines University (DMU) by providing crucial resources for the training of undergraduate and graduate students and supporting the growth of DMU's research enterprise.