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.
