No abstract

Rodriguez-Miguelez P, Thomas J, Seigler N, Crandall R, McKie KT, Forseen C, Harris RA. Evidence of microvascular dysfunction in patients with cystic fibrosis. Am J Physiol Heart Circ Physiol 310: H1479 -H1485, 2016. First published April 15, 2016 doi:10.1152/ajpheart.00136.2016.-Cystic fibrosis (CF) is a genetic, multisystemic disorder with broad clinical manifestations apart from the well-characterized pulmonary dysfunction. Recent findings have described impairment in conduit vessel function in patients with CF; however, whether microvascular function is affected in this population has yet to be elucidated. Using laser-Doppler imaging, we evaluated microvascular function through postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh). PORH [518 Ϯ 174% (CF) and 801 Ϯ 125% (control), P ϭ 0.039], LTH [1,338 Ϯ 436% (CF) and 1,574 Ϯ 620% (control), P ϭ 0.045], and iontophoresis with ACh [416 Ϯ 140% (CF) and 617 Ϯ 143% (control), P ϭ 0.032] were significantly lower in patients with CF than control subjects. In addition, the ratio of PORH to LTH was significantly (P ϭ 0.043) lower in patients with CF (55.3 Ϯ 5.1%) than control subjects (68.8 Ϯ 3.1%). Significant positive correlations between LTH and forced expiratory volume in 1 s (%predicted) (r ϭ 0.441, P ϭ 0.013) and between the PORH-to-LTH ratio and exercise capacity (r ϭ 0.350, P ϭ 0.049) were observed. These data provide evidence of microvascular dysfunction in patients with CF compared with control subjects. In addition, our data demonstrate a complex relationship between microvascular function and classical markers of disease severity (i.e., pulmonary function and exercise capacity) in CF. CYSTIC FIBROSIS (CF) is an inherited disorder that is predominantly characterized by pulmonary dysfunction; however, broader clinical manifestations, such as gastrointestinal, immune, endocrine, and musculoskeletal dysfunctions, are also present (36). Recently, our group reported conduit vascular endothelial dysfunction in young patients with CF (39). Importantly, this vascular impairment was observed in a population that exhibited preserved spirometric function and exercise capacity, which suggests a systemic consequence prior to the decrease in pulmonary function. Despite these recent observations, there appears to be a lack of understanding of the general functionality of the endothelium in CF.Impairments in endothelial function are highly related to a reduction in the bioavailability of nitric oxide (NO), a key vasodilator involved in the regulation of vessel tone and endothelium integrity (24). Decreases in NO balance have also been shown to contribute to impaired endothelial microvascular vasodilation (44). With use of laser-Doppler imaging technology, cutaneous blood flux can be quantified (45) to represent an accessible model of microvascular function (17). Postocclusive reactive hyperemia (PORH), local thermal hyperemia (LTH), and iontophoresis with acetylcholine (ACh), in combination with laser technology...

Oxidative stress and vascular endothelial dysfunction are established characteristics of cystic fibrosis (CF). Oxidative stress may contribute to vascular dysfunction via inhibition of nitric oxide (NO) bioavailability. Purpose. To determine if ingestion of a single antioxidant cocktail (AOC) improves vascular endothelial function in patients with CF. Methods. In 18 patients with CF (age 8-39 y), brachial artery flow-mediated dilation (FMD) was assessed using a Doppler ultrasound prior to and two hours following either an AOC (n=18; 1,000 mg vitamin C, 600 IU vitamin E, and 600 mg α-lipoic acid) or a placebo (n=9). In a subgroup of patients (n=9), changes in serum concentrations of α-tocopherol and lipid hydroperoxide (LOOH) were assessed following AOC and placebo. Results. A significant (p=0.032) increase in FMD was observed following AOC (Δ1.9±3.3%), compared to no change following placebo (Δ−0.8±1.9%). Moreover, compared with placebo, AOC prevented the decrease in α-tocopherol (Δ0.48±2.91 vs. −1.98±2.32 μM, p=0.024) and tended to decrease LOOH (Δ−0.2±0.1 vs. 0.1±0.1 μM, p=0.063). Conclusions. These data demonstrate that ingestion of an antioxidant cocktail can improve vascular endothelial function and improve oxidative stress in patients with CF, providing evidence that oxidative stress is a key contributor to vascular endothelial dysfunction in CF.

These data suggest that four weeks of sildenafil treatment can improve vascular endothelial function in patients with CF, likely through an increase in NOS3 phosphorylation.