Evidence of microvascular dysfunction in patients with cystic fibrosis

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...

The Coupling of Peripheral Blood Pressure and Ventilatory Responses during Exercise in Young Adults with Cystic Fibrosis

“…Further, and consistent with Hull et al [20, 36], our group has demonstrated that mild- to- moderate severity adult CF have blunted reductions in resting systemic vascular resistance in response to inhalation of the β 2 -selective agonist albuterol [19]. Thus, if increased blood pressure, underpinned by impaired peripheral vascular function [19–21, 24, 35, 36], does indeed parallel exaggerated slope during exercise in adult CF, demonstrating this calibration in the laboratory setting should help add to our understanding that the clinical implications of CF may extend to the entire cardiovascular system.…”

“…As such, consistent with observations and hypotheses of others [8, 12–14, 18–24], these data suggest compared to , understanding the mechanisms of low ventilatory efficiency (e.g., high slope) may be equally important in elucidating the origins poor exercise capacity in CF. With this, new and noteworthy, in a complementary manner that extends emerging work in this field questioning peripheral vascular function in CF [19–21, 24, 36], these data suggest unresolved pathways involved in peripheral blood pressure function may serve an important role in contributing to abnormal ventilatory and gas-exchange responses to exercise in CF.…”

“…Consistent with observations of Poore et al [24], pharmacologic studies in young adults with mild- to- moderate severity CF suggest these individuals have blunted reductions in systemic vascular resistance following acute inhalation of the β 2 -selective agonist albuterol, whilst implicating abnormal β 2 -adrenergic receptor function in failing to mediate vasodilatory control in response to acute changes in vasomotor tone [19]. Lastly, in an integrative study of experimental approaches akin to techniques of Poore et al [24] and Van Iterson et al [19], Rodriguez-Miguelez et al [21] demonstrated in young adults with mild- to- moderate severity CF that relative changes in postocclusive reactive hyperemia, local thermal hyperemia, and acetylcholine iontophoresis of the resting arm are blunted in CF, suggesting the presence of impaired microvascular function in these individuals. Thus, while the exact physiologic and biomolecular pathways involved in explaining those observations warrant future study [19, 21, 24], because techniques such as flow-mediated dilation or administration of albuterol or acetylcholine represent targetable pathways of studying peripheral vascular function in CF, those data broadly suggest there may be peripheral vascular dysfunction related to attenuated vasodilatory reserve and impaired sympatholysis associated with CF.…”

“…Although observations in adolescent or adult CF suggest in addition to impaired cardiac function [14, 22, 25, 32–34], these individuals may demonstrate abnormal peripheral function including skeletal muscle weakness or slowed muscle oxygenation kinetics [12, 18, 22, 23], which may cumulatively contribute to impaired aerobic exercise capacity coupled with ventilatory inefficiency, limited studies in adult CF have focused on describing the role of peripheral blood pressure [20, 35] in the context of questioning whether pulmonary dysfunction is accompanied by gross peripheral vascular abnormalities in these individuals [19, 21, 24, 36]. For example, whereas observations of Hull et al [20] (ergometry) or Schrage et al [35] (handgrip) do not suggest overt exacerbation of blood pressure during exercise in mild- to- moderate severity adult CF, it is both novel and relevant in understanding peripheral hemodynamic function in CF that Hull et al [20] demonstrated increased augmentation index in these individuals, suggesting the presence of increased arterial stiffness.…”

Lower cutaneous microvascular reactivity in adult cancer patients receiving chemotherapy

“…The drug delivery electrode contained 200 l of a 2% ACh solution (Sigma-Aldrich, St. Louis, MO), which is similar to previous investigations (40,45,47,65), applied to the small sponge on the electrode. After a 2-min baseline, a 100-A anodal current was used to deliver the ACh in seven successive 20-s doses, with an interval of 60 s. This delivery protocol was chosen because it is identical to previous investigations of cutaneous microvascular reactivity and results in no detectable current-induced or axon-mediated vasodilation (1,52,65). Current delivery was managed and confirmed with the available software (PeriIont Software; Perimed).…”