From the University of California, Davis.
Correspondence to: Carroll E. Cross, MD, School of Medicine, Division of Pulmonary and Critical Care Medicine, Patient Support Services Bldg, 4150 V St, Ste 3400, Sacramento, CA 95817; e-mail: email@example.com
Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Drs Cross and Morrissey have received support from the Cystic Fibrosis Foundation and Cystic Fibrosis Research Foundation and from numerous sources sponsoring clinical trials in subjects with cystic fibrosis. Ms Reverri has reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.
Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.
Numerous chronic inflammatory diseases that activate systemic inflammatory biomarkers, such as peridontitis,1 HIV,2 inflammatory bowel disease,3 rheumatoid arthritis,4 and even psoriasis,5 are reported to be associated with an increased incidence of cardiovascular disease (CVD). Respiratory tract (RT) diseases are among this roster of chronic inflammatory diseases. These include COPD,6 α1-antitrypsin deficiency,7 and possibly adult-onset asthma.8,9 Might cystic fibrosis (CF) join the crowd?
Despite the intense RT inflammation and activation of systemic markers of inflammation,10 there has been little attention focused on the incidence of CVD in patients with CF. It is now increasingly important to examine the risk and incidence of age-related comorbidities, including CVD, in patients with CF who are now living into middle age and beyond.
Risk factors suggesting that older patients with CF may be predisposed to CVD include pancreatic insufficiencies that render these patients susceptible to deficiencies in fat-soluble antioxidant vitamins and lipids in spite of supplementation.11,12 Additionally, a variety of multifaceted lipid abnormalities, some of which could potentially impact CVD risk, are recognized in CF.13 These include reduced high-density lipoprotein; reduced antiinflammatory ω-3 fatty acids, including eicosapentaenoic (20:5) and docosahexaenoic (22:6); increased proinflammatory arachidonic acid (20:4) metabolic processes; and abnormal cholesterol metabolism (ie, altered cellular distribution and trafficking).14-16 Although the cumulative dyslipidemias’ impact on atherosclerotic processes remains to be fully determined, several studies implicating CF in vascular pathobiology are beginning to accumulate.17-20
In this issue of CHEST (see page 939), Poore and colleagues21 report an association between CF and endothelial dysfunction in a cohort of 15 young patients with CF (aged 7-18 years). The patients with CF were fairly healthy, with relatively mild pulmonary function impairment (FEV1 %predicted, 88% ±22% [SD]), absence of overt CF-related diabetes, and elevated high-sensitivity C-reactive protein values (approximately four times the value of the demographically matched control subjects).21 Endothelial dysfunction is recognized as an early step in the development of atherosclerotic CVD. This study used a commonly used measure of endothelial dysfunction, brachial artery flow-mediated dilation (FMD), as measured by ultrasound. The demonstration of endothelial dysfunction in this young CF population is analogous to what has been recently reported in young patients with inflammatory bowel diseases who also have evidence of systemic inflammation.22
To what degree might the decreased FMD represent an intrinsic (CF transmembrane conductance regulator) or acquired (inflammatory) phenomenon? It would seem most likely that the mechanistic decrements of FMD would be similar to that of other inflammatory RT diseases (eg, “spillover” of inflammation and immune activation mediators from the RT into the systemic circulation).23 However, in the current study, correlations between FMD decrements and high-sensitivity C-reactive protein levels, the only biomarker of activated systemic inflammatory-immune processes interrogated, did not reach significance.
The authors hypothesize that the FMD abnormality may relate to abnormal vascular tissue nitric oxide (NO) generation in CF per se; this concept is perhaps supported by abnormal NO synthase activity known to be present in the CF RT24 and by the known expression of CF transmembrane conductance regulator protein in both endothelium and smooth muscle of vascular tissues.21 The study findings, which correlated FMD decrements with pulmonary function decreases (perhaps a surrogate for the degree of airway and systemic inflammation) and maximal exercise capacity (hypothesized to reflect the degree of NO-related vasodilation muscle blood flow during exercise), are compatible with this concept. Significant correlations were found between the percent decrease in FMD and the decrease in airflow, and between the FMD absolute change and the maximal work (peak ventilation and workload during exercise). It remains unclear how accumulated structural lung disease, active airway inflammation, and dynamic airflow function might alter exercise capacity.
The authors raise the intriguing possibility that the degree of reduced FMD could relate to a relative decrement in muscle blood flow that would be reflected in a reduced maximal exercise performance. This is a provocative concept. It is known that endothelial NO release contributes to the increase in muscle blood flow during exercise. This also represents an important circulatory adaption to exercise training effects,25 thus adding to theoretical constructs supporting the importance of exercise conditioning in cardiopulmonary rehabilitation.
As with other RT diseases with strong inflammatory components and an increased CVD risk, longitudinal studies of CF-related risk factors, including endothelial dysfunction, may yield better understanding of the mechanisms of CVD and potential therapeutic approaches. As mentioned by Poore and colleagues,21 it will be illuminating to further document possible CF-related decrements in NO production by vascular tissue and its influence on exercise-related muscle function. Since aging contributes to endothelial dysfunction and ultimately to CVD,26 it will be particularly important to perform longitudinal studies, including older patients with CF, and to design feasible interventions that could ameliorate this risk factor for CVD. As NO bioavailability in vascular tissues appears to be influenced by other inflammatory RT diseases, this concept has implications in RT diseases beyond CF in which muscle function appears impaired (eg, COPD). It is also tempting to continue to build on this emerging evidence—albeit inconclusive to date—that therapeutic strategies to reduce inflammation and immune activations and their accompanying “oxidative stress” may reduce CVD risk.27
Finally, it is encouraging that patients with CF are now experiencing an increased life expectancy. As such, in addition to the enlarging spectrum of nonpulmonary CF-related diseases facing the adult patients with CF,28 the usual adult diseases causing morbidity and mortality can be expected to become an increasing concern. This is perhaps punctuated by the almost 50% prevalence of CF-related diabetes, a well-recognized strong risk factor for atherosclerotic and microvascular CVD, in this population.29
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