Inflammation, oxidative stress, and cardiovascular ...

Free Radical Biology and Medicine 76 (2014) 261–277

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Free Radical Biology and Medicine journal homepage: www.elsevier.com/locate/freeradbiomed

Review Article

Inflammation, oxidative stress, and cardiovascular disease risk factors in adults with cystic fibrosis Elizabeth J. Reverri 1,a, Brian M. Morrissey b, Carroll E. Cross b,n, Francene M. Steinberg a a

Department of Nutrition, University of California Davis, One Shields Avenue, 3135 Meyer Hall, Davis, CA 95616, USA Adult Cystic Fibrosis Clinic and Division of Pulmonary-Critical Care Medicine, University of California Davis Medical Center, 4150 V Street, Sacramento, CA 95817, USA

b

art ic l e i nf o

a b s t r a c t

Article history: Received 28 February 2013 Received in revised form 31 July 2014 Accepted 5 August 2014 Available online 27 August 2014

Cystic fibrosis (CF) represents one of a number of localized lung and non-lung diseases with an intense chronic inflammatory component associated with evidence of systemic oxidative stress. Many of these chronic inflammatory diseases are accompanied by an array of atherosclerotic processes and cardiovascular disease (CVD), another condition strongly related to inflammation and oxidative stress. As a consequence of a dramatic increase in long-lived patients with CF in recent decades, the specter of CVD must be considered in these patients who are now reaching middle age and beyond. Buttressed by recent data documenting that CF patients exhibit evidence of endothelial dysfunction, a recognized precursor of atherosclerosis and CVD, the spectrum of risk factors for CVD in CF is reviewed here. Epidemiological data further characterizing the presence and extent of atherogenic processes in CF patients would seem important to obtain. Such studies should further inform and offer mechanistic insights into how other chronic inflammatory diseases potentiate the processes leading to CVDs. & 2014 Elsevier Inc. All rights reserved.

Keywords: Cystic fibrosis Atherosclerosis Cardiovascular disease risk factors

Contents Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic fibrosis, inflammation, and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cardiovascular disease, inflammation, and oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Historical reports of CVD in CF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CVD risk factors absent or minimally present in CF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elevated total cholesterol and LDL levels . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elevated triglycerides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Elevated blood pressure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cigarette smoking . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Obesity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . CVD risk factors likely to be present in CF . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Inflammatory RT diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Systemic inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Oxidative stress . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . High dietary fat . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reduced and dysfunctional HDL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Abbreviations: BMI, body mass index; COPD, chronic obstructive pulmonary disease; CF, cystic fibrosis; CFRD, CF-related diabetes; CFTR, CF transmembrane conductance regulator; CRP, high-sensitivity C-reactive protein; CVD, cardiovascular disease; DHA, docosahexaenoic acid; MPO, myeloperoxidase; NO, nitric oxide; NOS, nitric acid synthase; PMN, polymorphonuclear neutrophil leukocytes; PUFA, polyunsaturated fatty acids; RT, respiratory tract n Corresponding author. Fax: þ 1 916 734 7924. E-mail address: [email protected] (C.E. Cross). 1 Current affiliation, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, 711 Washington Street, Boston, MA 02111. http://dx.doi.org/10.1016/j.freeradbiomed.2014.08.005 0891-5849/& 2014 Elsevier Inc. All rights reserved.

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Low omega-3 lipids. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Vascular endothelial dysfunction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Prothrombotic factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Relative physical inactivity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Cystic fibrosis-related diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Post-lung transplant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Uncertain risk . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Future considerations and further directions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of Interest. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

Introduction Many diseases with chronic activations of inflammatoryimmune processes are accompanied with an incidence of cardiovascular disease (CVD) higher than the general population. Although inflammation-related reactive oxygen species (ROS) sources are believed to exert a strong influence on this high incidence, the mechanisms responsible for the increased cardiovascular morbidity and mortality remain to be fully clarified. In this review, we examine potential risk factors that impact CVD incidence in patients with cystic fibrosis (CF). Major contributions to the development of atherosclerosis and CVD are inflammation, oxidative stress, and endothelial dysfunction. Recently, evidence of endothelial dysfunction, a process believed to be mechanistically related to inflammation and oxidative stress and a harbinger of early atherosclerotic processes, has been described in young patients with CF. CF represents a disease with lifelong activations of inflammatory-immune processes with strong evidence of oxidative stress, but has yet to be associated with an increased incidence of CVD. The goal of this review is to elucidate risk factors for CVD in CF. These may represent future targets for treatment. We speculate that further interrogations of CF risk factors and incidences of CVD will contribute mechanistic insights relevant to the non-CF chronic inflammatory diseases associated with and increased incidence of CVD. A brief overview of current perspectives concerning the roles of inflammation and oxidative stress in CF and atherosclerosis is presented with comments concerning the few historical studies of patients with CF and CVD. CVD risk factors absent or minimally present and CVD risk factors that could potentially contribute to an increased incidence of CVD in CF are reviewed with an emphasis on risk factors as depicted in Fig. 1. Finally, future research directions that might increase understanding of the CVD risk factors of patients with chronic inflammatory disease such as CF are noted. Cystic fibrosis, inflammation, and oxidative stress CF is the most common lethal autosomal recessive disorder among Caucasians. In the United States its incidence is approximately one in 3500 live births; its prevalence is approximately 30,000 [1,2]. CF is caused by mutations in the CF transmembrane conductance regulator (CFTR) which result in reduced ion channel chloride transport. In the RT, this mutation results in decreased chloride secretion, elevated sodium reabsorption, and abnormal transcellular fluid transport, producing a hypohydrated viscous mucus with resultant decreased mucociliary clearance [2]. This pathology results in varying degrees of progressively more intense RT microbial colonization and infection with an accompanying overly exuberant activation of host inflammatory-immune processes dominated by a massive infiltration of polymorphonuclear

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neutrophil leukocytes (PMNs) into both airway and alveolar RT compartments [3]. These activated immune-inflammatory cells produce not only a wide spectrum of proinflammatory cytokines but also an excessive amount of reactive oxygen species and nitrogen species (RNS) believed to play a role in the progression of CF RT disease [4–7]. In most, but not all patients with CF, the secretory pathology involves the hepatobiliary and pancreatic ducts, which can, but not always, result in progressive pancreatic destruction with pancreatic exocrine and often eventual endocrine insufficiency and associated nutritional deficiencies [2]. The cornerstones of treatment in the United States include care in specialized multidisciplinary treatment centers with a focus on airway mucus clearance technologies, antibiotic therapies, and nutritional repletion with the more recent addition of inflammation suppression [2]. Biology-directed treatments have recently opened up new perspectives for the treatment of CF. In 2012, the first drug to address the underlying genetic defect of CF was approved by the FDA. This drug is of major benefit to the 3–5% of CF patients who have specific gating mutations of CFTR (i.e., G551D) [8], opening up the dawn of a new era of personalized CF treatments [9]. Although there is accelerating research activity to correct defects in the protein trafficking of the mutated CFTR to the plasma membrane or increase the opening time of the CFTR at the plasma membrane, thus far these agents are not expected to correct all of the inflammatory and oxidative manifestations of adults with moderate to advanced CF RT disease [8]. The primary cause of morbidity and mortality of CF is characterized by a vicious cycle of chronic RT infection, a heightened immune response, and prominent involvement of PMNs proteolytic and oxidative processes, resulting in progressively severe RT destruction and respiratory failure [10,11]. Why this exaggerated proinflammatory neutrophil-dominated immune response seen in patients with CF is ineffective at eradication of RT surface microorganisms is incompletely understood [12,13]. Although CF has been historically considered a pediatric disease, half the patients with CF are now adults of age 18 years and older [1]. The current predicted median survival is approaching 40s and even the 50s for those born in the 2000s [14,15]. This increase in life expectancy can be attributed to several factors, including earlier diagnosis with newborn screening (nationwide in 2010), more aggressive nutritional management strategies, intensified techniques of chest physiotherapy, comprehensive care in multidisciplinary CF centers, and better molecular understanding of CF pathobiology along with more specifically targeted therapies [8,16]. Among the specific targets in CF patients with ongoing established infective RT disease is that of neutrophil proteases and oxidants and other activated prooxidative inflammatory-immune system cascades known to be important players in CF pathobiology [4–7] Concomitant with the increase in life expectancy, age-related comorbidities are emerging that predictably will require more medical vigilance [16–19]. In CF, age-related comorbidities often

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players and processes remain less well defined. Nonetheless they currently receive much attention as a major risk factor for atherosclerosis and CVD. Historical reports of CVD in CF

Fig. 1. Depicted is an overview of cardiovascular risk factors that could potentially contribute to an increased incidence of cardiovascular disease in patients with cystic fibrosis.

develop, such as CF-related diabetes (CFRD) and its microvascular complications, and both joint and bone disease [20]. To date, there have been little data relating to CVD being among these expected comorbidities [21]. Cardiovascular disease, inflammation, and oxidative stress In the United States, over 80 million adults are estimated to have one or more types of CVD, including atherosclerotic coronary artery disease and myocardial infarction, congestive heart failure, cerebrovascular disease, and peripheral vascular disease. CVD represents the leading cause of mortality in the United States, being responsible for up to 20 million deaths per year. Its incidence increases with age and its presence contributes to the etiology and morbidity of many other chronic diseases (e.g., neurodegenerative diseases) [22]. Many various medical and scientific consensus guidelines have been put forth to reduce individual risk and public health burden of CVD. For example, Ideal Cardiovascular Health refers to the composite of seven health metrics: normal total cholesterol o200 mg/dl, normal blood pressure o120/80 mm Hg, not smoking or quitting smoking for more than a year, a normal body mass index (BMI) o25 kg/m2, a healthy diet consistent with the Dietary Approaches to Stop Hypertension eating plan, physical activity such as Z150 min of moderate intensity a week, and normal fasting plasma glucose o100 mg/dl. Achievement of these health metrics are categorized as ideal, intermediate, or poor and provide an overall health status that is monitored over time [23]. However, these so-called traditional risk factors for CVD only account for 50% of CVD, which emphasizes the importance of other less scored CVD risk factors [23]. Additional risk factors for CVD may include, but are not limited to, chronic and acute infection (and their associated systemic inflammatory-immune system activation states with accompanying degrees of oxidative stress and prothrombotic processes), obesity with sleep apnea, low omega-3 anti-inflammatory lipids, dyslipidemia not due to excess LDL or reduced HDL, and evidences of endothelial dysfunction. Atherosclerosis and CVD are unambiguously related to inflammation and its accompanying heightened oxidative processes involving arterial walls [24–26]. Newer atherosclerotic research agendas have broadened understanding of the complex interacting metabolic pathways related to atherogenic processes but have not diminished the importance of both inflammatory and oxidative pathways in CVD [27–34]. Although PMNs and various monocyte subtypes have precisely defined mechanistic roles in inflammatory and oxidative atherogenesis, the contributions of other inflammatory-immune

One of the earliest investigations of CVD in patients with CF examined autopsy specimens in children ages 6–13 with and without CF. Decreased aortic atherosclerotic processes, as scored by intimal microscopic lipid staining, were found in children with CF and it was speculated that low concentrations of circulating lipids contributed to the decreased aortic lipid accumulation [35]. Another early investigation involved autopsies on older children with CF and without CF, ages 10–24 years. Again, the frequency and extent of early aortic atherosclerotic lesions were found to be diminished in children with CF. These children had fewer fatty streaks and late fibromusculoelastic lesions than their age-matched control [36]. Intriguingly, four case reports have documented CVD in adults with CF [21]. All four patients were ages 40 years and older, ranging from 40 to 52 years. Three of the four adults with CF were male and three of the four also had CFRD. The only patient without CFRD had a documented strong family history of CVD. Two of the patients had medical work-ups revealing symptomatic coronary artery disease and myocardial infarction, respectively. In the other two patients, asymptomatic CVD was diagnosed. One patient participating in a research study was diagnosed with a previous silent myocardial infarction associated with coronary artery disease. Generalized atherosclerosis was noted in the autopsy report of the other patient [21,37,38]. Relatively few clinical studies have investigated CVD and/or its risk factors in adults with CF. With the exception of CFRD [17], even fewer recent studies have discussed CVD as a possible comorbidity in adults with CF [16,19,20]. Although adults with CF do not express many traditional risk factors for CVD, some classical and additional CVD risk factors have been identified and are as summarized in Table 1.

CVD risk factors absent or minimally present in CF Elevated total cholesterol and LDL levels Elevated cholesterol is a traditional risk factor for CVD, occurring in over 15% of the United States population [22,23]. In contrast, studies investigating a lipid profile in adults with CF have found that mean total cholesterol levels are either reduced or well within desirable levels [19,39–44]. This overall favorable lipid profile may be in part due to decreased lipid absorption in CF [45,46], despite the almost universal administration of pancreatic enzyme replacement therapy in CF patients with exocrine pancreatic insufficiency. A different lipid pattern emerges when adults with CF and pancreatic insufficiency are compared to adults with CF and Table 1 Cardiovascular disease (CVD) risk factors in cystic fibrosis (CF). Absent or minimally present

Present or postulated contributors

Elevated total cholesterol Elevated LDL cholesterol Elevated triglycerides Hypertension Cigarette smoking Obesity Advanced age

Activated inflammatory-immune processes Oxidative stress High dietary fat Low HDL cholesterol Low omega-3 lipids Endothelial dysfunction Prothrombotic factors Relative physical inactivity CF-related diabetes

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pancreatic sufficiency [46,47]. Adults with CF and pancreatic sufficiency, as a subgroup of CF, may have similar risks of CVD as seen in the general population. It has been suggested that this subgroup should be screened with a lipid panel when they reach adulthood and that they have regular interval follow-ups thereafter [47]. Like total cholesterol, elevated LDL is a major and independent risk factor for CVD [23]. Studies in adults with CF have found that mean LDL cholesterol levels are low or well within the optimal category [19,39,42,43,45,47]. Consistent with the different lipid pattern in adults with CF and pancreatic sufficiency, one study found that over 50% of this latter subgroup had above optimal LDL cholesterol levels [45]. There are other abnormalities of cholesterol, LDL, and related lipids which have been proposed to contribute to inflammatory and oxidative processes in CF. Abnormalities of ceramide, phospholipid, and sphingolipid metabolism have been described, as have abnormalities in intracellular distributions of cholesterol, including amounts reaching cellular plasma membranes [48–53]. Cholesterol and sphingolipid trafficking to the plasma membrane, if disordered in CF [50,51], could be expected to effect a number of plasma membrane proteins and their function [54]. Despite the hypocholesterolemia, oxylipids including oxysterols are elevated in CF due to nonenzymatic oxidative pathways [44]. Many of these species are known to be bioactive and carried in plasma LDL and HDL fractions where they are directly exposed to endothelial cells, thus being able to contribute to abnormalities of endothelial biology related to both CF and atherogenesis [55–58]. Few studies to date have investigated in detail the overall metabolism and kinetics of cholesterol, lipoproteins, and enzymatic and nonenzymatic oxylipid/oxysterol profiles in CF. It is likely that the abnormalities that exist are due to multiple interacting mechanisms including relatively high fat diets, abnormalities in lipid micelle formation and absorption secondary to deficiencies in liver bile and pancreatic secretions (despite pancreatic enzyme supplementation), lack of functional CFTR and/or mutated CFTR effects on intracellular cholesterol trafficking, and/or activations of activated inflammatory-immune system processes [45–50,59].

Elevated blood pressure Elevated blood pressure is a common traditional risk factor for CVD [61]. One-third of adults in the general population have high blood pressure or are on antihypertensive medication [22]. Several studies in adults with CF have included blood pressure as part of their descriptive clinical characteristics. These studies invariably report that both systolic and diastolic blood pressures tend to be in the lower ranges of “normal” in the large majority of adults with CF [19,39,40,62,63]. One study showed that reduced levels of BP rise with age in female carriers of the CF gene [64]. Interestingly, studies in CF mice appear to have reduced blood pressure compared to their control wild-type mice, possibly explained by diminished arterial reactivity [65]. Cigarette smoking Cigarette smoking has long been known to be a major factor for CVD, approximately doubling the risk [23]. An estimated 19% of United States adults smoke and an additional 37% are exposed to secondhand smoke [22]. In contrast, only approximately 1% of patients with CF smoke tobacco, although an estimated 13% may be exposed to some level of secondhand smoke [1]. Interestingly, studies have shown that cigarette smoke leads to CFTR dysfunction [66], even at sites remote from the RT [67]. Obesity Obesity is classified as a major risk factor for CVD [23]. Patients with CF are generally underweight compared to the general population. In patients with CF, lung disease severity and nutritional status (a reduced weight) are tightly intertwined [68]. The CF patient registry documents a strong association between a normal BMI and a better lung function. The median BMI for adults with CF is 22 [1], which falls in the low normal range. Elevated LDL cholesterol and insulin levels have all been independently associated with a higher BMI in adults with CF, when compared to the adults with CF who were underweight or normal weight [43]. In contrast, one-third of adults in the United States general population are obese [22].

Elevated triglycerides

CVD risk factors likely to be present in CF

Observational studies, supported by a plethora of basic experimental studies, have associated plasma triglyceride levels with a higher risk of CVD [60]. Although the magnitude and mechanisms of the effect remain controversial and incompletely characterized, triglycerides are known to have an effect on proatherogenic lipid metabolism of remnant lipoprotein particles including apolipoprotein CIII and may alter atheroprotective effects of HDL [60]. One-third of adults in the United States population have borderline high triglyceride levels [22]. Several studies in adults with CF found that mean triglyceride levels are within the optimal category [19,39–43,47]. However, one study found that adults with CF ages 30–39 had borderline high triglyceride levels, when compared to healthy adults from National Health and Nutrition Examination Survey trends from 1960–2002 [19]. Another study found that 16% of adults with CF had borderline high triglyceride levels and 5% had high triglyceride levels [45]. The hypertriglyceridemia in adults with CF occurs despite an increased energy expenditure and a decreased exogenous lipid absorption [46,59]. It can be concluded that a small subgroup of pancreatic sufficient CF patients may have elevated triglyceride levels and that the large majority of CF patients do not exhibit this possible risk factor for CVD.

Inflammatory RT diseases Numerous non-CF chronic inflammatory lung diseases are associated with an increased incidence of CVD and should be considered in the context of CF, which is itself among the most intense of these conditions. In addition to cigarette smoking, many inflammatory RT conditions have been linked to an increased risk of CVD [69]. Most RT diseases, usually characterized by reduced lung function, are accompanied by some degree of localized RT inflammation and less intense systemic inflammatory-immune system activation. In epidemiological studies, reduced lung function in the general population has even been linked to an increased incidence of CVD [70]. Cigarette smoking represents the strongest and best known risk factor for lung inflammatory disease accompanied by increased risk of CVD [22]. Nonallergic neutrophilic asthma has been recently associated with systemic inflammation, and this inflammatory phenotype is now recognized to have an increased incidence of CVD complications [71] as has bronchiectasis [72], another neutrophilic airway disease. Air pollution particulates, like cigarette smoke, contain a myriad of redox-active species such as metals and polyphenols including seminquinones/quinones. Inhaled particulates containing

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these substances have been associated with subclinical findings of systemic inflammation, endothelial dysfunction, and perturbations of coagulation factors including platelets, together contributing to an increased incidence of CVD [73]. COPD represents a disease which exhibits extensive evidences of oxidative stress in both RT and blood [74,75], evidences which are further increased with COPD exacerbations [76]. Importantly, COPD is now recognized as an important risk factor for CVD [77,78]; in later stages of COPD patients are as likely to die from CVD as from respiratory failure related to COPD [79,80]. The high incidence of CVD in COPD is believed to be related to lung inflammatory and oxidative processes triggering several biomarkers of inflammatoryimmune system activation in the systemic circulation [81–83]. In COPD this is often accompanied by endothelial dysfunction, and perturbations of clotting factors, including platelets [82–84]. The increased risk of CVD events during COPD exacerbations is almost surely related to the accompanying greater degree of RT and systemic activation of inflammatory-immune processes during exacerbations, including the increased priming of circulating PMNs [85,86]. The association with CVD appears to hold true for alpha-1-anti-trypsin deficiency [87], one type of COPD that does not necessarily have the confounding effects of cigarette smoking, but like CF is associated with exaggerated RT inflammatory-immune responses, in part possibly related to the folding and trafficking problems of their respective mutated proteins and thus invoking such pathways as ER stress responses [88,89]. Finally, lung infections, such as acute viral respiratory infections and acute bacterial pneumonia, including severe sepsis, have also been linked to an increased risk of CVD in susceptible populations [71,90,91]. These non-CF lung inflammatory diseases associated with increased risk of CVD strongly support the likelihood that patients with CF would be susceptible to an increased incidence of CVD as their survival age continues to increase to middle age and beyond. A simplistic scheme relating CF RT disease to systemic vascular pathobiology is shown in Fig. 2. Systemic inflammation Systemic inflammation is increasingly recognized as being involved in all phases of atherosclerotic processes [25,26,34] and

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is recognized to be a conditional risk factor for CVD [92–94]. It is now recognized that many localized chronic inflammatory diseases, including most of the rheumatic and connective tissue diseases [95], inflammatory bowel disease [96], psoriasis (highest risk in the younger and more severely afflicted) [97,98], severe periodontal disease [99,100], and including HIV [101,102], increase the risk of CVD [21,103]. It is highly likely that, as in patients with inflammatory lung disease, collateral activation of systemic inflammatory-immune processes plays an important role [94,103]. For example, rheumatoid arthritis is characterized by excessive joint inflammation as well as a 50% increased mortality from CVD [104]. These patients with rheumatoid arthritis meet some traditional risk factors for CVD, yet do not meet others with some even exhibiting inverse relationships [105]. This disorder has commanded an extensive literature concerning increased CVD risk factors including those related to dyslipidemia [106] and vascular reactivity dysfunction [107,108]. Interestingly, statin therapy appears to ameliorate the abnormalities of endothelial dysfunction in patients with rheumatoid arthritis [108], while antitumor necrosis factor-alpha therapies appear to decrease both the endothelial dysfunction [107] and the increased incidence of CVD [109,110]. Further rigorous mechanistic characterizations of these risk factors contributing to CVD in chronic diseases associated with high levels of innate and acquired immune system activations and accompanying oxidative stress are clearly still needed [103]. Patients with CF have both localized intense RT inflammation with varying degrees of systemic “spillover” activated inflammatory processes [111], as in the many aforementioned lung and non-lung inflammatory diseases. Patients with CF are also likely exposed to other systemic proinflammatory factors, such as those induced by a high saturated fat diet, and insulin resistance with hyperglycemia [112]. Their systemic inflammatory responses are evidenced by increases in circulating cytokines and chemokines, soluble adhesion molecules, and acute phase reactants such as fibrinogen and highsensitivity C-reactive protein (CRP) [113], all of which reflect the marked and persistent activated inflammatory processes in CF and could be considered to be proatherogenic [114]. The role of cytokines to prime and/or activate circulating PMN functions is well recognized. The presence of activated circulating PMNs with evidence of extracellular releases of granular myeloperoxidase

Fig. 2. Simplistic scheme relatively localized respiratory tract cystic fibrosis inflammatory disease processes to systemic vascular pathobiology.

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(MPO) is increasingly noted to be present in many chronic localized inflammatory diseases, many known to be associated with “spillover” increases in circulating proinflammatory cytokines [115]—these diseases include CF [116,117]. This is of particular relevance to CF, which is known to exhibit dysfunctional PMN MPO activity with increased extracellular MPO releases when activated [118]. In fact, a relationship between an increased MPO activity per circulating PMN and the severity of CF RT disease has already been shown [117]. Several epidemiological clinical studies have shown associations between increased plasma MPO levels derived from activated PMNs, endothelial dysfunction, and an increased incidence of CVD, likely attributed to the oxidative interactions of MPO and its products with constituents of circulating lipids and vascular wall tissues [118–121]. The PMN released MPO is of particular importance because it can bind to endothelial surfaces and diminish endothelial NO bioavailability by not only scavenging NO but also by providing ROS that promote NOS generations of ROS and/or uncouple NOS [121]. The effects of other activated PMN constituents such as proteases and peptides [122] are also likely to contribute to inflammation-related endothelial dysfunction. The increase in circulating adhesion molecules in CF [113] enforces the concept that PMN–endothelial interactions are likely to be a major factor in CF-related endothelial dysfunction. CRP is currently one of the best recognized inflammatory biomarkers of CVD risk. Since CRP is an acute phase reactant, high CRP levels reflect an acute phase response and potential elevated CVD risk, particularly when determined at a baseline level (e.g., not during an acute infection) [114]. Many studies have examined CRP levels cross-sectionally or at baseline in adults with CF when they were clinically stable. These CRP levels could represent a significant risk for CVD in CF patients [123–129]. Note, however, that there is some considerable variability in the literature with regard to using CRP alone as a risk factor for CVD [130,131]. Current pharmacological anti-inflammatory therapies for patients with CF are limited and may result in significant adverse side effects, so there is a continuing need for alternative therapies to better control inflammation in CF.

elevated plasma and urinary 8-isoprostaglandin-F2-alpha in patients with CF, indicating significant lipid peroxidation and revealing an imbalance of prooxidants and antioxidants in tissues and fluids communicating with the compartments containing these lipid constituents [158,173]. Supplementing with antioxidants would seemingly correct oxidative stress; however, there is little evidence for effectiveness at the clinical level, beyond supplementing lipophilic antioxidant micronutrients to normal levels as per usual care [5,6]. Large scale studies in the general population have even reported negative outcomes [34]. A Cochrane Review of randomized controlled trials comparing antioxidant micronutrient supplementation to placebo and usual care in patients with CF found that, based on only a few studies, antioxidants seem to decrease biomarkers of oxidative stress and increase quality of life, but have yet to demonstrate a change in lung function decline [180].

Oxidative stress

Traditionally, it has been considered that HDL cholesterol particles and their pleotrophic cargo play a major atheroprotective role in CVD by promoting free cholesterol cellular efflux and by damping inflammatory-immune, oxidative, and proliferative activities [186,187]. Several studies in adults with CF have reported mean HDL cholesterol levels in low normal and below widely recognized protective levels [19,39,42,43,45,47]. This would appear to be of a concern for patients with CF. However, the previously dogmatic concept that the quality of HDL mass alone will consistently translate to a reduction in CVD risk has been recently challenged. Using new techniques, a broader and staggeringly more complex context of HDL biology has emerged which not only further details HDL’s role in reverse cholesterol (and possibly that of toxic lipid oxidation products) transport, but also details its pleiotropic role in numerous other functions related to endothelial and cardiovascular health [188,189]. It is now recognized that HDLs transport a multitude of proteins and lipids that have the potential not only to determine particle fate but also to impact numerous biologic activities including proteolytic and antioxidative processes [190,191].The role of HDL cholesterol levels, in itself, to represent an atheroprotective risk factor is now controversial [192–196]. For example, some adults with genetically elevated HDL cholesterol have not demonstrated an association with reduced CVD risk [197], and some adults with genetically low HDL cholesterol have not shown evidence of premature CVD [198,199]. Additionally, some adults with elevated HDL cholesterol (which is rare in patients with CF) and elevated CRP levels (which is common in many patients with CF) have demonstrated an

It is well accepted that activation of inflammatory-immune processes is accompanied by a heightened production of oxidants, which are known to contribute to antimicrobial, signaling, adaptive, and reparative processes, and in excess, can also heighten inflammatory tissue injury processes [132]. It is thus not surprising that a level of oxidative stress is associated with many chronic inflammatory diseases, including both CF and CVD [4–7,25–27]. Oxidative stress is defined as an imbalance between the production of prooxidants and host antioxidant defenses and is considered to play and important role in both CF and CVD [132]. Contributors to oxidative stress in adults with CF include increased metabolic rates (thus presumably more mitochondrial reactive oxygen species production), increased activated inflammatoryimmune processes, malabsorption of lipophilic antioxidant micronutrients and PUFAs (e.g., resulting in less antioxidant PUFA metabolites), and disordered lipid and carbohydrate metabolism [4–7]. Many studies have investigated oxidative stress in patients with CF, although fewer studies have focused on systemic and functional biomarkers of oxidative stress [6,133]. As shown in Table 2, the evidence for oxidative stress in CF is especially robust. Importantly, the oxidative stress of CF can be expected to be amplified by the presence of CFRD [134–136] and during CF exacerbations [137–139]. Assessment of isoprostanes, products of omega-6-derived arachidonic acid (AA, 20:4) nonenzymatic lipid peroxidation, is often considered the gold standard of oxidative stress [178] and lipid peroxidation in vivo [179]. Two cross-sectional studies found

High dietary fat One of the adult CF guidelines for nutrition for decades has been to ingest a high fat diet (up to 40% of total calories) [181]. This high fat intake is recommended to compensate for a combination of maldigestion and/or malabsorption and the increased energy expenditure seen in most CF patients. Dietary fat not only provides the highest energy density of calories to promote energy balance, but also increases palatability and provides for more complete absorption of fat-soluble vitamins, essential fatty acids, etc. [181–184]. This higher fat intake generally does not worsen the lipid profile in adults with CF [41,47]. In contrast, recently reinforced nutrition recommendations to reduce the risk of CVD in the general population involve limiting the consumption of foods high in saturated fat, trans fat, and cholesterol and displacing fat calories with an eating pattern consistent with the Dietary Approaches to Stop Hypertension [23] and/or the Mediterranean diet [185]. Reduced and dysfunctional HDL

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Table 2 Evidence of oxidative stress in cystic fibrosis (CF)1. Respiratory tract (RT, largely sputum) Increased levels of RT neutrophils and their oxidative processes [140,141] Increased levels of RT protein carbonyls, chlorinated and nitrated proteins, and dityrosines [117,119–121,140,142–144] Increased levels of oxidative and proteased α1-antitrypsin [145] Decreased GSH levels in bronchoalveolar fluids [146,147] Increased levels of prooxidant cytokines [148] Elevated breath F2-isoprostane levels [149,150] Elevated breath pentane and ethane levels [151] Elevated breath CO levels [151,152] Increased HO-1 and ferritin in lung tissues [153] Increased prooxidant redox-active phenazines (e.g., pycocyanin) in patients with CF and Pseudomonas aeruginosa [154] Increased peroxidase levels [155] Increased metal and iron levels [156,157] Blood Elevated levels of plasma lipid peroxidation products [158] Increased susceptibility of lipoproteins to peroxidation [159] Decreased levels of anti-inflammatory antioxidant HDLs [19,39,42,43,45,47] Increased levels of prooxidant cytokines [126,160] Increased plasma protein carbonyl and dityrosine levels [161] Increased susceptibility of RBCs to peroxide-induced hemolysis [162] Decreased levels of plasma micronutrient antioxidants, most notably carotenoids [163–167] Increased levels of neutrophils and their products [165] Increased plasma oxysterols [44] Increased levels of F2-isoprostane levels [165] Vasculature Decreased endothelial vascular reactivity [168–170] Increased arterial stiffness [40,171,172] Urine Increased levels of F2-isoprostane levels [173] Increased levels of oxidative-induced DNA damage [174] 1

For comprehensive reviews, refer to [4–7,175–177].

unexpected increased risk for CVD [200,201]. It is now recognized that a higher level of structural, compositional, and functional heterogeneity exists in HDL subpopulations than formerly believed. For example, it is likely that assessments of certain HDL subspecies will more accurately reflect HDL atheroprotective effects [202]. In rheumatoid arthritis, another chronic inflammatory disease, reductions in specific HDL subfraction concentrations of cholesterol have been associated with systemic markers of disease activity and have been proposed to negatively impact CVD risk profiles [106,203]. In psoriasis, abnormal HDL reversed cholesterol transport is reported to improve after successful treatment [204]. These and other reports raise the possibility that, under the influence of activated systemic inflammatory-immune processes, HDL particles may undergo change to a proinflammatory or proatherogenic state [187]. For example, increased levels of extracellular MPO are known to be associated with more severe CF [205] and MPO-derived oxidants have been shown to significantly reduce HDL-mediated cholesterol efflux from cholesterol laden macrophages and negatively influence HDL-related atheroprotective processes [206,207]. It is highly likely that overall intensities of systemic activation of inflammatory-immune processes and their related prooxidative activities will impact HDL and its cargo of lipids and proteins, particle size, and metabolic kinetics, thus impacting the extent of overall HDL protectiveness against atherosclerosis and CVD [208,209]. More in-depth understandings of the HDL protein and lipid cargo and functionality are warranted before the HDL risk factors for atherosclerosis and CVD in CF patients can be clearly evaluated [210,211]. Such studies should also help find the potential for HDL to influence atherosclerotic and CVD processes in other patients with chronic non-CF-activated inflammatory-immune

processes which are known to have an elevated risk for CVD [94,103]. Low omega-3 lipids Patients with CF exhibit consistent alterations in levels of polyunsaturated fatty acids (PUFA) compared to non-CF subjects. The most consistently documented alterations relate to decreased levels of linoleic acid (18:2 n-6), an increase in its arachidonic acid (20:4 n-6) metabolites, and a decrease in docosahexaenoic acid (22:6 n-3) (DHA), a downstream metabolite of alphalinolenate (18:3 n-3) [48,49,212–217]. These PUFA alterations associated with CF have been recapitulated in both CFTR knockout and delta 508 knock-in mouse models of CF and in cultured RT epithelial cells lacking CFTR [217]. The magnitude of several of the PUFA alterations appears to correlate with disease severity [212,218], suggesting not only the impact of CFTR-related alterations on PUFA metabolism but also the affects of inflammatoryimmune system activations on PUFA metabolism (these activations generally intensify as CFTR-related RT disease progresses). The precise mechanisms for PUFA abnormalities in CF remain to be fully characterized. There are considerable data relating to the influences of CFTR on the elongase and desaturase enzymes responsible for the biosynthesis of the long chain omega-6 and omega-3 PUFAs [216–222]. Increased conversions of the omega-6 linoleate to arachidonic acid and decreased conversions of omega-3 alpha-linolenate to the major omega-3 PUFAs, including DHA, represent frequently described CFTR mutation effects on PUFA pathways [217]. These studies are supported by reports of increased arachidonic acid production and by increased arachidonic acid/DHA ratios in CF tissues as compared to non-CF tissues [217,223],

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perhaps related to pleomorphic effects of CFTR beyond its role as an ion channel [224]. It has been recently reported that CFTR-involved activations of AMP-activated protein kinase play a role in the increased n-6 fatty acid metabolism in CF [225]. Mechanisms relating to abnormalities in PUFA metabolism in CF have been recently thoroughly reviewed [217]. Hypothetically, the described PUFA abnormalities in CF could contribute to both CF and CVD pathobiologies. Increased production of omega-6 arachidonic acid-derived eicosanoids, such as the proinflammatory prostaglandins and leukotrienes and anti-inflammatory lipoxins and the decreased docosanoid metabolites of DHA and EPA, such as the proresolution resolvins and protectins, could be collectively expected to negatively impact both CF and CVD inflammatory and oxidative pathobiologies. The complexity of the PUFA abnormalities in CF is illustrated by the reported reductions in lipoxin levels, an anti-inflammatory metabolite of arachidonic acid, shown to be decreased in CF secretions and is yet to be mechanistically explained [226]. The reduced omega-3 PUFA metabolites in CF, much as the reported changes in intracellular cholesterol and sphingolipid metabolites [49–51], could potentially alter the biochemical and biophysical properties of membranes and modulate the functions of membrane proteins [217]. Finally, studies in the general population of omega-3 consumption are generally [227–231] but not always [232] associated with a reduction of several CVD risk factors, such as triglyceride level, heart rate, blood pressure, inflammation biomarkers, and endothelial dysfunction. Thus, CF patients, known to have reduced omega-3 PUFAs, would appear to be at some increased risk for CVD. Interestingly, a recent Cochrane review of four adult CF randomized placebo-controlled trials conducted with omega-3 supplements concluded that the CF patients showed some improvement in clinical status and reduction in inflammatory biomarkers with no adverse effects [233]. Although it is clear that loss of CFTR function accounts for consistent changes in PUFA levels, interpretative conclusions can be confounded by the possible effects if the specific CFTR genotype mutation, the degree of varying activation of CF-related infectious and inflammatory-immune system activations, and the degree of the lipid absorption abnormalities. The roles of PUFA abnormalities in overall CF pathophysiology and CVD risk remain uncertain. Vascular endothelial dysfunction The arterial wall comprises several layers, including the endothelium, which regulates numerous vascular activities, such as tone, vasomotion, inflammation, and remodeling. As such, vascular endothelial dysfunction is believed to represent an early atherogenic event and thus a risk factor for CVD [234,235]. Vascular endothelial cells are known to express functional CFTR protein [236], although its potential contribution to overall endothelial function is uncertain. The endothelium secretes several vasomodulating molecules (e.g., NO and endothelin-1) among a myriad of other atheroprotective and atherogenic factors [237,238]. The complex regulatory interplay among endothelial ROS generating systems and NO generating systems and their products is recognized to play a key role in vasculature redox-sensitive signal transduction and overall endothelial dysfunction [239,240], reduced production, and bioavailability of NO being widely recognized as a major factor in vascular dysfunction. Endothelium-dependent vasodilation function, including the bioavailability of NO, appears to decline with age and likely depends on the overall balance of several vasoconstricting and vasodilating factors [238,241]. NO synthase (NOS) NO production depends on L-arginine as a substrate for NOS along with reduced tetrahydrobiopterin and other cofactors [235,242]. Corruptions in endothelial NOS NO production and signaling are often considered an early common mechanism

underlying vascular reactivity abnormalities in many conditions related to CVD. Numerous CVD risk factors have been shown to be associated with endothelial dysfunction. It remains uncertain as to the degree to which L-arginine deficiency and disordered NO metabolism in some tissues, both of which are observed in patients with CF [243], contribute to the vascular dysfunction also being described in CF. Patients with end-stage CF have been reported to have vascular dysfunction associated with an overactive endothelin-1 vasoconstricting pathway [168]. Two other endothelium-derived factors, von Willebrand factor and P-selectin, have been found to be elevated in plasma of patients with CF, strengthening the concept that endothelial dysfunction occurs in this disease [169]. It has been hypothesized that this latter endothelial perturbation is likely related to the persistent activated systemic inflammatoryimmune processes existing in CF. Multiple noninvasive physiological parameters exist which are believed to reflect pathological endothelial cell function including imbalances or dysfunction of cellular releases of vasodilating and vasoconstricting substances [235,244,245]. These parameters are also believed to represent one of the earliest functional disturbances in the natural history of atherosclerosis, thus being a powerful predictor of potential CVD [245–247]. A common noninvasive functional technique used is brachial artery flow-mediated dilation [244–246]. Several provocative studies have now reported abnormalities in vascular reactivity parameters in patients with CF [40,170,171]. One recent study documented evidence of endothelial dysfunction in children with CF using brachial artery flow-mediated dilation [170]. This study design was unique in that it was also accompanied by exercise studies demonstrating a subnormal maximal exercise performance in these patients. It was hypothesized that subnormal exerciseinduced vasodilation could possibly explain the below predicted exercise performance. Another study by this group used brachial artery flow-mediated dilation in young patients with CF to assess the effects of acute oral administration of an antioxidant cocktail of vitamins C and E and alpha-lipoic acid. This antioxidant cocktail appeared to restore endothelial dysfunction [248]. This group has additionally reported that tetrahydrobiopterin administration, an important redox-reactive species and critical cofactor of endothelial NOS, also appeared to increase flow-mediated dilation in a healthy cohort of young CF patients [249]. This would be in keeping with the concept that reduced tetrahydrobiopterin levels may be compromised by systemic inflammatory and oxidant processes impacting vascular wall endothelial cells, perhaps explaining in part why many chronic inflammatory diseases with systemic inflammatory cell activations are associated with abnormalities in endothelial dysfunction including flow-mediated dilation [250,251]. Another study measured a parameter of conducting artery vascular stiffness expressed as the augmentation index to document vascular dysfunction in CF. This group hypothesized that premature vascular aging may be occurring in CF because arterial stiffness is related to both age and atherosclerotic processes [40]. As a followup to this study, the same vascular dysfunction parameter was measured before and after intravenous antibiotics administered for CF exacerbations. The antibiotic therapy was associated with significant reductions in vascular stiffness, indicating at least some reversibility of this parameter known to reflect not only physiology but also anatomy of conducting large arteries [171]. This is somewhat analogous to recent findings reporting the abnormally elevated aortic stiffness in COPD to decrease after a hospitalized exacerbation and to relate to overall functional status of COPD patients, likely reflecting the intensity of inflammatory and oxidative systemic stress during more severe active disease [252] and including sympathetic nervous system overactivity, vascular wall NO bioavailability, and activations of intravascular PMN activities [7,244,253–257].

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Although the evidence for endothelial dysfunction in CF is reasonably strong, overall CVD phenotypes in CF remain unclear, albeit they are under increasing recent scrutiny. Interpretations of the reported abnormalities in CF aortic distensibility, (e.g., increased aortic stiffness) and flow-mediated dilatation are confounded by the fact that CFTR protein itself is expressed in cardiac and vascular smooth muscle tissues [236,258,259]. Thus, it is possible that some cardiovascular effects in CF are specifically related to the absence of CFTR in vascular smooth muscle tissue. This possibility is strengthened by the recent finding that a potentiator of CFTR (e.g., ivacaftor) improves vascular tone in a genetic subgroup of CF patients (those with the G551D CFTR allele), as measured by vascular pulse wave velocity and augmentation index [261A]. In a similar vein, the lack of CFTR expression in sympathetic nervous system tissue [260] could conceivably play a role in the recognized autonomic nervous system abnormalities (sympathetic overactivity) that has been reported in studies of CF tissues and patients [261–263]. Further studies are needed to define whether or not and to what extent that CFTR-related effects on cardiovascular and nervous system tissues raise to clinical relevance. The high incidence of CFRD in CF also impacts interpretations of endothelial dysfunction in CF as diabetes is itself associated with several well-recognized abnormalities in vascular wall tissues [253] including NOS uncoupling [254]. Age is also a known risk factor for decrements in endothelial function (as it is for cardiomyocyte function), one factor being age-related reduced NO availability [255]. New paradigms for related inflammatory signaling in vascular endothelial cells are emerging [256], many of which have relevance for CF patients. For example, CF is associated with elevated plasma MPO and activated and netting neutrophils [11,116,264–266], factors known to be related to endothelial dysfunction [119,257]. A summary of possible contributions of dysfunctional CFTR on vascular tissues is presented in Table 3. It is readily apparent that there are compelling reasons to further explore the mechanistic underpinnings of impaired vascular functions and to longitudinally examine cardiovascular parameters in further detail in CF patients.

Prothrombotic factors Prothrombotic factors, such as elevated fibrinogen, are a conditional risk factor for CVD. Fibrinogen is part of the coagulation pathway and an acute phase reactant like CRP [92,267]. Consistent with systemic inflammation assessed by CRP, many studies in adults with CF have reported significantly elevated fibrinogen levels [268,269]. Similar to what has been described in COPD [83], CF patients have been described to have increased platelet activation and reactivity CF [270–272]. Low omega-3 polyunsaturated fatty acid levels could be another prothrombotic factor in patients with CF. Omega-3 polyunsaturated fatty acids have been shown to inhibit platelet function in the general population, thus suggesting a protective role for CVD [273,274]. The interactions between the inflammation and the coagulation pathway, including platelets, suggest the need for clinical studies in patients with CF that better characterize these clinical implications [275].

Relative physical inactivity Exercise is widely recognized to be atheroprotective and an important modifying risk factor for CVD [23]. For example, exercise disability and decreased physical activity are believed to contribute to the increased CVD incidence in patients with osteoarthritis [276]. Adult CF guidelines encourage exercise, specifically aerobic activities several times a week. Such measures are believed to increase RT mucus clearance [181,277]. Numerous studies have attempted to assess physical activity levels in adults with CF. These measurements vary in units from exercise time frames to calculated physical activity scores and are difficult to collectively compile. Not surprisingly, exercise levels are known to decrease with disease severity [277]. Generally recommended exercise training strategies suffer from a low adherence, as has been reported with other chronic diseases, and CF is no exception [278,279]. A Cochrane Review of seven studies that investigated aerobic and/or anaerobic physical training versus no prescribed program in patients with CF found that physical training improved exercise capacity, strength, and lung function. Although these effects were not consistent throughout all studies, there was no evidence that would discourage disciplined physical training [280]. The significance of exercise training in ameliorating several forms of endothelial dysfunction has recently been further documented [235,281–283] and favorably influences even later stages of atherogensis [284]. It is readily apparent that disciplined exercise activities should be an integral part of CF therapeutic strategies. Cystic fibrosis-related diabetes CFRD is the most common comorbidity in adults with CF [285]: upwards of 30% have CFRD and another 15–20% have impaired glucose tolerance, a precursor to CFRD [285,286]. The prevalence of CFRD increases with age [16]: the median age of diagnosis is 21 years [287] and approximately 50% have CFRD by 30 years [288]. While CFRD is a unique entity from type 1 and type 2 diabetes mellitus, it shares features of both in that CFRD is accompanied by both insulin deficiency and insulin resistance [288,289]. In the general population, both type 1 and type 2 diabetes mellitus are independent risk factors for CVD [23]. Diabetes mellitus has been shown to increase risk of CVD by twofold [290]. Although the pathogenesis of atherosclerosis in diabetes mellitus is complex and multifactorial, there are five general categories of pathobiological contributing mechanisms: metabolic factors, oxidation/glucoxidation processes, endothelial dysfunction, activated inflammatory-immune pathways, and prothrombotic factors [291,292]. As several of these same factors are also found in nondiabetic CF patients, and especially in CF patients with CFRD, it is readily apparent that patients with CFRD could be a particularly vulnerable CF subgroup with increased risk for CVD. Complications from CFRD, as in the conventional forms of diabetes, are likely related to the duration of CFRD and the level of glycemic control [293,294]. Three studies have reported microvascular complications: rates range from 10–36% for retinopathy, 10–21% for microalbuminuria, and 3–17% for neuropathy [288,293,294].

Table 3 Effects Effects Effects Effects Effects Effects Effects Effects n

of CFTRn on cardiomyocyte and/or vascular smooth muscle biology of CFTRn on endothelial cells of CFTRn on autonomic nervous system tissues of CFTRn on dysregulated NOS activities of CFTRn on vascular tissue ROS production of CF-related nutritional deficiencies on cardiovascular tissue (e.g., reduced micronutrient antioxidant levels) of CFTRn-related activated systemic-activated inflammatory-immune and coagulation systems on cardiovascular tissue pathobiology on dysfunctional HDL, LDL, and oxylipids on vascular tissue

And/or mutated CFTR.

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In contrast, macrovascular complications or deaths from atherosclerotic CVD have not been specifically and rigorously addressed [288], perhaps since most adults with CF have been thought to have few risk factors for CVD and have not lived long enough to develop CVD [293]. Finally there is recent concern that prediabetics without overt diabetes may be susceptible to an increased incidence of CVD [295], which could be of concern to older CF patients without overt CFRD. Post-lung transplant In 2012, there were approximately 200 lung transplants in patients with CF in the United States [1]. Conventional CVD risk factors and immunosuppressive regimes, including glucocorticoid use, may contribute to the vasculopathy and accelerated CVD development post-lung transplant [296,297]. In patients with CF, the overall 5-year post-lung transplant survival rate is around 70% and is associated with both CVD and non-CVD posttransplant comorbidities [298–301]. One study specifically and retrospectively analyzed CVD risk factors pre- and post-lung transplant in adults with CF. Posttransplant, 32% had significantly elevated total cholesterol and 42% elevated triglycerides, compared to the infrequent elevations of these lipids pretransplant [302]. Of note, the Framingham Risk Score was calculated at o10% for all but one adult with CF, indicating low risk for CVD over 10 years post-lung transplant. This low risk was ascribed to the low prevalence of tobacco smoking and the relatively young at transplant age in adults with CF [302]. Several studies have retrospectively analyzed post-lung transplant causes of mortality in patients with CF. Three deaths were attributed to myocardial infarction [298,303] and one to cerebrovascular disease [304]. A recent case study reports a myocardial infarction in a 19-year-old female who received a heart lung transplant 15 years earlier [305]. Uncertain risk Numerous other clinical conditions remain uncertain as to their potential contribution to atherosclerotic CVD risk factors in patients with CF, partly due to their controversy within the general population. These clinical conditions include issues related to reduced coenzyme Q10 levels in patients with CF [306] and often reduced levels of carotenoids, vitamin E, and vitamin D, all of which have even been touted as factors influencing the incidence and/or severity of atherosclerotic CVD [159,307–310]. Such factors as the “anti-inflammatory” agents NSAIDS, glucosteroids, and azithromycin have been touted as presenting an increased risk of CVD in the general population [297,311] but are frequently

prescribed to patients with CF. Finally, elevated homocysteine levels have been found in children with CF [312] and could represent another factor influencing CVD incidence [313].

Future considerations and further directions More information is needed to better understand the implications of potential CVD risk factors in patients with CF. A summary of issues needing further study is compiled in Table 4. A first step would be to monitor the development of atherogenic processes and CVD incidence in aging patients with CF. It would seem prudent to compile the data from CF patient registries, as a single center likely does not provide enough statistical power to analyze CVD events. Monitoring CF patient registries could also include the cardiac evaluations performed before transplantations as well as the status of cardiovascular system pathology from autopsy reports. Future studies could investigate patients with CF and their CVD health prospectively in longitudinal studies using various physiological and radiologic atherosclerotic parameters [314]. As noted by others, no screening or preventive health guidelines for CVD and/or its risk factors exist for CF as yet. Additional education would be required for healthcare professionals working with patients with CF, in order to provide optimal prevention and treatment strategies. Nutrition interventions, pharmacological approaches, and optimization of exercise routines would likely be prime candidates to investigate for optimal prevention and treatment strategies. Current nutrition recommendations for the general population may be too restrictive and not entirely applicable to the CF population. Studies of Mediterranean diets and omega-3 supplementations in patients with CF have shown some promise including a more favorable fat composition of higher monounsaturated fats and a lower omega-6:omega-3 polyunsaturated fatty acid ratio [315,316]. As suggested by others, the Mediterranean diet provides a good baseline for such nutrition interventions and may be an area to continue to explore [317]. This might be of particular importance to CF patients with evidences of advanced abnormalities of vascular reactivity [318]. Newer -omics methods, such as lipidomics, may provide further insight into the various lipid abnormalities in patients with CF with the ability to generate a more comprehensive metabolite signature [218,319]. Current pharmacological approaches for the general population for preventive CVD strategies do not meet the needs of adults with CF. In the landmark JUPITER trial, statin therapy was provided to relatively healthy adults with elevated CRP levels. The beneficial significant results went beyond the usual goal of lowering LDL cholesterol. They also included anti-inflammatory effects along with a decreased incidence of cardiovascular events. However, a small increased risk

Table 4 Cystic fibrosis (CF) and cardiovascular disease (CVD) risk: Needed future studies.

          

Do older adults with CF have an increased risk of atherosclerosis and CVD than non-CF adults? Do gender differences exist in risk of CVD in patients with CF? Do patients with CF and diabetes have a risk of CVD that differs from patients without CF and diabetes? To what extent do circulating neutrophils and their products (e.g., ROS, MPO, bioactive peptides) contribute to endothelial dysfunction in CF? To what extent do the elevated levels of pro- and anti-inflammatory cytokines, chemokines, and C-reactive protein in patients with CF impact their cardiovascular biology? To what extent does the dyslipidemia in patients with CF impact overall vascular biology? To what degree do the reduced levels of anti-inflammatory, antioxidant, and antiatherogenic plasma HDLs in patients with CF impact their overall cardiovascular risk? To what extent do aberrant coagulation (including platelet) function impact cardiovascular biology in patients with CF? What are the mechanisms of the abnormalities of endothelial function in CF? Is there intrinsic evidence of NO producing abnormalities because of the presence of mutated CFTR in endothelial cells? In cardiac myocytes? Do the known abnormalities in vascular reactivity in CF represent a harbinger of progressive CVD? To what degree do standard risk models for CVD (e.g., Framingham, 2013 ACC/AHA Pooled Cohort Equation) need to be modified for patients with chronic localized activated inflammatory immune processes? And for patients with CF? To what extent can behavioral, nutritional, and pharmacotherapeutic agents influence any of the listed possible cardiovascular risk pathobiologies in patients with chronic localized activated inflammatory-immune processes? And in patients with CF?

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of developing type 2 diabetes mellitus documented was documented [320], and this is concern because of the high prevalence of CFRD in patients with CF. These results have potential implications for adults with CF. There are two studies registered by ClinicalTrials.gov currently investigating statin therapy in patients with CF [321]. Similarly, one current pharmacological anti-inflammatory therapy for patients with CF is azithromycin [321]. This antibiotic was recently found to increase the risk of CVD death in patients from the general population, when compared to other antibiotics or no antibiotics. This particular therapy has the potential to contribute to CVD in patients with CF and outcomes should continue to be monitored [322]. Lastly, exercise strategies have been shown to improve vascular reactivity and should be of particular value in CF patients carrying a high risk of insulin resistance, prediabetes, and diabetes with regard to such CVD risk factors as abnormal vascular reactivity [323].

Conclusions Despite chronic infection, intensely activated local inflammatoryimmune processes accompanied by abundant evidence of oxidative stress, along with “spillover” systemic inflammation and oxidative stress, a myriad of evidence of altered lipid and lipoprotein metabolism, apparent activations of early atherogenic processes such as endothelial dysfunction, relative physical inactivity, and a high incidence of CFRD, more advanced atherosclerotic processes, and CVD have been rarely addressed in adults with CF. The available literature would suggest that CF patients do not exhibit many of the recognized classical risk factors for CVD but may exhibit biomarkers of premature vascular aging [324]. In marked contrast to COPD, another chronic inflammatory RT disease, a paucity of studies reviewing the nonpulmonary manifestations of CF have discussed CVD as a possible comorbidity. The presence of active chronic systemic inflammatory and oxidative processes, early manifestations of atherogenic vascular dysfunction and dyslipidemia in CF, should highlight the need to undertake more longitudinal studies of cardiovascular health in this disease [314]. Although there is growing evidence that some adults with CF have several pathophysiological factors that put them at a theoretical increased risk for CVD, it is unresolved how well-recognized CVD risk factors for the general population are applicable for patients with chronic localized activation of inflammatory-immune processes and evidence of oxidative stress, including adults with CF. Considerable heterogeneity of CVD risk factors undoubtedly exists among patients with CF due to the large subgroups of CF populations (e.g., patients with CF who are pancreatic sufficient, pancreatic insufficient, and pancreatic insufficient with CFRD). As is the case in other adults with chronic activations of inflammatory-immune oxidative processes, it is likely that a structured, multifunctional biochemical, physiological, and patient-oriented composite outcome will represent a more comprehensive measure of CVD risk in this group of patients. Preventing or delaying the onset of CVD in adults with CF, who are already afflicted by other adult health issues related to CF, presents an increasing concern, especially as this overall patient population continues to age [15–17,20].

Conflict of Interest The authors report no conflict of interest.

Acknowledgments Supported in part by CF Foundation grant to the University of California Davis Adult CF Clinic. Portions of the work completed by

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EJR performed in partial fulfillment of the requirement for the Ph.D. degree from the Graduate Group of Nutritional Biology, University of California, Davis. The authors thank Louis Infante for manuscript editorial assistance.

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