Adverse social determinants of health elevate uncontrolled hypertension risk: a cardio-oncology prospective cohort study.

The role of social determinants of health (SDOH) in controlling hypertension (HTN) in cancer patients is unknown. We hypothesize that high SDOH scores correlate with uncontrolled HTN in hypertensive cancer patients. In our prospective study, patients completed the Protocol for Responding to & Assessing Patients' Assets, Risks & Experiences questionnaire. After integrating home and clinic blood pressure readings, uncontrolled HTN was defined as systolic blood pressure greater than or equal to 140 mm Hg and/or diastolic blood pressure greater than or equal to 90 mm Hg. Using Cox regression, we analyzed the impact of SDOH on HTN control, adjusting for relevant factors. The study involved 318 participants (median age 66.4, median follow-up 166 days, SDOH score 6.5 ± 3.2), with stress, educational insecurity, and social isolation as prevalent adverse SDOH. High SDOH scores led to 77% increased risk of uncontrolled HTN (adjusted hazards ratio = 1.77; 95% confidence interval = 1.10 to 2.83, P = .018). Urban residents with high SDOH scores were at an even greater risk. Identifying SDOH and mitigating underlying factors may help control HTN, the most typical disease process treated in all cardio-oncology clinics.

Examining the interplay between cardiovascular disease and cancer incidence: Data from NHANES III and continuous.

Introduction: This study aimed to investigate the relationship between risk factors of cancer among individuals with existing cardiovascular disease (CVD). Methods: The analysis included 438 and 2100 CVD patients aged 65+ from NHANES-III and Continuous datasets, respectively. Competing risk models with subdistribution hazards ratio (aHR) were used to identify risk factors. Results: Females in NHANES-III had lower cancer risk (aHR 0.39, P = 0.001) compared to males. Poor physical activity was associated with increased cancer risk in both datasets (aHR 2.59 in NHANES-III, aHR 1.59 in Continuous). In NHANES-Continuous, age (aHR 1.07, P < 0.001) and current smoking (aHR 2.55, P = 0.001) also showed a significant association with developing cancer. No other factors investigated showed significant associations. Discussion: This study highlights the interplay between traditional risk factors and the elevated risk of cancer in CVD patients. Further research with larger samples and wider age ranges is needed to solidify these findings and inform intervention strategies.

Nocturnal blood pressure dipping, blood pressure variability, and cognitive function in early and middle-aged adults.

Higher nighttime blood pressure (BP), less BP dipping, and higher BP variability have been linked with worse cognitive function in the elderly. The goal of this study is to explore whether this relationship already exists in early and middle adulthood. We further examined whether ethnic differences between African Americans and European Americans in BP parameters can explain ethnic differences in cognitive function. 24-h ambulatory BP monitoring and cognitive function were obtained from 390 participants (average age: 37.2 years with a range of 25-50; 54.9% African Americans; 63.6% females). We observed that higher nighttime BP, decreased dipping, and higher variability were significantly associated with lower scores on the Picture Sequence Memory Test. Significant negative associations between variability and overall composite scores were also observed. No significant associations between average 24-h or daytime BP and cognitive function were observed. Ethnic differences in nighttime diastolic pressures and dipping can explain 6.81% to 10.8% of the ethnicity difference in the score of the Picture Sequence Memory Test (ps < .05). This study suggests that the associations of nighttime BP, dipping, and variability with cognitive function already exist in young and middle-aged adults. Ethnic differences in nighttime BP and dipping can at least partially explain ethnic differences in cognitive function. The stronger association of these parameters with cognitive function than daytime or average BP in this age range raises the importance of using ambulatory BP monitoring for more precise detection of abnormal BP patterns in young adulthood.

Evidence of increased cardiovascular disease risk in left-handed individuals.

Background: Approximately 10% of the world is left-handed (LH). Research suggests that LH individuals may have shorter lifespans compared to right-handed (RH) individuals. LH individuals also appear to have more cardiovascular disease (CVD) related conditions like diabetes and cancer. Thus, the present study sought to test the hypothesis that vascular function and heart rate variability (HRV), both key indicators of CVD risk, would be lower in LH compared to RH individuals. Methods: Three hundred seventy-nine participants, 18-50 years old, were enrolled. Flow-mediated dilation (FMD), a bioassay of vascular endothelial function and standard deviation of R-R interval (SDNN), a parameter of HRV, were evaluated as indices of CVD risk. Data are reported as mean ± SD. Results: 12.1% of the participants were LH. No differences in demographics or clinical laboratory values were observed between groups, except high-density lipoprotein (HDL) was higher (p = 0.033) in RH. FMD was significantly (p = 0.043) lower in LH (6.1% ± 3.2%) compared to RH (7.6% ± 3.8%), independent of age, sex, race, BMI, and HDL. Total power (p = 0.024) and low-frequency power (p = 0.003) were lower in LH compared to RH. Additionally, SDNN was lower (p = 0.041) in LH (47.4 ± 18.8 ms) compared to RH (54.7 ± 22.3 ms). A negative correlation between FMD and mean arterial pressure (r = -0.517; p < 0.001) was observed in LH; no relationships were observed in RH (all p > 0.05). Conclusion: Vascular endothelial function and HRV are lower in LH compared to RH. In addition, relationships between FMD and traditional CVD risk factors were only observed in LH. These data support an increased risk of CVD in LH.

Endogenous estradiol contributes to vascular endothelial dysfunction in premenopausal women with type 1 diabetes.

BACKGROUND: Endogenous estrogen is cardio-protective in healthy premenopausal women. Despite this favorable action of estrogen, animal models depict a detrimental effect of estradiol on vascular function in the presence of diabetes. The present study sought to determine the role of endogenous estradiol on endothelial function in women with type 1 diabetes. METHOD: 32 women with type 1 diabetes (HbA1c = 8.6 ± 1.7%) and 25 apparently healthy women (HbA1c = 5.2 ± 0.3%) participated. Flow-mediated dilation (FMD), a bioassay of nitric-oxide bioavailability and endothelial function was performed during menses (M) and the late follicular (LF) phase of the menstrual cycle to represent low and high concentrations of estrogen, respectively. In addition, a venous blood sample was collected at each visit to determine circulating concentrations of estradiol, thiobarbituric acid reactive substances (TBARS), and nitrate/nitrite (NOx), biomarkers of oxidative stress and nitric oxide, respectively. Data were collected in (1) 9 additional women with type 1 diabetes using oral hormonal birth control (HBC) (HbA1c = 8.3 ± 2.1%) during the placebo pill week and second active pill week, and (2) a subgroup of 9 demographically matched women with type 1 diabetes not using HBC (HbA1c = 8.9 ± 2.1%). RESULTS: Overall, estradiol was significantly increased during the LF phase compared to M in both type 1 diabetes (Δestradiol = 75 ± 86 pg/mL) and controls (Δestradiol = 71 ± 76 pg/mL); however, an increase in TBARS was only observed in patients with type 1 diabetes (ΔTBARS = 3 ± 13 µM) compared to controls (ΔTBARS = 0 ± 4 µM). FMD was similar (p = 0.406) between groups at M. In addition, FMD increased significantly from M to the LF phase in controls (p = 0.024), whereas a decrease was observed in type 1 diabetes. FMD was greater (p = 0.015) in patients using HBC compared to those not on HBC, independent of menstrual cycle phase. CONCLUSION: Endogenous estradiol increases oxidative stress and contributes to endothelial dysfunction in women with diabetes. Additionally, HBC use appears to be beneficial to endothelial function in type 1 diabetes.

Muscle oxygen utilization and ventilatory parameters during exercise in people with cystic fibrosis: Role of HbA1c.

INTRODUCTION: Glycated hemoglobin can interfere with oxygen delivery and CO2 removal during exercise. Additionally, pancreatic insufficiency increases oxidative stress and exacerbates exercise intolerance in people with cystic fibrosis (PwCF). This investigation sought to test the hypotheses that elevated Hemoglobin A1c (HbA1c) can negatively affect exercise parameters in PwCF and that reductions in oxidative stress can improve tissue oxygenation in individuals with elevated HbA1c. METHODS: Twenty four PwCF were divided into two groups; normal HbA1c <5.7% (N-HbA1c) and elevated HbA1c >5.7% (E-HbA1c). A maximal exercise test was conducted to obtain peak oxygen uptake (VO2peak), VO2 at ventilatory threshold (VT), ventilatory parameters (VE/VCO2 slope and end-tidal CO2 (petCO2)). Near-Infrared Spectroscopy (NIRS) was used to assess muscle oxygenated/deoxygenated hemoglobin during exercise. A subset of individuals with E-HbA1cwere given an antioxidant cocktail (AOC) for 4 weeks to determine the effects on tissue oxygenation during exercise. RESULTS: A negative relationship between HbA1c and VO2peak at VT was observed (r = -0.511; p = 0.018). In addition, a positive relationship between HbA1c and VE/VCO2 slope (r = 0.587;p = 0.005) and a negative relationship between HbA1c and petCO2 at maximal exercise (r = -0.472;p = 0.031) was observed. N-HbA1c had greater VO2peak (p = 0.021), VO2 at VT (p = 0.004), petCO2 (p = 0.002), and lower VE/VCO2 slope (p = 0.004) compared with E-HbA1c. Muscle deoxygenated hemoglobin at VT was higher in N-HbA1c vs. E-HbA1c and 4 weeks of AOC improved skeletal muscle utilization of oxygen. CONCLUSION: Findings demonstrate that glycated hemoglobin may lead to tissue oxygenation impairment and ventilation inefficiency during exercise in PwCF. In addition, antioxidant supplementation may lead to improved tissue oxygenation during exercise.

Allostatic load and cardiovascular outcomes in males with prostate cancer.

BACKGROUND: Cardiovascular disease (CVD) is the leading cause of death in men with prostate cancer (PC). Accumulated stress plays an important role in CVD development. The cumulative burden of chronic stress and life events can be measured using allostatic load (AL). METHODS: The initial cohort included males aged 18 years and older diagnosed with PC (2005-2019). AL was modeled as an ordinal variable (0-11). Fine-Gray competing risk regressions measured the impact of precancer diagnosis AL and postdiagnosis AL in 2-year major cardiac events (MACE). The effect of AL changes over time on MACE development was calculated via piecewise Cox regression (before, and 2 months, 6 months, and 1 year after PC diagnosis). RESULTS: We included 5261 PC patients of which 6.6% had a 2-year MACE. For every 1-point increase in AL before and within 60 days after PC diagnosis, the risk of MACE increased 25% (adjusted hazard ratio [aHR] =1.25, 95% confidence interval [CI] = 1.18 to 1.33) and 27% (aHR = 1.27, 95% CI = 1.20 to 1.35), respectively. Using AL as a time-varying exposure, the risk of MACE increased 19% (aHR = 1.19, 95% CI = 1.11 to 1.27), 22% (aHR = 1.22, 95% CI = 1.14 to 1.33), 28% (aHR = 1.28, 95% CI = 1.23 to 1.33), and 31% (aHR = 1.31, 95% CI = 1.27 to 1.35) for every 1-point increase in AL before, 2 months after, 6 months after, and 1 year after PC diagnosis, respectively. CONCLUSION: AL and its changes over time are associated with MACE in PC patients, suggesting a role of a biological measure of stress as a marker of CVD risk among men with PC.

The Exeter Activity Unlimited statement on physical activity and exercise for cystic fibrosis: methodology and results of an international, multidisciplinary, evidence-driven expert consensus.

BACKGROUND: The roles of physical activity (PA) and exercise within the management of cystic fibrosis (CF) are recognised by their inclusion in numerous standards of care and treatment guidelines. However, information is brief, and both PA and exercise as multi-faceted behaviours require extensive stakeholder input when developing and promoting such guidelines. METHOD: On 30th June and 1st July 2021, 39 stakeholders from 11 countries, including researchers, healthcare professionals and patients participated in a virtual conference to agree an evidence-based and informed expert consensus about PA and exercise for people with CF. This consensus presents the agreement across six themes: (i) patient and system centred outcomes, (ii) health benefits, iii) measurement, (iv) prescription, (v) clinical considerations, and (vi) future directions. The consensus was achieved by a stepwise process, involving: (i) written evidence-based synopses; (ii) peer critique of synopses; (iii) oral presentation to consensus group and peer challenge of revised synopses; and (iv) anonymous voting on final proposed synopses for adoption to the consensus statement. RESULTS: The final consensus document includes 24 statements which surpassed the consensus threshold (>80% agreement) out of 30 proposed statements. CONCLUSION: This consensus can be used to support health promotion by relevant stakeholders for people with CF.

The effects of whole-body vibration amplitude on glucose metabolism, inflammation, and skeletal muscle oxygenation.

Whole-body vibration (WBV) is an exercise mimetic that elicits beneficial metabolic effects. This study aims to investigate the effects of WBV amplitude on metabolic, inflammatory, and muscle oxygenation responses. Forty women and men were assigned to a high (HI; n = 20, Age: 31 ± 6 y) or a low-amplitude group (LO; n = 20, Age: 33 ± 6 y). Participants engaged in 10 cycles of WBV [1 cycle =1 min of vibration followed by 30 s of rest], while gastrocnemius muscle oxygen consumption (mVO2 ) was assessed using near-infrared spectroscopy (NIRS). Blood samples were collected PRE, POST, 1H, 3Hs, and 24H post-WBV and analyzed for insulin, glucose, and IL-6. In the LO group, Homeostatic Model Assessment for Insulin Resistant (HOMA-IR) at 3 h (0.7 ± 0.2) was significantly lower compared to PRE (1.1 ± 0.2; p = 0.018), POST (1.3 ± 0.3; p = 0.045), 1H (1.3 ± 0.3; p = 0.010), and 24H (1.4 ± 0.2; p < 0.001). In addition, at 24H, HOMA-IR was significantly lower in the LO when compared to the HI group (LO: 1.4 ± 0.2 vs. HI: 2.2 ± 0.4; p = 0.030). mVO2 was higher (p = 0.003) in the LO (0.93 ± 0.29 ml/min/100 ml) when compared to the HI group (0.63 ± 0.28 ml/min/100 ml). IL-6 at 3H (LO: 13.2 ± 2.7 vs. HI: 19.6 ± 4.0 pg·ml-1 ; p = 0.045) and 24H (LO: 4.2 ± 1.1 vs. HI: 12.5 ± 3.1 pg·ml-1 ; p = 0.016) was greater in the HI compared to the LO group. These findings indicate that low-amplitude WBV provides greater metabolic benefits compared to high-amplitude WBV.

Exercise improves angiogenic function of circulating exosomes in type 2 diabetes: Role of exosomal SOD3.

Exosomes, key mediators of cell-cell communication, derived from type 2 diabetes mellitus (T2DM) exhibit detrimental effects. Exercise improves endothelial function in part via the secretion of exosomes into circulation. Extracellular superoxide dismutase (SOD3) is a major secretory copper (Cu) antioxidant enzyme that catalyzes the dismutation of O2•- to H2 O2 whose activity requires the Cu transporter ATP7A. However, the role of SOD3 in exercise-induced angiogenic effects of circulating plasma exosomes on endothelial cells (ECs) in T2DM remains unknown. Here, we show that both SOD3 and ATP7A proteins were present in plasma exosomes in mice, which was significantly increased after two weeks of volunteer wheel exercise. A single bout of exercise in humans also showed a significant increase in SOD3 and ATP7A protein expression in plasma exosomes. Plasma exosomes from T2DM mice significantly reduced angiogenic responses in human ECs or mouse skin wound healing models, which was associated with a decrease in ATP7A, but not SOD3 expression in exosomes. Exercise training in T2DM mice restored the angiogenic effects of T2DM exosomes in ECs by increasing ATP7A in exosomes, which was not observed in exercised T2DM/SOD3-/- mice. Furthermore, exosomes overexpressing SOD3 significantly enhanced angiogenesis in ECs by increasing local H2 O2  levels in a heparin-binding domain-dependent manner as well as restored defective wound healing and angiogenesis in T2DM or SOD3-/- mice. In conclusion, exercise improves the angiogenic potential of circulating exosomes in T2DM in a SOD3-dependent manner. Exosomal SOD3 may provide an exercise mimetic therapy that supports neovascularization and wound repair in cardiometabolic disease.

Smoking cessation reduces systemic inflammation and circulating endothelin-1.

Smoking increases systemic inflammation and circulating endothelin-1 (ET-1), both of which contribute to an elevated risk of cardiovascular disease (CVD). The present study sought to test the hypothesis that a 12-week smoking cessation intervention would contribute to a long-term reduction in circulating ET-1, tumor necrosis factor-alpha (TNF-α), and interleukin-6 (IL-6). 30 individuals participated in a 12-week evidence-based smoking cessation program at Augusta University. Serum cotinine, plasma inflammatory cytokines, and plasma ET-1 were determined at baseline, immediately after the 12-week cessation program (end of treatment, EOT), and 12-months (12M) following the cessation program. Serum cotinine was significantly reduced (p < 0.001) at EOT and 12M following the smoking cessation program. Compared to BL (7.0 ± 1.6 pg/mL), TNF-α was significantly reduced at EOT (6.3 ± 1.5 pg/mL, p = 0.001) and 12M (5.2 ± 2.7 pg/mL, p < 0.001). ET-1 was significantly lower at EOT (1.9 ± 0.6 pg/mL, p = 0.013) and at 12M (2.0 ± 0.8 pg/mL, p = 0.091) following smoking cessation compared with BL (2.3 ± 0.6 pg/mL). BL concentrations of cotinine were significantly associated with basal ET-1 (r = 0.449, p = 0.013) and the change in cotinine at 12M following smoking cessation was significantly associated with the change in plasma ET-1 at 12M (r = 0.457, p = 0.011). Findings from the present pilot investigation demonstrate that a 12-week smoking cessation program reduces circulating concentrations of ET-1 and TNF-α for at least a year. The reduction in serum cotinine was associated with the decrease in circulating ET-1. The attenuation in ET-1 and inflammation may in part, contribute to the lower risk of CVD that is observed with smoking cessation.

Obesity and the Bidirectional Risk of Cancer and Cardiovascular Diseases in African Americans: Disparity vs. Ancestry.

Cardiovascular disease (CVD) and cancer often occur in the same individuals, in part due to the shared risk factors such as obesity. Obesity promotes adipose inflammation, which is pathogenically linked to both cardiovascular disease and cancer. Compared with Caucasians, the prevalence of obesity is significantly higher in African Americans (AA), who exhibit more pronounced inflammation and, in turn, suffer from a higher burden of CVD and cancer-related mortality. The mechanisms that underlie this association among obesity, inflammation, and the bidirectional risk of CVD and cancer, particularly in AA, remain to be determined. Socio-economic disparities such as lack of access to healthy and affordable food may promote obesity and exacerbate hypertension and other CVD risk factors in AA. In turn, the resulting pro-inflammatory milieu contributes to the higher burden of CVD and cancer in AA. Additionally, biological factors that regulate systemic inflammation may be contributory. Mutations in atypical chemokine receptor 1 (ACKR1), otherwise known as the Duffy antigen receptor for chemokines (DARC), confer protection against malaria. Many AAs carry a mutation in the gene encoding this receptor, resulting in loss of its expression. ACKR1 functions as a decoy chemokine receptor, thus dampening chemokine receptor activation and inflammation. Published and preliminary data in humans and mice genetically deficient in ACKR1 suggest that this common gene mutation may contribute to ethnic susceptibility to obesity-related disease, CVD, and cancer. In this narrative review, we present the evidence regarding obesity-related disparities in the bidirectional risk of CVD and cancer and also discuss the potential association of gene polymorphisms in AAs with emphasis on ACKR1.

Exercise Intolerance in Cystic Fibrosis: Importance of Skeletal Muscle.

PURPOSE: Exercise intolerance, evaluated by O2 consumption, predicts mortality in cystic fibrosis (CF). People with CF exhibit skeletal muscle dysfunctions that may contribute to an imbalance between O2 delivery and utilization. Sildenafil, a phosphodiesterase type 5 inhibitor, increases blood flow and improves O2 consumption, although the exact mechanisms in CF have yet to be elucidated. Thus, we hypothesized that exercise intolerance in CF is limited primarily by an impaired skeletal muscle O2 utilization, and sildenafil improves exercise tolerance in CF by addressing this mismatch between O2 demand and extraction. METHODS: Fifteen individuals with mild to moderate CF and 18 healthy controls completed an incremental exercise test and measurements of gaseous exchange, chronotropic response, hemodynamics, and O2 extraction and utilization. People with CF also completed a 4-wk treatment with sildenafil with a subsequent follow-up evaluation after treatment. RESULTS: Skeletal muscle O2 extraction and utilization during exercise were reduced in people with CF when compared with controls. Exercise capacity in our CF population was minimally limited by hemodynamic or chronotopic responses, whereas peripheral O2 extraction was more closely associated with exercise capacity. The study also demonstrated that 4 wk of sildenafil improved skeletal muscle O2 utilization during exercise to similar values observed in healthy individuals. CONCLUSIONS: Individuals with mild to moderate CF exhibit exercise intolerance secondary to a reduction in O2 utilization by the exercising skeletal muscle. The present study demonstrated that 4 wk of sildenafil treatment improves the capacity of the skeletal muscle to use O2 more efficiently during exercise. Findings from the present study highlight the importance of targeting skeletal muscle O2 utilization to improve exercise tolerance in CF.

VO2max as an exercise tolerance endpoint in people with cystic fibrosis: Lessons from a lumacaftor/ivacaftor trial.

BACKGROUND: The impact of lumacaftor/ivacaftor on exercise tolerance in people with cystic fibrosis (CF) has not been thoroughly studied. METHODS: We conducted a multisite Phase 4 trial comparing the impact of lumacaftor/ivacaftor on exercise tolerance with that of placebo in participants ≥ 12 years of age with CF homozygous for F508del-CFTR. The primary endpoint was relative change from baseline in maximum oxygen consumption (VO2max) during cardiopulmonary exercise testing (CPET) at Week 24. The key secondary endpoint was relative change from baseline in exercise duration during CPET at Week 24. Other secondary endpoints included changes in other indices of exercise tolerance and changes in CF assessments; safety and tolerability were assessed as an endpoint. RESULTS: Seventy participants were randomized to receive lumacaftor/ivacaftor (n = 34) or placebo (n = 36). The least-squares mean difference for lumacaftor/ivacaftor versus placebo in relative change in VO2max from baseline at Week 24 was -3.2% (95% CI: -9.2, 2.9; P=0.3021); the least-squares mean difference in relative change from baseline in exercise duration at Week 24 was -3.2% (95% CI: -8.0, 1.6). Safety results were consistent with the known lumacaftor/ivacaftor safety profile. CONCLUSIONS: Definitive conclusions regarding the impact of lumacaftor/ivacaftor on exercise tolerance cannot be drawn from these results; however, multicenter studies using CPETs can be reliably performed with multiple time points and conventional methods, provided that calibration can be achieved. Future studies of exercise tolerance may benefit from lessons learned from this study. NCT02875366.

Oxygen transport and utilisation during exercise in cystic fibrosis: contributors to exercise intolerance.

NEW FINDINGS: What is the topic of this review? This review highlights the central and peripheral mechanisms that alter oxygen transport and utilisation and thereby contribute to exercise limitation in people with cystic fibrosis, considering also viable therapeutic targets for intervention. What advances does it highlight? Although traditionally considered a respiratory condition, pathological intramuscular and cardiovascular changes in people with cystic fibrosis appear to be key determinants of exercise intolerance up until the later stages of respiratory disease. Even young, habitually active patients with normal lung function experience multisystemic abnormalities, which play a role in exercise intolerance. ABSTRACT: Cystic fibrosis (CF) is a complex condition, commonly associated with exercise limitation. The mechanisms responsible for this in CF are of interest, given that lower aerobic fitness is associated with an increased risk of being hospitalised with pulmonary exacerbation, a poorer quality of life and a poorer prognosis. Pathophysiological changes in lung function are considered central to CF, and may contribute to exercise limitation. However, it is now clear that the pathogenesis of exercise limitation in this population is multifactorial, with alterations in cardiovascular, muscle and pulmonary function contributing. Whilst some of these changes are attributable to respiratory disease per se, the CF transmembrane conductance regulator protein is also found in skeletal muscle and the vascular endothelium and can directly alter central and localised oxygen delivery, as well as the ability to effectively extract and utilise oxygen at the myocyte level. Since intense exercise poses considerable challenges to arterial oxygen content and/or blood flow and its supply to the working skeletal muscle, evaluating the exercise physiology of people with CF has helped us understand the mechanisms underlying exercise intolerance. Through several investigations over recent years, we have collectively demonstrated that people with CF exhibit reduced skeletal muscle oxygen extraction and utilisation during exercise, with a lesser contribution from haemodynamic or chronotropic mechanisms. Taken together, our findings highlight the importance of targeting mechanisms of skeletal muscle oxygen utilisation in CF to improve exercise tolerance and we offer potential therapeutic interventional strategies.

Sildenafil improves exercise capacity in patients with cystic fibrosis: a proof-of-concept clinical trial.

BACKGROUND: Exercise intolerance is a common phenotype observed in patients with cystic fibrosis (CF). Treatment with sildenafil, a phosphodiesterase type 5 (PDE5) inhibitor, has previously been shown to improve exercise capacity (VO2 peak) in other patient populations. Thus, the present study sought to determine the acute and subacute effects of sildenafil on exercise capacity in patients with CF. METHODS: The present investigation utilized a randomized, double-blind, placebo-controlled, crossover study with an acute dose of either sildenafil (50 mg) or placebo (n = 13, age 25 ± 10), followed by a 4 week open-label extension with sildenafil (20 mg, TID; n = 15, age 23 ± 11). A comprehensive evaluation of pulmonary function and a maximal exercise test were each performed at every visit. RESULTS: A significant increase in VO2 peak was observed after the acute sildenafil dose with no changes following placebo (77 ± 13 versus 72 ± 13% predicted; p = 0.033). In addition, after 4 weeks of treatment, patients showed a significant increase in exercise capacity (72 ± 12 versus 75 ± 12% predicted; p = 0.028) and exercise duration (409 ± 98 versus 427 ± 101 s; p = 0.014). A robust correlation (r = 0.656; p = 0.008) between baseline FEV1 (% predicted) and the change in exercise capacity following 4 weeks of treatment was identified. CONCLUSIONS: This proof-of-concept clinical trial demonstrates that sildenafil treatment can improve exercise capacity in patients with CF and that pulmonary function may play an important role in the effectiveness of treatment. Future investigations of sildenafil treatment in patients with CF are certainly warranted.

Endothelial Dysfunction in Cystic Fibrosis: Role of Oxidative Stress.

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.

Ethnic Differences in Nighttime Melatonin and Nighttime Blood Pressure: A Study in European Americans and African Americans.

BACKGROUND: Ethnic differences in nighttime blood pressure (BP) have long been documented with African Americans (AAs) having higher BP than European Americans (EAs). At present, lower nighttime melatonin, a key regulator of circadian rhythms, has been associated with higher nighttime BP levels in EAs. This study sought to test the hypothesis that AAs have lower nighttime melatonin secretion compared with EAs. We also determined if this ethnic difference in melatonin could partially explain the ethnic difference in nighttime BP. METHODS: A total of 150 young adults (71 AA; 46% females; mean age: 27.7 years) enrolled in the Georgia Stress and Heart study provided an overnight urine sample for the measurement of 6-sulfatoxymelatonin, a major metabolite of melatonin. Urine melatonin excretion (UME) was calculated as the ratio between 6-sulfatoxymelatonin concentration and creatinine concentration. Twenty-four-hour ambulatory BP was assessed and nighttime systolic BP (SBP) was used as a major index of BP regulation. RESULTS: After adjustment of age, sex, body mass index, and smoking, AAs had significantly lower UME (P = 0.002) and higher nighttime SBP than EAs (P = 0.036). Lower UME was significantly associated with higher nighttime SBP and this relationship did not depend on ethnicity. The ethnicity difference in nighttime SBP was significantly attenuated after adding UME into the model (P = 0.163). CONCLUSION: This study is the first to document the ethnic difference in nighttime melatonin excretion, demonstrating that AAs have lower melatonin secretion compared with EAs. Furthermore, the ethnic difference in nighttime melatonin can partially account for the established ethnic difference in nighttime SBP.

Assessment of endothelial function is reproducible in patients with cystic fibrosis.

BACKGROUND: New treatments have improved life-expectancy in patients with cystic fibrosis (CF); however, cardiovascular health remains an area of concern in this population. Flow-mediated dilation (FMD), a non-invasive assessment of vascular endothelial function that predicts future cardiovascular disease and events, is attenuated in patients with CF compared to controls. The reproducibility of FMD in CF; however, has yet to be evaluated. Thus, this study sought to examine the within-day, between-day, and between-month reproducibility of FMD in patients with CF. METHODS: Pulmonary function, baseline diameter (cm), peak diameter (cm), and FMD(%) were assessed 5 times (sessions A-E) over four visits in 13 patients with CF (six males, seven females, age range: 13-43 years old; mean forced expiratory volume in 1 s = 71% predicted). Sessions A and B (within-day), C (between-day), and D and E (between-month) were separated by 3 h, at least 10 days, and ~3 months, respectively. Reproducibility was assessed by: (1) paired t-tests, (2) coefficients of variation (CV), (3) CV prime, (4) Pearson's correlation (r), (5) intra-class correlation coefficient, and (6) Bland-Altman plots. Five acceptable parameters were required to determine reproducibility. RESULTS: Pulmonary function was stable throughout all visits. FMD(%) and baseline diameter (cm) satisfied all six reproducibility criteria for within-day, while peak diameter (cm) met five of six criteria. All six reproducibility criteria were met for all between-day and between-month assessments. CONCLUSION: The present study provides evidence that endothelial function assessed by FMD is reproducible in patients with CF not only within-day, but also between-day and between-month.

Tetrahydrobiopterin improves endothelial function in patients with cystic fibrosis.

Cystic fibrosis (CF) is a genetic disorder associated with vascular endothelial dysfunction. Nitric oxide (NO) plays a major role in maintaining vascular function, and tetrahydrobiopterin (BH4) is a critical determinant of NO bioavailability. Thus the purpose of this study was to investigate the effects of oral administration of BH4 on endothelial function in patients with CF. Twenty-nine patients with CF (18 ± 8 yr old) and 29 healthy matched controls were recruited. Patients with CF participated in a randomized trial where they received a 5 mg/kg dose of oral BH4 (BH4-5; n = 17) or a 20 mg/kg dose of oral BH4 (BH4-20; n = 12). On a separate visit, a subset of patients from each group was retested following a placebo (PLC; n = 9). Brachial artery flow-mediated dilation (FMD) was used to evaluate vascular endothelial function, and a plasma sample was obtained before and 3 h after treatment. Cultured endothelial cells were treated with plasma to assess NO bioavailability. Baseline FMD was lower in patients compared with controls (5.7 ± 3.4 vs. 8.4 ± 3.5%, respectively, P = 0.005). No change in FMD was observed following PLC or BH4-5 (∆FMD: -0.8 ± 1.9% and -0.5 ± 2.5%; P = 0.273 and 0.132, respectively). Treatment with BH4-20, however, resulted in significant improvements in FMD (∆FMD: 1.1 ± 1.4%) compared with BH4-5 ( P = 0.023) and PLC ( P = 0.017). Moreover, BH4-20 significantly decreased endothelial cell superoxide production and increased NO production. These data suggest that a single oral dose of BH4 at 20 mg/kg improves vascular endothelial function in patients with CF, likely via increased endothelial NO synthase coupling. These findings support the hypothesis that loss of BH4 bioactivity contributes, in part, to endothelial dysfunction in patients with CF. NEW & NOTEWORTHY For the first time, the present study documents that a single dose of oral BH4 can improve vascular endothelial function in patients with cystic fibrosis (CF), and our in vitro data suggest this is via decreasing uncoupled nitric oxide. These data provide insight into the important role of BH4 bioactivity in vascular dysfunction and provide the foundation for further investigation into the chronic effects of BH4 treatment in patients with CF.