APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO): Design and Rationale.

INTRODUCTION: Much of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes. METHODS: APOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys. RESULTS: The United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses. CONCLUSION: This article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

Ensuring respect for persons in COMPASS: a cluster randomised pragmatic clinical trial.

Cluster randomised clinical trials present unique challenges in meeting ethical obligations to those who are treated at a randomised site. Obtaining informed consent for research within the context of clinical care is one such challenge. In order to solve this problem it is important that an informed consent process be effective and efficient, and that it does not impede the research or the healthcare. The innovative approach to informed consent employed in the COMPASS study demonstrates the feasibility of upholding ethical standards without imposing undue burden on clinical workflows, staff members or patients who may participate in the research by virtue of their presence in a cluster randomised facility. The COMPASS study included 40 randomised sites and compared the effectiveness of a postacute stroke intervention with standard care. Each site provided either the comprehensive postacute stroke intervention or standard care according to the randomisation assignment. Working together, the study team, institutional review board and members of the community designed an ethically appropriate and operationally reasonable consent process which was carried out successfully at all randomised sites. This achievement is noteworthy because it demonstrates how to effectively conduct appropriate informed consent in cluster randomised trials, and because it provides a model that can easily be adapted for other pragmatic studies. With this innovative approach to informed consent, patients have access to the information they need about research occurring where they are seeking care, and medical researchers can conduct their studies without ethical concerns or unreasonable logistical impediments. TRIAL REGISTRATION NUMBER: NCT02588664, recruiting. This article covers the development of consent process that is currentlty being employed in the study.

Carotid arterial stiffness and its relationship to exercise intolerance in older patients with heart failure and preserved ejection fraction.

Heart failure with a preserved ejection fraction (HFpEF) is the dominant form of heart failure in the older population. The primary chronic symptom in HFpEF is severe exercise intolerance; however, its pathophysiology and therapy are not well understood. We tested the hypothesis that older patients with HFpEF have increased arterial stiffness beyond what occurs with normal aging and that this contributes to their severe exercise intolerance. Sixty-nine patients ≥60 years of age with HFpEF and 62 healthy volunteers (24 young healthy subjects ≤30 years and 38 older healthy subjects ≥60 years old) were examined. Carotid arterial stiffness was assessed using high-resolution ultrasound, and peak exercise oxygen consumption was measured using expired gas analysis. Peak exercise oxygen consumption was severely reduced in the HFpEF patients compared with older healthy subjects (14.1±2.9 versus 19.7±3.7 mL/kg per minute; P<0.001) and in both was reduced compared with young healthy subjects (32.0±7.2 mL/kg per minute; both P<0.001). In HFpEF compared with older healthy subjects, carotid arterial distensibility was reduced (0.97±0.45 versus 1.33±0.55×10(-3) mm Hg(-1); P=0.008) and Young's elastic modulus was increased (1320±884 versus 925±530 kPa; P<0.02). Carotid arterial distensibility was directly (0.28; P=0.02) and Young's elastic modulus was inversely (-0.32; P=0.01) related to peak exercise oxygen consumption. Carotid arterial distensibility is decreased in HFpEF beyond the changes attributed to normal aging and is related to peak exercise oxygen consumption. This supports the hypothesis that increased arterial stiffness contributes to exercise intolerance in HFpEF and is a potential therapeutic target.

Assessment of cardiovascular risk in collegiate football players and nonathletes.

UNLABELLED: Collegiate American football players may be at risk for cardiovascular disease. OBJECTIVE: to compare cardiovascular disease risk factors and cardiovascular structure and function parameters of football players, stratified by position, to a group of sedentary, nonathletes. PARTICIPANTS: twenty-six collegiate football players and 13 nonathletes participated in this study. METHODS: blood pressures, anthropometrics, and blood chemistries were obtained and analyzed using standardized procedures. Resting echocardiography was used to evaluate cardiac morphology and function. Brachial artery flow-mediated dilation was assessed using high-resolution ultrasonography. RESULTS: the prevalence of the metabolic syndrome was significantly higher amongst the linemen compared to the skill-position players (46% versus 0%, p < .05). Mildly abnormal wall thickness was noted in 20% of the football players. No significant differences in vascular function were observed between the groups. CONCLUSIONS: the increased prevalence of the metabolic syndrome and its components in the collegiate linemen may increase cardiovascular disease risk.

A randomized double-blind trial of enalapril in older patients with heart failure and preserved ejection fraction: effects on exercise tolerance and arterial distensibility.

BACKGROUND: Exercise intolerance is the primary symptom in older patients with heart failure and preserved ejection fraction (HFPEF); however, little is known regarding its mechanisms and therapy. METHODS AND RESULTS: Seventy-one stable elderly (70+/-1 years) patients (80% women) with compensated HFPEF and controlled blood pressure were randomized into a 12-month follow-up double-blind trial of enalapril 20 mg/d versus placebo. Assessments were peak exercise oxygen consumption; 6-minute walk test; Minnesota Living with HF Questionnaire; MRI; Doppler echocardiography; and vascular ultrasound. Compliance by pill count was excellent (94%). Twenty-five patients in the enalapril group versus 34 in the placebo group completed the 12-month follow-up. During follow-up, there was no difference in the primary outcome of peak exercise oxygen consumption (enalapril, 14.5+/-3.2 mL/kg/min; placebo, 14.3+/-3.4 mL/kg/min; P=0.99), or in 6-minute walk distance, aortic distensibility (the primary mechanistic outcome), left ventricle mass, or neurohormonal profile. The effect size of enalapril on peak exercise oxygen consumption was small (0.7%; 95% CI, 4.2% to 5.6%). There was a trend toward improved Minnesota Living with HF Questionnaire total score (P=0.07), a modest reduction in systolic blood pressure at peak exercise (P=0.02), and a marginal improvement in carotid arterial distensibility (P=0.04). CONCLUSIONS: In stable, older patients with compensated HFPEF and controlled blood pressure, 12 months of enalapril did not improve exercise capacity or aortic distensibility. These data, combined with those from large clinical event trials, suggest that angiotensin inhibition does not substantially improve key long-term clinical outcomes in this group of patients. This finding contrasts sharply with observations in HF with reduced EF and highlights our incomplete understanding of this important and common disorder.

Endurance exercise training in older patients with heart failure: results from a randomized, controlled, single-blind trial.

OBJECTIVES: To test the hypothesis that exercise training (ET) improves exercise capacity and other clinical outcomes in older persons with heart failure with reduced ejection fraction (HfrEF). DESIGN: Randomized, controlled, single-blind trial. SETTING: Outpatient cardiac rehabilitation program. PARTICIPANTS: Fifty-nine patients aged 60 and older with HFrEF recruited from hospital records and referring physicians were randomly assigned to a 16-week supervised ET program (n=30) or an attention-control, nonexercise, usual care control group (n=29). INTERVENTION: Sixteen-week supervised ET program of endurance exercise (walking and stationary cycling) three times per week for 30 to 40 minutes at moderate intensity regulated according to heart rate and perceived exertion. MEASUREMENTS: Individuals blinded to group assignment assessed four domains pivotal to HFrEF pathophysiology: exercise performance, left ventricular (LV) function, neuroendocrine activation, and health-related quality of life (QOL). RESULTS: At follow-up, the ET group had significantly greater exercise time and workload than the control group, but there were no significant differences between the groups for the primary outcomes: peak exercise oxygen consumption (VO(2) peak), ventilatory anaerobic threshold (VAT), 6-minute walk distance, QOL, LV volumes, EF, or diastolic filling. Other than serum aldosterone, there were no significant differences after ET in other neuroendocrine measurements. Despite a lack of a group "training" effect, a subset (26%) of individuals increased VO(2) peak by 10% or more and improved other clinical variables as well. CONCLUSION: In older patients with HFrEF, ET failed to produce consistent benefits in any of the four pivotal domains of HF that were examined, although the heterogeneous response of older patients with HFrEF to ET requires further investigation to better determine which patients with HFrEF will respond favorably to ET.

Validity and reliability of the North Carolina 6-minute cycle test.

PURPOSE: The purposes of this investigation were to determine (1) if the 6-minute cycle (6MC) test is a valid and reliable measure of physical performance in cardiac patients and (2) if physiologic responses to the 6-minute walk (6MW) and 6MC tests differ in men and women. METHODS: Subjects were 101 phase II cardiac rehabilitation patients aged 40 to 79 years. Each subject performed a maximal graded exercise test (MGXT), a 6MW test, and three 6MC tests on separate days. RESULTS: Pearson product moment correlation r values ranged from 0.78 to 0.89 (P = .001) when the three 6MC tests were compared with one another, indicating good test/retest reliability. The 6MC tests were all significantly and positively correlated to 6MW distance (P < .01), with r values ranging from 0.55 to 0.59. Each 6MC test was also correlated with maximal graded exercise test total time (P < .01), with r values ranging from 0.51 to 0.63, and with estimated maximal metabolic equivalents (P < .01), with r values ranging from 0.44 to 0.60. Although heart rate, systolic blood pressure, rate-pressure product, and rating of perceived exertion values for men were greater during the 6MC test than during the 6MW test (P < .001), no differences were seen in these parameters between tests in women (P = .166 to.260), with the exception of a greater exercise rating of perceived exertion seen during the 6MC test(P = .009). CONCLUSION: The North Carolina 6MC test seems to provide a valid and reliable measure of functional abilities in phase II cardiac rehabilitation participants. Men generally present with greater heart rate, systolic blood pressure, and rate-pressure product values during this test than do the women when compared with a standard 6MW test.

The relationship of a 6-min walk to VO(2 peak) and VT in older heart failure patients.

PURPOSE: To evaluate the relationship between a 6-min walk test (6-MWT) to peak oxygen consumption (VO(2 peak)) and ventilatory threshold (VT) in older heart failure (HF) patients, to validate the equation by Cahalin et al., and to develop a new equation to improve the prediction of VO(2 peak) from 6-MWT. METHODS: Older patients (>65 yr) with systolic or diastolic HF (N=97) performed an exercise test to peak exertion on an upright bicycle ergometer using an incremental protocol. Gas exchange measures were collected along with continuous electrocardiograph monitoring. 6-MWT was performed on an indoor track at a self-selected pace under standardized conditions. The formula of Cahalin et al. was used to predict VO(2 peak) from 6-MWT, and a new equation was generated from the measured VO(2 peak)-6-MWT relationship from this investigation. RESULTS: The correlation between 6-MWT and measured VO(2 peak) was moderate (r=0.54) with a standard error of estimate (SEE) of 2.48 mL.kg.min. The correlation between 6-MWT and VT was weak (r=0.23), whereas the correlation between VO(2 peak) and VT was strong (r=0.74). Correlations between the measured and predicted VO(2 peak) values were moderate (r=0.54) for both prediction equations, and the SEE was 2.83 versus 1.34 mL.kg.min for the Cahalin et al. and the new equation, respectively. CONCLUSION: These results indicate that 6-MWT does not accurately predict functional capacity in older HF patients, and questions the validity of using this test to determine functional capacity in older HF patients. Predicting VO(2 peak) from equations using 6-MWT also results in substantial variability and, consequently, should not be used in older HF patients where an accurate determination of functional capacity is essential.

Increasing daily walking improves glucose tolerance in overweight women.

BACKGROUND: Physical activity (PA) has been shown to benefit glucose tolerance. Walking is a convenient low-impact mode of PA and is reported to be the most commonly performed activity for those with diabetes. The purpose of this study was to determine whether a recommendation to accumulate 10,000 steps/day for 8 weeks was effective at improving glucose tolerance in overweight, inactive women. METHODS: Eighteen women (53.3 +/- 7.0 years old, 35.0 +/- 5.1 kg/m(2)) with a family history of type 2 diabetes completed a 4-week control period followed by an 8-week walking program with no changes in diet. The walking program provided a goal of accumulating at least 10,000 steps/day, monitored by a pedometer. RESULTS: During the control period, participants walked 4972 steps/day. During the intervention period, the participants increased their accumulated steps/day by 85% to 9213, which resulted in beneficial changes in 2-h postload glucose levels (P < 0.001), AUC(glucose) (P = 0.025), systolic blood pressure (P < 0.001), and diastolic blood pressure (P = 0.002). There were no changes in body mass, body fat percentage, and waist circumference during the walking intervention. CONCLUSIONS: The 10,000 steps/day recommendation resulted in improved glucose tolerance and a reduction in systolic and diastolic blood pressure in overweight women at risk for type 2 diabetes. This demonstrates that activity can be accumulated throughout the day and does not have to result in weight loss to benefit this population.