Lyndia C. Brumback

Arterial wave reflections and incident cardiovascular events and heart failure: MESA (Multiethnic Study of Atherosclerosis)

OBJECTIVES This study sought to assess the relationship between central pressure profiles and cardiovascular events (CVEs) in a large community-based sample. BACKGROUND Experimental and physiologic data mechanistically implicate wave reflections in the pathogenesis of left ventricular failure and cardiovascular disease, but their association with these outcomes in the general population is unclear. METHODS Aortic pressure waveforms were derived from a generalized transfer function applied to the radial pressure waveform recorded noninvasively from 5,960 participants in the Multiethnic Study of Atherosclerosis. The central pressure waveform was separated into forward and reflected waves using a physiologic flow waveform. Reflection magnitude (RM = [Reflected/Forward wave amplitude] × 100), augmentation index ([Second/First systolic peak] × 100) and pulse pressure amplification ([Radial/aortic pulse pressure] × 100) were assessed as predictors of CVEs and congestive heart failure (CHF) during a median follow-up of 7.61 years. RESULTS After adjustment for established risk factors, aortic AIx independently predicted hard CVEs (hazard ratio [HR] per 10% increase: 1.08; 95% confidence interval [CI]: 1.01 to 1.14; p = 0.016), whereas PPA independently predicted all CVEs (HR per 10% increase: 0.82; 95% CI: 0.70 to 0.96; p = 0.012). RM was independently predictive of all CVEs (HR per 10% increase: 1.34; 95% CI: 1.08 to 1.67; p = 0.009) and hard CVEs (HR per 10% increase: 1.46; 95% CI: 1.12 to 1.90; p = 0.006) and was strongly predictive of new-onset CHF (HR per 10% increase: 2.69; 95% CI: 1.79 to 4.04; p < 0.0001), comparing favorably to other risk factors for CHF as per various measures of model performance, reclassification, and discrimination. In a fully adjusted model, compared to nonhypertensive subjects with low RM, the HRs (95% CI) for hypertensive subjects with low RM, nonhypertensive subjects with high RM, and hypertensive subjects with high RM were 1.81 (0.85 to 3.86), 2.16 (1.07 to 5.01), and 3.98 (1.96 to 8.05), respectively. CONCLUSIONS Arterial wave reflections represent a novel strong risk factor for CHF in the general population.

Inhaled hypertonic saline in infants and children younger than 6 years with cystic fibrosis: the ISIS randomized controlled trial.

CONTEXT Inhaled hypertonic saline is recommended as therapy for patients 6 years or older with cystic fibrosis (CF), but its efficacy has never been evaluated in patients younger than 6 years with CF. OBJECTIVE To determine if hypertonic saline reduces the rate of protocol-defined pulmonary exacerbations in patients younger than 6 years with CF. DESIGN, SETTING, AND PARTICIPANTS The Infant Study of Inhaled Saline in Cystic Fibrosis (ISIS), a multicenter, randomized, double-blind, placebo-controlled trial conducted from April 2009 to October 2011 at 30 CF care centers in the United States and Canada. Participants were aged 4 to 60 months and had an established diagnosis of CF. A total of 344 patients were assessed for eligibility; 321 participants were randomized; 29 (9%) withdrew prematurely. INTERVENTION The active treatment group (n = 158) received 7% hypertonic saline and the control group (n = 163) received 0.9% isotonic saline, nebulized twice daily for 48 weeks. Both groups received albuterol or levalbuterol prior to each study drug dose. MAIN OUTCOME MEASURES Rate during the 48-week treatment period of protocol-defined pulmonary exacerbations treated with oral, inhaled, or intravenous antibiotics. RESULTS The mean pulmonary exacerbation rate (events per person-year) was 2.3 (95% CI, 2.0-2.5) in the active treatment group and 2.3 (95% CI, 2.1-2.6) in the control group; the adjusted rate ratio was 0.98 (95% CI, 0.84-1.15). Among participants with pulmonary exacerbations, the mean number of total antibiotic treatment days for a pulmonary exacerbation was 60 (95% CI, 49-70) in the active treatment group and 52 (95% CI, 43-61) in the control group. There was no significant difference in secondary end points including height, weight, respiratory rate, oxygen saturation, cough, or respiratory symptom scores. Infant pulmonary function testing performed as an exploratory outcome in a subgroup (n = 73, with acceptable measurements at 2 visits in 45 participants) did not demonstrate significant differences between groups except for the mean change in forced expiratory volume in 0.5 seconds, which was 38 mL (95% CI, 1-76) greater in the active treatment group. Adherence determined by returned study drug ampoules was at least 75% in each group. Adverse event profiles were also similar, with the most common adverse event of moderate or severe severity in each group being cough (39% of active treatment group, 38% of control group). CONCLUSION Among infants and children younger than 6 years with cystic fibrosis, the use of inhaled hypertonic saline compared with isotonic saline did not reduce the rate of pulmonary exacerbations over the course of 48 weeks of treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00709280.

Multicenter Evaluation of Infant Lung Function Tests as Cystic Fibrosis Clinical Trial Endpoints

RATIONALE The conducting of clinical trials in infants with cystic fibrosis (CF) has been hindered by lack of sensitive outcome measures. OBJECTIVES To evaluate safety, feasibility, and ability to detect abnormalities in lung function of serial pulmonary function tests (PFTs) in infants with CF. METHODS Multicenter observational study using a commercial device, rigorous training, ongoing quality control, and over-reading of data by an independent panel. Raised volume rapid thoracoabdominal compression technique and plethysmography were performed at enrollment and at 6 and 12 months, with an additional 1-month reproducibility visit. MEASUREMENTS AND MAIN RESULTS A total of 342 procedures were performed in 100 infants with CF at 10 centers. FRC measurements were acceptable at a higher proportion of study visits (89%) than raised volume (72%) or fractional lung volume (68%) measurements. Average Z scores for many parameters differed significantly from historical control values. Mean (95% confidence interval) Z scores were: -0.52 (-0.78 to -0.25) for forced expiratory flow at 75% (FEF₇₅) for FVC; 1.92 (1.39-2.45) for FRC; 1.22 (0.68-1.76) for residual volume; 0.87 (0.60-1.13) for FRC/total lung capacity; and 0.66 (0.27-1.06) for residual volume/total lung capacity. For future multicenter clinical trials using infant PFTs as primary endpoints, minimum detectable treatment effects are presented for several sample sizes. CONCLUSIONS In this 10-center study, key PFT measures were significantly different in infants with CF than in historical control subjects. However, infant PFTs do not yet appear ready as primary efficacy endpoints for multicenter clinical trials, particularly at inexperienced sites, based on acceptability rates, variability, and potentially large sample sizes required to detect reasonable treatment effects.

Association of Small Artery Elasticity With Incident Cardiovascular Disease in Older Adults

Functional biomarkers like large artery elasticity (LAE) and small artery elasticity (SAE) may predict cardiovascular disease (CVD) events beyond blood pressure. The authors examined the prognostic value of LAE and SAE for clinical CVD events among 6,235 Multi-Ethnic Study of Atherosclerosis participants who were initially aged 45-84 years and without symptomatic CVD. LAE and SAE were derived from diastolic pulse contour analysis. During a median 5.8 years of follow-up between 2000 and 2008, 454 adjudicated CVD events occurred, including 256 cases of coronary heart disease (CHD), 93 strokes, and 126 heart failures (multiple diagnoses were possible). After adjustment for age, race/ethnicity, sex, clinic, height, heart rate, body mass index, systolic and diastolic blood pressure, use of antihypertensive and cholesterol-lowering medications, smoking, total cholesterol, high density lipoprotein cholesterol, triglycerides, diabetes, and high-sensitivity C-reactive protein, the hazard ratio for any CVD per standard-deviation increase in SAE was 0.71 (95% confidence interval: 0.61, 0.83; P < 0.0001). The lowest (stiffest) SAE quartile had a hazard ratio of 2.28 (95% confidence interval: 1.55, 3.36) versus the highest (most elastic) quartile. The net reclassification index, conditional on base risk, was 0.11. SAE was significantly associated with future CHD, stroke, and heart failure. After adjustment, LAE was not significantly related to CVD. In asymptomatic participants free of overt CVD, lower SAE added prognostic information for CVD, CHD, stroke, and heart failure events.

Left ventricular structure and function in patients with rheumatoid arthritis, as assessed by cardiac magnetic resonance imaging

OBJECTIVE Heart failure is a major contributor to cardiovascular morbidity and mortality in patients with rheumatoid arthritis (RA), but little is known about myocardial structure and function in this population. This study was undertaken to assess the factors associated with progression to heart failure in patients with RA. METHODS With the use of cardiac magnetic resonance imaging, measures of myocardial structure and function were assessed in men and women with RA enrolled in the Evaluation of Subclinical Cardiovascular Disease and Predictors of Events in Rheumatoid Arthritis study, a cohort study of subclinical cardiovascular disease in patients with RA, in comparison with non-RA control subjects from a cohort enrolled in the Baltimore Multi-Ethnic Study of Atherosclerosis. RESULTS Measures of myocardial structure and function were compared between 75 patients with RA and 225 frequency-matched controls. After adjustment for confounders, the mean left ventricular mass was found to be 26 gm lower in patients with RA compared with controls (P < 0.001), an 18% difference. In addition, the mean left ventricular ejection fraction, cardiac output, and stroke volume were modestly lower in the RA group compared with controls. The mean left ventricular end systolic and end diastolic volumes did not differ between the groups. In patients with RA, higher levels of anti-cyclic citrullinated peptide (anti-CCP) antibodies and current use of biologic agents, but not other measures of disease activity or severity, were associated with significantly lower adjusted mean values for the left ventricular mass, end diastolic volume, and stroke volume, but not with ejection fraction. The combined associations of anti-CCP antibody level and biologic agent use with myocardial measures were additive, without evidence of interaction. CONCLUSION These findings suggest that the progression to heart failure in RA may occur through reduced myocardial mass rather than hypertrophy. Both modifiable and nonmodifiable factors may contribute to lower levels of left ventricular mass and volume.

Reflection Magnitude as a Predictor of Mortality The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}

Lung function distinguishes preschool children with CF from healthy controls in a multi-center setting.

Conducting clinical trials in cystic fibrosis (CF) preschoolers has been limited by lack of sensitive lung function measures performed across sites.

Inhaled hypertonic saline in infants and toddlers with cystic fibrosis: short-term tolerability, adherence, and safety†‡

Inhaled hypertonic saline (HS) is an attractive agent for chronic maintenance therapy in infants and toddlers with cystic fibrosis (CF) because it improves defective mucociliary clearance. Prior to undertaking a clinical trial of HS efficacy in young children with CF, tolerability, adherence, and safety must be established.

Methadone Medical Maintenance in Primary Care: An Implementation Evaluation

AbstractBACKGROUND: Methadone is effective treatment for opioid addiction, but regulations restrict its use. Methadone medical maintenance treats stabilized methadone patients in a medical setting, but only experimental programs have been studied. OBJECTIVE: To evaluate the implementation of the first methadone medical maintenance program established outside a reseach setting. DESIGN: One-year program evaluation. SETTING: A public hospital and a community opioid treatment program. PARTICIPANTS: Methadone patients with > 1 year of clinical stability. Eleven generalist physicians and 4 hospital pharmacists. INTERVENTIONS: Regulatory exemptions were requested. Physicians and pharmacists were trained. Patients were transferred to the medical setting and permitted 1-month supplies of methadone. MEASUREMENTS: Patient eligibility and willingness to enroll, treatment retention, urine toxicology results, change in addiction severity and functional status, medical services provided, patient and physician satisfaction, and physician attitudes toward methadone maintenance. RESULTS: Regulatory exemptions were obtained after a 14-month process, and the program was cited in federal policy as acceptable for widespread implementation. Forty-nine of 684 patients (7.2%) met stability criteria, and 30 enrolled. Twenty-eight were retained for 1 year, and 2 transferred to other programs. Two patients had opioid-positive urine tests and were managed in the medical setting. Previously unmet medical needs were addressed, and the Addiction Severity Index (ASI) medical composite score improved over time (P=.02). Patient and physicia satisfaction were high, and physician attitudes toward methadone maintenance treatment became more positive (P=.007). CONCLUSIONS: Methadone medical maintenance is complex to arrange but feasible outside a research setting, and can result in good clinical outcomes.

Reflection Magnitude as a Predictor of MortalityNovelty and Significance: The Multi-Ethnic Study of Atherosclerosis

Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P=0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P=0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P=0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P=0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P=0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis.Arterial wave reflections have been associated with mortality in an ethnically homogenous Asian population. It is unknown whether this association is present in a multiethnic population or whether it is independent of subclinical atherosclerosis. We hypothesized that reflection magnitude (defined as the ratio of the amplitude of the backward wave [Pb] to that of the forward wave [Pf]) is associated with all-cause mortality in a large multiethnic adult community-based sample. We studied 5984 participants enrolled in the Multi-Ethnic Study of Atherosclerosis who had analyzable arterial tonometry waveforms. During 9.8±1.7 years of follow-up, 617 deaths occurred, of which 134 (22%) were adjudicated cardiovascular deaths. In Cox proportional hazards models, each 10% increase in reflection magnitude was associated with a 31% increased risk for all-cause mortality (hazard ratio [HR]=1.31; 95% confidence interval [CI]=1.11–1.55; P =0.001). This relationship persisted after adjustment for various confounders and for markers of subclinical atherosclerosis (HR=1.23; 95% CI=1.01–1.51; P =0.04), including the coronary calcium score, ankle–brachial index, common carotid intima–media thickness, and ascending thoracic aortic Agatston score. Pb was independently associated with all-cause mortality in a similarly adjusted model (HR per 10 mm Hg increase in Pb=2.18; 95% CI=1.21–3.92; P =0.009). Reflection magnitude (HR=1.71; 95% CI=1.06–2.77; P =0.03) and Pb (HR=5.02; 95% CI=1.29–19.42; P =0.02) were mainly associated with cardiovascular mortality. In conclusion, reflection magnitude is independently associated with all-cause mortality in a multiethnic population initially free of clinically evident cardiovascular disease. This relationship persists after adjustment for a comprehensive set of markers of subclinical atherosclerosis. # Novelty and Significance {#article-title-33}