Results of the FUEL Trial.

BACKGROUND: The Fontan operation creates a total cavopulmonary connection, a circulation in which the importance of pulmonary vascular resistance is magnified. Over time, this circulation leads to deterioration of cardiovascular efficiency associated with a decline in exercise performance. Rigorous clinical trials aimed at improving physiology and guiding pharmacotherapy are lacking. METHODS: The FUEL trial (Fontan Udenafil Exercise Longitudinal) was a phase III clinical trial conducted at 30 centers. Participants were randomly assigned udenafil, 87.5 mg twice daily, or placebo in a 1:1 ratio. The primary outcome was the between-group difference in change in oxygen consumption at peak exercise. Secondary outcomes included between-group differences in changes in submaximal exercise at the ventilatory anaerobic threshold, the myocardial performance index, the natural log of the reactive hyperemia index, and serum brain-type natriuretic peptide. RESULTS: Between 2017 and 2019, 30 clinical sites in North America and the Republic of Korea randomly assigned 400 participants with Fontan physiology. The mean age at randomization was 15.5±2 years; 60% of participants were male, and 81% were white. All 400 participants were included in the primary analysis with imputation of the 26-week end point for 21 participants with missing data (11 randomly assigned to udenafil and 10 to placebo). Among randomly assigned participants, peak oxygen consumption increased by 44±245 mL/min (2.8%) in the udenafil group and declined by 3.7±228 mL/min (-0.2%) in the placebo group (P=0.071). Analysis at ventilatory anaerobic threshold demonstrated improvements in the udenafil group versus the placebo group in oxygen consumption (+33±185 [3.2%] versus -9±193 [-0.9%] mL/min, P=0.012), ventilatory equivalents of carbon dioxide (-0.8 versus -0.06, P=0.014), and work rate (+3.8 versus +0.34 W, P=0.021). There was no difference in change of myocardial performance index, the natural log of the reactive hyperemia index, or serum brain-type natriuretic peptide level. CONCLUSIONS: In the FUEL trial, treatment with udenafil (87.5 mg twice daily) was not associated with an improvement in oxygen consumption at peak exercise but was associated with improvements in multiple measures of exercise performance at the ventilatory anaerobic threshold. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02741115.

Design and rationale of the Fontan Udenafil Exercise Longitudinal (FUEL) trial.

The Fontan operation creates a circulation characterized by elevated central venous pressure and low cardiac output. Over time, these characteristics result in a predictable and persistent decline in exercise performance that is associated with an increase in morbidity and mortality. A medical therapy that targets the abnormalities of the Fontan circulation might, therefore, be associated with improved outcomes. Udenafil, a phosphodiesterase type 5 inhibitor, has undergone phase I/II testing in adolescents who have had the Fontan operation and has been shown to be safe and well tolerated in the short term. However, there are no data regarding the long-term efficacy of udenafil in this population. The Fontan Udenafil Exercise Longitudinal (FUEL) Trial is a randomized, double-blind, placebo-controlled phase III clinical trial being conducted by the Pediatric Heart Network in collaboration with Mezzion Pharma Co, Ltd. This trial is designed to test the hypothesis that treatment with udenafil will lead to an improvement in exercise capacity in adolescents who have undergone the Fontan operation. A safety extension trial, the FUEL Open-Label Extension Trial (FUEL OLE), offers the opportunity for all FUEL subjects to obtain open-label udenafil for an additional 12 months following completion of FUEL, and evaluates the long-term safety and tolerability of this medication. This manuscript describes the rationale and study design for FUEL and FUEL OLE. Together, these trials provide an opportunity to better understand the role of medical management in the care of those who have undergone the Fontan operation.

Atenolol versus losartan in children and young adults with Marfan's syndrome.

BACKGROUND: Aortic-root dissection is the leading cause of death in Marfan's syndrome. Studies suggest that with regard to slowing aortic-root enlargement, losartan may be more effective than beta-blockers, the current standard therapy in most centers. METHODS: We conducted a randomized trial comparing losartan with atenolol in children and young adults with Marfan's syndrome. The primary outcome was the rate of aortic-root enlargement, expressed as the change in the maximum aortic-root-diameter z score indexed to body-surface area (hereafter, aortic-root z score) over a 3-year period. Secondary outcomes included the rate of change in the absolute diameter of the aortic root; the rate of change in aortic regurgitation; the time to aortic dissection, aortic-root surgery, or death; somatic growth; and the incidence of adverse events. RESULTS: From January 2007 through February 2011, a total of 21 clinical centers enrolled 608 participants, 6 months to 25 years of age (mean [±SD] age, 11.5±6.5 years in the atenolol group and 11.0±6.2 years in the losartan group), who had an aortic-root z score greater than 3.0. The baseline-adjusted rate of change in the mean (±SE) aortic-root z score did not differ significantly between the atenolol group and the losartan group (-0.139±0.013 and -0.107±0.013 standard-deviation units per year, respectively; P=0.08). Both slopes were significantly less than zero, indicating a decrease in the aortic-root diameter relative to body-surface area with either treatment. The 3-year rates of aortic-root surgery, aortic dissection, death, and a composite of these events did not differ significantly between the two treatment groups. CONCLUSIONS: Among children and young adults with Marfan's syndrome who were randomly assigned to losartan or atenolol, we found no significant difference in the rate of aortic-root dilatation between the two treatment groups over a 3-year period. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00429364.).

Enalapril in infants with single ventricle: results of a multicenter randomized trial.

BACKGROUND: Angiotensin-converting enzyme inhibitor therapy improves clinical outcome and ventricular function in adults with heart failure. Infants with single-ventricle physiology have poor growth and are at risk for abnormalities in ventricular systolic and diastolic function. The ability of angiotensin-converting enzyme inhibitor therapy to preserve ventricular function and improve somatic growth and outcomes in these infants is unknown. METHODS AND RESULTS: The Pediatric Heart Network conducted a double-blind trial involving 230 infants with single-ventricle physiology randomized to receive enalapril (target dose 0.4 mg . kg(-1) . d(-1)) or placebo who were followed up until 14 months of age. The primary end point was weight-for-age z score at 14 months. The primary analysis was intention to treat. A total of 185 infants completed the study. There were 24 and 21 withdrawals or deaths in the enalapril and placebo groups, respectively (P=0.74). Weight-for-age z score was not different between the enalapril and placebo groups (mean+/-SE -0.62+/-0.13 versus -0.42+/-0.13, P=0.28). There were no significant group differences in height-for-age z score, Ross heart failure class, brain natriuretic peptide concentration, Bayley scores of infant development, or ventricular ejection fraction. The incidence of death or transplantation was 13% and did not differ between groups. Serious adverse events occurred in 88 patients in the enalapril group and 87 in the placebo group. CONCLUSIONS: Administration of enalapril to infants with single-ventricle physiology in the first year of life did not improve somatic growth, ventricular function, or heart failure severity. The results of this randomized trial do not support the routine use of enalapril in this population.

Effects of prolactin on TSC2-null Eker rat cells and in pulmonary lymphangioleiomyomatosis.

RATIONALE: Lymphangioleiomyomatosis, a cystic lung disease of women, is characterized by proliferation of smooth muscle-like lymphangioleiomyomatosis cells, which possess mutations in the tuberous sclerosis complex genes, TSC1/TSC2. Growth factors involved in lymphangioleiomyomatosis cell proliferation are unknown. Prolactin, an important reproductive hormone in women, is known to promote cell proliferation and survival in other tissues. OBJECTIVES: To determine the role of prolactin in signaling and proliferation in lymphangioleiomyomatosis. METHODS: Prolactin levels in the sera of patients with lymphangioleiomyomatosis were correlated with clinical status. Components of prolactin signal transduction pathways were assessed in lymphangioleiomyomatosis lesions from human lung explants by real-time reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. Prolactin effects on proliferation and signaling were quantified in tuberin-deficient and tuberin-expressing rat cells in vitro. MEASUREMENTS AND MAIN RESULTS: Higher prolactin levels in the sera of patients with lymphangioleiomyomatosis were associated with a faster rate of decline in FEV(1) and an increased history of pneumothorax (P < 0.01). Higher levels of prolactin and prolactin receptor mRNA and immunoreactivity were found in lymphangioleiomyomatosis lesions when compared with vascular smooth muscle cells in the same region of tissue. This was accompanied by evidence of activation of signal transducer and activator of transcription-1 (STAT1), STAT3, p44/42, and p38 mitogen-activated protein kinase. Tsc2(-/-) Eker rat embryonic fibroblasts expressed more prolactin receptor than did Tsc2(+/+) cells, and responded to prolactin with increased proliferation and activation of the same signaling pathways seen in vivo. CONCLUSIONS: Prolactin may be an important growth factor in the pathogenesis of lymphangioleiomyomatosis.

Progressive preclinical interstitial lung disease in rheumatoid arthritis.

BACKGROUND: Early detection and treatment for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA) may ameliorate disease progression. The objective of this study was to identify asymptomatic lung disease and potential therapeutic targets in patients having RA and preclinical ILD (RA-ILD). METHODS: Sixty-four adults with RA and 10 adults with RA and pulmonary fibrosis (RAPF) were referred to the National Institutes of Health, Bethesda, Maryland, and underwent high-resolution computed tomography (HRCT) and pulmonary physiology testing. Proteins capable of modulating fibrosis were quantified in alveolar fluid. RESULTS: Twenty-one of 64 patients (33%) having RA without dyspnea or cough had preclinical ILD identified by HRCT. Compared with patients without lung disease, patients with RA-ILD had statistically significantly longer histories of cigarette smoking (P< .001), increased frequencies of crackles (P= .02), higher alveolar-arterial oxygen gradients (P= .004), and higher HRCT scores (P< .001). The HRCT abnormalities progressed in 12 of 21 patients (57%) with RA-ILD. The alveolar concentrations of platelet-derived growth factor-AB and platelet-derived growth factor-BB were statistically significantly higher in patients having RA-ILD (mean [SE], 497.3 [78.6] and 1473 [264] pg/mL, respectively) than in patients having RA without ILD (mean [SE], 24.9 [42.4] and 792.7 [195.0] pg/mL, respectively) (P< .001 and P=.047, respectively). The concentrations of interferon gamma and transforming growth factor beta(2) were statistically significantly lower in patients having RAPF (mean [SE], 5.59 [1.11] pg/mL and 0.94 [0.46] ng/mL, respectively) than in patients having RA without ILD (mean [SE], 14.1 [1.9] pg/mL and 2.30 [0.39] ng/mL, respectively) (P=.001 and P=.006, respectively) or with preclinical ILD (mean [SD], 11.4 [2.6] pg/mL and 3.63 [0.66] ng/mL, respectively) (P=.04 and P=.007, respectively). Compared with patients having stable RA-ILD, patients having progressive RA-ILD had statistically significantly higher frequencies of treatment using methotrexate and higher alveolar concentrations of interferon gamma and transforming growth factor beta(1) (P=.046, P=.04, and P=.04, respectively). CONCLUSIONS: Asymptomatic preclinical ILD, which is detectable by HRCT, may be prevalent and progressive among patients having RA. Cigarette smoking seems to be associated with preclinical ILD in patients having RA, and treatment using methotrexate may be a risk factor for progression of preclinical ILD. Quantification of alveolar proteins indicates that potential pathogenic mechanisms seem to differ in patients having RA-ILD and symptomatic RAPF.

Functional state following the Fontan procedure.

BACKGROUND: Despite improvements in outcomes after completion of the Fontan circulation, long-term functional state varies. We sought to identify pre- and postoperative characteristics associated with overall function. METHODS AND RESULTS: We analyzed data from 476 survivors with the Fontan circulation enrolled in the Pediatric Heart Network Fontan Cross-sectional Study. Mean age at creation of the Fontan circulation was 3.4 plus or minus 2.1 years, with a range from 0.7 to 17.5 years, and time since completion was 8.7 plus or minus 3.4 years, the range being from 1.1 to 17.3 years. We calculated a functional score for the survivors by averaging the percentile ranks of ventricular ejection fraction, maximal consumption of oxygen, the physical summary score for the Child Health Questionnaire, and a function of brain natriuretic peptide. The mean calculated score was 49.5 plus or minus 17.3, with a range from 3 to 87. After adjustment for time since completion of the circulation, we found that a lower score, and hence worse functional state, was associated with: right ventricular morphology (p less than 0.001), higher ventricular end-diastolic pressure (p equals 0.003) and lower saturations of oxygen (p equals 0.047) prior to completion of the Fontan circulation, lower income for the caregiver (p equals 0.003), and, in subjects without a prior superior cavopulmonary anastomosis, arrhythmias after completion of the circulation (p equals 0.003). The model explained almost one-fifth (18%) of the variation in the calculated scores. The score was not associated with surgical centre, sex, age, weight, fenestration, or the period of stay in hospital after completion of the Fontan circuit. A validation model, using 71 subjects randomly excluded from initial analysis, weakly correlated (R equals 0.17, p equals 0.16) with the score calculated from the dataset. CONCLUSIONS: Right ventricular morphology, higher ventricular end-diastolic pressure and lower saturations of oxygen prior to completion of the Fontan circuit, lower income for the provider of care, and arrhythmias after creation of the circuit, are all associated with a worse functional state. Unmeasured factors also influence outcomes.

CA-125 in Disease Progression and Treatment of Lymphangioleiomyomatosis.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a destructive lung disease of women caused by proliferation of neoplastic-like LAM cells, with mutations in the TSC1/2 tumor suppressor genes. Based on case reports, levels of cancer antigen 125 (CA-125), an ovarian cancer biomarker, can be elevated in patients with LAM. We hypothesized that elevated serum CA-125 levels seen in some patients with LAM were due to LAM, not other malignancies, and might respond to sirolimus treatment. METHODS: Serum CA-125 levels were measured for 241 patients at each visit. Medical records were reviewed for co-morbidities, disease progression, and response to sirolimus treatment. CA-125 expression in LAM cells was determined by using immunohistochemical analysis. RESULTS: Almost 25% of patients with LAM had at least one elevated serum CA-125 measurement. Higher serum CA-125 levels correlated with lower FEV1, premenopausal status, and pleural effusion in a multivariate model (each P < .001). Serum CA-125 levels decreased following sirolimus treatment (P = .002). CA-125 and α-smooth muscle actin were co-expressed in LAM lung nodules. CONCLUSIONS: Higher serum CA-125 levels were associated with pleural effusions and reduced pulmonary function and were decreased with sirolimus therapy. LAM cells express CA-125. Some elevated serum CA-125 levels may reflect serosal membrane involvement.

Rationale and design of a randomized clinical trial of beta-blocker therapy (atenolol) versus angiotensin II receptor blocker therapy (losartan) in individuals with Marfan syndrome.

BACKGROUND: Cardiovascular disease, including aortic root dilation, dissection, and rupture, is the leading cause of mortality in patients with Marfan syndrome (MFS). The maximal aortic root diameter at the sinuses of Valsalva is considered the best predictor of adverse cardiovascular outcome. Although advances in therapy have improved life expectancy, affected individuals continue to suffer cardiovascular morbidity and mortality. Recent studies in an FBN1-targeted mouse model of MFS with aortic disease similar to that seen in humans showed that treatment with losartan normalized aortic root growth and aortic wall architecture. METHODS: The Pediatric Heart Network designed a randomized clinical trial to compare aortic root growth and other short-term cardiovascular outcomes in subjects with MFS receiving atenolol or losartan. Individuals 6 months to 25 years of age with a body surface area-adjusted aortic root z score >3.0 will be eligible for inclusion. The primary aim is to compare the effect of atenolol therapy with that of losartan therapy on the rate of aortic root growth over 3 years. Secondary end points include progression of aortic regurgitation; incidence of aortic dissection, aortic root surgery, and death; progression of mitral regurgitation; left ventricular size and function; echocardiographically derived measures of central aortic stiffness; skeletal and somatic growth; and incidence of adverse drug reactions. CONCLUSION: This randomized trial should make a substantial contribution to the management of individuals with MFS and expand our understanding of the mechanisms responsible for the aortic manifestations of this disorder.

Decline in lung function in patients with lymphangioleiomyomatosis treated with or without progesterone.

STUDY OBJECTIVE: Lymphangioleiomyomatosis (LAM), a disease affecting women and causing cystic lung lesions, and, in some instances, leading to respiratory failure and death, appears to be exacerbated by estrogens. Hence, hormonal therapy with progesterone is frequently employed; however, efficacy has not been demonstrated. Our aim was to determine whether progesterone administration slowed the decline in lung function in LAM. DESIGN: Retrospective study. SETTING: National Institutes of Health, Bethesda, MD. DESIGN AND SUBJECTS: The study population comprised 348 patients with LAM participating in a longitudinal research protocol. Declines in diffusion capacity of the lung for carbon monoxide (Dlco) and FEV(1) were measured in 275 patients observed for approximately 4 years. The declines in Dlco and FEV(1) of patients treated with progesterone, po (n = 67) or IM (n = 72), were compared with those of untreated patients (n = 136). MEASUREMENTS AND RESULTS: Overall yearly rates of decline in Dlco and FEV(1) were 2.4 +/- 0.4% predicted (0.69 +/- 0.07 mL/min/mm Hg) and 1.7 +/- 0.4% predicted (75 +/- 9 mL), respectively (mean +/- SEM). The most significant predictors of functional decline were initial lung function and age. After adjusting for initial FEV(1), age, and duration of disease, patients treated with IM progesterone tended to have lower rates of decline in FEV(1) than patients treated po (1.9 +/- 0.6% predicted vs 3.2 +/- 0.8% predicted, respectively; p = 0.081). However, there was no significant difference in rates of decline in FEV(1) between patients treated with IM progesterone and untreated patients (1.9 +/- 0.6% predicted vs 0.8 +/- 0.5% predicted, respectively; p = 0.520), and patients treated with po progesterone and untreated patients (3.2 +/- 0.8% predicted vs 0.8 +/- 0.5% predicted, respectively; p = 0.064). After adjusting for initial Dlco, rates of decline in Dlco were significantly higher in patients treated with po progesterone (3.6 +/- 0.7% predicted, p = 0.002) and IM progesterone (2.8 +/- 0.5% predicted, p = 0.022) than in untreated patients (1.6 +/- 0.6% predicted). CONCLUSIONS: Within the limitations of a retrospective study, our data suggest that progesterone therapy does not slow the decline in lung function in LAM.

Serum vascular endothelial growth factor-D levels in patients with lymphangioleiomyomatosis reflect lymphatic involvement.

BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare multisystem disorder affecting primarily women of child-bearing age, and characterized by cystic lung destruction, tumors of the kidney (angiomyolipomas [AMLs]), and involvement of the axial lymphatics (lymphangioleiomyomas). Patients with LAM experience loss of pulmonary function attributed to the proliferation of abnormal-appearing smooth muscle-like cells (LAM cells). It is possible to group the LAM population by the presence or absence of extrapulmonary involvement (eg, AMLs, lymphangioleiomyomas, chylous effusions). Serum vascular endothelial growth factor (VEGF)-D, a lymphangiogenic factor, is higher in LAM patients than in healthy volunteers and has been proposed as a tool in the differential diagnosis of cystic lung disease. We assessed serum VEGF-D concentrations in relationship to clinical phenotype in LAM patients. METHODS: Serum VEGF-D levels were quantified by enzyme immunosorbent assay for 111 patients with LAM and 40 healthy volunteers. VEGF-D levels in patients with pulmonary LAM, with or without extrapulmonary manifestations, were compared to those of healthy volunteers. RESULTS: Serum VEGF-D levels were greater in patients with LAM compared to those of healthy volunteers (p < 0.001). However, when patient samples were grouped based on the extent of lymphatic extrapulmonary involvement (eg, lymphangioleiomyomas and adenopathy), the statistical difference was maintained only for patients with LAM with lymphatic involvement (p < 0.001), not for those patients whose disease was restricted to the lung. Serum VEGF-D levels are a good biomarker for lymphatic involvement (area under the curve [AUC], 0.845; p < 0.0001), and a fair predictor for LAM disease (AUC, 0.751; p < 0.0001). Serum levels correlated to CT scan grade (p = 0.033). CONCLUSIONS: Serum VEGF-D concentration is a measure of lymphatic involvement in patients with LAM.

Surgical treatment of patients enrolled in the national registry of genetically triggered thoracic aortic conditions.

BACKGROUND: Genetic disorders are an important cause of thoracic aortic aneurysms (TAAs) in young patients. Despite advances in the treatment of genetically triggered TAAs, the optimal syndrome-specific treatment approach remains undefined. We used data from the National Institutes of Health-funded, multicenter National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions (GenTAC) to characterize the contemporary surgical treatment of patients with genetically triggered TAAs. METHODS: GenTAC's aim is to collect longitudinal clinical data and banked biospecimens from 2800 patients with genetically triggered TAAs. We analyzed data from the 606 patients (mean age, 37.5 years) enrolled in GenTAC to date whose clinical data were available. RESULTS: The patients' primary diagnoses included Marfan syndrome (35.8%), bicuspid aortic valve with aneurysm (29.2%), and familial TAAs and dissections (10.7%). Of these, 56.4% had undergone at least one operation; the most common indications were aneurysm (85.7%), valve dysfunction (65.8%), and dissection (25.4%). Surgical procedures included replacement of the aortic root (50.6%), ascending aorta (64.8%), aortic arch (27.9%), and descending or thoracoabdominal aorta (12.4%). Syndrome-specific differences in age, indications for operation, and procedure type were identified. CONCLUSIONS: Patients with genetically transmitted TAAs evaluated in tertiary care centers frequently undergo surgical repair. Aneurysm repairs most commonly involve the aortic root and ascending aorta; distal repairs are less common. Like TAAs themselves, complications of TAAs, including dissection and aortic valve dysfunction, are important indications for intervention. Future studies will focus on syndrome- and gene-specific phenotypes, biomarkers, treatments, and outcomes to improve the treatment of patients with TAAs.

Design and rationale of a randomized trial comparing the Blalock-Taussig and right ventricle-pulmonary artery shunts in the Norwood procedure.

OBJECTIVE: The initial palliative procedure for patients born with hypoplastic left heart syndrome and related single right ventricle anomalies, the Norwood procedure, remains among the highest risk procedures in congenital heart surgery. The classic Norwood procedure provides pulmonary blood flow with a modified Blalock-Taussig shunt. Improved outcomes have been reported in a few small, nonrandomized studies of a modification of the Norwood procedure that uses a right ventricle-pulmonary artery shunt to provide pulmonary blood flow. Other nonrandomized studies have shown no differences between the two techniques. METHODS: The Pediatric Heart Network designed a randomized clinical trial to compare outcomes for subjects undergoing a Norwood procedure with either the right ventricle-pulmonary artery or modified Blalock-Taussig shunt. Infants with a diagnosis of single, morphologically right ventricle anomaly who are undergoing a Norwood procedure are eligible for inclusion in this study. The primary outcome is death or cardiac transplant 12 months after random assignment. Secondary outcomes include postoperative morbidity after Norwood and stage II palliation procedures, right ventricular function and pulmonary arterial growth at stage II palliation, and neurodevelopmental outcomes at 14 months old. Incidence of adverse events will also be compared between treatment groups. CONCLUSION: This study will make an important contribution to the care of patients with hypoplastic left heart syndrome and related forms of single, morphologically right ventricle. It also establishes a model with which other operative interventions for patients with congenital cardiovascular malformations can be evaluated in the future.

Advances in and limitations of up-and-down methodology: a précis of clinical use, study design, and dose estimation in anesthesia research.

Sequential design methods for binary response variables exist for determination of the concentration or dose associated with the 50% point along the dose-response curve; the up-and-down method of Dixon and Mood is now commonly used in anesthesia research. There have been important developments in statistical methods that (1) allow the design of experiments for the measurement of the response at any point (quantile) along the dose-response curve, (2) demonstrate the risk of certain statistical methods commonly used in literature reports, (3) allow the estimation of the concentration or dose-the target dose-associated with the chosen quantile without the assumption of the symmetry of the tolerance distribution, and (4) set bounds on the probability of response at this target dose. This article details these developments, briefly surveys current use of the up-and-down method in anesthesia research, reanalyzes published reports using the up-and-down method for the study of the epidural relief of pain during labor, and discusses appropriate inferences from up-and-down method studies.

Genetic and morphologic determinants of pneumothorax in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis, a multisystem disease affecting women, is characterized by proliferation of abnormal smooth muscle-like cells in the lungs, leading to cystic destruction of the parenchyma and recurrent pneumothoraces. Clinical characteristics of lymphangioleiomyomatosis patients were analyzed to determine the relationship of pneumothoraces to disease progression. Patients were genotyped for polymorphisms in genes of extracellular matrix proteins collagen, elastin, and matrix metalloproteinase-1 to assess their association with pneumothoraces. Clinical data and polymorphisms in the genes for types I and III collagen, elastin, and matrix metalloproteinase-1 were compared with the prevalence of pneumothorax. Of 227 patients, 57% reported having had at least one pneumothorax. Cyst size on high-resolution computed tomography scans was associated with pneumothorax; patients with a history of pneumothorax were more likely to have larger cysts than patients who had no pneumothoraces. In patients with mild disease, those with a history of pneumothorax had a faster rate of decline in forced expiratory volume in 1 s (FEV(1); P = 0.001, adjusted for age) than those without. Genotype frequencies differed between patients with and without pneumothorax for polymorphisms in the types I and III collagen and matrix metalloproteinase-1 genes. Larger cysts may predispose lymphangioleiomyomatosis patients to pneumothorax, which, in early stages of disease, correlates with a more rapid rate of decline in FEV(1). Polymorphisms in types I and III collagen and matrix metalloproteinase-1 genes may cause differences in lung extracellular matrix that result in greater susceptibility to pneumothorax.

Bone mineral density in lymphangioleiomyomatosis.

Estrogen deficiency and pulmonary diseases are associated with bone mineral density (BMD) loss. Lymphangioleiomyomatosis (LAM), a disorder affecting women that is characterized by cystic lung lesions, is frequently treated with antiestrogen therapy, i.e., progesterone and/or oophorectomy. Therefore, we evaluated BMD yearly in 211 LAM patients to determine the prevalence of BMD abnormalities, whether antiestrogen therapy decreased BMD, and if treatment with bisphosphonates prevented bone loss. Abnormal BMD was found in 70% of the patients and correlated with severity of lung disease and age. Greater severity of lung disease, menopause, and oophorectomy were associated with greater decline in BMD. After adjusting for differences in initial lung function and BMD, we found similar rates of BMD decline in progesterone-treated (n = 122) and untreated patients (n = 89). After similar adjustments, we found that bisphosphonate-treated patients (n = 98) had lower rates of decline in lumbar spine BMD (-0.004 +/- 0.003 vs. -0.015 +/- 0.003 gm/cm(2), p = 0.036) and T-scores (-0.050 +/- 0.041 vs. -0.191 +/- 0.041, p < 0.001) than untreated patients (n = 113). We conclude that abnormal BMD was frequent in LAM. Progesterone therapy was not associated with changes in BMD; bisphosphonate therapy was associated with lower rates of bone loss. We recommend systematic evaluation of BMD and early treatment with bisphosphonates for patients with LAM.

Maximal oxygen uptake and severity of disease in lymphangioleiomyomatosis.

Lymphangioleiomyomatosis (LAM), a disease that occurs primarily in women, is characterized by cystic lung lesions causing respiratory failure, which may require lung transplantation. Lung diffusion (DLCO) and/or FEV1 are decreased, but frequently not in parallel with each other. Because cardiopulmonary exercise testing (CPET) provides information that is not obtainable from resting cardiopulmonary tests, we performed CPET in 217 LAM patients and correlated exercise data with clinical markers of severity, computed tomography scans, lung function, and histology. VO2max was decreased in 162 patients, of whom 28 did not reach anaerobic threshold; 29 had low oxygen uptake at anaerobic threshold, and 54 developed hypoxemia. Hypoxemia occurred even in patients with near normal DLCO and FEV1. VO2max decreased with an increasing score of histologic LAM severity and was correlated with computed tomography scans, the use of oxygen, and resting PaO2. DLCO and FEV1, however, were the only significant predictors of VO2max. We conclude that CPET uncovers the presence of exercise-induced hypoxemia and assists in grading the severity of disease and determining supplemental oxygen requirements in patients with LAM.