The "Goldilocks Effect" in Cystic Fibrosis: identification of a lung phenotype in the cftr knockout and heterozygous mouse

BACKGROUND: Cystic Fibrosis is a pleiotropic disease in humans with primary morbidity and mortality associated with a lung disease phenotype. However, knockout in the mouse of cftr, the gene whose mutant alleles are responsible for cystic fibrosis, has previously failed to produce a readily, quantifiable lung phenotype. RESULTS: Using measurements of pulmonary mechanics, a definitive lung phenotype was demonstrated in the cftr-/- mouse. Lungs showed decreased compliance and increased airway resistance in young animals as compared to cftr+/+ littermates. These changes were noted in animals less than 60 days old, prior to any long term inflammatory effects that might occur, and are consistent with structural differences in the cftr-/- lungs. Surprisingly, the cftr+/- animals exhibited a lung phenotype distinct from either the homozygous normal or knockout genotypes. The heterozygous mice showed increased lung compliance and decreased airway resistance when compared to either homozygous phenotype, suggesting a heterozygous advantage that might explain the high frequency of this mutation in certain populations. CONCLUSIONS: In the mouse the gene dosage of cftr results in distinct differences in pulmonary mechanics of the adult. Distinct phenotypes were demonstrated in each genotype, cftr-/-, cftr +/-, and cftr+/+. These results are consistent with a developmental role for CFTR in the lung

Pulmonary Pathophysiology the Essentials

23cmx15cm, 317hlm:illu

Medical Physiology : A Systems Approach

xiii, 761 hlm, ilus.; 21x27c

Abstract 17143: Obstructive and Central Sleep Apnea and Risk of Incident Atrial Fibrillation

INTRODUCTION: Prior studies have documented a higher prevalence of atrial fibrillation (AF) in those with obstructive sleep apnea (OSA). OSA has been associated with AF recurrence following cardioversion and ablation, and with prevalent and incident AF in cross-sectional and retrospective studies. Central sleep apnea (CSA) also has been associated with AF in patients with heart failure. However, data from prospective cohorts are sparse and few studies have evaluated the association of CSA with AF in population studies. METHODS: We assessed the association of OSA and CSA with incident AF among 3,420 subjects without a history of AF in the Sleep Heart Health Study (SHHS), a prospective, community-based study designed to evaluate the cardiovascular consequences of sleep disordered breathing. Subjects underwent overnight polysomnography at baseline and were followed over time for the development of incident AF, documented at any time after baseline polysomnogram until the end of follow-up. OSA was defined as an obstructive apnea-hypopnea index ≥ 5 and CSA was defined as a central apnea index ≥ 5. RESULTS: At baseline, the sample include 1499 men (44.4%) with a mean age of 62.4 (±10.9); 1569 (45.9%) subjects met criteria for mild to severe OSA and 54 (1.6%) for CSA. Over a mean follow-up of 8.2 years, 382 cases of incident AF were identified. The prevalence of both OSA and CSA was higher among those who developed AF compared to those who did not (OSA 49% vs 44%, p=0.001 and CSA 5% vs 1.2%, p=0.001). After adjustment for multiple AF risk factors, CSA was associated with an approximately 2-fold increased odds of incident AF (RR=2.38, 95% CI, 1.15-4.94; p = 0.02). The association persisted after exclusion of 258 subjects with a history of heart failure (RR=2.78, 95% CI, 1.28-6.04; p = 0.01). We did not find a significant association of OSA with incident AF (Table). CONCLUSION: In our prospective, community-based cohort baseline CSA was associated with incident AF