The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation of disease is not well understood. One of the main roadblocks to mechanistic insight remains a lack of high-resolution structural information about multiprotein complexes within the cardiac sarcomere. One example is the tropomyosin (Tm) overlap region of the thin filament that is crucial for the function of the cardiac sarcomere. To address this central question, we devised coupled experimental and computational modalities to characterize the baseline function and structure of the Tm overlap, as well as the effects of mutations causing divergent patterns of ventricular remodeling on both structure and function. Because the Tm overlap contributes to the cooperativity of myofilament activation, we hypothesized that mutations that enhance the interactions between overlap proteins result in more cooperativity, and conversely, those that weaken interaction between these elements lower cooperativity. Our results suggest that the Tm overlap region is affected differentially by dilated cardiomyopathy-associated Tm D230N and hypertrophic cardiomyopathy-associated human cardiac troponin T (cTnT) R92L. The Tm D230N mutation compacts the Tm overlap region, increasing the cooperativity of the Tm filament, contributing to a dilated cardiomyopathy phenotype. The cTnT R92L mutation causes weakened interactions closer to the N-terminal end of the overlap, resulting in decreased cooperativity. These studies demonstrate that mutations with differential phenotypes exert opposite effects on the Tm–Tn overlap, and that these effects can be directly correlated to a molecular level understanding of the structure and dynamics of the component proteins.
Background/AimsPresently, there is paucity of information about clinical predictors, especially esophageal motor abnormalities, for long segment Barrett's esophagus (LSBE) as compared with short segment Barrett's esophagus (SSBE). The aims of this study are to compare the frequency of esophageal function abnormalities between patients with LSBE and those with SSBE and to determine their clinical predictors.
MethodsThis was a multicenter cohort study that included all patients with a diagnosis of BE who underwent high-resolution esophageal manometry. Motility disorders were categorized as hypercontractile disorders or hypocontractile disorders and their frequency was compared between patients with LSBE and those with SSBE. Multivariable logistic regression modeling was used to calculate the odds of being diagnosed with LSBE relative to SSBE for demographics, comorbidities, medication use, endoscopic findings, and the type of motility disorders.
ResultsA total of 148 patients with BE were identified, of which 89 (60.1%) had SSBE and 59 (39.9%) LSBE. Patients with LSBE had a significantly larger hiatal hernia and higher likelihood of erosive esophagitis than patients with SSBE (P = 0.002). Patients with LSBE had a significantly lower mean LES resting pressure, distal contractile integral, distal latency, and significantly higher failed swallows and hypocontractile motility disorders than those with SSBE (P < 0.05). Hiatal hernia and hypocontractile motility disorder increased the odds of LSBE by 38.0% and 242.0%, as opposed to SSBE.
ConclusionsThe presence of a hypocontractile motility disorder increased the risk for LSBE. Furthermore, the risk for LSBE was directly associated with the length of the hiatal hernia.
While esomeprazole significantly reduced esophageal acid exposure during conscious awakenings and recumbent-awake and asleep periods, it did not decrease the number and duration of conscious awakening or duration of recumbent-awake period.
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