Nakhleh N.,CNRS Developmental Biology Laboratory |
Nakhleh N.,Jersey Shore University Medical Center |
Francis R.,CNRS Developmental Biology Laboratory |
Francis R.,University of Pittsburgh |
And 28 more authors.
Circulation | Year: 2012
Background-Patients with congenital heart disease (CHD) and heterotaxy show high postsurgical morbidity/mortality, with some developing respiratory complications. Although this finding is often attributed to the CHD, airway clearance and left-right patterning both require motile cilia function. Thus, airway ciliary dysfunction (CD) similar to that of primary ciliary dyskinesia (PCD) may contribute to increased respiratory complications in heterotaxy patients. Methods and Results-We assessed 43 CHD patients with heterotaxy for airway CD. Videomicrocopy was used to examine ciliary motion in nasal tissue, and nasal nitric oxide (nNO) was measured; nNO level is typically low with PCD. Eighteen patients exhibited CD characterized by abnormal ciliary motion and nNO levels below or near the PCD cutoff values. Patients with CD aged 6 years show increased respiratory symptoms similar to those seen in PCD. Sequencing of all 14 known PCD genes in 13 heterotaxy patients with CD, 12 without CD, 10 PCD disease controls, and 13 healthy controls yielded 0.769, 0.417, 1.0, and 0.077 novel variants per patient, respectively. One heterotaxy patient with CD had the PCD causing DNAI1 founder mutation. Another with hyperkinetic ciliary beat had 2 mutations in DNAH11, the only PCD gene known to cause hyperkinetic beat. Among PCD patients, 2 had known PCD causing CCDC39 and CCDC40 mutations. Conclusions-Our studies show that CHD patients with heterotaxy have substantial risk for CD and increased respiratory disease. Heterotaxy patients with CD were enriched for mutations in PCD genes. Future studies are needed to assess the potential benefit of prescreening and prophylactically treating heterotaxy patients for CD. © 2012 American Heart Association, Inc.
Michler R.E.,Yeshiva University |
Smith P.K.,Duke University |
Parides M.K.,Mount Sinai School of Medicine |
Ailawadi G.,University of Virginia |
And 25 more authors.
New England Journal of Medicine | Year: 2016
BACKGROUND: In a trial comparing coronary-artery bypass grafting (CABG) alone with CABG plus mitral-valve repair in patients with moderate ischemic mitral regurgitation, we found no significant difference in the left ventricular end-systolic volume index (LVESVI) or survival after 1 year. Concomitant mitral-valve repair was associated with a reduced prevalence of moderate or severe mitral regurgitation, but patients had more adverse events. We now report 2-year outcomes. METHODS: We randomly assigned 301 patients to undergo either CABG alone or the combined procedure. Patients were followed for 2 years for clinical and echocardiographic outcomes. RESULTS: At 2 years, the mean (±SD) LVESVI was 41.2±20.0 ml per square meter of bodysurface area in the CABG-alone group and 43.2±20.6 ml per square meter in the combined-procedure group (mean improvement over baseline, -14.1 ml per square meter and -14.6 ml per square meter, respectively). The rate of death was 10.6% in the CABG-alone group and 10.0% in the combined-procedure group (hazard ratio in the combined-procedure group, 0.90; 95% confidence interval, 0.45 to 1.83; P = 0.78). There was no significant between-group difference in the rank-based assessment of the LVESVI (including death) at 2 years (z score, 0.38; P = 0.71). The 2-year rate of moderate or severe residual mitral regurgitation was higher in the CABG-alone group than in the combined-procedure group (32.3% vs. 11.2%, P<0.001). Overall rates of hospital readmission and serious adverse events were similar in the two groups, but neurologic events and supraventricular arrhythmias remained more frequent in the combined-procedure group. CONCLUSIONS: In patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not lead to significant differences in left ventricular reverse remodeling at 2 years. Mitral-valve repair provided a more durable correction of mitral regurgitation but did not significantly improve survival or reduce overall adverse events or readmissions and was associated with an early hazard of increased neurologic events and supraventricular arrhythmias. Copyright © 2016 Massachusetts Medical Society.
Rogers T.,U.S. National Institutes of Health |
Ratnayaka K.,U.S. National Institutes of Health |
Ratnayaka K.,Childrens National Medical Center |
Schenke W.H.,U.S. National Institutes of Health |
And 9 more authors.
Circulation: Cardiovascular Interventions | Year: 2015
Percutaneous access for mitral interventions is currently limited to transapical and transseptal routes, both of which have shortcomings. We hypothesized that the left atrium could be accessed directly through the posterior chest wall under imaging guidance. Methods and Results-We tested percutaneous transthoracic left atrial access in 12 animals (10 pigs and 2 sheep) under realtime magnetic resonance imaging or X-ray fluoroscopy plus C-arm computed tomographic guidance. The pleural space was insufflated with CO2 to displace the lung, an 18F sheath was delivered to the left atrium, and the left atrial port was closed using an off-the-shelf nitinol cardiac occluder. Animals were survived for a minimum of 7 days. The left atrial was accessed, and the port was closed successfully in 12/12 animals. There was no procedural mortality and only 1 hemodynamically insignificant pericardial effusion was observed at follow-up. We also successfully performed the procedure on 3 human cadavers. A simulated trajectory to the left atrium was present in all of 10 human cardiac computed tomographic angiograms analyzed. Conclusions-Percutaneous transthoracic left atrial access is feasible without instrumenting the left ventricular myocardium. In our experience, magnetic resonance imaging offers superb visualization of anatomic structures with the ability to monitor and address complications in real-time, although X-ray guidance seems feasible. Clinical translation seems realistic based on human cardiac computed tomographic analysis and cadaver testing. This technique could provide a direct nonsurgical access route for future transcatheter mitral implantation. © 2015 American Heart Association, Inc.
Van Beers E.J.,Office of Biostatistics Research |
Van Beers E.J.,University Utrecht |
Yang Y.,Office of Biostatistics Research |
Raghavachari N.,Office of Biostatistics Research |
And 9 more authors.
Circulation Research | Year: 2015
RATIONALE:: Patients with sickle cell disease (SCD) have markers of chronic inflammation, but the mechanism of inflammation and its relevance to patient survival are unknown. OBJECTIVE:: To assess the relationship between iron, inflammation, and early death in SCD. METHODS AND RESULTS:: Using peripheral blood mononuclear cell transcriptome profile hierarchical clustering, we classified 24 patients and 10 controls in clusters with significantly different expression of genes known to be regulated by iron. Subsequent gene set enrichment analysis showed that many genes associated with the high iron cluster were involved in the toll-like receptor system (TLR4, TLR7, and TLR8) and inflammasome complex pathway (NLRP3, NLRC4, and CASP1). Quantitative PCR confirmed this classification and showed that ferritin light chain, TLR4, and interleukin-6 expression were >100-fold higher in patients than in controls (P<0.001). Further linking intracellular iron and inflammation, 14 SCD patients with a ferroportin Q248H variant that causes intracellular iron accumulation had significantly higher levels of interleukin-6 and C-reactive protein compared with 14 matched SCD patients with the wild-type allele (P<0.05). Finally, in a cohort of 412 patients followed for a median period of 47 months (interquartile range, 24-82), C-reactive protein was strongly and independently associated with early death (hazard ratio, 3.0; 95% confidence interval, 1.7-5.2; P<0.001). CONCLUSIONS:: Gene expression markers of high intracellular iron in patients with SCD are associated with markers of inflammation and mortality. The results support a model in which intracellular iron promotes inflammatory pathways, such as the TLR system and the inflammasome, identifying important new pathways for additional investigation. © 2014 American Heart Association, Inc.
Geller N.L.,Office of Biostatistics Research |
Kim D.-Y.,U.S. National Institutes of Health |
Tian X.,Office of Biostatistics Research
Chest | Year: 2016
This article describes the use of smart technology by investigators and patients to facilitate lung disease clinical trials and make them less costly and more efficient. By "smart technology" we include various electronic media, such as computer databases, the Internet, and mobile devices. We first describe the use of electronic health records for identifying potential subjects and then discuss electronic informed consent. We give several examples of using the Internet and mobile technology in clinical trials. Interventions have been delivered via the World Wide Web or via mobile devices, and both have been used to collect outcome data. We discuss examples of new electronic devices that recently have been introduced to collect health data. While use of smart technology in clinical trials is an exciting development, comparison with similar interventions applied in a conventional manner is still in its infancy. We discuss advantages and disadvantages of using this omnipresent, powerful tool in clinical trials, as well as directions for future research. Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.
PubMed | Office of Biostatistics Research and University of Pittsburgh
Type: | Journal: Frontiers in pediatrics | Year: 2015
Dexmedetomidine (dex) is commonly used in intensive care due to its effective sedation and analgesia with few adverse effects and minimal respiratory depression. However, we recently observed that exposing mouse epithelial respiratory cells to dex decreased ciliary beat frequency (CBF), suggesting dex may pose pulmonary risk.The purpose of this study is to determine the effects of dex at clinically relevant doses on CBF in human respiratory epithelia.Human nasal epithelial cilia were obtained from the inferior nasal turbinate with a rhinoprobe and placed in culture medium at 15C and 37C. At 5 and 30min, video-microscopy was used to assess CBF, either without (control) or with different concentrations (1, 5, and 10nM) of dex, fentanyl (fen), and dex+fen combination.At 15C, CBF was lower in the dex group compared to controls at 5 and 30min. At 37C, there was a significant increase in CBF with dex at 5 and 30min, except for dex at 5nM after 5min, which showed a significant decrease. At 15C the combination of dex+fen showed a positive interaction, causing less ciliary inhibition as expected. In contrast, no interaction between drugs was seen between dex and fen at 37C.At low temperatures, dex reduces CBF in human respiratory epithelia, whereas dex increases CBF at physiologic temperature in vitro. Whether these effects translate into clinical consequences during hypothermia, as with cardiopulmonary bypass surgery will require further studies.