Mary Beth Brown

Effectiveness of Cardiac Resynchronization Therapy by QRS Morphology in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT)

Background— This study aimed to determine whether QRS morphology identifies patients who benefit from cardiac resynchronization therapy with a defibrillator (CRT-D) and whether it influences the risk of primary and secondary end points in patients enrolled in the Multicenter Automatic Defibrillator Implantation Trial–Cardiac Resynchronization Therapy (MADIT-CRT) trial. Methods and Results— Baseline 12-lead ECGs were evaluated with regard to QRS morphology. Heart failure event or death was the primary end point of the trial. Death, heart failure event, ventricular tachycardia, and ventricular fibrillation were secondary end points. Among 1817 patients with available sinus rhythm ECGs at baseline, there were 1281 (70%) with left bundle-branch block (LBBB), 228 (13%) with right bundle-branch block, and 308 (17%) with nonspecific intraventricular conduction disturbances. The latter 2 groups were defined as non-LBBB groups. Hazard ratios for the primary end point for comparisons of CRT-D patients versus patients who only received an implantable cardioverter defibrillator (ICD) were significantly (P<0.001) lower in LBBB patients (0.47; P<0.001) than in non-LBBB patients (1.24; P=0.257). The risk of ventricular tachycardia, ventricular fibrillation, or death was decreased significantly in CRT-D patients with LBBB but not in non-LBBB patients. Echocardiographic parameters showed significantly (P<0.001) greater reduction in left ventricular volumes and increase in ejection fraction with CRT-D in LBBB than in non-LBBB patients. Conclusions— Heart failure patients with New York Heart Association class I or II and ejection fraction ⩽30% and LBBB derive substantial clinical benefit from CRT-D: a reduction in heart failure progression and a reduction in the risk of ventricular tachyarrhythmias. No clinical benefit was observed in patients with a non-LBBB QRS pattern (right bundle-branch block or intraventricular conduction disturbances). Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00180271.

Adipose Stem Cell Treatment in Mice Attenuates Lung and Systemic Injury Induced by Cigarette Smoking

RATIONALE Adipose-derived stem cells express multiple growth factors that inhibit endothelial cell apoptosis, and demonstrate substantial pulmonary trapping after intravascular delivery. OBJECTIVES We hypothesized that adipose stem cells would ameliorate chronic lung injury associated with endothelial cell apoptosis, such as that occurring in emphysema. METHODS Therapeutic effects of systemically delivered human or mouse adult adipose stem cells were evaluated in murine models of emphysema induced by chronic exposure to cigarette smoke or by inhibition of vascular endothelial growth factor receptors. MEASUREMENTS AND MAIN RESULTS Adipose stem cells were detectable in the parenchyma and large airways of lungs up to 21 days after injection. Adipose stem cell treatment was associated with reduced inflammatory infiltration in response to cigarette smoke exposure, and markedly decreased lung cell death and airspace enlargement in both models of emphysema. Remarkably, therapeutic results of adipose stem cells extended beyond lung protection by rescuing the suppressive effects of cigarette smoke on bone marrow hematopoietic progenitor cell function, and by restoring weight loss sustained by mice during cigarette smoke exposure. Pulmonary vascular protective effects of adipose stem cells were recapitulated by application of cell-free conditioned medium, which improved lung endothelial cell repair and recovery in a wound injury repair model and antagonized effects of cigarette smoke in vitro. CONCLUSIONS These results suggest a useful therapeutic effect of adipose stem cells on both lung and systemic injury induced by cigarette smoke, and implicate a lung vascular protective function of adipose stem cell derived paracrine factors.

The fastest runner on artificial legs: different limbs, similar function?

The recent competitive successes of a bilateral, transtibial amputee sprint runner who races with modern running prostheses has triggered an international controversy regarding the relative function provided by his artificial limbs. Here, we conducted three tests of functional similarity between this amputee sprinter and competitive male runners with intact limbs: the metabolic cost of running, sprinting endurance, and running mechanics. Metabolic and mechanical data, respectively, were acquired via indirect calorimetry and ground reaction force measurements during constant-speed, level treadmill running. First, we found that the mean gross metabolic cost of transport of our amputee sprint subject (174.9 ml O(2)*kg(-1)*km(-1); speeds: 2.5-4.1 m/s) was only 3.8% lower than mean values for intact-limb elite distance runners and 6.7% lower than for subelite distance runners but 17% lower than for intact-limb 400-m specialists [210.6 (SD 13.2) ml O(2)*kg(-1)*km(-1)]. Second, the speeds that our amputee sprinter maintained for six all-out, constant-speed trials to failure (speeds: 6.6-10.8 m/s; durations: 2-90 s) were within 2.2 (SD 0.6)% of those predicted for intact-limb sprinters. Third, at sprinting speeds of 8.0, 9.0, and 10.0 m/s, our amputee subject had longer foot-ground contact times [+14.7 (SD 4.2)%], shorter aerial [-26.4 (SD 9.9)%] and swing times [-15.2 (SD 6.9)%], and lower stance-averaged vertical forces [-19.3 (SD 3.1)%] than intact-limb sprinters [top speeds = 10.8 vs. 10.8 (SD 0.6) m/s]. We conclude that running on modern, lower-limb sprinting prostheses appears to be physiologically similar but mechanically different from running with intact limbs.

Mechanisms of lung endothelial barrier disruption induced by cigarette smoke: role of oxidative stress and ceramides.

The epithelial and endothelial cells lining the alveolus form a barrier essential for the preservation of the lung respiratory function, which is, however, vulnerable to excessive oxidative, inflammatory, and apoptotic insults. Whereas profound breaches in this barrier function cause pulmonary edema, more subtle changes may contribute to inflammation. The mechanisms by which cigarette smoke (CS) exposure induce lung inflammation are not fully understood, but an early alteration in the epithelial barrier function has been documented. We sought to investigate the occurrence and mechanisms by which soluble components of mainstream CS disrupt the lung endothelial cell barrier function. Using cultured primary rat microvascular cell monolayers, we report that CS induces endothelial cell barrier disruption in a dose- and time-dependent manner of similar magnitude to that of the epithelial cell barrier. CS exposure triggered a mechanism of neutral sphingomyelinase-mediated ceramide upregulation and p38 MAPK and JNK activation that were oxidative stress dependent and that, along with Rho kinase activation, mediated the endothelial barrier dysfunction. The morphological changes in endothelial cell monolayers induced by CS included actin cytoskeletal rearrangement, junctional protein zonula occludens-1 loss, and intercellular gap formation, which were abolished by the glutathione modulator N-acetylcysteine and ameliorated by neutral sphingomyelinase inhibition. The direct application of ceramide recapitulated the effects of CS, by disrupting both endothelial and epithelial cells barrier, by a mechanism that was redox and apoptosis independent and required Rho kinase activation. Furthermore, ceramide induced dose-dependent alterations of alveolar microcirculatory barrier in vivo, measured by two-photon excitation microscopy in the intact rat. In conclusion, soluble components of CS have direct endothelial barrier-disruptive effects that could be ameliorated by glutathione modulators or by inhibitors of neutral sphingomyelinase, p38 MAPK, JNK, and Rho kinase. Amelioration of endothelial permeability may alleviate lung and systemic vascular dysfunction associated with smoking-related chronic obstructive lung diseases.

Two-Photon Imaging within the Murine Thorax without Respiratory and Cardiac Motion Artifact

Intravital microscopy has been recognized for its ability to make physiological measurements at cellular and subcellular levels while maintaining the complex natural microenvironment. Two-photon microscopy (TPM), using longer wavelengths than single-photon excitation, has extended intravital imaging deeper into tissues, with minimal phototoxicity. However, due to a relatively slow acquisition rate, TPM is especially sensitive to motion artifact, which presents a challenge when imaging tissues subject to respiratory and cardiac movement. Thoracoabdominal organs that cannot be exteriorized or immobilized during TPM have generally required the use of isolated, pump-perfused preparations. However, this approach entails significant alteration of normal physiology, such as a lack of neural inputs, increased vascular resistance, and leukocyte activation. We adapted techniques of intravital microscopy that permitted TPM of organs maintained within the thoracoabdominal cavity of living, breathing rats or mice. We obtained extended intravital TPM imaging of the intact lung, arguably the organ most susceptible to both respiratory and cardiac motion. Intravital TPM detected the development of lung microvascular endothelial activation manifested as increased leukocyte adhesion and plasma extravasation in response to oxidative stress inducers PMA or soluble cigarette smoke extract. The pulmonary microvasculature and alveoli in the intact animal were imaged with comparable detail and fidelity to those in pump-perfused animals, opening the possibility for TPM of other thoracoabdominal organs under physiological and pathophysiological conditions.

High-sweat Na+ in cystic fibrosis and healthy individuals does not diminish thirst during exercise in the heat

Sweat Na(+) concentration ([Na(+)]) varies greatly among individuals and is particularly high in cystic fibrosis (CF). The purpose of this study was to determine whether excess sweat [Na(+)] differentially impacts thirst drive and other physiological responses during progressive dehydration via exercise in the heat. Healthy subjects with high-sweat [Na(+)] (SS) (91.0 ± 17.3 mmol/l), Controls with average sweat [Na(+)] (43.7 ± 9.9 mmol/l), and physically active CF patients with very high sweat [Na(+)] (132.6 ± 6.4 mmol/l) cycled in the heat without drinking until 3% dehydration. Serum osmolality increased less (P < 0.05) in CF (6.1 ± 4.3 mosmol/kgH(2)O) and SS (8.4 ± 3.0 mosmol/kgH(2)O) compared with Control (14.8 ± 3.5 mosmol/kgH(2)O). Relative change in plasma volume was greater (P < 0.05) in CF (-19.3 ± 4.5%) and SS (-18.8 ± 3.1%) compared with Control (-14.3 ± 2.3%). Thirst during exercise and changes in plasma levels of vasopressin, angiotensin II, and aldosterone relative to percent dehydration were not different among groups. However, ad libitum fluid replacement was 40% less, and serum NaCl concentration was lower for CF compared with SS and Control during recovery. Despite large variability in sweat electrolyte loss, thirst appears to be appropriately maintained during exercise in the heat as a linear function of dehydration, with relative contributions from hyperosmotic and hypovolemic stimuli dependent upon the magnitude of salt lost in sweat. CF exhibit lower ad libitum fluid restoration following dehydration, which may reflect physiological cues directed at preservation of salt balance over volume restoration.

Running-specific prostheses permit energy cost similar to nonamputees.

UNLABELLED Improvements in prosthesis design have facilitated participation in competitive running for persons with lower limb loss (AMP). PURPOSE The purpose of this study was to examine the physiological responses of AMP using a run-specific prosthesis (RP) versus a traditional prosthesis (P) and cross-referenced with nonamputee controls (C) matched by training status, age, gender, and body composition during level treadmill running (TM). METHODS Twelve trained runners completed a multistage submaximal TM exercise during which HR and oxygen uptake (VO(2)) were obtained. Steady state measures at 134 m x min(-1) were compared between RP and P in AMP. AMP using RP (AMP-RP) and C also performed a continuous speed-incremented maximal TM test until volitional fatigue. RESULTS RP elicited lower HR and VO(2) compared with P in AMP. Using RP, AMP achieved similar VO(2max) and peak TM speed compared with C but with higher HR(max). Relative HR (%HR(max)) and oxygen uptake (%VO(2max)), the regression intercept, slope, SEE, and Pearsons r correlation were not different between AMP-RP and C. %HR(max) calculated with the published equation, %HR(max) = 0.73(%VO(2max)) + 30, was not significantly different from actual %HR(max) for AMP-RP or C in any stage. CONCLUSIONS RP permits AMP to attain peak TM speed and aerobic capacity similar to trained nonamputees and significantly attenuates HR and energy cost of submaximal running compared with a P. Use of RP confers no physiological advantage compared with nonamputee runners because energy cost at the set speed was not significantly different for AMP-RP. Current equations on the basis of the relative HR-VO(2) relationship seem appropriate to prescribe exercise intensity for persons with transtibial amputations using RP.

Active Trafficking of Alpha 1 Antitrypsin across the Lung Endothelium

The homeostatic lung protective effects of alpha-1 antitrypsin (A1AT) may require the transport of circulating proteinase inhibitor across an intact lung endothelial barrier. We hypothesized that uninjured pulmonary endothelial cells transport A1AT to lung epithelial cells. Purified human A1AT was rapidly taken up by confluent primary rat pulmonary endothelial cell monolayers, was secreted extracellularly, both apically and basolaterally, and was taken up by adjacent rat lung epithelial cells co-cultured on polarized transwells. Similarly, polarized primary human lung epithelial cells took up basolaterally-, but not apically-supplied A1AT, followed by apical secretion. Evidence of A1AT transcytosis across lung microcirculation was confirmed in vivo by two-photon intravital microscopy in mice. Time-lapse confocal microscopy indicated that A1AT co-localized with Golgi in the endothelium whilst inhibition of the classical secretory pathway with tunicamycin significantly increased intracellular retention of A1AT. However, inhibition of Golgi secretion promoted non-classical A1AT secretion, associated with microparticle release. Polymerized A1AT or A1AT supplied to endothelial cells exposed to soluble cigarette smoke extract had decreased transcytosis. These results suggest previously unappreciated pathways of A1AT bidirectional uptake and secretion from lung endothelial cells towards the alveolar epithelium and airspaces. A1AT trafficking may determine its functional bioavailablity in the lung, which could be impaired in individuals exposed to smoking or in those with A1AT deficiency.

Counterpoint: Artificial legs do not make artificially fast running speeds possible

“Extraordinary claims require extraordinary evidence.”—Carl Sagan There is insufficient evidence to conclude that modern running specific prostheses (RSP) provide physiological or biomechanical advantages over biological legs. A grand total of n = 7 metabolic running economy values for

Neonatal hyperoxic lung injury favorably alters adult right ventricular remodeling response to chronic hypoxia exposure.

The development of pulmonary hypertension (PH) requires multiple pulmonary vascular insults, yet the role of early oxygen therapy as an initial pulmonary vascular insult remains poorly defined. Here, we employ a two-hit model of PH, utilizing postnatal hyperoxia followed by adult hypoxia exposure, to evaluate the role of early hyperoxic lung injury in the development of later PH. Sprague-Dawley pups were exposed to 90% oxygen during postnatal days 0-4 or 0-10 or to room air. All pups were then allowed to mature in room air. At 10 wk of age, a subset of rats from each group was exposed to 2 wk of hypoxia (Patm = 362 mmHg). Physiological, structural, and biochemical endpoints were assessed at 12 wk. Prolonged (10 days) postnatal hyperoxia was independently associated with elevated right ventricular (RV) systolic pressure, which worsened after hypoxia exposure later in life. These findings were only partially explained by decreases in lung microvascular density. Surprisingly, postnatal hyperoxia resulted in robust RV hypertrophy and more preserved RV function and exercise capacity following adult hypoxia compared with nonhyperoxic rats. Biochemically, RVs from animals exposed to postnatal hyperoxia and adult hypoxia demonstrated increased capillarization and a switch to a fetal gene pattern, suggesting an RV more adept to handle adult hypoxia following postnatal hyperoxia exposure. We concluded that, despite negative impacts on pulmonary artery pressures, postnatal hyperoxia exposure may render a more adaptive RV phenotype to tolerate late pulmonary vascular insults.