Ectocytosis renders T cell receptor signaling self-limiting at the immune synapse.

Cytotoxic T lymphocytes (CTLs) kill virus-infected and cancer cells through T cell receptor (TCR) recognition. How CTLs terminate signaling and disengage to allow serial killing has remained a mystery. TCR activation triggers membrane specialization within the immune synapse, including the production of diacylglycerol (DAG), a lipid that can induce negative membrane curvature. We found that activated TCRs were shed into DAG-enriched ectosomes at the immune synapse rather than internalized through endocytosis, suggesting that DAG may contribute to the outward budding required for ectocytosis. Budding ectosomes were endocytosed directly by target cells, thereby terminating TCR signaling and simultaneously disengaging the CTL from the target cell to allow serial killing. Thus, ectocytosis renders TCR signaling self-limiting.

Intravenous calcium as a pressor in a swine model of hypoxic pseudo-pulseless electrical mechanical activity-a preliminary report.

BACKGROUND: Pseudo-pulseless electrical activity (pseudo-PEA) is a lifeless form of profound cardiac shock characterized by measurable cardiac mechanical activity without clinically detectable pulses. Pseudo-PEA may constitute up to 40% of reported cases of cardiac arrest. Resuscitation from pseudo-PEA is often associated with hypotension refractory to catecholamine pressors. We hypothesized that this post-resuscitation state may be associated with hypocalcemic hypotension responsive to intravenous calcium. METHODS: Using pre-existing data from our hypoxic swine pseudo-PEA model, we measured blood pressure, hemodynamics, and electrolytes. Physiological data were analyzed on a heartbeat by heartbeat basis. The midpoint of the calcium response was defined using change of curvature feature detection. Hemodynamic parameters were shifted such that the value at the midpoint was equal to zero. RESULTS: In 9 animals with refractory hypotension, we administered 37 boluses of intravenous calcium in the dosage range of 5-20 mg. Comparisons were made between the average values in the time period 40-37 s before the midpoint and 35-40 s after the midpoint. Of the 37 administered boluses, 34 manifested a change in the blood pressure, with mean aortic pressure, systolic and diastolic pressures all increasing post bolus administration. CONCLUSIONS: Administration of intravenous calcium may be associated with a pressor-like response in refractory hypotension after resuscitation from pseudo-PEA. Relative ionized hypocalcemia may cause hypotension after resuscitation from pseudo-PEA. Therapy with intravenous calcium should be further investigated in this setting.

Effect of compression waveform and resuscitation duration on blood flow and pressure in swine: One waveform does not optimally serve.

BACKGROUND: Chest compression (CC) research primarily focuses on finding the 'optimum' compression waveform using a variety of compression efficacy metrics. Blood flow is rarely measured systematically with high fidelity. Using a programmable mechanical chest compression device, we studied the effect of inter-compression pauses in a swine model of cardiac arrest, testing the hypothesis that a single 'optimal' CC waveform exists based on measurements of resulting blood flow. METHODS: Hemodynamics were studied in 9 domestic swine (∼30 kg) using multiple flow probes and standard physiological monitoring. After 10 min of ventricular fibrillation, five mechanical chest compression waveforms (5.1 cm, varying inter-compression pauses) were delivered for 2 min each in a semi-random pattern, totaling 50 compression minutes. Linear Mixed Models were used to estimate the effect of compression waveform on hemodynamics. RESULTS: Blood flow and pressure decayed significantly with time in both arteries and veins. No waveform maximized blood flow in all vessels simultaneously and the waveform generating maximal blood flow in a specific vessel changed over time in all vessels. A flow mismatch between paired arteries and veins, e.g. abdominal aorta and inferior vena cava, also developed over time. The waveform with the slowest rate and shortest duty cycle had the smallest mismatch between flows after about 30 min of CPR. CONCLUSIONS: This data challenges the concept of a single optimal CC waveform. Time dependent physiological response to compressions and no single compression waveform optimizing flow in all vessels indicate that current descriptions of CPR don't reflect patient physiology.

Real-Time Ventricular Fibrillation Amplitude-Spectral Area Analysis to Guide Timing of Shock Delivery Improves Defibrillation Efficacy During Cardiopulmonary Resuscitation in Swine.

BACKGROUND: The ventricular fibrillation amplitude spectral area (AMSA) predicts whether an electrical shock could terminate ventricular fibrillation and prompt return of spontaneous circulation. We hypothesized that AMSA can guide more precise timing for effective shock delivery during cardiopulmonary resuscitation. METHODS AND RESULTS: Three shock delivery protocols were compared in 12 pigs each after electrically induced ventricular fibrillation, with the duration of untreated ventricular fibrillation evenly stratified into 6, 9, and 12 minutes: AMSA-Driven (AD), guided by an AMSA algorithm; Guidelines-Driven (GD), according to cardiopulmonary resuscitation guidelines; and Guidelines-Driven/AMSA-Enabled (GDAE), as per GD but allowing earlier shocks upon exceeding an AMSA threshold. Shocks delivered using the AD, GD, and GDAE protocols were 21, 40, and 62, with GDAE delivering only 2 AMSA-enabled shocks. The corresponding 240-minute survival was 8/12, 6/12, and 2/12 (log-rank test, P=0.035) with AD exceeding GDAE (P=0.026). The time to first shock (seconds) was (median [Q1-Q3]) 272 (161-356), 124 (124-125), and 125 (124-125) (P<0.001) with AD exceeding GD and GDAE (P<0.05); the average coronary perfusion pressure before first shock (mm Hg) was 16 (9-30), 10 (6-12), and 3 (-1 to 9) (P=0.002) with AD exceeding GDAE (P<0.05); and AMSA preceding the first shock (mV·Hz, mean±SD) was 13.3±2.2, 9.0±1.6, and 8.6±2.0 (P<0.001) with AD exceeding GD and GDAE (P<0.001). The AD protocol delivered fewer unsuccessful shocks (ie, less shock burden) yielding less postresuscitation myocardial dysfunction and higher 240-minute survival. CONCLUSIONS: The AD protocol improved the time precision for shock delivery, resulting in less shock burden and less postresuscitation myocardial dysfunction, potentially improving survival compared with time-fixed, guidelines-driven, shock delivery protocols.

Regulated complex assembly safeguards the fidelity of Sleeping Beauty transposition.

The functional relevance of the inverted repeat structure (IR/DR) in a subgroup of the Tc1/mariner superfamily of transposons has been enigmatic. In contrast to mariner transposition, where a topological filter suppresses single-ended reactions, the IR/DR orchestrates a regulatory mechanism to enforce synapsis of the transposon ends before cleavage by the transposase occurs. This ordered assembly process shepherds primary transposase binding to the inner 12DRs (where cleavage does not occur), followed by capture of the 12DR of the other transposon end. This extra layer of regulation suppresses aberrant, potentially genotoxic recombination activities, and the mobilization of internally deleted copies in the IR/DR subgroup, including Sleeping Beauty (SB). In contrast, internally deleted sequences (MITEs) are preferred substrates of mariner transposition, and this process is associated with the emergence of Hsmar1-derived miRNA genes in the human genome. Translating IR/DR regulation to in vitro evolution yielded an SB transposon version with optimized substrate recognition (pT4). The ends of SB transposons excised by a K248A excision+/integration- transposase variant are processed by hairpin resolution, representing a link between phylogenetically, and mechanistically different recombination reactions, such as V(D)J recombination and transposition. Such variants generated by random mutation might stabilize transposon-host interactions or prepare the transposon for a horizontal transfer.

Ventricular Fibrillation Waveform Changes during Controlled Coronary Perfusion Using Extracorporeal Circulation in a Swine Model.

BACKGROUND: Several characteristics of the ventricular fibrillation (VF) waveform have been found predictive of successful defibrillation and hypothesized to reflect the myocardial energy state. In an open-chest swine model of VF, we modeled "average CPR" using extracorporeal circulation (ECC) and assessed the time course of coronary blood flow, myocardial metabolism, and myocardial structure in relation to the amplitude spectral area (AMSA) of the VF waveform without artifacts related to chest compression. METHODS: VF was induced and left untreated for 8 minutes in 16 swine. ECC was then started adjusting its flow to maintain a coronary perfusion pressure of 10 mmHg for 10 minutes. AMSA was calculated in the frequency domain and analyzed continuously with a 2.1 s timeframe and a Tukey window that moved ahead every 0.5 s. RESULTS: AMSA progressively declined during untreated VF. With ECC, AMSA increased from 7.0 ± 1.9 mV·Hz (at minute 8) to 12.8 ± 3.3 mV·Hz (at minute 14) (p < 0.05) without subsequent increase and showing a modest correlation with coronary blood flow of borderline statistical significance (r = 0.489, p = 0.0547). Myocardial energy measurements showed marked reduction in phosphocreatine and moderate reduction in ATP with increases in ADP, AMP, and adenosine along with myocardial lactate, all indicative of ischemia. Yet, ischemia did not resolve during ECC despite a coronary blood flow of ~ 30% of baseline. CONCLUSION: AMSA increased upon return of coronary blood flow during ECC. However, the maximal level was reached after ~ 6 minutes without further change. The significance of the findings for determining the optimal timing for delivering an electrical shock during resuscitation from VF remains to be further explored.

Developing a kinematic understanding of chest compressions: the impact of depth and release time on blood flow during cardiopulmonary resuscitation.

BACKGROUND: Effective cardiopulmonary resuscitation is a critical component of the pre-hospital treatment of cardiac arrest victims. Mechanical chest compression (MCC) devices enable the delivery of MCC waveforms that could not be delivered effectively by hand. While chest compression generated blood flow has been studied for more than 50 years, the relation between sternum kinematics (depth over time) and the resulting blood flow have not been well described. Using a five parameter MCC model, we studied the effect of MCC depth, MCC release time, and their interaction on MCC generated blood flow in a highly instrumented swine model of cardiac arrest. METHODS: MCC hemodynamics were studied in 17 domestic swine (~30 kg) using multiple extra-vascular flow probes and standard physiological monitoring. After 10 min of untreated ventricular fibrillation, mechanical MCC were started. MCC varied such that sternal release occurred over 100, 200, or 300 ms. MCC were delivered at a rate of 100 per min and at a depth of 1.25″ (n = 9) or at a depth of 1.9″ (n = 8) for a total of 18 min. Transitions between release times occurred every 2 min and were randomized. Linear Mixed Models were used to estimate the effect of MCC depth, MCC release time, and the interaction between MCC depth and release time on physiological outcomes. RESULTS: Blood pressures were optimized by a 200 ms release. End tidal carbon dioxide (EtCO2) was optimized by a 100 ms release. Blood flows were significantly lower at a 300 ms release than at either a 100 or 200 ms release (p < 0.05). 1.9″ deep MCC improved EtCO2, right atrial pressure, coronary perfusion pressure, inferior vena cava blood flow, carotid blood flow, and renal vein blood flow relative to 1.25″ MCC. CONCLUSIONS: Deeper MCC improved several hemodynamic parameters. Chest compressions with a 300 ms release time generated less blood flow than chest compressions with faster release times. MCC release time is an important quantitative metric of MCC quality and, if optimized, could improve MCC generated blood flows and pressures.

Cardiac autonomic dysfunction and arterial stiffness among children and adolescents with attention deficit hyperactivity disorder treated with stimulants.

OBJECTIVE: To compare markers of cardiovascular health in youth diagnosed with attention deficit hyperactivity disorder (ADHD) by the use of stimulant medication with healthy controls. STUDY DESIGN: Children and adolescents (n = 85; mean age 11.2 ± 2.8 years; 66 boys) diagnosed with ADHD using a stimulant and 53 siblings without ADHD (mean age 11.1 ± 3.8 years; 28 boys) were included in this cross-sectional study. Measured variables included blood pressure, heart rate (HR), HR variability: SD of the RR interval and low frequency to high frequency ratio, carotid-radial pulse wave velocity, carotid artery augmentation index (AIx), radial artery AIx, brachial artery flow-mediated dilation, and digital reactive hyperemic index. RESULTS: Compared with control patients, participants with ADHD had greater resting systolic blood pressure (3.9 mm Hg, 95% CI [1.2-6.7], P = .005), diastolic blood pressure (5.5 mm Hg, 95% CI [3.2-7.8], P < .001), HR (9.2 beats/min, 95% CI [6.0-12.3], P < .001), low frequency to high frequency ratio (0.55, 95% CI [0.22-0.89], P = .001), carotid AIx (7.2%, 95% CI [1.9-12.5], P = .008), and pulse wave velocity (0.36 m/s, 95% CI [-0.05, 0.78], P = .089), and lower SD of the RR interval (-33.7 milliseconds, 95% CI [-46.1, -21.3], P < .001). Neither flow-mediated dilation nor reactive hyperemic index was significantly different. CONCLUSIONS: Children and adolescents being treated with a stimulant medication for ADHD exhibited signs of altered cardiac autonomic function, characterized by increased sympathetic tone, and showed evidence of arterial stiffening.

Evaluation of traditional and novel measures of cardiac function to detect anthracycline-induced cardiotoxicity in survivors of childhood cancer.

PURPOSE: Cardiovascular disease is the leading noncancer cause of death among survivors of childhood cancer. Ejection fraction (EF) and fractional shortening (FS) are common echocardiographic measures of cardiac function, but newer imaging modalities may provide additional information about preclinical disease. This study aimed to evaluate these modalities in detection of anthracycline-induced cardiac toxicity. METHODS: We compared mean radial displacement, EF, and FS among 17 adult survivors of childhood cancer exposed to ≥ 300 mg/m(2) of anthracyclines to 17 age- and sex-matched healthy controls. Survivors with a history of cardiac-directed radiation, diabetes, or heart disease were excluded. RESULTS: Survivors (35% male), mostly with history of treatment for a solid tumor, had a median age at diagnosis of 15 years (1-20) and 27 years (18-50) at evaluation. Median anthracycline exposure was 440 (range 300-645) mg/m(2). FS (35.5 vs. 39.6%, p < 0.01) and radial displacement (5.6 vs. 6.7 mm, p = 0.02) were significantly lower in survivors compared to controls, respectively. Although the mean EF was lower in survivors versus controls (55.4 vs. 59.7%), it was not statistically significant (p = 0.057). All echocardiographic measures were inversely associated with anthracycline dose, though radial displacement was no longer significantly correlated with anthracycline dose after controlling for survival time (p = 0.07), while EF remained correlated (p = 0.003). IMPLICATIONS FOR CANCER SURVIVORS: Radial displacement, EF, and FS are lower in childhood cancer survivors compared to controls. In this study, radial displacement added no new information beyond the traditional measures, but clinical utility remains undetermined and requires further longitudinal study.

Mechanical versus manual chest compressions in out-of-hospital cardiac arrest: a meta-analysis.

OBJECTIVE: The objective of this study was to conduct a meta-analysis of literature examining rates of return of spontaneous circulation from load-distributing band and piston-driven chest compression devices as compared with manual cardiopulmonary resuscitation. DATA SOURCES: Searches were conducted in MEDLINE, the ClinicalTrials.gov registry, and bibliographies on manufacturer websites for studies written in English. STUDY SELECTION: Selection criteria for the meta-analysis required that studies must be human controlled (randomized, historical, or case-control) investigations with confirmed out-of-hospital cases. DATA EXTRACTION: A total of 12 studies (load-distributing band cardiopulmonary resuscitation versus manual cardiopulmonary resuscitation = 8, piston-driven cardiopulmonary resuscitation versus manual cardiopulmonary resuscitation = 4), comprising a total of 6,538 subjects with 1,824 return of spontaneous circulation events, met the selection criteria. DATA SYNTHESIS: Random effects models were used to assess the relative effect of treatments on return of spontaneous circulation. Compared with manual cardiopulmonary resuscitation, load-distributing band cardiopulmonary resuscitation had significantly greater odds of return of spontaneous circulation (odds ratio, 1.62 [95% CI, 1.36, 1.92], p < 0.001). The treatment effect for piston-driven cardiopulmonary resuscitation was similar to manual cardiopulmonary resuscitation (odds ratio, 1.25 [95% CI, 0.92, 1.68];p = 0.151). The corresponding difference in percentages of return of spontaneous circulation rates from cardiopulmonary resuscitation was 8.3% for load-distributing band cardiopulmonary resuscitation and 5.2% for piston-driven cardiopulmonary resuscitation. Compared with manual cardiopulmonary resuscitation, combining both mechanical cardiopulmonary resuscitation devices produced a significant treatment effect in favor of higher odds of return of spontaneous circulation with mechanical cardiopulmonary resuscitation devices (odds ratio, 1.53 [95% CI, 1.32, 1.78], p < 0.001). CONCLUSION: The ability to achieve return of spontaneous circulation with mechanical chest compression devices is significantly improved when compared with manual chest compressions. In the case of load-distributing band cardiopulmonary resuscitation, it was superior to manual cardiopulmonary resuscitation as the odds of return of spontaneous circulation were over 1.6 times greater. The robustness of these findings should be tested in large randomized clinical trials.

Torsion and dyssynchrony differences between chronically paced and non-paced heart failure patients.

BACKGROUND: Chronic right ventricular pacing may lead to left ventricular dyssynchrony, systolic dysfunction, remodeling, and heart failure. Cardiac mechanics may differ between paced and nonpaced heart failure patients, and their optimal treatment may also differ. METHODS AND RESULTS: Echocardiograms were analyzed using tissue Doppler imaging and speckle tracking echocardiography in 20 patients with chronic right ventricular pacing for complete heart block (RVP group), 29 nonpaced patients with different heart failure etiologies but ejection fractions similar to the RVP group (HF group), and 25 control subjects without pacemakers or heart failure (control group). Left ventricle volumes were smaller in RVP than HF (end-diastolic volume = 93.6 ± 25.1 mL vs. 112.1 ± 22.8 mL), but intraventricular longitudinal and radial dyssynchrony were similar. Dyssynchrony within the septum was greater (number of segments lengthening during systole = 1.9 ± 1.7 vs. 0.9 ± 1.8), systolic torsion was lower (6.2 ± 7.3° vs. 10.6 ± 4.2°), untwisting was delayed (time from peak torsion to peak untwist rate = 188 ± 141 ms vs. 102 ± 73 ms), and apical rotation was reversed in more subjects (35% vs 0%) in RVP than HF groups (P < .05 for all). CONCLUSIONS: Intraventricular dyssynchrony was similar between RVP and HF groups with similar ejection fraction. However, RVP subjects had smaller ventricles, greater dyssynchrony within the septum, lower torsion, altered apical rotation, and delayed untwisting.

Intramural dyssynchrony and response to cardiac resynchronization therapy in patients with and without previous right ventricular pacing.

AIMS: Right ventricular (RV) pacing is an iatrogenic cause of heart failure (HF) that has not been well studied. We assessed whether HF patients paced from the right ventricle (RVp) adversely remodel and respond to cardiac resynchronization therapy (CRT) in a similar way to HF patients without right ventricular pacing (nRVp). METHODS AND RESULTS: Echocardiograms were performed before and ∼5 months after CRT in 31 RVp and 49 nRVp HF patients. Longitudinal intraventricular dyssynchrony using tissue Doppler imaging (TDI) was calculated as the standard deviation of time to peak systolic displacement by tissue tracking (SD-TT) of 12 segments. Longitudinal dyssynchrony within a wall (intramural dyssynchrony) was assessed by two methods: quantifying the number of segments with initial abnormal apical displacement (IMD score) and using a cross-correlation synchrony index (CCSI). Despite similar ejection fractions (EFs) of 28% prior to CRT, left ventricular end-diastolic volume was significantly smaller (143±54 vs. 183±62, P=0.004) in RVp. The standard deviation of time to peak systolic displacement by tissue tracking (83.4±34.9 vs. 67.9±26.6, P=0.03) and IMD score (3.1±1.8 vs. 1.3±1.7, P<0.001) were greater in RVp. Cardiac resynchronization therapy significantly improved EF and volumes in both groups. Ejection fraction increased more in RVp (12.8±9.2% vs. 7.4±7.6%, P=0.007). Intraventricular dyssynchrony and both measures of intramural septal dyssynchrony improved to a greater extent post-CRT in RVp. CONCLUSION: Right ventricular pacing patients differ from nRVp HF patients in that they have smaller ventricles and greater intraventricular and intramural septal dyssynchrony. Right ventricular pacing HF patients respond better to CRT with greater improvements in EF, and intraventricular and intramural septal dyssynchrony.

Intramural dyssynchrony from acute right ventricular apical pacing in human subjects with normal left ventricular function.

Ventricular pacing causes early myocardial shortening at the pacing site and pre-stretch at the opposing ventricular wall. This contraction pattern is energetically inefficient and may lead to decreased cardiac function. This study was designed to describe the acute effects of right ventricular apical (RV(a)) pacing on dyssynchrony and systolic function in human subjects with normal left ventricular (LV) function and compare these effects to pacing from alternate ventricular sites. Patients (n = 26) undergoing an electrophysiology evaluation were studied during atrial pacing (AAI) and dual chamber pacing from the RV(a), left ventricular free wall (LV(fw)), and the combination of RV(a) and LV(fw) (BiV). Tissue Doppler imaging was used to measure intramural dyssynchrony by utilizing an integrated cross-correlation synchrony index (CCSI) from the apical 4-chamber view. RV(a) and BiV pacing significantly reduced systolic function as measured by longitudinal systolic contraction amplitude (SCA(long)) (p < 0.05) and LV velocity time integral (VTI) (p < 0.05) compared to AAI and LV(fw) pacing. RV(a) (and to a lesser extent BiV) pacing resulted in septal and lateral intramural dyssynchrony as indicated by significantly (p < 0.05) lower CCSI values as compared to AAI. CCSI was significantly (p < 0.05) worse during RV(a) than LV(fw) pacing. In patients with normal LV function, acute ventricular pacing in the RV(a) alone, or in conjunction with LV(fw) pacing (BiV), results in impaired regional and global LV systolic function and intramural dyssynchrony as compared to LV(fw) pacing alone.

Multi-plane mechanical dyssynchrony in cardiac resynchronization therapy.

BACKGROUND: The aims of this study were to assess the ability of several echo measures of dyssynchrony to predict CRT response and to characterize the global effect of CRT. HYPOTHESIS: We hypothesized that after CRT there would be significant reductions in mechanical dyssynchrony in all 3 orthogonal planes of cardiac motion and that those patients with significant dyssynchrony prior to implant would have the best echocardiographic response. METHODS: Standard echocardiograms were performed pre-CRT and post-CRT (138 +/- 63d) in 70 heart failure patients. Longitudinal dyssynchrony was calculated as the standard deviation (SD) of time to peak systolic displacement and velocity of 12 segments from 3 apical views. Using midventricular short axis views and speckle-tracking methods, the SD of time to peak radial and circumferential strain in 6 segments were calculated. Cardiac resynchronization therapy echo response was defined as > or = 15% decrease in left ventricular end-systolic volume. RESULTS: Cardiac resynchronization therapy significantly improved systolic function in the longitudinal, radial, and circumferential planes. The CRT echo response rate was 57%. Echo responders (CRT(R)) had significantly (P < .05) more dyssynchrony at baseline as compared to nonresponders (CRT(NR)). Cardiac resynchronization therapy significantly (P < .05) reduced longitudinal and radial, but not circumferential, dyssynchrony in CRT(R). Dyssynchrony was unchanged in CRT(NR). Receiver-operator characteristic (ROC) curve analysis indicated significant, but modest sensitivity and specificity for longitudinal and radial intraventricular dyssynchrony and for interventricular dyssynchrony. Combining radial and longitudinal dyssynchrony measures improved positive prediction of CRT response. CONCLUSIONS: Cardiac resynchronization therapy improves left ventricular function in 3 orthogonal planes of motion. Longitudinal, radial, and interventricular dyssynchrony modestly predict reverse remodeling.

Chronic baroreflex activation by the Rheos system: an overview of results from European and North American feasibility studies.

The baroreflex, whose role is well-known in short-term blood pressure regulation, has until recently been unexploited as a practical therapy for hypertension. Recent advancements in approach and technology embodied in the Rheos System have enabled chronic electrical activation of the baroreflex. Chronic results from feasibility studies indicate that Rheos Therapy has an acceptable safety profile and may lead to long-term control of pressure in drug-resistant hypertension patients. Other effects include significant reductions in left ventricular mass and left atrial size. The spectrum of therapeutic impact suggests that Rheos Therapy may improve long-term outcomes in drug-resistant hypertension and possibly benefit related populations. Larger-scale study in randomized, controlled trials are ongoing to verify chronic benefits.

Results of the Prospective Minnesota Study of ECHO/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) study.

BACKGROUND: Retrospective single-center studies have shown that measures of mechanical dyssynchrony before cardiac resynchronization therapy (CRT), or acute changes after CRT, predict response better than QRS duration. The Prospective Minnesota Study of Echocardiographic/TDI in Cardiac Resynchronization Therapy (PROMISE-CRT) study was a prospective multicenter study designed to determine whether acute (1 week) changes in mechanical dyssynchrony were associated with response to CRT. METHODS AND RESULTS: Nine Minnesota Heart Failure Consortium centers enrolled 71 patients with standard indications for CRT. Left ventricular (LV) size, function, and mechanical dyssynchrony (echocardiography [ECHO], tissue Doppler imaging [TDI], speckle-tracking echocardiography [STE]) as well as 6-minute walk distance and Minnesota Living with Heart Failure Questionnaire scores were measured at baseline and 3 and 6 months after CRT. Acute change in mechanical dyssynchrony was not associated with clinical response to CRT. Acute change in STE radial dyssynchrony explained 73% of the individual variation in reverse remodeling. Baseline measures of mechanical dyssynchrony were associated with reverse remodeling (but not clinical) response, with 4 measures each explaining 12% to 30% of individual variation. CONCLUSIONS: Acute changes in radial mechanical dyssynchrony, as measured by STE, and other baseline mechanical dyssynchrony measures were associated with CRT reverse remodeling. These data support the hypothesis that acute improvement in LV mechanical dyssynchrony is an important mechanism contributing to LV reverse remodeling with CRT.

Tubulin acetylation and histone deacetylase 6 activity in the lung under cyclic load.

Previous studies from our lab have demonstrated that upon exposure to physiologic levels of cyclic stretch, alveolar epithelial cells demonstrate a significant decrease in the amount of polymerized tubulin (Geiger et al., Gene Therapy 2006;13:725-731). However, not all microtubules are disassembled, although the mechanisms or implications of this were unknown. Using immunofluorescence microscopy, Western blotting, and immunohistochemistry approaches, we have compared the levels of acetylated tubulin in stretched and unstretched A549 cells and in murine lungs. In cultured cells exposed to cyclic stretch (10% change in basement membrane surface area at 0.25 Hz), nearly all of the remaining microtubules were acetylated, as demonstrated using immunofluorescence microscopy. In murine lungs ventilated for 20 minutes at 12 to 20 ml/kg followed by 48 hours of spontaneous breathing or for 3 hours at 16 to 40 ml/kg, levels of acetylated tubulin were increased in the peripheral lung. In both our in vitro and in vivo studies, we have found that mild to moderate levels of cyclic stretch significantly increases tubulin acetylation in a magnitude- and duration-dependent manner. This appears to be due to a decrease in histone deacetylase 6 activity (HDAC6), the major tubulin deacetylase. Since it has been previously shown that acetylated microtubules are positively correlated to a more stable population of microtubules, this result suggests that microtubule stability may be increased by cyclic stretch, and that tubulin acetylation is one way in which cells respond to changes in exogenous mechanical forces.

Diet revision in overweight children: effect on autonomic and vascular function.

In an effort to determine the effect of a 5-month dietary modification on measures of vascular and cardiac autonomic (cANS) function in overweight (OW) children, 15 OW children had standard non-invasive measures of vascular and cANS function assessed pre- and post intervention. Body fat percentage and cANS, but not vascular, function changed significantly after the intervention. Changes in body composition in OW children due to dietary modification alone can result in modest improvements in indices of cardiac risk.

Aerobic-exercise training improves ventilatory efficiency in overweight children.

The objective of this study was to investigate the effect of an 8-week aerobic-exercise training program on ventilatory threshold and ventilatory efficiency in overweight children. Twenty overweight children (BMI > 85th percentile) performed a graded cycle exercise test at baseline and were then randomly assigned to 8 weeks of stationary cycling (n = 10) or a nonexercising control group (n = 10). Ventilatory variables were examined at ventilatory threshold (VT), which was determined via the Dmax method. After 8 weeks, significant improvements occurred in the exercise group compared with the control group for oxygen uptake at VT (exercise = 1.03 +/- 0.13 to 1.32 +/- 0.12 L/min vs. control = 1.20 +/- 0.10 to 1.11 +/- 0.10 L/min, p < .05) and ventilatory equivalent of carbon dioxide (VE/VCO2) at VT (exercise = 32.8 +/- 0.80 to 31.0 +/- 0.53 vs. control = 30.3 +/- 0.88 to 31.7 +/- 0.91, p < .05). Aerobic-exercise training might help reverse the decrements in cardiopulmonary function observed over time in overweight children.