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Background: Cardiac contractility modulation (CCM) signals are nonexcitatory electrical signals delivered during the absolute refractory period intended to improve contraction. We previously tested the safety and efficacy of CCM in 428 NYHA functional class III/IV heart failure patients with EF #35% and narrow QRSrandomizedtooptimalmedicaltreatment(OMT)plusCCM(n5215)versusOMTalone(n5213)and found no significant effect on ventilatory anaerobic threshold (VAT), the study’s primary end point. In the present analysis, we sought to identify if there was a subgroup of patients who showed a response to CCM. Methods and Results: The protocol specified that multiregression analysis would be used to determine if baselineEF,NYHAfunctional class,pVO2,oretiologyofheartfailure influencedtheimpactofCCM onAT. Etiology and baseline pVO2 did not affect efficacy. However, baseline NYHA functional class III and EF $25% were significant predictors of increased efficacy. In this subgroup (comprising 97 OMTand 109 CCM patients, w48% of the entire population) VAT increased by 0.10 6 2.36 in CCM versus � 0.54 6 1.83 mL kg � 1 min � 1 in OMT (P 5 .03) and pVO2 increased by 0.34 6 3.11 in CCM versus � 0.97 6 2.31 (P 5 .001) at 24 weeks compared with baseline; 44% of CCM versus 23% of OMT subjects showed improvement of $1 class in NYHA functional class (P 5 .002), and 59% of CCM versus 42% of OMT subjects showed a $10-point reduction in Minnesota Living with Heart Failure Questionnaire (P 5 .01). All of these findings were similar to those seen at 50 weeks. Conclusions: The results of this retrospective hypothesis-generating analysis indicate that CCM significantlyimprovesobjectiveparametersofexercisetoleranceinasubgroupofpatientscharacterizedbynormal QRS duration, NYHA functional class III symptoms, and EF O25%. (J Cardiac Fail 2011;17:710e717)

Background: Success of cardiac resynchronization therapy (CRT) depends on altering electrical ventricular activation (VA) to achieve mechanical benefit. That increases in stimulus strength (SS) can affect VA has been demonstrated previously in cardiomyopathy patients undergoing ablation. Objective: To determine whether increasing SS can alter VA during CRT. Methods: In 71 patients with CRT devices, left ventricle (LV) pacing was performed at escalating SS. Timing from pacing stimulus to right ventricular (RV) electrogram, ECG morphology, and maximal QRS duration on 12 lead ECG were recorded. Results: Demographics: Baseline QRS duration 153 ± 25 ms, ischemic cardiomyopathy 48%, ejection fraction 24%± 7%. With increased SS, conduction time from LV to right ventricle (RV) decreased from 125 ± 56 ms to 111 ± 59 ms (P = 0.006). QRS duration decreased from 212 ± 46 ms to 194 ± 42 ms (P = 0.0002). A marked change in QRS morphology occurred in 11/71 patients (15%). The RV ring was the anode in 6, while the RV coil was the anode in 5. Sites with change in QRS morphology showed decrease in conduction time from LV to RV from 110 ± 60 ms to 64 ± 68 ms (P = 0.04). Twelve patients (16%) had diaphragmatic stimulation with increased SS. Conclusions: Increasing LV SS reduces QRS duration and conduction time from LV to RV. Recognition of significant QRS morphology change is likely clinically important during LV threshold programming to avoid unintended VA change.

Liposomal formulations have been used to encapsulate and deliver a wide variety of therapeutic and diagnostic agents. Their circulation can be prolonged by the addition of neutral, hydrophilic polymers such as poly(ethylene glycol) (PEG) to the outer surface. An extended circulation lifetime allows them to take advantage of the enhanced permeability and retention effect (EPR), resulting in increased delivery to target sites. Incorporation of PEG also prevents aggregation and aids in the formation of uniform, small mono-disperse particles. This is often accomplished with the use of PEG-lipid conjugates, PEG molecules with a hydrophobic domain to anchor them into the liposomal bilayer upon formulation. Here we present data showing that some commonly used PEG-lipids are chemically unstable due to the presence of carboxylic ester bonds. This instability limits their utility in aqueous environments common to many liposomal preparations. To address this problem, we designed and synthesized three alternative PEG-lipids. Using SPLP (PEG-stabilized liposomal vesicles encapsulating plasmid DNA) as a model system, we investigated the properties of the novel PEG-lipids. An accelerated stability study was conducted at 37 degrees C for 42 days to confirm chemical stability and an in vivo model was used to assess the pharmacokinetics, toxicity and activity of the SPLP. We show that the novel PEG-lipids are more stable in liposomal formulation, less toxic upon systemic administration, and accordingly, are suitable replacements for the PEG-lipids described previously.

Prior research has shown a higher incidence of a repressive adaptive style in children with cancer. To explore whether repressive adaptation in this population is premorbid or reactive, adaptive style was assessed longitudinally in children with cancer at the time of diagnosis and at 6 months and 1 year after diagnosis. Comparison groups included healthy children and children with other serious but nonmalignant chronic illnesses. At diagnosis, children with cancer showed a higher incidence of a repressive adaptive style than healthy children, and the incidence of repressive adaptation remained stable over time. Children with other chronic illnesses also showed levels of repressive adaptive style comparable to the cancer group. These findings suggest a shift toward repressiveness in response to the diagnosis of cancer that is then maintained over time and necessitate further examination of the health consequences of adaptive style in this population.