Informed consent in clinical research: Consensus recommendations for reform identified by an expert interview panel.

BACKGROUND: Informed consent is the cornerstone for protection of human subjects in clinical trials. However, a growing body of evidence suggests that reform of the informed consent process in the United States is needed. METHODS: The Clinical Trials Transformation Initiative conducted interviews with 25 experienced observers of the informed consent process to identify limitations and actionable recommendations for change. RESULTS: There was broad consensus that current practices often fail to meet the ethical obligation to inform potential research participants during the informed consent process. The most frequent single recommendation, which would affect all participants in federally regulated clinical research, was reform of the informed consent document. The interviews also identified the need for reform of clinical research review by institutional review boards, including transitioning to a single institutional review board for multi-site trials. CONCLUSION: The consensus recommendations from the interviewees provide a framework for meaningful change in the informed consent process. Although some proposed changes are feasible for rapid implementation, others such as substantive reform of the informed consent document may require change in federal regulations.

Xenografted adult human mesenchymal stem cells provide a platform for sustained biological pacemaker function in canine heart.

BACKGROUND: Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the "dose" of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged pacemakers. METHODS AND RESULTS: A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression. I(HCN2) was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic pacemakers. Studies encompassed 6 weeks. I(HCN2) for all cells was 32.1+/-1.3 pA/pF (mean+/-SE) at -150 mV. Pacemaker function in intact dogs required 10 to 12 days to fully stabilize and persisted consistently through day 42 in dogs receiving > or =700,000 hMSCs (approximately 40% of which carried current). Rhythms were catecholamine responsive. Tissues from animals killed at 42 days manifested neither apoptosis nor humoral or cellular rejection. CONCLUSIONS: hMSCs provide a means for administering catecholamine-responsive biological pacemakers that function stably for 6 weeks and manifest no cellular or humoral rejection at that time. Cell doses >700,000 are sufficient for pacemaking when administered to left ventricular myocardium.

Development, validation, and application of a microsimulation model to predict stroke and mortality in medically managed asymptomatic patients with significant carotid artery stenosis.

OBJECTIVE: To develop a model to predict stroke-free survival and mortality over a multiyear time frame for a trial-excluded population of medically managed asymptomatic patients with significant carotid artery stenosis. METHODS: We calibrated, validated, and applied a Monte Carlo microsimulation model. For calibration we adjusted general-population mortality and stroke risks to capture these risks specific to asymptomatic carotid stenosis patients. For validation, we compared model-predicted and actual stroke-free survival curves and stroke counts from a population of comparable patients. For application, the validated model predicted stroke-free survival for a hypothetical medically managed arm of a recent single-arm carotid revascularization trial. RESULTS: For each month in the 60-month time frame, the model-predicted and actual calibration trial stroke-free survival curves were not statistically different (P > 0.62). In validation, the calibrated model's stroke-free survival curvematched the actual curve from an independent population; beyond 24 months, the model-predicted and actual curves were not statistically different (P > 0.32). We also compared model-predicted and actual number of strokes from the independent trial. The model predicted 187.25 strokes (95% confidence interval 161.49-213.01), while the actual number was 171.6, within 1.22 standard deviations of the simulated mean. CONCLUSIONS: Given the absence of medically managed populations in recent carotid stenosis trials, our model can estimate stroke-free survival and mortality data for these patients. The model may also estimate the effectiveness of novel medical and procedural therapies for stroke prevention. These effectiveness estimates can inform the development of policies, guidelines, or cost-effectiveness analyses when only single-arm trial data exist.

Contractile reserve and calcium regulation are depressed in myocytes from chronically unloaded hearts.

BACKGROUND: Chronic cardiac unloading of the normal heart results in the reduction of left ventricular (LV) mass, but effects on myocyte contractile function are not known. METHODS AND RESULTS: Cardiac unloading and reduction in LV mass were induced by heterotopic heart transplantation to the abdominal aorta in isogenic rats. Contractility and [Ca(2+)](i) regulation in LV myocytes were studied at both 2 and 5 weeks after transplantation. Native in situ hearts from recipient animals were used as the controls for all experiments. Contractile function indices in myocytes from 2-week unloaded and native (control) hearts were similar under baseline conditions (0.5 Hz, 1.2 mmol/L [Ca(2+)](o), and 36 degrees C) and in response to stimulation with high [Ca(2+)](o) (range 2.5 to 4.0 mmol/L). In myocytes from 5-week unloaded hearts, there were no differences in fractional cell shortening and peak-systolic [Ca(2+)](i) at baseline; however, time to 50% relengthening and time to 50% decline in [Ca(2+)](i) were prolonged compared with controls. Severe defects in fractional cell shortening and peak-systolic [Ca(2+)](i) were elicited in myocytes from 5-week unloaded hearts in response to high [Ca(2+)](o). However, there were no differences in the contractile response to isoproterenol between myocytes from unloaded and native hearts. In 5-week unloaded hearts, but not in 2-week unloaded hearts, LV protein levels of phospholamban were increased (345% of native heart values). Protein levels of sarcoplasmic reticulum Ca(2+) ATPase and the Na(+)/Ca(2+) exchanger were not changed. CONCLUSIONS: Chronic unloading of the normal heart caused a time-dependent depression of myocyte contractile function, suggesting the potential for impaired performance in states associated with prolonged cardiac atrophy.

Neuregulins regulate cardiac parasympathetic activity: muscarinic modulation of beta-adrenergic activity in myocytes from mice with neuregulin-1 gene deletion.

BACKGROUND: Neuregulins are required for maintenance of acetylcholine receptor-inducing activity of nicotinic receptors in neurons and skeletal muscle, but effects of neuregulins on muscarinic receptors are not known. In the normal heart, parasympathetic activation counterbalances beta-adrenergic activation. To test the hypothesis that neuregulins modify parasympathetic function in the heart, we studied cardiomyocytes from mice heterozygous for neuregulin-1 gene deletion (NRG-1+/-) and examined the effects of beta-adrenergic stimulation on contractility in the presence and absence of the muscarinic agonist carbachol. METHODS AND RESULTS: We evaluated contraction and intracellular Ca2+ transients ([Ca2+]i) in left ventricular (LV) myocytes loaded with Fluo-3 from NRG-1+/- and wild-type (WT) mice. Under baseline conditions (0.5 Hz, 1.5 mmol/L [Ca2+]o, 25 degrees C), characteristics of myocyte contraction/relengthening and systolic/diastolic [Ca2+]i were not different between WT and NRG-1+/- mice. The steady-state increases in fractional shortening (FS) and peak-systolic [Ca2+]i in response to isoproterenol were similar in both groups. In WT myocytes stimulated with isoproterenol, carbachol decreased FS, peak-systolic [Ca2+]i, and cAMP levels. In NRG-1+/- myocytes, carbachol did not attenuate either FS or peak-systolic [Ca2+]i, associated with the failure to decrease cAMP levels. Investigation of muscarinic receptor signaling showed no difference of LV protein levels of muscarinic M2 receptors or G protein Galpha(i1,2), Galpha(i3), and Galpha(o) subunits. CONCLUSIONS: Cardiomyocytes deficient in neuregulin signaling are unable to adequately counterbalance beta-adrenergic activation by inhibitory parasympathetic activity. This mechanism may contribute to the known increased risk of heart failure in injured human hearts when neuregulin signaling is suppressed.

Effects of tai chi mind-body movement therapy on functional status and exercise capacity in patients with chronic heart failure: a randomized controlled trial.

PURPOSE: To examine the effects of a 12-week tai chi program on quality of life and exercise capacity in patients with heart failure. METHODS: Thirty patients with chronic stable heart failure and left ventricular ejection fraction < or =40% (mean [+/- SD] age, 64 +/- 13 years; mean baseline ejection fraction, 23% +/- 7%; median New York Heart Association class, 2 [range, 1 to 4]) were randomly assigned to receive usual care (n = 15), which included pharmacologic therapy and dietary and exercise counseling, or 12 weeks of tai chi training (n = 15) in addition to usual care. Tai chi training consisted of a 1-hour class held twice weekly. Primary outcomes included quality of life and exercise capacity. Secondary outcomes included serum B-type natriuretic peptide and plasma catecholamine levels. For 3 control patients with missing data items at 12 weeks, previous values were carried forward. RESULTS: At 12 weeks, patients in the tai chi group showed improved quality-of-life scores (mean between-group difference in change, -25 points, P = 0.001), increased distance walked in 6 minutes (135 meters, P = 0.001), and decreased serum B-type natriuretic peptide levels (-138 pg/mL, P = 0.03) compared with patients in the control group. A trend towards improvement was seen in peak oxygen uptake. No differences were detected in catecholamine levels. CONCLUSION: Tai chi may be a beneficial adjunctive treatment that enhances quality of life and functional capacity in patients with chronic heart failure who are already receiving standard medical therapy.