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Effect of transendocardial delivery of autologous bone marrow mononuclear cells on functional capacity, left ventricular function, and perfusion in chronic heart failure: the FOCUS-CCTRN trial.

CONTEXT Previous studies using autologous bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy have demonstrated safety and suggested efficacy. OBJECTIVE To determine if administration of BMCs through transendocardial injections improves myocardial perfusion, reduces left ventricular end-systolic volume (LVESV), or enhances maximal oxygen consumption in patients with coronary artery disease or LV dysfunction, and limiting heart failure or angina. DESIGN, SETTING, AND PATIENTS A phase 2 randomized double-blind, placebo-controlled trial of symptomatic patients (New York Heart Association classification II-III or Canadian Cardiovascular Society classification II-IV) with a left ventricular ejection fraction of 45% or less, a perfusion defect by single-photon emission tomography (SPECT), and coronary artery disease not amenable to revascularization who were receiving maximal medical therapy at 5 National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network (CCTRN) sites between April 29, 2009, and April 18, 2011. INTERVENTION Bone marrow aspiration (isolation of BMCs using a standardized automated system performed locally) and transendocardial injection of 100 million BMCs or placebo (ratio of 2 for BMC group to 1 for placebo group). MAIN OUTCOME MEASURES Co-primary end points assessed at 6 months: changes in LVESV assessed by echocardiography, maximal oxygen consumption, and reversibility on SPECT. Phenotypic and functional analyses of the cell product were performed by the CCTRN biorepository core laboratory. RESULTS Of 153 patients who provided consent, a total of 92 (82 men; average age: 63 years) were randomized (n = 61 in BMC group and n = 31 in placebo group). Changes in LVESV index (-0.9 mL/m(2) [95% CI, -6.1 to 4.3]; P = .73), maximal oxygen consumption (1.0 [95% CI, -0.42 to 2.34]; P = .17), and reversible defect (-1.2 [95% CI, -12.50 to 10.12]; P = .84) were not statistically significant. There were no differences found in any of the secondary outcomes, including percent myocardial defect, total defect size, fixed defect size, regional wall motion, and clinical improvement. CONCLUSION Among patients with chronic ischemic heart failure, transendocardial injection of autologous BMCs compared with placebo did not improve LVESV, maximal oxygen consumption, or reversibility on SPECT. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00824005.

Effect of Intracoronary Delivery of Autologous Bone Marrow Mononuclear Cells 2 to 3 Weeks Following Acute Myocardial Infarction on Left Ventricular Function The LateTIME Randomized Trial

CONTEXT Clinical trial results suggest that intracoronary delivery of autologous bone marrow mononuclear cells (BMCs) may improve left ventricular (LV) function when administered within the first week following myocardial infarction (MI). However, because a substantial number of patients may not present for early cell delivery, the efficacy of autologous BMC delivery 2 to 3 weeks post-MI warrants investigation. OBJECTIVE To determine if intracoronary delivery of autologous BMCs improves global and regional LV function when delivered 2 to 3 weeks following first MI. DESIGN, SETTING, AND PATIENTS A randomized, double-blind, placebo-controlled trial (LateTIME) of the National Heart, Lung, and Blood Institute-sponsored Cardiovascular Cell Therapy Research Network of 87 patients with significant LV dysfunction (LV ejection fraction [LVEF] ≤45%) following successful primary percutaneous coronary intervention (PCI) between July 8, 2008, and February 28, 2011. INTERVENTIONS Intracoronary infusion of 150 × 10(6) autologous BMCs (total nucleated cells) or placebo (BMC:placebo, 2:1) was performed within 12 hours of bone marrow aspiration after local automated cell processing. MAIN OUTCOME MEASURES Changes in global (LVEF) and regional (wall motion) LV function in the infarct and border zone between baseline and 6 months, measured by cardiac magnetic resonance imaging. Secondary end points included changes in LV volumes and infarct size. RESULTS A total of 87 patients were randomized (mean [SD] age, 57 [11] years; 83% men). Harvesting, processing, and intracoronary delivery of BMCs in this setting was feasible. Change between baseline and 6 months in the BMC group vs placebo for mean LVEF (48.7% to 49.2% vs 45.3% to 48.8%; between-group mean difference, -3.00; 95% CI, -7.05 to 0.95), wall motion in the infarct zone (6.2 to 6.5 mm vs 4.9 to 5.9 mm; between-group mean difference, -0.70; 95% CI, -2.78 to 1.34), and wall motion in the border zone (16.0 to 16.6 mm vs 16.1 to 19.3 mm; between-group mean difference, -2.60; 95% CI, -6.03 to 0.77) were not statistically significant. No significant change in LV volumes and infarct volumes was observed; both groups decreased by a similar amount at 6 months vs baseline. CONCLUSION Among patients with MI and LV dysfunction following reperfusion with PCI, intracoronary infusion of autologous BMCs vs intracoronary placebo infusion, 2 to 3 weeks after PCI, did not improve global or regional function at 6 months. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00684060.

Frequent Diagnostic Errors in Cardiac PET/CT Due to Misregistration of CT Attenuation and Emission PET Images: A Definitive Analysis of Causes, Consequences, and Corrections

Cardiac PET combined with CT is rapidly expanding despite artifactual defects and false-positive results due to misregistration of PET and CT attenuation correction data—the frequency, cause, and correction of which remain undetermined. Methods: Two hundred fifty-nine consecutive patients underwent diagnostic rest–dipyridamole myocardial perfusion PET/CT using 82Rb, a 16-slice PET/CT scanner, helical CT attenuation correction with breathing and also at end-expiratory breath-hold, and averaged cine CT data during breathing. Misregistration on superimposed PET/CT fusion images was objectively measured in millimeters and correlated with associated quantitative size and severity of PET defects. Misregistration artifacts were defined as PET defects with corresponding misregistration on helical CT-PET fusion images that resolved after correct coregistration using a repeat CT scan, cine CT averaged attenuation during normal breathing, or shifted cine CT data that coregistered with PET data. Results: Misregistration of standard helical CT PET images caused artifactual PET defects in 103 of 259 (40%) patients that were moderate to severe in 59 (23%) (P = 0.0000) and quantitatively normalized on cine or shifted cine CT PET (P = 0.0000). Quantitative misregistration was a powerful predictor of artifact size and severity (P = 0.0000), particularly for transaxial misregistration >6 mm occurring in anterior or lateral areas in 76%, in inferior areas in 16%, and at the apex in 8% of 103 artifactual defects. Conclusion: Misregistration of helical CT attenuation and PET emission images causes artifactual defects with false-positive results in 40% of patients that normalize on cine CT PET using averaged CT attenuation data during normal breathing comparable to normal breathing during PET emission scanning and shifting cine CT images to coregister visually with PET.

Effect of percutaneous mitral repair with the MitraClip ® device on mitral valve area and gradient

AIMS Percutaneous repair of mitral regurgitation (MR) by leaflet apposition using a clip deployed via transseptal catheterisation is undergoing evaluation. METHODS AND RESULTS In order to detect the potential for clinically significant left ventricular inflow obstruction after percutaneous repair, we measured mitral valve area (MVA) and mean transmitral gradient (MVG) echocardiographically in 96 patients implanted with a clip followed for up to 24 months. By planimetry, the mean MVA decreased from 6.0 +/- 1.3 cm2 to 3.6 +/- 1.2 cm2 (p < 0.05) (range 1.9 to 7.6 cm2) after clip placement, and remained unchanged after 24 months of follow-up (3.5 +/- 0.8 cm2). The mean MVG increased after clip placement from 1.7 +/- 0.9 mmHg to 4.1 +/- 2.2 mmHg (p < 0.05), and did not increase further to 24 months (3.8 +/- 1.9 mmHg). There were no differences in MVA or MVG between patients who received 1-clip (69%) and those receiving 2-clips (31%). Patients with functional MR (23%) had a slightly smaller MVA, both at baseline and after clip placement, but did not differ from degenerative MR patients at later follow-up. After 2 years of follow-up, no patient required surgery for LV inflow obstruction. CONCLUSIONS Mitral repair with the MitraClip device for MR decreases MVA without significant mitral obstruction. After 2 years of follow-up, no patient required surgery for LV inflow obstruction, and these results were not influenced by the use of more than 1 clip or the aetiology of MR.

Reducing Radiation Dose in Rest–Stress Cardiac PET/CT by Single Poststress Cine CT for Attenuation Correction: Quantitative Validation

Cardiac PET/CT is optimized by cine CT with dedicated shift software for manual correction of attenuation–emission misregistration. Separate rest and stress CT scans incur greater radiation dose to patients than does standard helical PET/CT or “pure” PET using rotating rod attenuation sources. To reduce radiation dose, we tested quantitative accuracy of using a single poststress cine CT attenuation scan for reconstructing rest perfusion images to eliminate resting CT attenuation scans. Methods: A total of 250 consecutive patients underwent diagnostic rest-dipyridamole myocardial perfusion PET/CT with 82Rb and a 16-slice PET/CT scanner using averaged cine CT attenuation data during breathing at rest and stress. After correcting for any attenuation–emission misregistration, we quantitatively compared resting perfusion images reconstructed using rest cine CT attenuation data with the same resting emission data reconstructed with poststress cine CT attenuation data. Automated software quantifying average regional quadrant activity, severity, size, and combined size and severity of perfusion defects was used for this comparison. Results: Resting perfusion images reconstructed using rest cine CT attenuation data were quantitatively comparable to resting images reconstructed with poststress cine CT attenuation data with no clinically significant differences. Twenty-five (10%) of 250 cases required shifting of stress cine CT attenuation data to achieve optimal attenuation–emission coregistration with resting perfusion data. Eliminating rest CT attenuation scans reduced CT radiation dose by 50% below rest-plus-stress cine CT protocols. Conclusion: Resting perfusion images reconstructed using poststress cine CT attenuation data are quantitatively comparable to resting images reconstructed with resting cine CT attenuation data. Eliminating the rest CT scan reduces CT radiation dose by 50%.

Quantification of myocardial segmental function in acute and chronic ischemic heart disease and implications for cardiovascular cell therapy trials: A review from the NHLBI-cardiovascular cell therapy research network

Global left ventricular (LV) ejection fraction (LVEF) has been used as a measure of improvement in LV function following cell therapy. Although the impact of cell therapy on LVEF in short- and long-term follow-up has been generally positive, there is concern that research evaluating regional therapeutics (e.g., cell or gene therapy) may require analysis of regional LV function localized to the site of intervention. Regional LV assessment is traditionally performed with qualitative or quantitative analysis of wall thickening within 16 myocardial segments, but advances in noninvasive imaging permit an increasingly more detailed and accurate evaluation of LV function. Wall-thickness measurements can now include evaluation of over 1,000 myocardial segments. In addition to higher resolution measures of wall thickening, automated assessments of myocardial segment deformation, such as strain imaging, exist. Strain imaging allows for direct evaluation of the mechanical properties that may improve following regional therapeutic intervention. Improvements in regional LV function may also be assessed by determining regional ejection fraction (EF). Regional EF offers the advantage of summarizing the end result of all of the complex deformations in the adjacent myocardial segments. Although regional EF and strain imaging, as compared with wall thickening, enhance detection of improvement in complex measures of regional myocardial function, it remains unclear whether such measures are better able to predict meaningful improvement in clinical outcomes.

Ischemic time is a better predictor than door‐to‐balloon time for mortality and infarct size in ST‐elevation myocardial infarction

Current guidelines for ST‐elevation myocardial infarction (STEMI) recommend early revascularization with optimal ischemic time (IT) < 120 min and door‐to‐balloon (D2B) time < 90 min. The focus of most studies has been D2B time, while IT is not frequently reported. We tested the hypothesis that total IT is a better predictor than D2B time for mortality and infarct size.

Eosinophilic pericarditis and myocarditis

A 58-year-old African-American woman with long-standing asthma presented with a 1 month history of severe dyspnea on exertion, orthopnea, and weight loss. One week before hospitalization, she could only sleep sitting in a chair. She was found to have 50% eosinophils on peripheral blood smear …

Quantification of Myocardial Segmental Function in Acute and Chronic Ischemic Heart Disease and Implications for Cardiovascular Cell Therapy Trials

Global left ventricular (LV) ejection fraction (LVEF) has been used as a measure of improvement in LV function following cell therapy. Although the impact of cell therapy on LVEF in short- and long-term follow-up has been generally positive, there is concern that research evaluating regional therapeutics (e.g., cell or gene therapy) may require analysis of regional LV function localized to the site of intervention. Regional LV assessment is traditionally performed with qualitative or quantitative analysis of wall thickening within 16 myocardial segments, but advances in noninvasive imaging permit an increasingly more detailed and accurate evaluation of LV function. Wall-thickness measurements can now include evaluation of over 1,000 myocardial segments. In addition to higher resolution measures of wall thickening, automated assessments of myocardial segment deformation, such as strain imaging, exist. Strain imaging allows for direct evaluation of the mechanical properties that may improve following regional therapeutic intervention. Improvements in regional LV function may also be assessed by determining regional ejection fraction (EF). Regional EF offers the advantage of summarizing the end result of all of the complex deformations in the adjacent myocardial segments. Although regional EF and strain imaging, as compared with wall thickening, enhance detection of improvement in complex measures of regional myocardial function, it remains unclear whether such measures are better able to predict meaningful improvement in clinical outcomes.

Restrictive Left Ventricular Filling Pattern with Preserved Systolic Function Assessed by Doppler Echocardiography: Clinical, Echocardiographic and Prognostic Implications

From an echocardiographic laboratory database, echocardiographic characteristics of clinical and cardiovascular mortality were compared in patients with restrictive pattern of left ventricular filling (RPLVF) and left ventricular ejection fraction (LVEF) >50% (n = 36), with patients with RPLVF and LVEF <50% (n = 120) and echocardiographic controls (n = 160). Preserved LVEF was found in 21% of the patients with RPLVF. Mortality in patients with RPLVF was worst compared with echocardiographic controls regardless of their underlying LVEF after 2.7 ± 1 years of follow-up. Patients with RPLVF had distinctive predictors of cardiovascular death, with clinical and echocardiographic characteristics according to their LVEF.