Objectives This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS ...(CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction) trial. Background Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown. Methods Autologous CDCs (12.5 to 25 × 106 ) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients. Results In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI. Conclusions Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction CADUCEUS; NCT00893360 )
Summary Background Cardiosphere-derived cells (CDCs) reduce scarring after myocardial infarction, increase viable myocardium, and boost cardiac function in preclinical models. We aimed to assess ...safety of such an approach in patients with left ventricular dysfunction after myocardial infarction. Methods In the prospective, randomised CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction (CADUCEUS) trial, we enrolled patients 2–4 weeks after myocardial infarction (with left ventricular ejection fraction of 25–45%) at two medical centres in the USA. An independent data coordinating centre randomly allocated patients in a 2:1 ratio to receive CDCs or standard care. For patients assigned to receive CDCs, autologous cells grown from endomyocardial biopsy specimens were infused into the infarct-related artery 1·5–3 months after myocardial infarction. The primary endpoint was proportion of patients at 6 months who died due to ventricular tachycardia, ventricular fibrillation, or sudden unexpected death, or had myocardial infarction after cell infusion, new cardiac tumour formation on MRI, or a major adverse cardiac event (MACE; composite of death and hospital admission for heart failure or non-fatal recurrent myocardial infarction). We also assessed preliminary efficacy endpoints on MRI by 6 months. Data analysers were masked to group assignment. This study is registered with ClinicalTrials.gov , NCT00893360. Findings Between May 5, 2009, and Dec 16, 2010, we randomly allocated 31 eligible participants of whom 25 were included in a per-protocol analysis (17 to CDC group and eight to standard of care). Mean baseline left ventricular ejection fraction (LVEF) was 39% (SD 12) and scar occupied 24% (10) of left ventricular mass. Biopsy samples yielded prescribed cell doses within 36 days (SD 6). No complications were reported within 24 h of CDC infusion. By 6 months, no patients had died, developed cardiac tumours, or MACE in either group. Four patients (24%) in the CDC group had serious adverse events compared with one control (13%; p=1·00). Compared with controls at 6 months, MRI analysis of patients treated with CDCs showed reductions in scar mass (p=0·001), increases in viable heart mass (p=0·01) and regional contractility (p=0·02), and regional systolic wall thickening (p=0·015). However, changes in end-diastolic volume, end-systolic volume, and LVEF did not differ between groups by 6 months. Interpretation We show intracoronary infusion of autologous CDCs after myocardial infarction is safe, warranting the expansion of such therapy to phase 2 study. The unprecedented increases we noted in viable myocardium, which are consistent with therapeutic regeneration, merit further assessment of clinical outcomes. Funding US National Heart, Lung and Blood Institute and Cedars-Sinai Board of Governors Heart Stem Cell Center.
In an international study, the authors evaluated the diagnostic performance of coronary angiography by means of 64-row multidetector computed tomography (CT). The technique accurately identified ...obstructive coronary lesions, but the positive and negative predictive values were inadequate for this technology to replace conventional coronary angiography with the use of contrast medium.
In this study, coronary angiography by means of 64-row multidetector computed tomography (CT) accurately identified obstructive coronary lesions, but the positive and negative predictive values were inadequate for this technology to replace conventional coronary angiography.
Coronary artery disease is the leading cause of death in the United States.
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In symptomatic patients, diagnosis of the presence and severity of coronary artery disease is critical for determining appropriate clinical management.
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Indirect evaluation of coronary stenosis, such as through stress testing, has limited diagnostic ability as compared with direct conventional coronary angiography.
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Conventional coronary angiography reveals the extent, location, and severity of coronary obstructive lesions, which are potent predictors of outcome,
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and identifies high-risk patients who may benefit from revascularization.
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Thus, invasive coronary angiography, despite the associated risks, remains the . . .
A total of 1509 patients who had legacy pacemakers or defibrillators underwent 2103 MRIs according to a prespecified safety protocol. No long-term clinically significant adverse events were reported.
Cardiosphere-derived cells (CDCs) isolated from human endomyocardial biopsies reduce infarct size and improve cardiac function in mice. Safety and efficacy testing in large animals is necessary for ...clinical translation.
Mesenchymal stem cells, which resemble CDCs in size and thrombogenicity, have been associated with infarction after intracoronary infusion. To maximize CDC engraftment while avoiding infarction, we optimized the infusion protocol in 19 healthy pigs. A modified cocktail of CDCs in calcium-free PBS, 100 U/mL of heparin, and 250 microg/mL of nitroglycerin eliminated infusion-related infarction. Subsequent infusion experiments in 17 pigs with postinfarct left ventricular dysfunction showed CDC doses > or =10(7) but <2.5 x 10(7) result in new myocardial tissue formation without infarction. In a pivotal randomized study, 7 infarcted pigs received 300,000 CDCs/kg (approximately 10(7) total) and 7 received placebo (vehicle alone). Cardiac magnetic resonance imaging 8 weeks later showed CDC treatment decreased relative infarct size (19.2% to 14.2% of left ventricle infarcted, P=0.01), whereas placebo did not (17.7% to 15.3%, P=0.22). End-diastolic volume increased in placebo, but not in CDC-treated animals. Hemodynamically, the rate of pressure change (dP/dt) maximum and dP/dt minimum were significantly better with CDC infusion. There was no difference between groups in the ability to induce ventricular tachycardia, nor was there any tumor or ectopic tissue formation.
Intracoronary delivery of CDCs in a preclinical model of postinfarct left ventricular dysfunction results in formation of new cardiac tissue, reduces relative infarct size, attenuates adverse remodeling, and improves hemodynamics. The evidence of efficacy without obvious safety concerns at 8 weeks of follow-up motivates human studies in patients after myocardial infarction and in chronic ischemic cardiomyopathy.
This study sought to report full 1-year results, detailed magnetic resonance imaging analysis, and determinants of efficacy in the prospective, randomized, controlled CADUCEUS (CArdiosphere-Derived ...aUtologous stem CElls to reverse ventricUlar dySfunction) trial.
Cardiosphere-derived cells (CDCs) exerted regenerative effects at 6 months in the CADUCEUS trial. Complete results at the final 1-year endpoint are unknown.
Autologous CDCs (12.5 to 25 × 10(6)) grown from endomyocardial biopsy specimens were infused via the intracoronary route in 17 patients with left ventricular dysfunction 1.5 to 3 months after myocardial infarction (MI) (plus 1 infused off-protocol 14 months post-MI). Eight patients were followed as routine-care control patients.
In 13.4 months of follow-up, safety endpoints were equivalent between groups. At 1 year, magnetic resonance imaging revealed that CDC-treated patients had smaller scar size compared with control patients. Scar mass decreased and viable mass increased in CDC-treated patients but not in control patients. The single patient infused 14 months post-MI responded similarly. CDC therapy led to improved regional function of infarcted segments compared with control patients. Scar shrinkage correlated with an increase in viability and with improvement in regional function. Scar reduction correlated with baseline scar size but not with a history of temporally remote MI or time from MI to infusion. The changes in left ventricular ejection fraction in CDC-treated subjects were consistent with the natural relationship between scar size and ejection fraction post-MI.
Intracoronary administration of autologous CDCs did not raise significant safety concerns. Preliminary indications of bioactivity include decreased scar size, increased viable myocardium, and improved regional function of infarcted myocardium at 1 year post-treatment. These results, which are consistent with therapeutic regeneration, merit further investigation in future trials. (CArdiosphere-Derived aUtologous stem CElls to reverse ventricUlar dySfunction CADUCEUS; NCT00893360).
The impact of surface trabeculae and papillary muscles on the hemodynamics of the left ventricle (LV) is investigated using numerical simulations. Simulations of ventricular flow are conducted for ...two different models of the LV derived from high-resolution cardiac computed tomography (CT) scans using an immersed boundary method-based flow solver. One model comprises a trabeculated left ventricle (TLV) that includes both trabeculae and papillary muscles, while the second model has a smooth left ventricle that is devoid of any of these surface features. Results indicate that the trabeculae and papillary muscles significantly disrupt the vortices that develop during early filling in the TLV model. Large recirculation zones are found to form in the wake of the papillary muscles; these zones enhance the blockage provided by the papillary muscles and create a path for the mitral jet to penetrate deeper into the ventricular apex during diastole. During systole, the trabeculae enhance the apical washout by ‘squeezing’ the flow from the apical region. Finally, the trabeculae enhance viscous dissipation rate of the ventricular flow, but this effect is not significant in the overall power budget.
RATIONALE:Although accumulating data support the efficacy of intramyocardial cell-based therapy to improve left ventricular (LV) function in patients with chronic ischemic cardiomyopathy undergoing ...CABG, the underlying mechanism and impact of cell injection site remain controversial. Mesenchymal stem cells (MSCs) improve LV structure and function through several effects including reducing fibrosis, neoangiogenesis, and neomyogenesis.
OBJECTIVE:To test the hypothesis that the impact on cardiac structure and function after intramyocardial injections of autologous MSCs results from a concordance of prorecovery phenotypic effects.
METHODS AND RESULTS:Six patients were injected with autologous MSCs into akinetic/hypokinetic myocardial territories not receiving bypass graft for clinical reasons. MRI was used to measure scar, perfusion, wall thickness, and contractility at baseline, at 3, 6, and 18 months and to compare structural and functional recovery in regions that received MSC injections alone, revascularization alone, or neither. A composite score of MRI variables was used to assess concordance of antifibrotic effects, perfusion, and contraction at different regions. After 18 months, subjects receiving MSCs exhibited increased LV ejection fraction (+9.4±1.7%, P=0.0002) and decreased scar mass (−47.5±8.1%; P<0.0001) compared with baseline. MSC-injected segments had concordant reduction in scar size, perfusion, and contractile improvement (concordant score2.93±0.07), whereas revascularized (0.5±0.21) and nontreated segments (−0.07±0.34) demonstrated nonconcordant changes (P<0.0001 versus injected segments).
CONCLUSIONS:Intramyocardial injection of autologous MSCs into akinetic yet nonrevascularized segments produces comprehensive regional functional restitution, which in turn drives improvement in global LV function. These findings, although inconclusive because of lack of placebo group, have important therapeutic and mechanistic hypothesis-generating implications.
CLINICAL TRIAL REGISTRATION:URLhttp://clinicaltrials.gov/show/NCT00587990. Unique identifierNCT00587990.
Objectives The goal of this study was to explore the feasibility of targeted imaging of the angiotensin II type 1 receptor (AT1R) in cardiac tissue, using clinical hybrid positron emission ...tomography/computed tomography (PET/CT). Background AT1R is an attractive imaging target due to its key role in various cardiac pathologies, including post-infarct left ventricular remodeling. Methods Using the novel AT1R ligand 11 C-KR31173, dynamic PET/CT was performed in young farm pigs under healthy conditions (n = 4) and 3 to 4 weeks after experimental myocardial infarction (n = 5). Ex vivo validation was carried out by immunohistochemistry and polymerase chain reaction. First-in-man application was performed in 4 healthy volunteers at baseline and under AT1R blocking. Results In healthy pigs, myocardial KR31173 retention was detectable, regionally homogeneous, and specific for AT1R, as confirmed by blocking experiments. Metabolism in plasma was low (85 ± 2% of intact tracer after 60 min). After myocardial infarction, KR31173 retention, corrected for regional perfusion, revealed AT1R up-regulation in the infarct area relative to remote myocardium, whereas retention was elevated in both regions when compared with myocardium of healthy controls (8.7 ± 0.8% and 7.1 ± 0.3%/min vs. 5.8 ± 0.4%/min for infarct and remote, respectively, vs. healthy controls; p < 0.01 each). Postmortem analysis confirmed AT1R up-regulation in remote and infarct tissue. First-in-man application was safe, and showed detectable and specific myocardial KR31173 retention, albeit at a lower level than pigs (left ventricular average retention: 1.2 ± 0.1%/min vs. 4.4 ± 1.2%/min for humans vs. pigs; p = 0.04). Conclusions Noninvasive imaging of cardiac AT1R expression is feasible using clinical PET/CT technology. Results provide a rationale for broader clinical testing of AT1R-targeted molecular imaging.
Magnetic resonance imaging (MRI) is avoided in most patients with implanted cardiac devices because of safety concerns.
To define the safety of a protocol for MRI at the commonly used magnetic ...strength of 1.5 T in patients with implanted cardiac devices.
Prospective nonrandomized trial. (ClinicalTrials.gov registration number: NCT01130896) SETTING: One center in the United States (94% of examinations) and one in Israel.
438 patients with devices (54% with pacemakers and 46% with defibrillators) who underwent 555 MRI studies.
Pacing mode was changed to asynchronous for pacemaker-dependent patients and to demand for others. Tachyarrhythmia functions were disabled. Blood pressure, electrocardiography, oximetry, and symptoms were monitored by a nurse with experience in cardiac life support and device programming who had immediate backup from an electrophysiologist.
Activation or inhibition of pacing, symptoms, and device variables.
In 3 patients (0.7% 95% CI, 0% to 1.5%), the device reverted to a transient back-up programming mode without long-term effects. Right ventricular (RV) sensing (median change, 0 mV interquartile range {IQR}, -0.7 to 0 V) and atrial and right and left ventricular lead impedances (median change, -2 Ω IQR, -13 to 0 Ω, -4 Ω IQR, -16 to 0 Ω, and -11 Ω IQR, -40 to 0 Ω, respectively) were reduced immediately after MRI. At long-term follow-up (61% of patients), decreased RV sensing (median, 0 mV, IQR, -1.1 to 0.3 mV), decreased RV lead impedance (median, -3 Ω, IQR, -29 to 15 Ω), increased RV capture threshold (median, 0 V, IQR, 0 to 0.2 Ω), and decreased battery voltage (median, -0.01 V, IQR, -0.04 to 0 V) were noted. The observed changes did not require device revision or reprogramming.
Not all available cardiac devices have been tested. Long-term in-person or telephone follow-up was unavailable in 43 patients (10%), and some data were missing. Those with missing long-term capture threshold data had higher baseline right atrial and right ventricular capture thresholds and were more likely to have undergone thoracic imaging. Defibrillation threshold testing and random assignment to a control group were not performed.
With appropriate precautions, MRI can be done safely in patients with selected cardiac devices. Because changes in device variables and programming may occur, electrophysiologic monitoring during MRI is essential.
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