Does transendocardial injection of mesenchymal stem cells improve myocardial function locally or globally?: An analysis from the Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis (POSEIDON) randomized trial.

RATIONALE: Transendocardial stem cell injection (TESI) with mesenchymal stem cells improves remodeling in chronic ischemic cardiomyopathy, but the effect of the injection site remains unknown. OBJECTIVE: To address whether TESI exerts its effects at the site of injection only or also in remote areas, we hypothesized that segmental myocardial scar and segmental ejection fraction improve to a greater extent in injected than in noninjected segments. METHODS AND RESULTS: Biplane ventriculographic and endocardial tracings were recorded. TESI was guided to 10 sites in infarct-border zones. Sites were mapped according to the 17-myocardial segment model. As a result, 510 segments were analyzed in 30 patients before and 13 months after TESI. Segmental early enhancement defect (a measure of scar size) was reduced by TESI in both injected (-43.7 ± 4.4%; n=95; P<0.01) and noninjected segments (-25.1 ± 7.8%; n=148; P<0.001; between-group comparison P<0.05). Conversely, segmental ejection fraction (a measure of contractile performance) improved in injected scar segments (19.9 ± 3.3-26.3 ± 3.5%; P=0.003) but not in noninjected scar segments (21.3 ± 2.6-23.5 ± 3.2%; P=0.20; between-group comparison P<0.05). Furthermore, segmental ejection fraction in injected scar segments improved to a greater degree in patients with baseline segmental ejection fraction <20% (12.1 ± 1.2-19.9 ± 2.7%; n=18; P=0.003), versus <20% (31.7 ± 3.4-35.5 ± 3.3%; n=12; P=0.33, between-group comparison P<0.0001). CONCLUSIONS: These findings illustrate a dichotomy in regional responses to TESI. Although scar size reduction was evident in all scar segments, scar size reduction and ventricular functional responses preferentially occurred at the sites of TESI versus non-TESI sites. Furthermore, improvement was greatest when segmental left ventricular dysfunction was severe.

Cardiac Physiology for Radiologists: Review of Relevant Physiology for Interpretation of Cardiac MR Imaging and CT.

Cardiac computed tomography (CT) and magnetic resonance (MR) imaging provide clinicians with important insights into cardiac physiology and pathology. However, not all radiologists understand the language and concepts of cardiac physiology that are used daily by cardiologists. This review article covers basic cardiac physiology as it relates to cardiac CT and MR imaging. Topics include a review of the cardiac cycle and left ventricular pressure-volume loops as they relate to different pathologic states, evaluation of cardiac function, and calculation of key parameters such as left ventricular volumes and the ejection fraction. The hemodynamics of cardiac shunts are covered, with an emphasis on factors important to cardiologists, including the ratio of pulmonary flow to systemic flow. Additionally, valvular physiologic function is reexamined, with a focus on understanding pressure gradients within the heart and also the changes associated with valvular pathologic conditions, including measurement of regurgitant fractions in patients with valvular insufficiency. Understanding these basic concepts will help radiologists tailor the reporting of cardiac studies to clinically relevant information.

ECG-gated MDCT after aortic and mitral valve surgery.

OBJECTIVE: The purpose of this article is to review the utility of ECG-gated MDCT in evaluating postsurgical findings in aortic and mitral valves. Normal and pathologic findings after aortic and mitral valve corrective surgery are shown in correlation with the findings of the traditionally used imaging modalities echocardiography and fluoroscopy to assist in accurate noninvasive anatomic and dynamic evaluation of postsurgical valvular abnormalities. CONCLUSION: Because of its superior spatial and adequate temporal resolution, ECG-gated MDCT has emerged as a robust diagnostic tool in the evaluation and treatment of patients with postsurgical valvular abnormalities.

Transendocardial mesenchymal stem cells and mononuclear bone marrow cells for ischemic cardiomyopathy: the TAC-HFT randomized trial.

IMPORTANCE: Whether culture-expanded mesenchymal stem cells or whole bone marrow mononuclear cells are safe and effective in chronic ischemic cardiomyopathy is controversial. OBJECTIVE: To demonstrate the safety of transendocardial stem cell injection with autologous mesenchymal stem cells (MSCs) and bone marrow mononuclear cells (BMCs) in patients with ischemic cardiomyopathy. DESIGN, SETTING, AND PATIENTS: A phase 1 and 2 randomized, blinded, placebo-controlled study involving 65 patients with ischemic cardiomyopathy and left ventricular (LV) ejection fraction less than 50% (September 1, 2009-July 12, 2013). The study compared injection of MSCs (n=19) with placebo (n = 11) and BMCs (n = 19) with placebo (n = 10), with 1 year of follow-up. INTERVENTIONS: Injections in 10 LV sites with an infusion catheter. MAIN OUTCOMES AND MEASURES: Treatment-emergent 30-day serious adverse event rate defined as a composite of death, myocardial infarction, stroke, hospitalization for worsening heart failure, perforation, tamponade, or sustained ventricular arrhythmias. RESULTS: No patient had a treatment-emergent serious adverse events at day 30. The 1-year incidence of serious adverse events was 31.6% (95% CI, 12.6% to 56.6%) for MSCs, 31.6% (95% CI, 12.6%-56.6%) for BMCs, and 38.1% (95% CI, 18.1%-61.6%) for placebo. Over 1 year, the Minnesota Living With Heart Failure score improved with MSCs (-6.3; 95% CI, -15.0 to 2.4; repeated measures of variance, P=.02) and with BMCs (-8.2; 95% CI, -17.4 to 0.97; P=.005) but not with placebo (0.4; 95% CI, -9.45 to 10.25; P=.38). The 6-minute walk distance increased with MSCs only (repeated measures model, P = .03). Infarct size as a percentage of LV mass was reduced by MSCs (-18.9%; 95% CI, -30.4 to -7.4; within-group, P = .004) but not by BMCs (-7.0%; 95% CI, -15.7% to 1.7%; within-group, P = .11) or placebo (-5.2%; 95% CI, -16.8% to 6.5%; within-group, P = .36). Regional myocardial function as peak Eulerian circumferential strain at the site of injection improved with MSCs (-4.9; 95% CI, -13.3 to 3.5; within-group repeated measures, P = .03) but not BMCs (-2.1; 95% CI, -5.5 to 1.3; P = .21) or placebo (-0.03; 95% CI, -1.9 to 1.9; P = .14). Left ventricular chamber volume and ejection fraction did not change. CONCLUSIONS AND RELEVANCE: Transendocardial stem cell injection with MSCs or BMCs appeared to be safe for patients with chronic ischemic cardiomyopathy and LV dysfunction. Although the sample size and multiple comparisons preclude a definitive statement about safety and clinical effect, these results provide the basis for larger studies to provide definitive evidence about safety and to assess efficacy of this new therapeutic approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00768066.

Comparison of allogeneic vs autologous bone marrow­derived mesenchymal stem cells delivered by transendocardial injection in patients with ischemic cardiomyopathy: the POSEIDON randomized trial.

CONTEXT: Mesenchymal stem cells (MSCs) are under evaluation as a therapy for ischemic cardiomyopathy (ICM). Both autologous and allogeneic MSC therapies are possible; however, their safety and efficacy have not been compared. OBJECTIVE: To test whether allogeneic MSCs are as safe and effective as autologous MSCs in patients with left ventricular (LV) dysfunction due to ICM. DESIGN, SETTING, AND PATIENTS: A phase 1/2 randomized comparison (POSEIDON study) in a US tertiary-care referral hospital of allogeneic and autologous MSCs in 30 patients with LV dysfunction due to ICM between April 2, 2010, and September 14, 2011, with 13-month follow-up. INTERVENTION: Twenty million, 100 million, or 200 million cells (5 patients in each cell type per dose level) were delivered by transendocardial stem cell injection into 10 LV sites. MAIN OUTCOME MEASURES: Thirty-day postcatheterization incidence of predefined treatment-emergent serious adverse events (SAEs). Efficacy assessments included 6-minute walk test, exercise peak VO2, Minnesota Living with Heart Failure Questionnaire (MLHFQ), New York Heart Association class, LV volumes, ejection fraction (EF), early enhancement defect (EED; infarct size), and sphericity index. RESULTS: Within 30 days, 1 patient in each group (treatment-emergent SAE rate, 6.7%) was hospitalized for heart failure, less than the prespecified stopping event rate of 25%. The 1-year incidence of SAEs was 33.3% (n = 5) in the allogeneic group and 53.3% (n = 8) in the autologous group (P = .46). At 1 year, there were no ventricular arrhythmia SAEs observed among allogeneic recipients compared with 4 patients (26.7%) in the autologous group (P = .10). Relative to baseline, autologous but not allogeneic MSC therapy was associated with an improvement in the 6-minute walk test and the MLHFQ score, but neither improved exercise VO2 max. Allogeneic and autologous MSCs reduced mean EED by −33.21% (95% CI, −43.61% to −22.81%; P < .001) and sphericity index but did not increase EF. Allogeneic MSCs reduced LV end-diastolic volumes. Low-dose concentration MSCs (20 million cells) produced greatest reductions in LV volumes and increased EF. Allogeneic MSCs did not stimulate significant donor-specific alloimmune reactions. CONCLUSIONS: In this early-stage study of patients with ICM, transendocardial injection of allogeneic and autologous MSCs without a placebo control were both associated with low rates of treatment-emergent SAEs, including immunologic reactions. In aggregate, MSC injection favorably affected patient functional capacity, quality of life, and ventricular remodeling. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01087996.

Primary systemic amyloidosis presenting as constrictive pericarditis.

The most frequent presentation of cardiac amyloidosis is with endomyocardial deposition, and resultant restrictive cardiomyopathy. We present a case of primary systemic amyloidosis causing constrictive pericarditis (CP) and congestive heart failure without clinical evidence of endomyocardial deposition. A comprehensive evaluation by noninvasive and invasive studies facilitated the differentiation of CP from restrictive cardiomyopathy and the patient was effectively treated with pericardectomy. To our knowledge, this is the first documented case of primary systemic amyloidosis causing selective CP with successful antemortem diagnosis and treatment in a young man.

Danon disease: characteristic late gadolinium enhancement pattern on cardiac magnetic resonance imaging.

Danon disease is a rare entity associated with the clinical triad of mental retardation, skeletal myopathy, and severe hypertrophic cardiomyopathy. We report two cases of Danon disease and describe the results of the cardiac magnetic resonance imaging studies that were conducted to assess the pattern of cardiac hypertrophy.

Discordance Between Radiologic Findings and Molecular Testing in Patients With Underlying Hematologic Malignancy and Coronavirus Disease 2019.

Severe acute respiratory syndrome coronavirus 2 is associated with severe disease in patients with hematologic malignancy. We report a series of patients with underlying hematologic malignancy and coronavirus disease of 2019 with discrepancy between radiographic findings and molecular testing. Initial chest x-ray findings should raise suspicion in immunosuppressed patients with typical clinical presentation even with negative initial testing.

Randomized Comparison of Allogeneic Versus Autologous Mesenchymal Stem Cells for Nonischemic Dilated Cardiomyopathy: POSEIDON-DCM Trial.

BACKGROUND: Although human mesenchymal stem cells (hMSCs) have been tested in ischemic cardiomyopathy, few studies exist in chronic nonischemic dilated cardiomyopathy (NIDCM). OBJECTIVES: The authors conducted a randomized comparison of safety and efficacy of autologous (auto) versus allogeneic (allo) bone marrow-derived hMSCs in NIDCM. METHODS: Thirty-seven patients were randomized to either allo- or auto-hMSCs in a 1:1 ratio. Patients were recruited between December 2011 and July 2015 at the University of Miami Hospital. Patients received hMSCs (100 million) by transendocardial stem cell injection in 10 left ventricular sites. Treated patients were evaluated at baseline, 30 days, and 3-, 6-, and 12-months for safety (serious adverse events [SAE]), and efficacy endpoints: ejection fraction, Minnesota Living with Heart Failure Questionnaire, 6-min walk test, major adverse cardiac events, and immune biomarkers. RESULTS: There were no 30-day treatment-emergent SAEs. Twelve-month SAE incidence was 28.2% with allo-hMSCs versus 63.5% with auto-hMSCs (p = 0.1004 for the comparison). One allo-hMSC patient developed an elevated (>80) donor-specific calculated panel reactive antibody level. The ejection fraction increased in allo-hMSC patients by 8.0 percentage points (p = 0.004) compared with 5.4 with auto-hMSCs (p = 0.116; allo vs. auto p = 0.4887). The 6-min walk test increased with allo-hMSCs by 37.0 m (p = 0.04), but not auto-hMSCs at 7.3 m (p = 0.71; auto vs. allo p = 0.0168). MLHFQ score decreased in allo-hMSC (p = 0.0022) and auto-hMSC patients (p = 0.463; auto vs. allo p = 0.172). The major adverse cardiac event rate was lower, too, in the allo group (p = 0.0186 vs. auto). Tumor necrosis factor-α decreased (p = 0.0001 for each), to a greater extent with allo-hMSCs versus auto-hMSCs at 6 months (p = 0.05). CONCLUSIONS: These findings demonstrated safety and clinically meaningful efficacy of allo-hMSC versus auto-hMSC in NIDCM patients. Pivotal trials of allo-hMSCs are warranted based on these results. (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis in Dilated Cardiomyopathy [PoseidonDCM]; NCT01392625).

Effect of aging on human mesenchymal stem cell therapy in ischemic cardiomyopathy patients.

BACKGROUND: The role of patient age in the efficacy of mesenchymal stem cell (MSC) therapy in ischemic cardiomyopathy (ICM) is controversial. OBJECTIVES: This study sought to determine whether the therapeutic effect of culture-expanded MSCs persists, even in older subjects. METHODS: Patients with ICM who received MSCs via transendocardial stem cell injection (TESI) as part of the TAC-HFT (Transendocardial Autologous Cells in Ischemic Heart Failure) (n = 19) and POSEIDON (Percutaneous Stem Cell Injection Delivery Effects on Neomyogenesis) (n = 30) clinical trials were divided into 2 age groups: younger than 60 and 60 years of age and older. Functional capacity was measured by 6-min walk distance (6MWD) and quality of life using the Minnesota Living With Heart Failure Questionnaire (MLHFQ) score, measured at baseline, 6 months, and 1 year post-TESI. Various cardiac imaging parameters, including absolute scar size, were compared at baseline and 1 year post-TESI. RESULTS: The mean 6MWD was similar at baseline and increased at 1 year post-TESI in both groups: 48.5 ± 14.6 m (p = 0.001) for the younger and 35.9 ± 18.3 m (p = 0.038) for the older participants (p = NS between groups). The older group exhibited a significant reduction in MLHFQ score (-7.04 ± 3.54; p = 0.022), whereas the younger than 60 age group had a borderline significant reduction (-11.22 ± 5.24; p = 0.058) from baseline (p = NS between groups). Although there were significant reductions in absolute scar size from baseline to 1 year post-TESI, the effect did not differ by age. CONCLUSIONS: MSC therapy with TESI in ICM patients improves 6MWD and MLHFQ score and reduces myocardial infarction size. Importantly, older individuals did not have an impaired response to MSC therapy.

Synergistic Effects of Combined Cell Therapy for Chronic Ischemic Cardiomyopathy.

BACKGROUND: Both bone marrow-derived mesenchymal stem cells (MSCs) and c-kit(+) cardiac stem cells (CSCs) improve left ventricular remodeling in porcine models and clinical trials. Using xenogeneic (human) cells in immunosuppressed animals with acute ischemic heart disease, we previously showed that these 2 cell types act synergistically. OBJECTIVES: To more accurately model clinical applications for heart failure, this study tested whether the combination of autologous MSCs and CSCs produce greater improvement in cardiac performance than MSCs alone in a nonimmunosuppressed porcine model of chronic ischemic cardiomyopathy. METHODS: Three months after ischemia/reperfusion injury, Göttingen swine received transendocardial injections with MSCs alone (n = 6) or in combination with cardiac-derived CSCs (n = 8), or placebo (vehicle; n = 6). Cardiac functional and anatomic parameters were assessed using cardiac magnetic resonance at baseline and before and after therapy. RESULTS: Both groups of cell-treated animals exhibited significantly reduced scar size (MSCs -44.1 ± 6.8%; CSC/MSC -37.2 ± 5.4%; placebo -12.9 ± 4.2%; p < 0.0001), increased viable tissue, and improved wall motion relative to placebo 3 months post-injection. Ejection fraction (EF) improved (MSCs 2.9 ± 1.6 EF units; CSC/MSC 6.9 ± 2.8 EF units; placebo 2.5 ± 1.6 EF units; p = 0.0009), as did stroke volume, cardiac output, and diastolic strain only in the combination-treated animals, which also exhibited increased cardiomyocyte mitotic activity. CONCLUSIONS: These findings illustrate that interactions between MSCs and CSCs enhance cardiac performance more than MSCs alone, establish the safety of autologous cell combination strategies, and support the development of second-generation cell therapeutic products.

Multislice CT in thoracic trauma.

The introduction of CT imaging in the 1970s revolutionized all aspects of medical care, perhaps nowhere more so than in the evaluation of acutely injured patients. Just as single-slice helical scanning was a great advance over conventional CT, the capabilities of MSCT are proving to be dramatically superior to single-slice methods. Improved contrast bolus imaging, thinner slices, and isotropic voxels should enable the trauma radiologist to identify both major organ system disruption and subtle injuries more promptly. Multiplanar and three-dimensional reconstructions, a forte of MSCT, facilitate rapid communication of disease states with surgeons and others involved in the care of injured patients. In many centers, whole-body CT is beginning to supplant plain films of the chest and spine in the evaluation of severe trauma victims; the cost-effectiveness of such methods is still under evaluation.

Thoracic radiology in kidney and liver transplantation.

Renal transplantation accounts for more than half of all solid organ transplants performed in the U.S., and the liver is the second most commonly transplanted solid organ. Although abdominal imaging procedures are commonplace in these patients, there has been relatively little attention paid to thoracic imaging applications. Preoperative imaging is crucial to aid in the exclusion of infectious or malignant disease. In the perioperative time period, thoracic imaging focuses both on standard intensive care unit care, including monitoring devices and their complications, and on the early infections that can occur. Postoperative management is divided into three time periods, and the principles governing the occurrence of infections and malignancies are reviewed. Anatomic and pathologic aspects unique to kidney and liver transplantation patients are also discussed.

The imaging spectrum of pulmonary tuberculosis in AIDS.

SUMMARY: Pulmonary tuberculosis (TB) is the major opportunistic infection of acquired immunodeficiency syndrome (AIDS) on a worldwide basis. The purpose of this pictorial essay is to illustrate and review the spectrum of imaging findings associated with pulmonary TB in patients with AIDS and to describe important factors that may complicate the radiographic follow-up of patients being treated for TB.

Update on lung disease in AIDS.

Pulmonary disorders remain an important complication of HIV infection, even in the current era of potent antiretroviral therapy. Using an integrated approach that combines radiographic pattern recognition with knowledge of a patient's clinical symptoms, laboratory data, immune status level, demographic information, and drug therapy can enhance the interpretation of imaging studies in HIV-infected patients. Although chest radiography remains the mainstay of imaging the HIV-positive patient with respiratory symptoms, CT plays an increasingly important secondary role in selected cases.

Pitfalls in the diagnosis of acute pulmonary embolism on spiral computer tomography.

Spiral computer tomography (CT) has become a widely accepted clinical tool in the diagnosis of acute pulmonary embolism. The accuracy of computed tomography in diagnosing pulmonary embolism has increased over the past 10 years, parallel to technological improvements. However, as with most imaging techniques, interpretative pitfalls may occur for a variety of reasons. These include technical problems caused by respiratory motion artifact, improper bolus timing, streak artifact, and patient body habitus. In addition, misinterpretation of normal bronchovascular anatomy may lead to an erroneous diagnosis. This article discusses the various diagnostic pitfalls and methods to minimize and overcome them.

Radiographic and electrocardiography-gated noncontrast cardiac CT assessment of lead perforation: modality comparison and interobserver agreement.

BACKGROUND: Pacemaker or implantable cardioverter-defibrillator lead extraction may be required because of infection, malfunction, or breakage. The preprocedural identification of lead tip position may help ensure safe performance of the procedure. OBJECTIVE: To analyze the ability of chest radiography and CT imaging to characterize lead tip position and identify perforation in a population of patients who underwent lead extraction. METHODS: Among patients who underwent lead extraction between November 2008 and April 2011, a nonrandom subset of 50 patients with 116 leads was selected for retrospective analysis. All patients had undergone chest radiography and thin-section electrocardiography-gated noncontrast cardiac CT. Two radiologists independently evaluated the imaging studies, using oblique multiplanar image reconstruction techniques for the CT examinations. Beam hardening artifacts were graded (0-3). Likelihood of perforation on each imaging study was graded on a 5-point scale. RESULTS: Among 116 leads, 17 were identified as perforated on CT, 12 leads were equivocal, and 87 were not perforated. Interobserver agreement for CT perforation vs nonperforation was good (κ = 0.71); weighted kappa for the entire 5-point scale was moderate (κ = 0.54). Beam hardening artifacts were common, with a mean value of 2.1. The 2 observers identified perforation on chest radiography with an average sensitivity of 15% compared with CT. The 2 observers did not agree on any cases of chest radiographic perforation (κ = -0.1). CONCLUSION: Electrocardiography-gated noncontrast cardiac CT imaging with oblique multiplanar analysis can identify potential lead perforation with a moderate-to-good level of interobserver agreement. Chest radiography demonstrates poor sensitivity and interobserver agreement compared with CT.

Multidetector computed tomography diagnosis and cine imaging of left main coronary arterial dissection.

Coronary artery dissection (CD) is a rare cause of acute myocardial ischemia. It is often diagnosed by invasive coronary angiography, which is the principal diagnostic tool and gold standard in the diagnosis and triage of patients with CD. More recently, electrocardiogram-gated multidetector computerized tomography has emerged as a complementary imaging tool primarily for follow-up purposes. To our knowledge, this is the first published report of the primary diagnosis and dynamic cine interrogation of a left main CD using retrospective electrocardiogram-gated multidetector computerized tomography, which was not disclosed on invasive coronary angiography.