Pilot Study of F18-Florbetapir in the Early Evaluation of Cardiac Amyloidosis.

Background: Cardiac amyloidosis is an increasingly recognized etiology of heart failure, in part due to the rise of non-invasive nuclear bone scintigraphy. Molecular imaging using positron emission tomography (PET) has promised the direct visualization of cardiac amyloid fibrils. We sought to assess the performance of F18-florbetapir PET in patients with a potential for cardiac amyloidosis in order to identify early disease. Methods: We performed a pilot study of 12 patients: one with asymptomatic transthyretin cardiac amyloidosis, seven with a potential for developing cardiac amyloidosis (two smoldering myeloma and five with extracardiac biopsy demonstrating transthyretin amyloid deposits and negative technetium pyrophosphate scans), and four controls. Patients were imaged with PET/CT in listmode 10-20 min after receiving F18-florbetapir. Static images were created from this acquisition, and mean standardized uptake values (SUVs) of the left ventricular myocardium, blood pool, paraspinal muscles, and liver were calculated. Results: All 12 patients demonstrated radiotracer uptake in the myocardium with mean SUV of 2.3 ± 0.4 and blood pool SUV of 0.8 ± 0.1. The patient with cardiac amyloidosis had SUV of 3.3, while mean SUV for patients at risk was 2.3 ± 0.4 and for controls was 2.2 ± 0.3. After 3 years of follow-up, one patient with SUV below the mean was subsequently diagnosed with ATTR cardiac amyloidosis. Conclusion: In this cohort, PET with F18-florbetapir demonstrated non-specific radiotracer uptake in the myocardium in all patients using a static image protocol; though, the highest values were noted in a patient with ATTR cardiac amyloidosis. There was no difference in the intensity of F18-florbetapir uptake in at-risk patients and controls. Future studies should continue to investigate metabolic PET tracers and protocols in cardiac amyloidosis, including in early disease.

Arrhythmias in Cardiac Sarcoidosis Bench to Bedside: A Case-Based Review.

Cardiac sarcoidosis is a component of an often multiorgan granulomatous disease of still uncertain cause. It is being recognized with increasing frequency, mainly as the result of heightened awareness and new diagnostic tests, specifically cardiac magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography scans. The purpose of this case-based review is to highlight the potentially life-saving importance of making the early diagnosis of cardiac sarcoidosis using these new tools and to provide a framework for the optimal care of patients with this disease. We will review disease mechanisms as currently understood, associated arrhythmias including conduction abnormalities, and atrial and ventricular tachyarrhythmias, guideline-directed diagnostic criteria, screening of patients with extracardiac sarcoidosis, and the use of pacemakers and defibrillators in this setting. Treatment options, including those related to heart failure, and those which may help clarify disease mechanisms are included.

Impella RP as a bridge to cardiac transplant for refractory late right ventricular failure in setting of left ventricular assist device.

Right ventricular (RV) failure remains a major complication after surgical implantation of a left ventricular assist device (LVAD). While the use of a percutaneous RV assist device has been described as a short-term bridge to recovery in end-stage heart failure patients with early post-operative RV failure after index LVAD implant, management of refractory late RV failure remains challenging in these patients. We report the first successful case of extended Impella RP use as a safe and effective bridge to orthotopic heart transplant in an LVAD patient with refractory, haemodynamically significant late RV failure. The Impella RP provided support for 37 days. Haemodynamically intolerant arrhythmia precluded use of inotropic support. No adverse complications related to percutaneous Impella RP support were seen. We also review potential considerations for mechanical circulatory support strategies in this setting: central RV assist device cannulation requires sternotomy incision that can impact subsequent cardiac surgeries, while percutaneous Protek Duo insertion requires adequate vessel size and patency. With an LVAD in situ, veno-arterial extracorporeal membrane oxygenation was not considered for isolated RV support in this case. The patient is currently over 6 months post-orthotopic heart transplant.

Myocardial viability: heart failure perspective.

PURPOSE OF REVIEW: This review highlights the different imaging modalities available to assess myocardial viability in patients with heart failure and coronary artery disease (CAD) being considered for revascularization. RECENT FINDINGS: Myocardial viability can be determined by a variety of cardiac imaging modalities. Recent studies have confirmed the use of cardiovascular magnetic resonance imaging (CMR) in patients with heart failure and CAD, suggesting that those who undergo revascularization but have evidence of residual viable or 'jeopardized' myocardium have increased mortality compared with those who achieve complete revascularization. The PET and Recovery Following Revascularization (PARR)-2 trial assessed whether viability noted on PET imaging in patients with severe LV dysfunction correlated with recovery of LV function and response to revascularization. The 5-year extension of the PARR-2 study noted a significant decrease in the composite outcome of cardiac death, myocardial infarction, or cardiac hospitalization in patient assessments adherent to PET-guided viability recommendations. SUMMARY: On the basis of the current available data, viability testing is reasonable in individuals with ICM, as identified by coronary angiography in whom complete revascularization can be achieved. Whenever available, the use of CMR or PET is preferred because of better resolution and increased sensitivity to detect myocardial viability.

α-Enolase Causes Proinflammatory Activation of Pulmonary Microvascular Endothelial Cells and Primes Neutrophils Through Plasmin Activation of Protease-Activated Receptor 2.

UNLABELLED: Proinflammatory activation of vascular endothelium leading to increased surface expression of adhesion molecules and neutrophil (PMN) sequestration and subsequent activation is paramount in the development of acute lung injury and organ injury in injured patients. We hypothesize that α-enolase, which accumulates in injured patients, primes PMNs and causes proinflammatory activation of endothelial cells leading to PMN-mediated cytotoxicity. METHODS: Proteomic analyses of field plasma samples from injured versus healthy patients were used for protein identification. Human pulmonary microvascular endothelial cells (HMVECs) were incubated with α-enolase or thrombin, and intercellular adhesion molecule-1 surface expression was measured by flow cytometry. A two-event in vitro model of PMN cytotoxicity HMVECs activated with α-enolase, thrombin, or buffer was used as targets for lysophosphatidylcholine-primed or buffer-treated PMNs. The PMN priming activity of α-enolase was completed, and lysates from both PMNs and HMVECs were immunoblotted for protease-activated receptor 1 (PAR-1) and PAR-2 and coprecipitation of α-enolase with PAR-2 and plasminogen/plasmin. RESULTS: α-Enolase increased 10.8-fold in injured patients (P < 0.05). Thrombin and α-enolase significantly increased intercellular adhesion molecule-1 surface expression on HMVECs, which was inhibited by antiproteases, induced PMN adherence, and served as the first event in the two-event model of PMN cytotoxicity. α-Enolase coprecipitated with PAR-2 and plasminogen/plasmin on HMVECs and PMNs and induced PMN priming, which was inhibited by tranexamic acid, and enzymatic activity was not required. CONCLUSIONS: α-Enolase increases after injury and may activate pulmonary endothelial cells and prime PMNs through plasmin activity and PAR-2 activation. Such proinflammatory endothelial activation may predispose to PMN-mediated organ injury.

Aptamer-based multiplexed proteomic technology for biomarker discovery.

BACKGROUND: The interrogation of proteomes ("proteomics") in a highly multiplexed and efficient manner remains a coveted and challenging goal in biology and medicine. METHODOLOGY/PRINCIPAL FINDINGS: We present a new aptamer-based proteomic technology for biomarker discovery capable of simultaneously measuring thousands of proteins from small sample volumes (15 µL of serum or plasma). Our current assay measures 813 proteins with low limits of detection (1 pM median), 7 logs of overall dynamic range (~100 fM-1 µM), and 5% median coefficient of variation. This technology is enabled by a new generation of aptamers that contain chemically modified nucleotides, which greatly expand the physicochemical diversity of the large randomized nucleic acid libraries from which the aptamers are selected. Proteins in complex matrices such as plasma are measured with a process that transforms a signature of protein concentrations into a corresponding signature of DNA aptamer concentrations, which is quantified on a DNA microarray. Our assay takes advantage of the dual nature of aptamers as both folded protein-binding entities with defined shapes and unique nucleotide sequences recognizable by specific hybridization probes. To demonstrate the utility of our proteomics biomarker discovery technology, we applied it to a clinical study of chronic kidney disease (CKD). We identified two well known CKD biomarkers as well as an additional 58 potential CKD biomarkers. These results demonstrate the potential utility of our technology to rapidly discover unique protein signatures characteristic of various disease states. CONCLUSIONS/SIGNIFICANCE: We describe a versatile and powerful tool that allows large-scale comparison of proteome profiles among discrete populations. This unbiased and highly multiplexed search engine will enable the discovery of novel biomarkers in a manner that is unencumbered by our incomplete knowledge of biology, thereby helping to advance the next generation of evidence-based medicine.