Multiparametric assessment of left atrial remodeling using 18F-FDG PET/CT cardiac imaging: A pilot study.

BACKGROUND: Left atrial (LA) remodeling is associated with structural, electric, and metabolic LA changes. Integrated evaluation of these features in vivo is lacking. METHODS: Patients undergoing 18F-fluorodeoxyglucose (FDG) PET-CT during a hyperinsulinemic-euglycemic clamp were classified into sinus rhythm (SR), paroxysmal AF (PAF), and persistent AF (PerAF). The LA was semiautomatically segmented, and global FDG uptake was quantified using standardized uptake values (SUVmax and SUVmean) in gated, attenuation-corrected images and normalized to LA blood pool activity. Regression was used to relate FDG data to AF burden and critical patient factors. Continuous variables were compared using t-tests or Mann-Whitney tests. RESULTS: 117 patients were included (76% men, age 66.4 ± 11.0, ejection fraction (EF) 25[22-35]%) including those with SR (n = 48), PAF (n = 55), and PerAF (n = 14). Patients with any AF had increased SUVmean (2.3[1.5-2.4] vs 2.0[1.5-2.5], P = 0.006), SUVmax (4.4[2.8-6.7] vs 3.2[2.3-4.3], P < 0.001), uptake coefficient of variation (CoV) 0.28[0.22-0.40] vs 0.25[0.2-0.33], P < 0.001), and hypometabolic scar (32%[14%-53%] vs 16.5%[0%-38.5%], P = 0.01). AF burden correlated with increased SUVmean, SUVmax, CoV, and scar independent of age, gender, EF, or LA size (P < 0.03 for all). CONCLUSIONS: LA structure and metabolism can be assessed using FDG PET/CT. Greater AF burden correlates with the increased LA metabolism and scar.

Safety of regadenoson positron emission tomography stress testing in orthotopic heart transplant patients.

OBJECTIVES: We sought to determine the safety of regadenoson (REG) stress testing in patients who have undergone orthotopic heart transplantation (OHT). BACKGROUND: Routine screening for cardiac allograft vasculopathy (CAV) is necessary after OHT. Adenosine stress is contraindicated after heart transplantation due to supersensitivity in denervated hearts. Safety of regadenoson stress following OHT has not been well studied. METHODS: We retrospectively reviewed data from OHT patients (N = 123) who were referred to REG stress testing. Medical records were reviewed to determine hemodynamic and ECG response to regadenoson and to identify adverse reactions. RESULTS: No serious adverse events occurred. No life-threatening arrhythmias or hemodynamic changes occurred. Common side-effects related to regadenoson were observed, dyspnea being the most frequent (66.7%). On average the heart rate rose from 82.8 ± 12 to 95.7 ± 13.4 bpm (P < 0.001), systolic blood pressure decreased from 138.7 ± 20.9 to 115.9 ± 23.9 mmHg (P < 0.001) and mean arterial pressure decreased from 103.5 ± 14.1 to 84.72 ± 15.90 mmHg (P < 0.001) during stress protocol. There was no sustained ventricular tachycardia, ventricular fibrillation, or second-or third-degree atrioventricular block. CONCLUSION: Regadenoson stress testing appears to be well tolerated and safe in OHT patients.

Relationship of non-invasive quantification of myocardial blood flow to arrhythmic events in patients with implantable cardiac defibrillators.

BACKGROUND: Ischemia contributes to arrhythmogenesis though its role is incompletely understood. Abnormal myocardial perfusion measured by PET imaging may predict ventricular arrhythmias (VAs) in a high-risk population. METHODS: Patients with implantable cardiac defibrillators who had undergone rubidium-82 cardiac PET imaging were identified. Patients were stratified by median MBF and MFR values for analysis. The Cox proportional hazards model was used to assess the impact of myocardial perfusion on survival free of VT independent of critical covariates. RESULTS: A total of 159 patients (124 (78%) males, median age 65.9 years, IQR [56.76-72.63]) were followed for 1.43 years IQR [0.83-2.21]. VA occurred in 29 patients (23.7%). After adjustment for ejection fraction, age, and sex, impaired stress MBF was associated with an increased risk of VA (adjusted HR per ml/min/g 1.52, 95% CI (1.01-2.31), P = 0.04). Summed rest and stress scores were not predictive of VA. Among patients with severe LV dysfunction, stress MBF remained an independent predictor of VA (adjusted HR per 1 ml/min/g HR 1.69, 95% CI (1.03-11.36), P = 0.03), while residual EF, summed rest, and summed stress scores were not (P > 0.05). CONCLUSIONS: Impaired stress myocardial blood flow was associated with less survival free of ventricular arrhythmias.

Safety of regadenoson stress testing in patients with pulmonary hypertension.

OBJECTIVES: We sought to determine the safety of regadenoson stress testing in patients with PH. BACKGROUND: PH is increasingly recognized at more advanced ages. As many as one-third of patients with PH have coronary artery disease. Because of their physical limitations, patients with PH are unable to adequately exercise. Regadenoson can potentially have an adverse impact due to their tenuous hemodynamics. Current guidelines suggest performing a coronary angiography in patients with PH who have angina or multiple coronary risk factors. METHODS: We identified 67 consecutive patients with confirmed PH by catheterization (mean PA > 25 mmHg not due to left heart disease) who underwent MPI with regadenoson stress. Medical records were reviewed to determine hemodynamic and ECG response to regadenoson. RESULTS: No serious events occurred. Common side effects related to regadenoson were observed, dyspnea being the most common (70.6%). No syncope occurred. Heart rate increased from 74.6 ± 14 to 96.3 ± 18.3 bpm, systolic blood pressure increased from 129.8 ± 20.9 to 131.8 ± 31 mmHg, and diastolic blood pressure decreased from 77.1 ± 11.4 to 72.9 ± 15.3 mmHg. There was no ventricular tachycardia, ventricular fibrillation, or second- or third-degree atrioventricular block. CONCLUSION: Regadenoson stress MPI appears to be well tolerated and safe in patients with PH.

ELISA-based measurement of antibody responses and PCR-based detection profiles can distinguish between active infection and early clearance of Borrelia burgdorferi.

Borrelia burgdorferi is a spirochetal bacterium that causes Lyme disease. These studies address whether current research methods using either ELISA to detect seroconversion to B. burgdorferi antigens or PCR quantification of bacterial DNA within tissues can accurately distinguish between a productive infection versus a B. burgdorferi exposure that is rapidly cleared by the innate responses. Mice receiving even minimal doses of live B. burgdorferi produced significantly more B. burgdorferi-specific IgM and IgG than groups receiving large inocula of heat-killed bacteria. Additionally, sera from mice injected with varied doses of killed B. burgdorferi recognized unique borrelial antigens compared to mice infected with live B. burgdorferi. Intradermal injection of killed B. burgdorferi resulted in rapid DNA clearance from skin, whereas DNA was consistently detected in skin inoculated with viable B. burgdorferi. These data indicate that both ELISA-based serological analyses and PCR-based methods of assessing B. burgdorferi infection clearly distinguish between an established infection with live bacteria and exposure to large numbers of bacteria that are promptly cleared by the innate responses.

Prevalence and outcome of sepsis and septic shock in intensive care units in Addis Ababa, Ethiopia: A prospective observational study.

BACKGROUND: Sepsis and septic shock are the major causes of morbidity and mortality in Intensive care Units (ICUs) in low and middle-income countries. However, little is known about their prevalence and outcome in these settings. The study aimed to assess the prevalence and outcome of sepsis and septic shock in ICUs in Addis Ababa, Ethiopia. METHODS: A prospective observational study was conducted from March 2017 to February 2018 in four selected ICUs in Addis Ababa from a total of twelve hospitals having ICU services. There were 1145 total ICU admissions during the study period. All admissions into those ICUs with sepsis, severe sepsis, and septic shock using the Systemic Inflammatory Response Syndrome (SIRS) criteria (SEPSIS-2) during the study period were screened for sepsis or septic shock based on the new sepsis definition (SEPSIS-3). All patients with sepsis and septic shock during ICU admission were included and followed for 28 days of ICU admission. Data analysis was done using the Statistical Package for Social Sciences (SPSS) software version 20.0. RESULTS: A total of 275 patients were diagnosed with sepsis and septic shock. The overall prevalence of sepsis and septic shock was 26.5 per 100 ICU admissions. The most frequent source of sepsis was respiratory infection (53.1%). The median length of stay in the ICUs was 5 (IQR, 2-8) days. The most common bacterium isolate was Pseudomonas aeroginosa (34.5%). The ICU and 28-day mortality rate was 41.8% and 50.9% respectively. Male sex, modified Sequential Organ Failure Assessment score ≥10 on day 1 of ICU admission, and comorbidity of HIV or malignancy were the independent predictors of 28-day mortality. CONCLUSION: Sepsis and septic shock are common among our ICU admissions, and are associated with a high mortality rate.

Light chain deposition disease presenting as an atrial mass: a case report and review of literature.

Light chain deposition disease (LCDD) also known as nonamyloidotic immunoglobulin deposition disease is a rare systemic disorder due to the abnormal deposition of immunoglobulin in multiple organs caused by the clonal proliferation of B lymphocytes and plasma cells. Renal involvement is the most common with cardiac manifestations being the most common extra renal presentation of the disease. Renal involvement is not always associated with LCDD. Isolated cardiac involvement can manifest in a wide variety of ways: heart failure, cardiomyopathy, arrhythmias, angina, myocardial infarction, etc. We hereby present an unusual case of 59-year-old female who presented to clinic for routine follow up. A murmur on physical exam was evaluated with echocardiogram which led to the discovery of an incidental right atrial mass. Cardiac magnetic resonance imaging was completed 6 months later for follow up which showed increasing size of the mass. The mass was excised and found to be consistent with LCDD. To the best of our knowledge, this is the first reported case of LCDD manifesting as an atrial mass. Through this case report and review of literature we would like to generate awareness among our fellow pathologists and clinicians to maintain a high level of suspicion for LCDD as it can manifest in many unusual ways, with or without kidney involvement.

Identification of Burkholderia mallei and Burkholderia pseudomallei adhesins for human respiratory epithelial cells.

BACKGROUND: Burkholderia pseudomallei and Burkholderia mallei cause the diseases melioidosis and glanders, respectively. A well-studied aspect of pathogenesis by these closely-related bacteria is their ability to invade and multiply within eukaryotic cells. In contrast, the means by which B. pseudomallei and B. mallei adhere to cells are poorly defined. The purpose of this study was to identify adherence factors expressed by these organisms. RESULTS: Comparative sequence analyses identified a gene product in the published genome of B. mallei strain ATCC23344 (locus # BMAA0649) that resembles the well-characterized Yersinia enterocolitica autotransporter adhesin YadA. The gene encoding this B. mallei protein, designated boaA, was expressed in Escherichia coli and shown to significantly increase adherence to human epithelial cell lines, specifically HEp2 (laryngeal cells) and A549 (type II pneumocytes), as well as to cultures of normal human bronchial epithelium (NHBE). Consistent with these findings, disruption of the boaA gene in B. mallei ATCC23344 reduced adherence to all three cell types by ~50%. The genomes of the B. pseudomallei strains K96243 and DD503 were also found to contain boaA and inactivation of the gene in DD503 considerably decreased binding to monolayers of HEp2 and A549 cells and to NHBE cultures.A second YadA-like gene product highly similar to BoaA (65% identity) was identified in the published genomic sequence of B. pseudomallei strain K96243 (locus # BPSL1705). The gene specifying this protein, termed boaB, appears to be B. pseudomallei-specific. Quantitative attachment assays demonstrated that recombinant E. coli expressing BoaB displayed greater binding to A549 pneumocytes, HEp2 cells and NHBE cultures. Moreover, a boaB mutant of B. pseudomallei DD503 showed decreased adherence to these respiratory cells. Additionally, a B. pseudomallei strain lacking expression of both boaA and boaB was impaired in its ability to thrive inside J774A.1 murine macrophages, suggesting a possible role for these proteins in survival within professional phagocytic cells. CONCLUSIONS: The boaA and boaB genes specify adhesins that mediate adherence to epithelial cells of the human respiratory tract. The boaA gene product is shared by B. pseudomallei and B. mallei whereas BoaB appears to be a B. pseudomallei-specific adherence factor.

Viable Borrelia burgdorferi enhances interleukin-10 production and suppresses activation of murine macrophages.

Although it is capable of eliciting strong innate and adaptive immune responses, Borrelia burgdorferi often evades immune clearance through largely unknown mechanisms. Our previous studies determined that infected interlukin-10-/- (IL-10-/-) mice show significantly lower B. burgdorferi levels than wild-type (B6) mice and that IL-10 inhibits innate immune responses critical for controlling B. burgdorferi infection. To determine whether virulent B. burgdorferi preferentially enhances IL-10 production, we developed an in vitro coculture medium (RPMI.B) in which both B. burgdorferi and primary macrophages (Mphis) remain viable. B. burgdorferi grew at similar rates and was able to regulate expression of immunoreactive proteins with similar kinetics in RPMI.B and in traditional BSK medium; in contrast, B. burgdorferi cultured in conventional tissue culture medium (RPMI) rapidly lost viability. Coculture of viable B. burgdorferi in RPMI.B with Mphis resulted in more rapid and significant increases in IL-10 transcripts and secreted proteins than coculture with nonviable B. burgdorferi in RPMI, which corresponded with decreased production of proinflammatory cytokines. Addition of live B. burgdorferi to Mphis in RPMI.B also elicited substantially higher IL-10 levels than heat-killed bacteria elicited, confirming that increased IL-10 production was not inherent to coculture in RPMI.B. Transfer of supernatants from B. burgdorferi-stimulated Mphis into naïve Mphi cultures resulted in suppressed activation upon subsequent stimulation with different bacterial agonists, and this suppression was obviated by IL-10-specific antibody. In vivo analyses determined that murine skin samples exhibited substantial upregulation of IL-10 within 24 h of injection of B. burgdorferi. Together, these results suggest that viable B. burgdorferi can suppress early Mphi responses during infection by causing increased release of IL-10.

Reduced Myocardial Flow Reserve by Positron Emission Tomography Predicts Cardiovascular Events After Cardiac Transplantation.

BACKGROUND: We evaluated the diagnostic and prognostic value of quantification of myocardial flow reserve (MFR) with positron emission tomography (PET) in orthotopic heart transplant patients. METHODS AND RESULTS: We retrospectively identified orthotopic heart transplant patients who underwent rubidium-82 cardiac PET imaging. The primary outcome was the composite of cardiovascular death, acute coronary syndrome, coronary revascularization, and heart failure hospitalization. Cox regression was used to evaluate the association of MFR with the primary outcome. The relationship of MFR and cardiac allograft vasculopathy severity in patients with angiography within 1 year of PET imaging was assessed using Spearman rank correlation and logistic regression. A total of 117 patients (median age, 60 years; 71% men) were identified. Twenty-one of 62 patients (34%) who underwent angiography before PET had cardiac allograft vasculopathy. The median time from orthotopic heart transplant to PET imaging was 6.4 years (median global MFR, 2.31). After a median of 1.4 years, 22 patients (19%) experienced the primary outcome. On an unadjusted basis, global MFR (hazard ratio, 0.22 per unit increase; 95% confidence interval, 0.09-0.50; P<0.001) and stress myocardial blood flow (hazard ratio, 0.48 per unit increase; 95% confidence interval, 0.29-0.79; P=0.004) were associated with the primary outcome. Decreased MFR independently predicted the primary outcome after adjustment for other variables. In 42 patients who underwent angiography within 12 months of PET, MFR and stress myocardial blood flow were associated with moderate-severe cardiac allograft vasculopathy (International Society of Heart and Lung Transplantation grade 2-3). CONCLUSIONS: MFR assessed by cardiac rubidium-82 PET imaging is a predictor of cardiovascular events after orthotopic heart transplant and is associated with cardiac allograft vasculopathy severity.

Identifying Important Gaps in Randomized Controlled Trials of Adult Cardiac Arrest Treatments: A Systematic Review of the Published Literature.

BACKGROUND: Cardiac arrest is a major public health concern worldwide. The extent and types of randomized controlled trials (RCT)-our most reliable source of clinical evidence-conducted in these high-risk patients over recent years are largely unknown. METHODS AND RESULTS: We performed a systematic review, identifying all RCTs published in PubMed, EMBASE, Scopus, Web of Science, and the Cochrane Library from 1995 to 2014 that focused on the acute treatment of nontraumatic cardiac arrest in adults. We then extracted data on the setting of study populations, types and timing of interventions studied, risk of bias, outcomes reported, and how these factors have changed over time. Over this 20-year period, 92 RCTs were published containing 64 309 patients (median, 225.5 per trial). Of these, 81 RCTs (88.0%) involved out-of-hospital cardiac arrest, whereas 4 (4.3%) involved in-hospital cardiac arrest and 7 (7.6%) included both. Eighteen RCTs (19.6%) were performed in the United States, 68 (73.9%) were performed outside the United States, and 6 (6.5%) were performed in both settings. Thirty-eight RCTs (41.3%) evaluated drug therapy, 39 (42.4%) evaluated device therapy, and 15 (16.3%) evaluated protocol improvements. Seventy-four RCTs (80.4%) examined interventions during the cardiac arrest, 15 (16.3%) examined post cardiac arrest treatment, and 3 (3.3%) studied both. Overall, reporting of the risk of bias was limited. The most common outcome reported was return of spontaneous circulation: 86 (93.5%) with only 22 (23.9%) reporting survival beyond 6 months. Fifty-three RCTs (57.6%) reported global ordinal outcomes, whereas 15 (16.3%) reported quality-of-life. RCTs in the past 5 years were more likely to be focused on protocol improvements and postcardiac arrest care. CONCLUSIONS: Important gaps in RCTs of cardiac arrest treatments exist, especially those examining in-hospital cardiac arrest, protocol improvement, postcardiac arrest care, and long-term or quality-of-life outcomes.

Monocytic CCR2(+) myeloid-derived suppressor cells promote immune escape by limiting activated CD8 T-cell infiltration into the tumor microenvironment.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of cells that accumulate during tumor formation, facilitate immune escape, and enable tumor progression. MDSCs are important contributors to the development of an immunosuppressive tumor microenvironment that blocks the action of cytotoxic antitumor T effector cells. Heterogeneity in these cells poses a significant barrier to studying the in vivo contributions of individual MDSC subtypes. Herein, we show that granulocyte-macrophage colony stimulating factor, a cytokine critical for the numeric and functional development of MDSC populations, promotes expansion of a monocyte-derived MDSC population characterized by expression of CD11b and the chemokine receptor CCR2. Using a toxin-mediated ablation strategy to target CCR2-expressing cells, we show that these monocytic MDSCs regulate entry of activated CD8 T cells into the tumor site, thereby limiting the efficacy of immunotherapy. Our results argue that therapeutic targeting of monocytic MDSCs would enhance outcomes in immunotherapy.

Borrelia burgdorferi binding of host complement regulator factor H is not required for efficient mammalian infection.

The causative agent of Lyme disease, Borrelia burgdorferi, is naturally resistant to its host's alternative pathway of complement-mediated killing. Several different borrelial outer surface proteins have been identified as being able to bind host factor H, a regulator of the alternative pathway, leading to a hypothesis that such binding is important for borrelial resistance to complement. To test this hypothesis, the development of B. burgdorferi infection was compared between factor H-deficient and wild-type mice. Factor B- and C3-deficient mice were also studied to determine the relative roles of the alternative and classical/lectin pathways in B. burgdorferi survival during mammalian infection. While it was predicted that B. burgdorferi should be impaired in its ability to infect factor H-deficient animals, quantitative analyses of bacterial loads indicated that those mice were infected at levels similar to those of wild-type and factor B- and C3-deficient mice. Ticks fed on infected factor H-deficient or wild-type mice all acquired similar numbers of bacteria. Indirect immunofluorescence analysis of B. burgdorferi acquired by feeding ticks from the blood of infected mice indicated that none of the bacteria had detectable levels of factor H on their outer surfaces, even though such bacteria express high levels of surface proteins capable of binding factor H. These findings demonstrate that the acquisition of host factor H is not essential for mammalian infection by B. burgdorferi and indicate that additional mechanisms are employed by the Lyme disease spirochete to evade complement-mediated killing.

IL-10 deficiency promotes increased Borrelia burgdorferi clearance predominantly through enhanced innate immune responses.

Borrelia burgdorferi is capable of persistently infecting a variety of hosts despite eliciting potent innate and adaptive immune responses. Preliminary studies indicated that IL-10-deficient (IL-10(-/-)) mice exhibit up to 10-fold greater clearance of B. burgdorferi from target tissues compared with wild-type mice, establishing IL-10 as the only cytokine currently known to have such a significant effect on spirochetal clearance. To further delineate these IL-10-mediated immune effects, kinetic studies indicated that spirochete dissemination to target tissues is similar in both wild-type and IL-10(-/-) mouse strains, and that enhanced clearance of B. burgdorferi in IL-10(-/-) mice is correlated with increased B. burgdorferi-specific Ab as early as 2 wk postinfection. Immunoblot analysis indicated that Abs produced by infected IL-10(-/-) and wild-type mice recognize similar ranges of spirochetal Ags. Immune sera from IL-10(-/-) and wild-type mice also exhibited similar bactericidal activity in vitro, and passive transfer of these immune sera into B. burgdorferi-infected SCID mice caused similar reductions of bacterial numbers in target tissues. Infectious dose studies indicated that 8-fold more B. burgdorferi were needed to efficiently infect naive IL-10(-/-) mice, suggesting these animals possess higher innate barriers to infection. Moreover, macrophages derived from IL-10(-/-) mice exhibit enhanced proinflammatory responses to B. burgdorferi stimulation compared with wild-type controls, and these responses are not significantly affected by the presence of immune serum. These findings confirm that B. burgdorferi clearance by innate immune responses is more efficient in the absence of IL-10, and these activities are not directly related to increased levels of B. burgdorferi-specific Ab.