Impact of Microvascular Obstruction on the Assessment of Coronary Flow Reserve,Index of Microcirculatory Resistance,and Fractional Flow Reserve After ST-Segment Elevation Myocardial Infarction

Background

Invasive assessment of coronary physiology (IACP) offers important prognostic insights in ST-segment elevation myocardial infarction (STEMI) but the dynamics of coronary recovery are poorly understood.

Objectives

This study sought to examine the evolution of coronary flow reserve (CFR), index of microcirculatory resistance (IMR), ratio of distal coronary pressure (Pd) to mean aortic pressure (Pa), and fractional flow reserve (FFR) in patients undergoing primary percutaneous coronary intervention (PPCI).

Methods

82 patients with STEMI underwent IACP at PPCI. Repeat IACP was performed in 61 patients (74%) at day 1 and in 46 patients (56%) at 6 months. Contrast-enhanced cardiac magnetic resonance imaging (CMR) was performed in 45 patients (55%) at day 1 and in 41 patients (50%) at 6 months. Changes in IACP were compared between patients with and without microvascular obstruction (MVO) on CMR.

Results

MVO was present in 21 of 45 patients (47%). Patients with MVO had lower CFR at PPCI and day 1 (p < 0.05) and a trend toward higher IMR values (p = 0.07). At 6 months, CFR and IMR were not significantly different between the groups. Baseline flow and Pd/Pa remained stable over time but FFR reduced significantly between PPCI and 6 months (p = 0.008); this reduction was mainly observed in patients with MVO (p = 0.006) but not in those without MVO (p = 0.21).

Conclusions

In PPCI-treated patients with STEMI, coronary microcirculation begins to recover within 24 h and recovery progresses further by 6 months. FFR significantly reduces from baseline to 6 months. The presence of MVO indicates a highly dysfunctional microcirculation.     

Cells infected with herpes simplex virus 1 export to uninfected cells exosomes containing STING,viral mRNAs,and microRNAs

STING (stimulator of IFN genes) activates the IFN-dependent innate immune response to infection on sensing the presence of DNA in cytosol. The quantity of STING accumulating in cultured cells varies; it is relatively high in some cell lines [e.g., HEp-2, human embryonic lung fibroblasts (HEL), and HeLa] and low in others (e.g., Vero cells). In a preceding publication we reported that STING was stable in four cell lines infected with herpes simplex virus 1 and that it was actively stabilized in at least two cell lines derived from human cancers. In this report we show that STING is exported from HEp-2 cells to Vero cells along with virions, viral mRNAs, microRNAs, and the exosome marker protein CD9. The virions and exosomes copurified. The quantity of STING and CD9 exported from one cell line to another was inoculum-size–dependent and reflected the levels of STING and CD9 accumulating in the cells in which the virus inoculum was made. The export of STING, an innate immune sensor, and of viral mRNAs whose major role may be in silencing viral genes in latently infected neurons, suggests that the virus has evolved mechanisms that curtail rather than foster the spread of infection under certain conditions.The stimulator of IFN genes (STING) is a sensor of cytoplasmic DNA and activates immune responses to intracellular pathogens (1–3). Knockout of STING exacerbates the pathogenicity of herpes simplex virus (HSV-1) and of other pathogens in mice (2, 3). Two observations reported earlier add to the role of STING in HSV-1 infected cells. Specifically, (i) STING was readily detectable and stable in four different cell lines infected with wild-type virus (4). The stability of STING in cells infected with an HSV-1 mutant lacking the gene encoding ICP0 (infected cell protein no. 0), a key viral regulatory protein, varied. STING was stable in ΔICP0 mutant virus infected cells derived from normal tissues but was rapidly degraded in infected cells derived from human cancers (4). Implicit in this observation is that ICP0 is required to stabilize STING, although STING could also be stabilized in the absence of ICP0 by a cellular function. (ii) Depletion of STING increased wild-type virus yield 10-fold in cells derived from normal tissues but decreased the yield by the same amount in cells derived from human cancer (4). Thus, at least in cells derived from normal tissues, HSV-1 expresses ICP0 that enables the stabilization of STING even though STING is inimical to virus growth. The results of these studies suggest that HSV-1 recruits STING for a specific function, even though the persistence of STING is not beneficial to virus growth, at least in cells derived from normal tissues (4).Here we report that STING, along with viral RNAs contained in structures that coprecipitate with exosome marker proteins, is exported from the cells in which virus is produced to uninfected cells. The quantities introduced into uninfected cells are dose-dependent and reflect the amounts produced in donor cells.Cells continuously secrete a large number of microvesicles, macromolecular complexes, and small molecules into the extracellular space (5, 6). Of the secreted microvesicles, exosomes are 30–120 nm in diameter, containing nucleic acid and proteins, and are perceived to be carriers of this cargo between diverse locations. They are distinguished in their genesis by being budded into endosomes to form multivesicular bodies (MVBs) in the cytoplasm. The exosomes are released to extracellular fluids by fusion of these multivesicular bodies with the cell surface, resulting in secretion (7–10).Several pathogens use the exosomes to manipulate their microenvironment (11, 12). Viruses, especially small retroviruses such as HIV, use the exosome pathway for egress and immune evasion (13–15). The hepatitis C virus uses exosomes for invasion and spread (16–18). EBV-infected cells release exosomes containing the latent membrane protein 1 to induce T-cell anergy (19–23). In the case of human cytomegalovirus the exosomes carrying viral antigens exacerbate the transplant rejection process (24). It is likely that viruses that establish long-term, latent, or chronic infections modulate exosomes to enhance their persistence (11).Here we report that the exosomes secreted by HSV-1–infected cells deliver to uninfected cells the innate immune sensor STING along with viral RNAs. We speculate that in the long run the strategy serves the virus to fulfill its mission: to spread effectively from person to person.     

Genetic variability of VEGF pathway genes in six randomized phase III trials assessing the addition of bevacizumab to standard therapy

Background

Despite extensive translational research, no validated biomarkers predictive of bevacizumab treatment outcome have been identified.

Methods

We performed a meta-analysis of individual patient data from six randomized phase III trials in colorectal, pancreatic, lung, renal, breast, and gastric cancer to explore the potential relationships between 195 common genetic variants in the vascular endothelial growth factor (VEGF) pathway and bevacizumab treatment outcome.

Results

The analysis included 1,402 patients (716 bevacizumab-treated and 686 placebo-treated). Twenty variants were associated (P < 0.05) with progression-free survival (PFS) in bevacizumab-treated patients. Of these, 4 variants in EPAS1 survived correction for multiple testing (q < 0.05). Genotype-by-treatment interaction tests revealed that, across these 20 variants, 3 variants in VEGF-C (rs12510099), EPAS1 (rs4953344), and IL8RA (rs2234671) were potentially predictive (P < 0.05), but not resistant to multiple testing (q > 0.05). A weak genotype-by-treatment interaction effect was also observed for rs699946 in VEGF-A, whereas Bayesian genewise analysis revealed that genetic variability in VHL was associated with PFS in the bevacizumab arm (q < 0.05). Variants in VEGF-A, EPAS1, and VHL were located in expression quantitative loci derived from lymphoblastoid cell lines, indicating that they affect the expression levels of their respective gene.

Conclusions

This large genetic analysis suggests that variants in VEGF-A, EPAS1, IL8RA, VHL, and VEGF-C have potential value in predicting bevacizumab treatment outcome across tumor types. Although these associations did not survive correction for multiple testing in a genotype-by-interaction analysis, they are among the strongest predictive effects reported to date for genetic variants and bevacizumab efficacy.     

Efficacy of the hypomethylating agents as frontline, salvage, or consolidation therapy in adults with acute myeloid leukemia (AML)

The hypomethylating agents (HAs), azacitidine and decitabine, have emerged as an alternative to initial and salvage therapy in patients with acute myeloid leukemia (AML). Little is known about how AML responds to hypomethylating agents after standard therapy, and the activity of these agents in a real-world setting is not well studied. We retrospectively examined data for 75 consecutive AML patients at Wake Forest from 2002 to 2011 treated with HAs either as first-line (n?=?34), salvage (n?=?28), or consolidation (n?=?13) therapy. We collected data on age, gender, race, Charlson comorbidity index (CCI), cytogenetics, type of treatment, complete remission (CR), complete remission with incomplete count recovery (CRi), and survival. Statistical analysis was performed using Kaplan–Meier estimates and Cox proportional hazards models. Frontline response rate (CR + CRi) was 26.5 %, and median overall survival (OS) was 3.4 months (95 % CI 1.3–7.4), with 18 % alive at 1 year. In the salvage cohort, the response rate was significantly lower compared to frontline (3.6 versus 26.5 %, p?=?0.017). Despite the reduced response, OS from time of HA treatment was longer than frontline at 8.2 months (CI 4.8–10.3). In the consolidation cohort, OS was 13.8 months (CI 8.0–21.6) with one patient in remission more than 30 months from diagnosis. These data suggest that prior cytotoxic therapy decreases marrow response rates to HAs but not survival. Furthermore, use of hypomethylating agents for consolidation resulted in a median overall survival over 1 year in a cohort of older patients. This suggests that hypomethylating agents have activity in all phases of AML treatment.     

COVID-19 and ischemic stroke: a systematic review and meta-summary of the literature

Journal of Thrombosis and Thrombolysis - Acute ischemic stroke (AIS) is a life-threatening complication of coronavirus disease 2019 (COVID-19) infection. Increasing reports suggest an association...     

The Importance of Public Health Agency Independence: Marcellus Shale Gas Drilling in Pennsylvania

Public health often deals with inconvenient truths. These are best communicated and acted on when public health agencies are independent of the organizations or individuals for whom the truths are inconvenient. The importance of public health independence is exemplified by the lack of involvement of the Pennsylvania Department of Health in responding to health concerns about shale gas drilling. Pennsylvania Department of Health involvement has been forestalled by the state governor, who has intensely supported shale gas development.The decline in independence of governmental public health agencies was deplored in the seminal 1988 Institute of Medicine report The Future of Public Health.1 Further decline has been noted,2 as has evidence of the importance of public health agency independence in high-stakes issues with powerful industries such as tobacco control policies3 and waste control at industrial food animal production sites.4An example of the perils of the lack of public health agency independence in high-stakes issues is evident in Pennsylvania in relation to the sudden burst of Marcellus shale drilling activity. Public concerns about potential adverse health impacts have been repeatedly voiced, and instances of groundwater contamination have been well publicized.5–8 An American Public Health Association policy statement has addressed the role of public health professionals in this issue.5 Yet full control of the Pennsylvania Department of Health (PADOH) by a governor strongly supporting shale gas drilling, along with the lack of independent local county and municipal public health agencies in affected areas, has effectively prevented public health authorities from responding.