ACR Appropriateness Criteria® Pulmonary Arteriovenous Malformation (PAVM): 2023 Update.

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Pulmonary arteriovenous malformation (PAVM): 2023 update

Pulmonary arteriovenous malformations (PAVMs) occur in 30% to 50% of patients with hereditary hemorrhagic telangiectasia. Clinical presentations vary from asymptomatic disease to complications resulting from the right to left shunting of blood through the PAVM such as paradoxical stroke, brain abscesses, hypoxemia, and cardiac failure. Radiology plays an important role both in the diagnosis and treatment of PAVM. Based on different clinical scenarios, the appropriate imaging study has been reviewed and is presented in this document. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Congenital or Acquired Heart Disease.

Pediatric heart disease is a large and diverse field with an overall prevalence estimated at 6 to 13 per 1,000 live births. This document discusses appropriateness of advanced imaging for a broad range of variants. Diseases covered include tetralogy of Fallot, transposition of great arteries, congenital or acquired pediatric coronary artery abnormality, single ventricle, aortopathy, anomalous pulmonary venous return, aortopathy and aortic coarctation, with indications for advanced imaging spanning the entire natural history of the disease in children and adults, including initial diagnosis, treatment planning, treatment monitoring, and early detection of complications. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Nontraumatic Aortic Disease.

Nontraumatic aortic disease can be caused by a wide variety of disorders including congenital, inflammatory, infectious, metabolic, neoplastic, and degenerative processes. Imaging examinations such as radiography, ultrasound, echocardiography, catheter-based angiography, CT, MRI, and nuclear medicine examinations are essential for diagnosis, treatment planning, and assessment of therapeutic response. Depending upon the clinical scenario, each of these modalities has strengths and weaknesses. Whenever possible, the selection of a diagnostic imaging examination should be based upon the best available evidence. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment. The purpose of this document is to assist physicians select the most appropriate diagnostic imaging examination for nontraumatic aortic diseases.

Prevalence and characteristics of coronary microvascular dysfunction among chest pain patients in the emergency department.

AIMS: Coronary microvascular dysfunction (CMD) is common in patients with non-obstructive coronary arteries but has not been described in low-risk symptomatic patients. We therefore assessed the prevalence and characteristics of CMD in low to moderate risk patients with chest pain in an emergency department. METHODS AND RESULTS: We used three-dimensional Rb82 cardiac positron emission tomography/computed tomography to diagnose coronary artery disease (known or new regional defect, any coronary calcification) and CMD (low coronary flow reserve without coronary artery disease) in chest pain patients after being ruled out for acute myocardial infarction. Exclusions included age 30 years or less, acute myocardial infarction, hemodynamic instability, heart failure and dialysis. Among 195 participants undergoing cardiac positron emission tomography/computed tomography, 42% had CMD, 36% had coronary artery disease and 22% had normal flows; 70% were women and 84% were obese. Patients with CMD and coronary artery disease had significantly lower coronary flow reserve than normal patients (mean coronary flow reserve 1.6 and 1.9 vs. 2.6, respectively, P<0.05). However, CMD patients were younger (mean age 51 vs. 61 years), and had fewer traditional cardiac risk factors (P<0.05) than patients with coronary artery disease. Nearly one third (31%) of patients had a prior emergency department visit for chest pain within three years of index presentation. Women were four times as likely to have CMD as men (adjusted odds ratio 4.2; 95% confidence interval 1.8, 9.6) after controlling for age, race, hypertension, diabetes, smoking, dyslipidemia, obesity and family history of coronary artery disease. CONCLUSIONS: Despite their low-risk profile, nearly one half of symptomatic and mostly obese emergency department patients without evidence of myocardial infarction or coronary artery disease had CMD. The results could explain the high rates of return visits associated with chest pain, although their application to the general emergency department population require validation.

Cardiac Complications of Cancer Therapy: Pathophysiology, Identification, Prevention, Treatment, and Future Directions.

PURPOSE OF REVIEW: Cardiotoxicity is an important complication of cancer therapy. With a significant improvement in the overall survival and prognosis of patients undergoing cancer therapy, cardiovascular toxicity of cancer therapy has become an important public health issue. Several well-established as well as newer anticancer therapies such as anthracyclines, trastuzumab, and other HER2 receptor blockers, antimetabolites, alkylating agents, tyrosine kinase inhibitors, angiogenesis inhibitors, checkpoint inhibitors, and thoracic irradiation are associated with significant cardiotoxicity. RECENT FINDINGS: Cardiovascular imaging employing radionuclide imaging, echocardiography, and magnetic resonance imaging is helpful in early detection of the cardiotoxicity and prevention of overt heart failure. These techniques also provide important tools for understanding the mechanism of cardiotoxicity of these modalities, which would help develop strategies for the prevention of cardiac morbidity and mortality related to the use of these agents. An understanding of the mechanism of the cardiotoxicity of cancer therapies can help prevent and treat their adverse cardiovascular consequences. Clinical implementation of algorithms based upon cardiac imaging and several non-imaging biomarkers can prevent cardiac morbidity and mortality associated with the use of cardiotoxic cancer therapies.

Cardio-oncology: the Nuclear Option.

PURPOSE OF REVIEW: Cardio-oncology focuses increased effort to decrease cancer treatment-related cardiotoxicity while continuing to improve outcomes. We sought to synthesize the latest in nuclear cardiology as it pertains to the assessment of left ventricular function in preventative guidelines and comparison to other modalities, novel molecular markers of pre-clinical cardiotoxicity, and its role in cardiac amyloid diagnosis. RECENT FINDINGS: Planar ERNA (equilibrium radionuclide angiocardiography) provides a reliable and proven means of monitoring and preventing anthracycline cardiotoxicity, and SPECT ERNA using solid-state gamma cameras may provide reproducible assessments of left ventricular function with reduced radiation exposure. While certain chemotherapeutics have vascular side effects, the use of stress perfusion imaging has still not been adequately studied for routine use. Similarly, markers of apoptosis, inflammation, and sympathetic nerve dysfunction are promising, but are still not ready for uniform usage. SPECT tracers can assist in nonbiopsy diagnosis of cardiac amyloid. Nuclear cardiology is a significant contributor to the multimodality approach to cardio-oncology.

Ranolazine and Microvascular Angina by PET in the Emergency Department: Results From a Pilot Randomized Controlled Trial.

PURPOSE: Coronary microvascular dysfunction (CMD) is a common but underdiagnosed cause of chest pain. Literature is scant regarding effective treatments. We explored the effect of ranolazine on coronary flow reserve (CFR) among symptomatic patients with CMD. METHODS: This pilot double-blinded randomized controlled trial included emergency department patients with chest pain and CMD admitted to an observation unit between June 2014 and November 2015. Participants were assessed by cardiac Rb-82 positron emission tomography and computed tomography imaging at baseline and 30 days. CMD was defined as CFR <2 corrected for rate pressure product or <2.5 uncorrected, with no evidence of obstructive or nonobstructive coronary artery disease or calcification. Patients with infarction, hypertensive urgency, heart failure, or prescribed QTc-prolonging drugs were excluded. Participants were assigned to ranolazine or placebo in a 2:1 ratio. Primary outcome was change in CFR at 30 days. FINDINGS: We enrolled 31 patients (71% female, mean [SD] age 50 [6] years) with CMD (mean [SD] corrected CFR 1.6 [0.3]). Ranolazine improved CFR at 30 days by 17% (P = 0.005) compared with 0% with placebo (P = 0.67). However, there was no significant difference in the primary outcome as measured by mean change in CFR (0.27 ranolazine compared with 0.06 placebo; 95% CI, -0.08 to 0.62). IMPLICATIONS: The emergency department offers a unique venue to diagnose CMD with acute symptoms. In an exploratory randomized controlled trial of symptomatic patients with CMD and no coronary artery disease, promising results were seem with ranolazine and CFR improving at 30 days. Large robust clinical trials are needed to verify improvement of CMD in a sex-specific model. ClinicalTrials.gov identifier NCT02052011.

The role and clinical effectiveness of multimodality imaging in the management of cardiac complications of cancer and cancer therapy.

With the increasing number of individuals living with a current or prior diagnosis of cancer, it is important for the cardiovascular specialist to recognize the various complications of cancer and its therapy on the cardiovascular system. This is true not only for established cancer therapies, such as anthracyclines, that have well established cardiovascular toxicities, but also for the new targeted therapies that can have "off target" effects in the heart and vessels. The purpose of this informational statement is to provide cardiologists, cardiac imaging specialists, cardio-oncologists, and oncologists an understanding of how multimodality imaging may be used in the diagnosis and management of the cardiovascular complications of cancer therapy. In addition, this document is meant to provide useful general information concerning the cardiovascular complications of cancer and cancer therapy as well as established recommendations for the monitoring of specific cardiotoxic therapies.

AMPK is critical for mitochondrial function during reperfusion after myocardial ischemia.

AMP-activated kinase (AMPK) is a stress responsive kinase that regulates cellular metabolism and protects against cardiomyocyte injury during ischemia-reperfusion (IR). Mitochondria play an important role in cell survival, but the specific actions of activated AMPK in maintaining mitochondrial integrity and function during reperfusion are unknown. Thus, we assessed the consequences of AMPK inactivation on heart mitochondrial function during reperfusion. Mouse hearts expressing wild type (WT) or kinase-dead (KD) AMPK were studied. Mitochondria isolated from KD hearts during reperfusion had intact membrane integrity, but demonstrated reduced oxidative capacity, increased hydrogen peroxide production and decreased resistance to mitochondrial permeability transition pore opening compared to WT. KD hearts showed increased activation of the mitogen activated protein kinase kinase 4 (MKK4) and downstream c-Jun terminal kinase (JNK) and greater necrosis during reperfusion after coronary occlusion. Transgenic expression of mitochondrial catalase (MCAT) prevented the excessive cardiac JNK activation and attenuated the increased myocardial necrosis observed during reperfusion in KD mice. Inhibition of JNK increased the resistance of KD hearts to mPTP opening, contractile dysfunction and necrosis during IR. Thus, intrinsic activation of AMPK is critical to prevent excess mitochondrial reactive oxygen production and consequent JNK signaling during reperfusion, thereby protecting against mPTP opening, irreversible mitochondrial damage and myocardial injury.

Elevated CK-MB with a normal troponin does not predict 30-day adverse cardiac events in emergency department chest pain observation unit patients.

BACKGROUND: Prior studies indicate that an elevated creatinine kinase (CK)-MB imparts poor prognosis in patients with acute coronary syndrome despite a normal troponin. Its prognosis in the undifferentiated chest pain observation unit (CPU) population remains undefined. OBJECTIVE: To compare rates and predictors of 30-day adverse cardiac events in 2 cohorts (CK ±/MB+ vs. normal [CK ±/MB-]) in low-moderate-risk CPU patients. METHODS: Consecutive CPU patients were followed in a retrospective cohort study for primary outcome (acute coronary syndrome, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, abnormal stress test, cardiac hospitalization, or death within 30 days) by using standardized chart reviews and national death registry. Exclusions were: those aged 30 years or younger, positive troponin, ischemic electrocardiogram, hemodynamic instability, heart failure, or dialysis. RESULTS: Between January 2006 and April 2009, 2979 patients were eligible, of which 350 excluded and 2629 analyzed. MB+ compared with normal patients were more likely to be: older (mean, 53.4 ± 14 vs. 51.5 ± 12 years; P = 0.04); male (71% vs. 40%; P = 0.01); renal insufficient (5% vs. 2%; P = 0.01); hypertensive (50% vs. 44%; P = 0.04); dyslipidemic (44% vs. 33%; P = 0.01) obese (55% vs. 43%; P = 0.01); and with known coronary artery disease (14% vs. 5%; P < 0.01). Composite adverse events were 213 (8%) and did not significantly differ for either initial MB+ vs. normal (9.1%, 8.0%; odds ratio, 1.1, 0.7-1.9) or serial MB+ vs. normal (7.5%, 7.4%; odds ratio, 1.0, 0.5-1.8). In a multiple logistic regression model, male sex, diabetes, and prior CAD predicted adverse events, whereas CK-MB along with race, hypertension, smoking, dyslipidemia, family history, and obesity did not. CONCLUSIONS: Elevated CK-MB does not add value to serial troponin testing in low-moderate-risk CPU patients.

Role of uncoupling protein 3 in ischemia-reperfusion injury, arrhythmias, and preconditioning.

Overexpression of mitochondrial uncoupling proteins (UCPs) attenuates ischemia-reperfusion (I/R) injury in cultured cardiomyocytes. However, it is not known whether UCPs play an essential role in cardioprotection in the intact heart. This study evaluated the cardioprotective efficacy of UCPs against I/R injury and characterized the mechanism of UCP-mediated protection in addition to the role of UCPs in ischemic preconditioning (IPC). Cardiac UCP3 knockout (UCP3(-/-)) and wild-type (WT) mice hearts were subjected to ex vivo and in vivo models of I/R injury and IPC. Isolated UCP3(-/-) mouse hearts were retrogradely perfused and found to have poorer recovery of left ventricular function compared with WT hearts under I/R conditions. In vivo occlusion of the left coronary artery resulted in twofold larger infarcts in UCP3(-/-) mice compared with WT mice. Moreover, the incidence of in vivo I/R arrhythmias was higher in UCP3(-/-) mice. Myocardial energetics were significantly impaired with I/R, as reflected by a decreased ATP content and an increase in the AMP-to-ATP ratio. UCP3(-/-) hearts generated more reactive oxygen species (ROS) than WT hearts during I/R. Pretreatment of UCP3(-/-) hearts with the pharmacological uncoupling agent carbonyl cyanide p-(trifluoromethoxy)phenylhydrazone improved postischemic functional recovery. Also the protective efficacy of IPC was abolished in UCP3(-/-) mice. We conclude that UCP3 plays a critical role in cardioprotection against I/R injury and the IPC phenomenon. There is increased myocardial vulnerability to I/R injury in hearts lacking UCP3. The mechanisms of UCP3-mediated cardioprotection include regulation of myocardial energetics and ROS generation by UCP3 during I/R.

Endothelial-derived neuregulin is an important mediator of ischaemia-induced angiogenesis and arteriogenesis.

AIMS: Neuregulins (NRG) are growth factors that are synthesized by endothelial cells (ECs) and bind to erbB receptors. We have shown previously that NRG is proangiogenic in vitro, and that NRG/erbB signalling is important for autocrine endothelial angiogenic signalling in vitro. However, the role of NRG in the angiogenic response to ischaemia is unknown. We hypothesized that endothelial NRG is required for ischaemia-induced angiogenesis in vivo and that exogenous administration of NRG will enhance angiogenic responses after ischaemic insult. METHODS AND RESULTS: An endothelial-selective inducible NRG knockout mouse was created and subjected to femoral artery ligation. Endothelial NRG deletion significantly decreased blood flow recovery (by 40%, P < 0.05), capillary density, α(v)ß(3) integrin activation, and arteriogenesis after ischaemic injury. Isolated ECs from knockout mice demonstrated significantly impaired cord formation in vitro, suggesting that NRG signalling performs an important cell autonomous function. Recombinant human NRG (rNRG) has not only reversed the angiogenic defect in knockout mice but also accelerated blood flow recovery in wild-type mice. CONCLUSION: Endothelial production of NRG is required for angiogenesis and arteriogenesis induced by ischaemic injury. Furthermore, exogenous administration of rNRG can enhance this process, suggesting a potential role for NRG in vascular disease.

Endothelium-derived neuregulin protects the heart against ischemic injury.

BACKGROUND: Removal of cardiac endothelial cells (EC) has been shown to produce significant detrimental effects on the function of adjacent cardiac myocytes, suggesting that EC play a critical role in autocrine/paracrine regulation of the heart. Despite this important observation, the mediators of the protective function of EC remain obscure. Neuregulin (NRG, a member of the epidermal growth factor family) is produced by EC and cardiac myocytes contain receptors (erbB) for this ligand. We hypothesized that NRG is an essential factor produced by EC, which promotes cardioprotection against ischemic injury. METHODS AND RESULTS: We demonstrate that human cardiac EC express and release NRG in response to hypoxia-reoxygenation. Under conditions where hypoxia--reoxygenation causes significant cardiac myocyte cell death, NRG can significantly decrease apoptosis of isolated adult ventricular myocytes. Coculturing adult murine myocytes with human umbilical vein, murine lung microvascular, or human coronary artery EC can also protect myocytes against hypoxia--reoxygenation--induced apoptosis. These protective effects are abolished by NRG gene deletion or silencing of NRG expression in EC. Finally, endothelium-selective deletion of NRG in vivo leads to significantly decreased tolerance to ischemic insult, as demonstrated by impaired postischemic contractile recovery in a perfused whole-organ preparation and larger infarct sizes after coronary artery ligation. CONCLUSION: Together, these data demonstrate that EC-derived NRG plays an important role in cardiac myocyte protection against ischemic injury in the heart and supports the idea that manipulation of this signaling pathway may be an important clinical target in this setting.

Activation of the aryl hydrocarbon receptor by doxorubicin mediates cytoprotective effects in the heart.

AIMS: Doxorubicin (DOX) is a highly effective chemotherapeutic agent; however, cumulative dose-dependent cardiotoxicity is a significant side effect of this therapy. Because DOX is a polyaromatic hydrocarbon, we hypothesized that it will be metabolized by the activation of the aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor that is involved in the metabolism of numerous xenobiotic agents. These studies were performed to determine whether DOX activates AhR and whether this activation modulates the toxicity of DOX in cardiomyocytes. METHODS AND RESULTS: Treatment with DOX induced AhR migration to the nucleus, increased AhR binding with its co-factor, aryl hydrocarbon receptor nuclear translocator-1 (ARNT1), and increased the expression of AhR-regulated phase I (CYP1A1) and phase II (GSTA1) drug-metabolizing enzymes in both cardiomyocytes and in the intact heart. Knockdown of AhR in H9C2 cells abolished DOX-induced increases in CYP1A1 and GSTA1 expression. Similar results were obtained by treating adult rat ventricular myocytes with the AhR antagonist, CH-223191. Taken together, these findings indicate that DOX-induced upregulation of CYP1A1 and GSTA1 expression is AhR dependent. AhR null mice treated with 10 mg/kg DOX did not show any activation of CYP1A1 or GSTA1 expression. Moreover, lack of AhR in vivo resulted in a significant decrease in left ventricular function compared with wild-type animals, and increased p53 activation and apoptosis in the heart after treatment with DOX. CONCLUSIONS: These findings indicate that AhR plays an important role in DOX metabolism by the heart and further demonstrate that AhR is cardioprotective against DOX-induced cardiotoxicity.

Uncoupling protein downregulation in doxorubicin-induced heart failure improves mitochondrial coupling but increases reactive oxygen species generation.

PURPOSE: Doxorubicin-based chemotherapy is limited by the development of dose-dependent left ventricular dysfunction and congestive heart failure caused by reactive oxygen species (ROS). Uncoupling proteins (UCP) can inhibit mitochondrial ROS production as well as decrease myocyte damage from exogenous ROS. Prior studies have shown that cardiac UCP2 and UCP3 mRNA expression is decreased with acute doxorubicin treatment. However, the expression of UCP protein in hearts with doxorubicin cardiotoxicity and the resultant changes in mitochondrial function and oxidant stress have not been determined. METHODS: Heart failure was induced in Sprague-Dawley rats with intraperitoneal injections of doxorubicin (2 mg/kg t.i.w., total dose: 18 mg/kg). Mitochondria were isolated from mice receiving doxorubicin or saline injections for determination of UCP2 and UCP3 expression. In addition, mitochondrial respiration, ATP synthesis and ROS production were determined. RESULTS: Doxorubicin-induced heart failure was associated with significant decreases in UCP2 and UCP3 protein expression compared with nonfailing hearts (P < 0.05). While the rates of state 3 and state 4 respiration and ATP synthesis were lower in mitochondria isolated from failing hearts, the respiratory control ratio was 15% higher (P < 0.05), and the ratio of ATP production to oxygen consumption was 25% higher (P < 0.05) in mitochondria from failing hearts, indicating greater coupling between citric acid cycle flux and mitochondrial ATP synthesis. However, the decrease in UCP expression was associated with 50% greater mitochondrial ROS generation (P < 0.05). CONCLUSIONS: Downregulation of myocardial UCP2 and UCP3 in the setting of doxorubicin-induced heart failure is associated with improved efficiency of ATP synthesis, which might compensate for abnormal energy metabolism. However, this beneficial effect is counterbalanced by greater oxidant stress.

Metalloproteinase-dependent cleavage of neuregulin and autocrine stimulation of vascular endothelial cells.

Inflammation is often accompanied by robust angiogenesis. Vascular endothelial cells (ECs) express erbB receptors and their ligand, neuregulin-1, and can respond to neuregulin by proliferation and angiogenesis. We hypothesized that some growth factor-like responses of ECs to inflammatory cytokines can be explained by cleavage of transmembrane neuregulin with subsequent release of its extracellular epidermal growth factor-like-containing domain and autocrine activation. Using a model of cultured human ECs, we found that interleukin-6 or interferon-gamma causes rapid cleavage and release of transmembrane neuregulin. Inhibitors of metalloproteinases abolish this effect. The addition of an inhibitor of tumor necrosis factor-alpha converting enzyme (TACE) blocks cytokine-induced neuregulin release. Silencing of TACE expression increases the amount of basal proneuregulin present in ECs but does not block neuregulin release in response to phorbol myristate acetate (PMA), suggesting that other proteinases are responsible for mediating protein kinase C-dependent cleavage. Cytokines capable of inducing neuregulin cleavage stimulated ERK activation and in vitro angiogenesis (Matrigel cord formation). This effect is blocked by inhibitors that block neuregulin cleavage, erbB protein tyrosine kinase inhibitors, or antineuregulin-neutralizing antibodies. Cytokine-activated metalloproteinase cleavage of neuregulin may play an important role in autocrine activation of EC signaling pathways, contributing to key biological effects, perhaps including inflammation-associated angiogenesis.