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Background: The rupture of atherosclerotic plaque contributes significantly to cardiovascular disease. Plasma concentrations of bilirubin—a byproduct of heme catabolism—inversely associate with risk of cardiovascular disease, although the link between bilirubin and atherosclerosis remains unclear. Methods: To assess the role of bilirubin in atherosclerotic plaque stability, we crossed Bvra −/− with Apoe −/− mice and used the tandem stenosis model of plaque instability. Human coronary arteries were obtained from heart transplant recipients. Analysis of bile pigments, heme metabolism, and proteomics were performed by liquid chromatography tandem mass spectrometry. MPO (myeloperoxidase) activity was determined by in vivo molecular magnetic resonance imaging, liquid chromatography tandem mass spectrometry analysis, and immunohistochemical determination of chlorotyrosine. Systemic oxidative stress was evaluated by plasma concentrations of lipid hydroperoxides and the redox status of circulating Prx2 (peroxiredoxin 2), whereas arterial function was assessed by wire myography. Atherosclerosis and arterial remodeling were quantified by morphometry and plaque stability by fibrous cap thickness, lipid accumulation, infiltration of inflammatory cells, and the presence of intraplaque hemorrhage. Results: Compared with Bvra +/+ Apoe −/− tandem stenosis littermates, Bvra −/− Apoe −/− tandem stenosis mice were deficient in bilirubin, showed signs of increased systemic oxidative stress, endothelial dysfunction, as well as hyperlipidemia, and had a higher atherosclerotic plaque burden. Heme metabolism was increased in unstable compared with stable plaque of both Bvra +/+ Apoe −/− and Bvra −/− Apoe −/− tandem stenosis mice and in human coronary plaques. In mice, Bvra deletion selectively destabilized unstable plaque, characterized by positive arterial remodeling and increased cap thinning, intraplaque hemorrhage, infiltration of neutrophils, and MPO activity. Proteomic analysis confirmed Bvra deletion enhanced extracellular matrix degradation, recruitment and activation of neutrophils, and associated oxidative stress in unstable plaque. Conclusions: Bilirubin deficiency, resulting from global Bvra deletion, generates a proatherogenic phenotype and selectively enhances neutrophil-mediated inflammation and destabilization of unstable plaque, thereby providing a link between bilirubin and cardiovascular disease risk.

Conversion of the redox probe hydroethidine (HE) to 2-chloroethidium (2-Cl-E

Near-infrared autofluorescence (NIRAF) in unstable atherosclerotic plaque has been suggested as a novel imaging technology for high-risk atherosclerosis. Intraplaque hemorrhage (IPH) and bilirubin, derived from the subsequent degradation of heme, have been proposed as the source of NIRAF, although their roles and the underlying mechanism responsible for NIRAF remain unclear. To test the proposed role of bilirubin as the source of NIRAF in high-risk atherosclerosis, Biliverdin reductase a gene and apolipoprotein E gene double-knockout (Bvra−/−Apoe−/−) mice were subjected to the Western diet and tandem stenosis (TS) surgery, as a model of both bilirubin deficiency and plaque instability. Human coronary arteries containing atherosclerotic plaques were obtained from heart transplant recipients. The NIRAF was determined by in vivo fluorescence emission computed tomography, and ex vivo infrared imaging. The cholesterol content was quantified by HPLC with UV detection. In Bvra+/+Apoe−/− TS mice, the NIRAF intensity was significantly higher in unstable plaque than in stable plaque, yet the NIRAF in unstable plaque was undistinguishable in Bvra+/+Apoe−/− and littermate Bvra−/−Apoe−/− TS mice. Moreover, the unstable plaque in TS mice exhibited a lower NIRAF compared with highly cellular plaque that lacked most of the features of unstable plaque. In human coronary arteries, the NIRAF associated with cholesterol-rich, calcified lesions, rather than just cholesterol-rich lesions. The NIRAF in atherosclerotic plaque can be dissociated from IPH and bilirubin, such that the compositional meaning of an elevated NIRAF remains obscure.

Intracellular myeloperoxidase (MPO) plays a specific role in the innate immune response; however, upon release into the extracellular space in the setting of inflammation, drives oxidative tissue injury. Extracellular MPO has recently been shown to be abundant in unstable atheroma and causally linked to plaque destabilization, erosion, and rupture, identifying it as a potential target for the surveillance and treatment of vulnerable atherosclerosis. Through the compartmentalization of MPO’s protective and deleterious effects, extracellular MPO can be selectively detected using non-invasive molecular imaging and targeted by burgeoning pharmacotherapies. Given its causal relationship to plaque destabilization coupled with an ability to preserve its beneficial properties, MPO is potentially a superior translational inflammatory target compared with other immunomodulatory therapies and imaging biomarkers utilized to date. This review explores the role of MPO in plaque destabilization and provides insights into how it can be harnessed in the management of patients with vulnerable atherosclerotic plaque.

We present a case of recurrent isolated cardiac sarcoidosis, 3 years post-heart transplantation. The case highlights the scarcity of data on the utility of immunosuppression in cardiac sarcoidosis and, in particular, raises questions about the optimal immunosuppression regimen in transplant recipients. (Level of Difficulty: Advanced.), Graphical abstract

Background: People living with HIV (PLHIV) have a higher incidence of cardiovascular disease and complications after intervention, including in-stent thrombosis. The frequency of potential drug-drug interactions in the setting of acute coronary syndrome (ACS) with antiretroviral therapy (ART) and dual-antiplatelet therapy (DAPT) regimens remains unclear. We sought to determine the frequency of potential drug-drug interactions in a cohort of people living with HIV who were investigated for coronary disease and initiated on DAPT as per Australian ACS Guidelines. Methods: A retrospective audit was performed in a single tertiary hospital in PLHIV presenting with symptomatic coronary artery disease (CAD) receiving DAPT. Patients were grouped based on exposure to a protease inhibitor or efavirenz and etravirine, given that these were found to have the greatest potential interactions with DAPT. Results: Fifty-three patients received DAPT, of which 31 (58%) had a potential drug-drug interaction. Clopidogrel was the most frequent P2Y12 inhibitor prescribed, accounting for 47 (87%) of the interactions. Twenty-six patients were on a protease inhibitor, of which 21 (81%) had a potential drug-drug interaction. There were 11 instances of efavirenz and 3 of etravirine use, of which all resulted in potential drug-drug interactions (100%, respectively). Conclusion: Potential drug-drug interactions were very common in PLHIV needing DAPT. The widespread use of clopidogrel in DAPT regimens resulted in a high rate of drug-drug interactions. An awareness of interactions and guidelines around P2Y12 inhibitor selection may help reduce the rate of in-stent thrombosis for PLHIV and improve clinical outcomes.

We read with great interest the paper by Lemesle et al. ([1][1]) published recently in JACC: Cardiovascular Interventions , comparing early versus delayed invasive strategies for the management of non–ST-segment elevation acute coronary syndrome (NSTEACS) in the setting of P2Y12-ADP antagonist

Purpose Most heart failure patients undergoing ventricular assist device (VAD) implantation are managed with guideline-based therapy including the implantation of defibrillation capable device (ICD). Prior to surgery, programming allowing therapy with lower threshold could be lifesaving. After surgery, the defibrillator should be reprogrammed to protect the patient against painful, unnecessary shocks, as the circulation will be supported even in ventricular fibrillation. Difficulties in interrogation of ICD in patients with both HeartMate-II and HeartMate3 devices have been previously reported, related to the VAD-produced electromagnetic interference. Most cases result in a problem of communication between the ICD and the corresponding interrogating console. Methods An electronic search was performed to identify all articles and abstracts published on the topic until July 2019. To the list, we added one case from our clinical experience as well as manufacturer described cases of incompatibility. Results We identified 473 publications. Fourteen publications were ultimately included. Those publications described 22 patients with device interrogation issues post VAD implantation. To regain control of the device complete replacement of the ICD/CRT/PM was performed in 10 patients, and in one the implantation side was changed. In 11 cases a shielding technique was successfully utilized. From the data, we can extract the names of 14 devices with a documented communication problem. There were no reported cases of adverse interaction between HeartWare and ICDs. Conclusion Given the reported VAD-associated EMI interaction with ICD interrogation due to interruption of the handshake-signal to initiate ICD interrogation, it is likely all the variants of one specific ICD (1 lead, 2 lead, CRT) will also suffer from the same problem. More ex-vivo research is needed to better understand the phenomenon, and clinicians and patients with the listed ICDs need to be aware of the potential loss of ICD control with HM2 or HM3.

Background Relapse of acute lymphoblastic leukaemia (ALL) causes significant morbidity. Extramedullary relapse is seldom isolated to one site and almost always coexists with extensive marrow disease. Leukaemic infiltration of the myocardium is a well described entity, evident in up to 44% of patients at post-mortem examination; however, ante-mortem diagnosis remains difficult and rare. As a result, myocardial involvement in the absence of any other foci of relapse has only seldom been reported. Case summary Here, we present an unusual case of isolated gross intracardiac relapse of ALL in a patient presenting with chest pain and fevers. Both cardiac magnetic resonance imaging and endomyocardial biopsy were utilized in the diagnosis and identified leukaemic infiltrate in the absence of peripheral lymphoblasts. Discussion Despite evidence supporting a positive correlation between peripheral lymphocyte count and myocardial infiltration, our case highlights the rare and hypothesis-driving occurrence of myocardial infiltration with a complete absence of a peripheral lymphoblastosis. The report highlights the utility of modern histopathological and imaging modalities in the diagnosis of isolated myocardial relapse of ALL and provides insight into the aetiologies driving this process.

Background Acute coronary syndrome (ACS) is a significant contributor to both morbidity and mortality in Australia. Generally speaking, sufferers of ACS who live in rural areas and are treated at rural hospitals have poorer outcomes than those living in metropolitan areas. Aims To characterise the differences in the management and outcomes of rural and metropolitan populations in the context of ACS, as well as identify factors responsible for these differences and suggest how they may be addressed.

Human immunodeficiency virus (HIV) infection is considered a chronic, treatable disease, although treatment is associated with increased rates of coronary artery disease (CAD). We analyzed the utility of coronary CTA in the assessment of CAD among HIV patients and explored whether HIV patients are at greater risk of associated morbidity and mortality compared to HIV-negative controls.In a retrospective, single center cohort study 97 males without history of previous coronary artery disease who had undergone coronary CTA between 2011 and 2014 was analyzed, including 32 HIV positive patients and 65 matched HIV negative controls. Presence and composition of coronary plaque was determined by coronary CTA. Data on subsequent coronary events and coronary intervention was collected.Patients with HIV had higher rates of non-calcified plaque (0.8 ± 1.5 versus 0.3 ± 0.7, p = 0.03) compared to negative controls. At a median follow-up of 38 months, patients with HIV were at greater risk of non-ST elevation acute coronary syndrome (16% versus 3%, p 0.04), although there was no difference in the combined endpoint of all acute coronary syndromes (19% versus 6%, p = 0.08). Following baseline coronary TCA, there was a higher rate of coronary intervention in patients without HIV (mean time to event 9.9 ± 3.3 versus 20.6 ± 4.9 months, p 0.04).Patients with HIV more pronounces coronary atherosclerosis on coronary CTA and higher rates of non-ST elevation acute coronary syndromes compared to negative controls.

Cardiovascular disease (CVD) has a higher incidence in patients with HIV infection. This study sought to determine whether HIV-infected patients with established CVD were being managed according to national guidelines. Data were collected from Australian general practitioners for 77 HIV-infected patients with a median age of 59 (range 54–64). There was good adherence to guidelines with regards to anti-platelet (84%; n = 65; 95% confidence interval (CI) 74–92%) and statin therapy (97%; n = 75; 95% CI 91–100%), despite a failure to meet cholesterol targets, with only 31% (n = 24; 95% CI 21–42%) of the cohort meeting low-density lipoprotein target values. Similarly, there was limited adherence to guidelines regarding the prescriptions of medications for those with established hypertension (66%; n = 51; 95% CI 55–77%), body mass index targets met (40%; n = 31; 95% CI 29–52%), and depression screening (32%; n = 25; 95% CI 22–44%). This Australian audit provides insight into adherence to guidelines for individuals with CVD and HIV, suggesting that current screening and management practices for these patients falls short of guidelines, particularly in relation to cholesterol management.

Human immunodeficiency virus (HIV) infection is now considered a chronic, treatable disease, although treatment is associated with increased rates of coronary artery disease (CAD). Screening of this at-risk population remains contentious; we therefore assessed the utility of CT coronary angiography

Aims Cardiac involvement with sarcoidosis is a major cause of morbidity and mortality in affected individuals. Cardiac magnetic resonance (CMR) imaging promises a new and more accurate assessment of cardiac sarcoidosis by identifying typical patterns of myocardial fibrosis. We assessed the utility of CMR in the prediction of adverse outcomes. Methods and results One hundred and six CMR patients with biopsy-proven extracardiac and/or presumed cardiac sarcoidosis were enrolled. Late gadolinium enhancement (LGE) on CMR typical of sarcoidosis was used to determine the presence of cardiac involvement. Clinical endpoints and medical records were assessed and those with implantable cardioverter–defibrillators (ICDs) underwent device interrogation. Survival rates of patients with cardiac sarcoidosis were compared with those with only extracardiac disease. CMR identified 32 (30%) individuals as having cardiac sarcoidosis; the remaining 74 (70%) had only extracardiac disease. At a mean follow-up time of 36.8 ± 20.5 months, patients with cardiac sarcoidosis had a higher rate of the composite cardiac endpoint—comprising sudden cardiac death (SCD) and ventricular tachyarrhythmia—compared with those with only extracardiac disease ( P < 0.001). There was a higher rate of SCD or ICD-aborted SCD in patients with cardiac sarcoidosis vs. those without ( P = 0.005). In patients with cardiac sarcoidosis, the rate of SCD was lower in those with an ICD compared with those without ( P < 0.02). Conclusions Patients with evidence of cardiac sarcoidosis on CMR have higher rates of adverse cardiovascular events than those with only extracardiac disease. In patients with sarcoidosis detected on CMR, the presence of an ICD is associated with a lower rate of SCD.