Improvements in early interventions after acute myocardial infarction (AMI), notably, the increased use of timely reperfusion therapy, have increased survival dramatically in recent decades. Despite this, maladaptive ventricular remodelling and subsequent heart failure (HF) following AMI remain a significant clinical challenge, particularly because several pre-clinical strategies to attenuate remodelling have failed to translate into clinical practice. Monocytes and macrophages, pleiotropic cells of the innate immune system, are integral in both the initial inflammatory response to injury and subsequent wound healing in many tissues, including the heart. However, maladaptive immune cell behaviour contributes to ventricular remodelling in mouse models, prompting experimental efforts to modulate the immune response to prevent the development of HF. Seminal work in macrophage biology defined macrophages as monocyte-derived cells that are comprised of two populations, pro-inflammatory M1 macrophages and reparative M2 macrophages, and initial investigations into cardiac macrophage populations following AMI suggested they aligned well to this model. However, more recent data, in the heart and other tissues, demonstrate remarkable heterogeneity and plasticity in macrophage development, phenotype, and function. These recent insights into macrophage biology may explain the failure of non-specific immunosuppressive strategies and offer novel opportunities for therapeutic targeting to prevent HF following AMI. Here, we summarize the traditional monocyte-macrophage paradigm, experimental evidence for the significance of these cells in HF after AMI, and the potential relevance of emerging evidence that refutes canonical models of monocyte and macrophage biology.

Background: Acute myocarditis (AM) is thought to be a rare cardiovascular complication of COVID-19, although minimal data are available beyond case reports. We aim to report the prevalence, baseline characteristics, in-hospital management, and outcomes for patients with COVID-19–associated AM on the basis of a retrospective cohort from 23 hospitals in the United States and Europe. Methods: A total of 112 patients with suspected AM from 56 963 hospitalized patients with COVID-19 were evaluated between February 1, 2020, and April 30, 2021. Inclusion criteria were hospitalization for COVID-19 and a diagnosis of AM on the basis of endomyocardial biopsy or increased troponin level plus typical signs of AM on cardiac magnetic resonance imaging. We identified 97 patients with possible AM, and among them, 54 patients with definite/probable AM supported by endomyocardial biopsy in 17 (31.5%) patients or magnetic resonance imaging in 50 (92.6%). We analyzed patient characteristics, treatments, and outcomes among all COVID-19–associated AM. Results: AM prevalence among hospitalized patients with COVID-19 was 2.4 per 1000 hospitalizations considering definite/probable and 4.1 per 1000 considering also possible AM. The median age of definite/probable cases was 38 years, and 38.9% were female. On admission, chest pain and dyspnea were the most frequent symptoms (55.5% and 53.7%, respectively). Thirty-one cases (57.4%) occurred in the absence of COVID-19–associated pneumonia. Twenty-one (38.9%) had a fulminant presentation requiring inotropic support or temporary mechanical circulatory support. The composite of in-hospital mortality or temporary mechanical circulatory support occurred in 20.4%. At 120 days, estimated mortality was 6.6%, 15.1% in patients with associated pneumonia versus 0% in patients without pneumonia ( P =0.044). During hospitalization, left ventricular ejection fraction, assessed by echocardiography, improved from a median of 40% on admission to 55% at discharge (n=47; P <0.0001) similarly in patients with or without pneumonia. Corticosteroids were frequently administered (55.5%). Conclusions: AM occurrence is estimated between 2.4 and 4.1 out of 1000 patients hospitalized for COVID-19. The majority of AM occurs in the absence of pneumonia and is often complicated by hemodynamic instability. AM is a rare complication in patients hospitalized for COVID-19, with an outcome that differs on the basis of the presence of concomitant pneumonia.

AimsThe potential of remote ischaemic conditioning (RIC) to ameliorate myocardial ischaemia-reperfusion injury (IRI) remains controversial. We aimed to analyse the pre-clinical evidence base to ascertain the overall effect and variability of RIC in animal in vivo models of myocardial IRI. Furthermore, we aimed to investigate the impact of different study protocols on the protective utility of RIC in animal models and identify gaps in our understanding of this promising therapeutic strategy.Methods and resultsOur primary outcome measure was the difference in mean infarct size between RIC and control groups in in vivo models of myocardial IRI. A systematic review returned 31 reports, from which we made 22 controlled comparisons of remote ischaemic preconditioning (RIPreC) and 21 of remote ischaemic perconditioning and postconditioning (RIPerC/RIPostC) in a pooled random-effects meta-analysis. In total, our analysis includes data from 280 control animals and 373 animals subject to RIC. Overall, RIPreC reduced infarct size as a percentage of area at risk by 22.8% (95% CI 18.8–26.9%), when compared with untreated controls (P < 0.001). Similarly, RIPerC/RIPostC reduced infarct size by 22.2% (95% CI 17.1–25.3%; P < 0.001). Interestingly, we observed significant heterogeneity in effect size (T2 = 92.9% and I2 = 99.4%; P < 0.001) that could not be explained by any of the experimental variables analysed by meta-regression. However, few reports have systematically characterized RIC protocols, and few of the included in vivo studies satisfactorily met study quality requirements, particularly with respect to blinding and randomization.ConclusionsRIC significantly reduces infarct size in in vivo models of myocardial IRI. Heterogeneity between studies could not be explained by the experimental variables tested, but studies are limited in number and lack consistency in quality and study design. There is therefore a clear need for more well-performed in vivo studies with particular emphasis on detailed characterization of RIC protocols and investigating the potential impact of gender. Finally, more studies investigating the potential benefit of RIC in larger species are required before translation to humans.

BackgroundEarly revascularization of ischemic organs is key to improving outcomes, yet consequent reperfusion injury may be harmful. Reperfusion injury is largely attributed to excess mitochondrial production of reactive oxygen species (ROS). Sulfide inhibits mitochondria and reduces ROS production. Ammonium tetrathiomolybdate (ATTM), a copper chelator, releases sulfide in a controlled and novel manner, and may offer potential therapeutic utility.Methods and findingsIn vitro, ATTM releases sulfide in a time-, pH-, temperature-, and thiol-dependent manner. Controlled sulfide release from ATTM reduces metabolism (measured as oxygen consumption) both in vivo in awake rats and ex vivo in skeletal muscle tissue, with a superior safety profile compared to standard sulfide generators. Given intravenously at reperfusion/resuscitation to rats, ATTM significantly reduced infarct size following either myocardial or cerebral ischemia, and conferred survival benefit following severe hemorrhage. Mechanistic studies (in vitro anoxia/reoxygenation) demonstrated a mitochondrial site of action (decreased MitoSOX fluorescence), where the majority of damaging ROS is produced.ConclusionsThe inorganic thiometallate ATTM represents a new class of sulfide-releasing drugs. Our findings provide impetus for further investigation of this compound as a novel adjunct therapy for reperfusion injury.

Alleviating myocardial injury associated with ST elevation myocardial infarction is central to improving the global burden of coronary heart disease. The chemokine stromal cell-derived factor 1α (SDF-1α) has dual potential benefit in this regard. Firstly, SDF-1α is up-regulated in experimental and clinical studies of acute myocardial infarction (AMI) and regulates stem cell migration to sites of injury. SDF-1α delivery to the myocardium after AMI is associated with improved stem cell homing, angiogenesis, and left ventricular function in animal models, and improvements in heart failure and quality of life in humans. Secondly, SDF-1α may have a role in remote ischaemic conditioning (RIC), the phenomenon whereby non-lethal ischaemia–reperfusion applied to an organ or tissue remote from the heart protects the myocardium from lethal ischaemia–reperfusion injury (IRI). SDF-1α is increased in the serum of rats subjected to RIC and protects against myocardial IRI in ex vivo studies. Despite these potential pleiotropic effects, a limitation of SDF-1α is its short plasma half-life due to cleavage by dipeptidyl peptidase-4 (DPP-4). However, DPP-4 inhibitors increase the half-life of SDF-1α by preventing its degradation and are also protective against lethal IRI. In summary, SDF-1 potentially delivers a ‘two-pronged’ defence of the myocardium: acutely protecting it from IRI while simultaneously stimulating repair by recruiting stem cells to the site of injury. In this article we examine the evidence for acute and chronic cardioprotective roles of SDF-1α and discuss potential therapeutic manipulations of this mechanism with DPP-4 inhibitors to protect against lethal tissue injury in the clinical setting.

Due to its poor capacity for regeneration, the heart is particularly sensitive to the loss of contractile cardiomyocytes. The onslaught of damage caused by ischaemia and reperfusion, occurring during an acute myocardial infarction and the subsequent reperfusion therapy, can wipe out upwards of a billion cardiomyocytes. A similar program of cell death can cause the irreversible loss of neurons in ischaemic stroke. Similar pathways of lethal cell injury can contribute to other pathologies such as left ventricular dysfunction and heart failure caused by cancer therapy. Consequently, strategies designed to protect the heart from lethal cell injury have the potential to be applicable across all three pathologies. The investigators meeting at the 10th Hatter Cardiovascular Institute workshop examined the parallels between ST-segment elevation myocardial infarction (STEMI), ischaemic stroke, and other pathologies that cause the loss of cardiomyocytes including cancer therapeutic cardiotoxicity. They examined the prospects for protection by remote ischaemic conditioning (RIC) in each scenario, and evaluated impasses and novel opportunities for cellular protection, with the future landscape for RIC in the clinical setting to be determined by the outcome of the large ERIC-PPCI/CONDI2 study. It was agreed that the way forward must include measures to improve experimental methodologies, such that they better reflect the clinical scenario and to judiciously select combinations of therapies targeting specific pathways of cellular death and injury.

Heart failure is rapidly increasing in prevalence and will redraw the global landscape for cardiovascular health. Alleviating and repairing cardiac injury associated with myocardial infarction (MI) is key to improving this burden. Homing signals mobilize and recruit stem cells to the ischaemic myocardium where they exert beneficial paracrine effects. The chemoattractant cytokine SDF-1α and its associated receptor CXCR4 are upregulated after MI and appear to be important in this context. Activation of CXCR4 promotes both cardiomyocyte survival and stem cell migration towards the infarcted myocardium. These effects have beneficial effects on infarct size, and left ventricular remodelling and function. However, the timing of endogenous SDF-1α release and CXCR4 upregulation may not be optimal. Furthermore, current ELISA-based assays cannot distinguish between active SDF-1α, and SDF-1α inactivated by dipeptidyl peptidase 4 (DPP4). Current therapeutic approaches aim to recruit the SDF-1α-CXCR4 pathway or prolong SDF-1α life-time by preventing its cleavage by DPP4. This review assesses the evidence supporting these approaches and proposes SDF-1α as an important confounder in recent studies of DPP4 inhibitors.

Background ST‐segment elevation myocardial infarction is increasingly common in octogenarians, and optimal management in this cohort is uncertain. This study aimed to describe the outcomes of octogenarians with ST‐segment elevation myocardial infarction treated by primary percutaneous coronary intervention.Methods and ResultsWe analyzed 10 249 consecutive patients with ST‐segment elevation myocardial infarction treated with primary percutaneous coronary intervention between 2005 and 2011 at 8 tertiary cardiac centers across London, United Kingdom. The primary end point was all‐cause mortality at a median follow‐up of 3 years. In total, 1051 patients (10.3%) were octogenarians, with an average age of 84.2 years, and the proportion increased over the study period (P=0.04). In‐hospital mortality (7.7% vs 2.4%, P<0.0001) and long‐term mortality (51.6% vs 12.8%, P<0.0001) were increased in octogenarians compared with patients aged <80 years, and age was an independent predictor of mortality in a fully adjusted model (hazard ratio 1.07, 95% CI 1.07–1.09, P<0.0001). Time‐stratified analysis revealed an increasingly elderly and more complex cohort over time. Nonetheless, long‐term mortality rates among octogenarians remained static over time, and this may be attributable to improved percutaneous coronary intervention techniques, including significantly higher rates of radial access and lower bleeding complications. Variables associated with bleeding complications were similar between octogenarian and younger cohorts.ConclusionsIn this large registry, octogenarians undergoing primary percutaneous coronary intervention had a higher rate of complications and mortality compared with a younger population. Over time, octogenarians undergoing primary percutaneous coronary intervention increased in number, age, and complexity. Nevertheless, in‐hospital outcomes were reasonable, and long‐term mortality rates were static.