The RNA editor ADAR2 promotes immune cell trafficking by enhancing endothelial responses to interleukin-6 during sterile inflammation.

Immune cell trafficking constitutes a fundamental component of immunological response to tissue injury, but the contribution of intrinsic RNA nucleotide modifications to this response remains elusive. We report that RNA editor ADAR2 exerts a tissue- and stress-specific regulation of endothelial responses to interleukin-6 (IL-6), which tightly controls leukocyte trafficking in IL-6-inflamed and ischemic tissues. Genetic ablation of ADAR2 from vascular endothelial cells diminished myeloid cell rolling and adhesion on vascular walls and reduced immune cell infiltration within ischemic tissues. ADAR2 was required in the endothelium for the expression of the IL-6 receptor subunit, IL-6 signal transducer (IL6ST; gp130), and subsequently, for IL-6 trans-signaling responses. ADAR2-induced adenosine-to-inosine RNA editing suppressed the Drosha-dependent primary microRNA processing, thereby overwriting the default endothelial transcriptional program to safeguard gp130 expression. This work demonstrates a role for ADAR2 epitranscriptional activity as a checkpoint in IL-6 trans-signaling and immune cell trafficking to sites of tissue injury.

Exogenous Transforming Growth Factor-ß1 and Its Helminth-Derived Mimic Attenuate the Heart's Inflammatory Response to Ischemic Injury and Reduce Mature Scar Size.

Coronary reperfusion after acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischemic heart muscle. However, subsequent inflammatory responses within the infarct lead to further loss of viable myocardium. Transforming growth factor (TGF)-ß1 is a potent anti-inflammatory cytokine released in response to tissue injury. The aim of this study was to investigate the protective effects of TGF-ß1 after MI. In patients with STEMI, there was a significant correlation (P = 0.003) between higher circulating TGF-ß1 levels at 24 hours after MI and a reduction in infarct size after 3 months, suggesting a protective role of early increase in circulating TGF-ß1. A mouse model of cardiac ischemia reperfusion was used to demonstrate multiple benefits of exogenous TGF-ß1 delivered in the acute phase. It led to a significantly smaller infarct size (30% reduction, P = 0.025), reduced inflammatory infiltrate (28% reduction, P = 0.015), lower intracardiac expression of inflammatory cytokines IL-1ß and chemokine (C-C motif) ligand 2 (>50% reduction, P = 0.038 and 0.0004, respectively) at 24 hours, and reduced scar size at 4 weeks (21% reduction, P = 0.015) after reperfusion. Furthermore, a low-fibrogenic mimic of TGF-ß1, secreted by the helminth parasite Heligmosomoides polygyrus, had an almost identical protective effect on injured mouse hearts. Finally, genetic studies indicated that this benefit was mediated by TGF-ß signaling in the vascular endothelium.

Heart Disease and Ageing: The Roles of Senescence, Mitochondria, and Telomerase in Cardiovascular Disease.

During ageing molecular damage leads to the accumulation of several hallmarks of ageing including mitochondrial dysfunction, cellular senescence, genetic instability and chronic inflammation, which contribute to the development and progression of ageing-associated diseases including cardiovascular disease. Consequently, understanding how these hallmarks of biological ageing interact with the cardiovascular system and each other is fundamental to the pursuit of improving cardiovascular health globally. This review provides an overview of our current understanding of how candidate hallmarks contribute to cardiovascular diseases such as atherosclerosis, coronary artery disease and subsequent myocardial infarction, and age-related heart failure. Further, we consider the evidence that, even in the absence of chronological age, acute cellular stress leading to accelerated biological ageing expedites cardiovascular dysfunction and impacts on cardiovascular health. Finally, we consider the opportunities that modulating hallmarks of ageing offer for the development of novel cardiovascular therapeutics.

Rapid fall in circulating non-classical monocytes in ST elevation myocardial infarction patients correlates with cardiac injury.

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.

Telomerase as a Therapeutic Target in Cardiovascular Disease.

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.

CDKN1B/p27 is localized in mitochondria and improves respiration-dependent processes in the cardiovascular system-New mode of action for caffeine.

We show that the cyclin-dependent kinase inhibitor 1B (CDKN1B)/p27, previously known as a cell cycle inhibitor, is also localized within mitochondria. The migratory capacity of endothelial cells, which need intact mitochondria, is completely dependent on mitochondrial p27. Mitochondrial p27 improves mitochondrial membrane potential, increases adenosine triphosphate (ATP) content, and is required for the promigratory effect of caffeine. Domain mapping of p27 revealed that the N-terminus and C-terminus are required for those improvements. Further analysis of those regions revealed that the translocation of p27 into the mitochondria and its promigratory activity depend on serine 10 and threonine 187. In addition, mitochondrial p27 protects cardiomyocytes against apoptosis. Moreover, mitochondrial p27 is necessary and sufficient for cardiac myofibroblast differentiation. In addition, p27 deficiency and aging decrease respiration in heart mitochondria. Caffeine does not increase respiration in p27-deficient animals, whereas aged mice display improvement after 10 days of caffeine in drinking water. Moreover, caffeine induces transcriptome changes in a p27-dependent manner, affecting mostly genes relevant for mitochondrial processes. Caffeine also reduces infarct size after myocardial infarction in prediabetic mice and increases mitochondrial p27. Our data characterize mitochondrial p27 as a common denominator that improves mitochondria-dependent processes and define an increase in mitochondrial p27 as a new mode of action of caffeine.

Kinetics Analysis of Circulating MicroRNAs Unveils Markers of Failed Myocardial Reperfusion.

BACKGROUND: Failed myocardial reperfusion occurs in approximately 50% of patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI). It manifests as microvascular obstruction (MVO) on cardiac magnetic resonance (CMR) imaging. Although prognostically important, MVO is not routinely screened for. Our aim was to investigate the kinetics of circulating short noncoding ribonucleic acids [microRNAs (miRNAs)] following PPCI and their association with MVO in STEMI patients. METHODS: Screening of 2083 miRNAs in plasma from STEMI patients with (n = 6) and without (n = 6) MVO was performed by next-generation sequencing. Two candidate miRNAs were selected and quantified at 13 time points within 3 h postreperfusion in 20 STEMI patients by reverse transcription and quantitative PCR. Subsequently, these 2 miRNAs were measured in a "validation" STEMI cohort (n = 50) that had CMR imaging performed at baseline and 3 months post-PPCI to evaluate their association with MVO. RESULTS: miR-1 and miR-133b were rapidly released following PPCI in a monophasic or biphasic pattern. Both miRNAs were enriched in circulating microparticles. A second miR-1 peak (90-180 min postreperfusion) seemed to be associated with a higher index of microvascular resistance. In addition, miR-1 and miR-133b levels at 90 min post-PPCI were approximately 3-fold (P = 0.001) and 4.4-fold (P = 0.008) higher in patients with MVO, respectively. Finally, miR-1 was significantly increased in a subgroup of patients with worse left ventricular (LV) functional recovery 3 months post-PPCI. CONCLUSIONS: miR-1 and miR-133b levels increase within 3 h of PPCI. They are positively associated with MVO and worse LV functional recovery post-PPCI.

Inflammageing in the cardiovascular system: mechanisms, emerging targets, and novel therapeutic strategies.

In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term 'inflammageing', which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be 'druggable' by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1ß, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the 'druggability' of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.

Effect of ciclosporin on safety, lymphocyte kinetics and left ventricular remodelling in acute myocardial infarction.

AIMS: Following a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention. METHODS: In this double-blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks. RESULTS: Mean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: -4.0 to 4.1). CD3 T-lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/µL, control vs ciclosporin) and increased to 1454 vs 1650 cells/µL at 24 hours. CONCLUSION: In our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T-lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted. (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674).

Telomerase Mediates Lymphocyte Proliferation but Not the Atherosclerosis-Suppressive Potential of Regulatory T-Cells.

OBJECTIVE: Atherosclerosis is an age-related disease characterized by systemic oxidative stress and low-grade inflammation. The role of telomerase and telomere length in atherogenesis remains contentious. Short telomeres of peripheral leukocytes are predictive for coronary artery disease. Conversely, attenuated telomerase has been demonstrated to be protective for atherosclerosis. Hence, a potential causative role of telomerase in atherogenesis is critically debated. APPROACH AND RESULTS: In this study, we used multiple mouse models to investigate the regulation of telomerase under oxidative stress as well as its impact on atherogenesis in vitro and in vivo. Using primary lymphocytes and myeloid cell cultures, we demonstrate that cultivation under hyperoxic conditions induced oxidative stress resulting in chronic activation of CD4+ cells and significantly reduced CD4+ T-cell proliferation. The latter was telomerase dependent because oxidative stress had no effect on the proliferation of primary lymphocytes isolated from telomerase knockout mice. In contrast, myeloid cell proliferation was unaffected by oxidative stress nor reliant on telomerase. Telomerase reverse transcriptase deficiency had no effect on regulatory T-cell (Treg) numbers in vivo or suppressive function ex vivo. Adoptive transfer of telomerase reverse transcriptase-/- Tregs into Rag2-/- ApoE-/- (recombination activating gene 2/apolipoprotein E) double knockout mice demonstrated that telomerase function was not required for the ability of Tregs to protect against atherosclerosis. However, telomere length was critical for Treg function. CONCLUSIONS: Telomerase contributes to lymphocyte proliferation but plays no major role in Treg function, provided that telomere length is not critically short. We suggest that oxidative stress may contribute to atherosclerosis via suppression of telomerase and acceleration of telomere attrition in Tregs.

Microvessels of the heart: Formation, regeneration, and dysfunction.

This issue of microcirculation focusses on the special topic of "microvessels of the heart" and contains five state-of-the-art reviews and one expert article that reflect current efforts to address the major gaps in our understanding of these key microvessels. In the adult heart, most attention until recently (especially among the clinical cardiology community) has been given to the main coronary arteries, which are the culprit vessels in patients with coronary artery disease, including its most serious manifestation, acute MI. However, due to major advances in efficiently reopening the acutely blocked coronary arteries, MI is no longer the killer disease it once was. In contrast, there are few treatment options for patients who develop microvascular obstruction during acute MI. Indeed, we have a very poor understanding of this disease, or even how heart vessels are initially formed in development. This is surprising in light of the essential nature of the cardiac microvessels for efficient cardiac function throughout life. The articles in this issue are from six keynote speakers at the 66th annual meeting of the BMS at Newcastle University and review our understanding of these key vessels from initial development to their role in adult heart disease.

Myocardial ischemia and reperfusion leads to transient CD8 immune deficiency and accelerated immunosenescence in CMV-seropositive patients.

RATIONALE: There is mounting evidence of a higher incidence of coronary heart disease in cytomegalovirus-seropositive individuals. OBJECTIVE: The aim of this study was to investigate whether acute myocardial infarction triggers an inflammatory T-cell response that might lead to accelerated immunosenescence in cytomegalovirus-seropositive patients. METHODS AND RESULTS: Thirty-four patients with acute myocardial infarction undergoing primary percutaneous coronary intervention were longitudinally studied within 3 months after reperfusion (Cohort A). In addition, 54 patients with acute myocardial infarction and chronic myocardial infarction were analyzed in a cross-sectional study (Cohort B). Cytomegalovirus-seropositive patients demonstrated a greater fall in the concentration of terminally differentiated CD8 effector memory T cells (TEMRA) in peripheral blood during the first 30 minutes of reperfusion compared with cytomegalovirus-seronegative patients (-192 versus -63 cells/µL; P=0.008), correlating with the expression of programmed cell death-1 before primary percutaneous coronary intervention (r=0.8; P=0.0002). A significant proportion of TEMRA cells remained depleted for ≥3 months in cytomegalovirus-seropositive patients. Using high-throughput 13-parameter flow cytometry and human leukocyte antigen class I cytomegalovirus-specific dextramers, we confirmed an acute and persistent depletion of terminally differentiated TEMRA and cytomegalovirus-specific CD8(+) cells in cytomegalovirus-seropositive patients. Long-term reconstitution of the TEMRA pool in chronic cytomegalovirus-seropositive postmyocardial infarction patients was associated with signs of terminal differentiation including an increase in killer cell lectin-like receptor subfamily G member 1 and shorter telomere length in CD8(+) T cells (2225 versus 3397 bp; P<0.001). CONCLUSIONS: Myocardial ischemia and reperfusion in cytomegalovirus-seropositive patients undergoing primary percutaneous coronary intervention leads to acute loss of antigen-specific, terminally differentiated CD8 T cells, possibly through programmed cell death-1-dependent programmed cell death. Our results suggest that acute myocardial infarction and reperfusion accelerate immunosenescence in cytomegalovirus-seropositive patients.

Cellular Senescence, Mitochondrial Dysfunction, and Their Link to Cardiovascular Disease.

Cardiovascular diseases (CVDs), a group of disorders affecting the heart or blood vessels, are the primary cause of death worldwide, with an immense impact on patient quality of life and disability. According to the World Health Organization, CVD takes an estimated 17.9 million lives each year, where more than four out of five CVD deaths are due to heart attacks and strokes. In the decades to come, an increased prevalence of age-related CVD, such as atherosclerosis, coronary artery stenosis, myocardial infarction (MI), valvular heart disease, and heart failure (HF) will contribute to an even greater health and economic burden as the global average life expectancy increases and consequently the world's population continues to age. Considering this, it is important to focus our research efforts on understanding the fundamental mechanisms underlying CVD. In this review, we focus on cellular senescence and mitochondrial dysfunction, which have long been established to contribute to CVD. We also assess the recent advances in targeting mitochondrial dysfunction including energy starvation and oxidative stress, mitochondria dynamics imbalance, cell apoptosis, mitophagy, and senescence with a focus on therapies that influence both and therefore perhaps represent strategies with the most clinical potential, range, and utility.

Risk stratification following complex PCI: clinical versus anatomical risk stratification including "post PCI residual SYNTAX-score" as quantification of incomplete revascularization.

BACKGROUND: EuroSCORE and completeness of revascularization predicts long-term survival after multivessel PCI (MV-PCI). The SYNTAX-Score has also been proposed to predict clinical outcome. The prognostic impact of these scores to predict long-term survival after PCI has not yet been compared. METHODS AND RESULTS: Long-term survival was assessed in 740 patients undergoing MV-PCI. We calculated EuroSCORE, SYNTAX-Score, STS-Score, the clinical SYNTAX-Score (CSS), and the "post-PCI residual SYNTAX-Score." Mean follow-up time was 4.5 ± 2.5 years. 341 patients (46%) were treated for ACS (STEMI N = 191; NSTEMI N = 150). 113 patients (15%) underwent PCI of left main coronary artery. The EuroSCORE was significantly lower for stable patients compared to patients with ACS (stable 4.1 ± 4.5, NSTEMI 13.9 ± 13.3, STEMI 18.1 ± 18.7, p < 0.001). The differences in the SYNTAX-Score were less obvious but even significant (stable 14.9 ± 8.6, NSTEMI 17.8 ± 9.9, STEMI 18.3 ± 9.0; p < 0.001). Patients in the highest tertiles of each risk score experienced a dramatically elevated mortality rate compared to the extremely low mortality rate in the lower tertiles (p log-rank <0.001). This comparison remained significant for the EuroSCORE and STS-Score but not for the SYNTAX-Score, when analysis was restricted to stable patients. The multivariate Cox-regression-analysis confirmed the logistic EuroSCORE, EuroSCORE II, and the STS-Score as independent predictors of long-term mortality, whereas the SYNTAX-Score (including residual form) and the CSS had no predictive value. CONCLUSION: The EuroSCORE and the STS-Score outperforms the SYNTAX-Score and the CSS in predicting long-term survival following MV-PCI. In addition, the residual SYNTAX-Score predicts long-term survival not independently.

Mortality outcome of out-of-hours primary percutaneous coronary intervention in the current era.

AIMS: To assess the impact of the time of primary percutaneous coronary intervention (PPCI) on in-hospital and long-term all-cause mortality in ST-segment elevation myocardial infarction (STEMI). METHODS AND RESULTS: The study retrospectively analyses the prospectively collected data on 2571 consecutive PPCI-treated STEMI patients between March 2008 and June 2011. Of these, 1036 patients (40.3%) underwent PPCI during a weekday between 08:00 and 18:00 (routine-hours group) and 1535 patients (59.7%) underwent PPCI on a weekday between 18:00 and 08:00 or a weekend (out-of-hours group). Compared with the routine-hours group, the out-of-hours group had a lower mean age, fewer patients with previous angina, longer call-to-hospital time, and fewer multivessel PCI. The overall in-hospital mortality rate was 4.5% with no significant difference [0.2%, 95% confidence interval (CI): -1.4 to 1.9%] between the routine-hours group (4.3%) and the out-of-hours group (4.6%) (adjusted odds ratio: 1.33, 95% CI: 0.73-2.40, P = 0.35). During a mean follow-up period of 560 days, 295 patients (11.5%) died, 12.2% in the routine-hours group and 11.0% in the out-of-hours group (difference of -0.1%, 95% CI: -0.4 to 0.2%). In the multiple Cox proportional hazards model, there was no difference in mortality between the two groups (adjusted hazard ratio: 1.09, 95% CI: 0.82-1.46, P = 0.57). Similarly, no increase in mortality was seen in patients who underwent PPCI later at night (22:00-06:00). CONCLUSION: This study of real-world, unselected STEMI patients demonstrates that in a large, well-staffed centre, PPCI outside routine-working hours is safe with no difference in outcome of in-hospital and long-term mortality compared with PPCI during routine-working hours.

Impact of thrombus aspiration during primary percutaneous coronary intervention on mortality in ST-segment elevation myocardial infarction.

AIMS: To assess the impact of thrombus aspiration during primary percutaneous coronary intervention (PPCI) on the mortality of patients with ST-elevation myocardial infarction (STEMI) patients. METHODS AND RESULTS: Retrospective analysis of prospectively collected data on 2567 consecutive PPCI-treated STEMI patients between 2008 and 2011. Cox proportional hazard models and multiple logistic regression analysis were used to adjust for known covariates. Thrombectomy was performed in 1095 patients (42.7%). Post-PPCI thrombolysis in myocardial infarction 3 flow was more frequently achieved in the thrombectomy group [adjusted odds ratio (OR); 1.92, 95% confidence interval (CI): 1.34-2.76, P = 0.0004]. Overall in-hospital and longer term (mean follow-up 9.9 months) mortality rates were 4.5 and 9.0%, respectively. Thrombectomy was associated with a significant reduction in in-hospital (adjusted OR: 0.51, 95% CI: 0.29-0.93, P = 0.027) and longer term mortality [adjusted hazard ratio (HR): 0.69, 95% CI: 0.48-0.96, P = 0.028]. With propensity weighting, the adjusted HR for longer term mortality for thrombectomy was 0.43 (95% CI: 0.19-0.97; P = 0.042). The association between thrombectomy and reduced longer term mortality was only significant in those with a total ischaemic time ≤180min (P = 0.001) but not in patients with a total ischaemic time >180min (P = 0.99). CONCLUSION: This study of real-world, unselected STEMI patients demonstrates that thrombus aspiration during PPCI is associated with a significant reduction in mortality, especially in those with a short total ischaemic time. These findings support the use of thrombectomy during PPCI in this group of patients.

Arginine Vasopressin Plays a Role in Microvascular Dysfunction After ST-Elevation Myocardial Infarction.

Background Coronary microvascular dysfunction (CMD) predicts mortality after ST-elevation-myocardial infarction (STEMI). Arginine vasopressin (AVP) may be implicated, but data in humans are lacking, and no study has investigated the link between arginine vasopressin and invasive measures of CMD. Methods and Results We invasively assessed CMD in 55 patients with STEMI treated with primary percutaneous coronary intervention (PPCI), by measuring the index of microcirculatory resistance after PPCI. In a separate group of 45 patients with STEMI/PPCI, recruited for a clinical trial, we measured infarct size and microvascular obstruction with cardiac magnetic resonance (CMR) imaging at 1 week and 12 weeks post-STEMI. Serum copeptin was measured at 4 time points before and after PPCI in all patients with STEMI. Plasma copeptin levels fell from 92.5 pmol/L before reperfusion to 6.4 pmol/L at 24 hours. Copeptin inversely correlated with diastolic, but not systolic, blood pressure (r=-0.431, P=0.001), suggesting it is released in response to myocardial ischemia. Persistently raised copeptin at 24 hours was correlated with higher index of microcirculatory resistance (r=0.372, P=0.011). Patients with microvascular obstruction on early CMR imaging showed a trend toward higher admission copeptin, which was not statistically significant. Copeptin levels were not associated with infarct size on either early or late CMR. Conclusions Patients with CMD after STEMI have persistently elevated copeptin at 24 hours, suggesting arginine vasopressin may contribute to microvascular dysfunction. Arginine vasopressin receptor antagonists may represent a novel therapeutic option in patients with STEMI and CMD.

Fractalkine/CX3CR1 in Dilated Cardiomyopathy: A Potential Future Target for Immunomodulatory Therapy?

Dilated cardiomyopathy (DCM) is a cardiac condition with structural and functional impairment, where either the left ventricle or both ventricular chambers are enlarged, coinciding with reduced systolic pump function (reduced ejection fraction, rEF). The prevalence of DCM is more than 1:250 individuals, and mortality largely due to heart failure in two-third of cases, and sudden cardiac death in one-third of patients. Damage to the myocardium, whether from a genetic or environmental cause such as viruses, triggers inflammation and recruits immune cells to the heart to repair the myocardium. Examination of myocardial biopsy tissue often reveals an inflammatory cell infiltrate, T lymphocyte (T cell) infiltration, or other activated immune cells. Despite medical therapy, adverse outcomes for DCM remain. The evidence base and existing literature suggest that upregulation of CX3CR1, migration of immune cells, together with cytomegalovirus (CMV) seropositivity is associated with worse outcomes in patients with dilated cardiomyopathy. We hypothesise that this potentially occurs through cardiac inflammation and fibrosis, resulting in adverse remodelling. Immune modulators to target this pathway may potentially improve outcomes above and beyond current guideline-recommended therapy.

Very Early Discharge After Primary Percutaneous Coronary Intervention for ST-Elevation Myocardial Infarction: Mortality Outcomes at Six Months.

BACKGROUND: Current guidelines recommend that low risk patients presenting with ST-segment elevation myocardial infarction (STEMI) and undergoing uncomplicated primary percutaneous coronary intervention (PPCI) can be discharged home in 48-72 h. We report the safety of early discharge in STEMI patients undergoing uncomplicated PPCI after 24-h stay in-hospital. METHODS: We performed a retrospective analysis of prospectively collected data of consecutive patients presenting with STEMI between January 2014 and December 2020. One- and 6-month mortality rates were compared between patients who underwent next day (early discharge group) and two days in-hospital stay (standard discharge group). RESULTS: Of 6119 STEMI patients, 4033 were included in the analysis, of whom 1674 (42 %) underwent early discharge. Patients in the early discharge group were younger, more likely to be male, and had a lower peak troponin. Both groups had similar ischemia- and door-to-balloon time, but anterior STEMI were less frequent in the early discharge group. The 1- and 6-month mortality rate for the whole cohort was 0.6 % and 1.3 %, respectively. After adjustment, there were no significant differences in the 1-month [HR 0.54; 95 % CI (0.20 to 1.47), P = 0.23] and 6-month mortality [HR 0.73; 95 % CI (0.38 to 1.41), P = 0.35] between early and standard discharge groups. Age, admission heart rate and chronic obstructive lung disease were identified as independent predictors of 6-month mortality in patients who underwent early discharge strategy. CONCLUSION: Our data confirms safety of next day discharge of patients presenting with STEMI after successful PPCI and uncomplicated post-procedural course.