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Patients with chronic obstructive pulmonary disease (COPD) may suffer from acute episodes of worsening dyspnea, often associated with increased cough, sputum, and/or sputum purulence. These exacerbations of COPD (ECOPDs) impact health status, accelerate lung function decline, and increase the risk of hospitalization. Importantly, close to 20% of patients are readmitted within 30 days after hospital discharge, with great cost to the person and society. Approximately 25% and 65% of patients hospitalized for an ECOPD die within 1 and 5 years, respectively. Patients with COPD are usually older and frequently have concomitant chronic diseases, including heart failure, coronary artery disease, arrhythmias, interstitial lung diseases, bronchiectasis, asthma, anxiety, and depression, and are also at increased risk of developing pneumonia, pulmonary embolism, and pneumothorax. All of these morbidities not only increase the risk of subsequent ECOPDs but can also mimic or aggravate them. Importantly, close to 70% of readmissions after an ECOPD hospitalization result from decompensation of other morbidities. These observations suggest that in patients with COPD with worsening dyspnea but without the other classic characteristics of ECOPD, a careful search for these morbidities can help detect them and allow appropriate treatment. For most morbidities, a thorough clinical evaluation supplemented by appropriate clinical investigations can guide the healthcare provider to make a precise diagnosis. This perspective integrates the currently dispersed information available and provides a practical approach to patients with COPD complaining of worsening respiratory symptoms, particularly dyspnea. A systematic approach should help improve outcomes and the personal and societal cost of ECOPDs.

As current therapies for cardiovascular disease (CVD), predominantly based on lipid lowering, still face an unacceptable residual risk, novel treatment strategies are being explored. Besides lipids, inflammatory processes play a major role in the pathogenesis of atherosclerosis, the underlying cause of the majority of CVD. The first clinical trials targeting the interleukin-1β-inflammasome axis have shown that targeting this pathway is successful in reducing cardiovascular events but did not decrease overall CVD mortality. Hence, novel and improved immunotherapeutics to treat CVD are being awaited. In this review we highlight novel immunotherapeutic approaches in CVD as well as future challenges ahead.

Objective Type D personality, a joint tendency toward negative affectivity and social inhibition, has been linked to adverse events in patients with heart disease, although with inconsistent findings. Here, we apply an individual patient-data meta-analysis to data from 19 prospective cohort studies (N = 11,151) to investigate the prediction of adverse outcomes by type D personality in patients with acquired cardiovascular disease. Method For each outcome (all-cause mortality, cardiac mortality, myocardial infarction, coronary artery bypass grafting, percutaneous coronary intervention, major adverse cardiac event, any adverse event), we estimated type D's prognostic influence and the moderation by age, sex, and disease type. Results In patients with cardiovascular disease, evidence for a type D effect in terms of the Bayes factor (BF) was strong for major adverse cardiac event (BF = 42.5; odds ratio [OR] = 1.14) and any adverse event (BF = 129.4; OR = 1.15). Evidence for the null hypothesis was found for all-cause mortality (BF = 45.9; OR = 1.03), cardiac mortality (BF = 23.7; OR = 0.99), and myocardial infarction (BF = 16.9; OR = 1.12), suggesting that type D had no effect on these outcomes. This evidence was similar in the subset of patients with coronary artery disease (CAD), but inconclusive for patients with heart failure (HF). Positive effects were found for negative affectivity on cardiac and all-cause mortality, with the latter being more pronounced in male than female patients. Conclusion Across 19 prospective cohort studies, type D predicts adverse events in patients with CAD, whereas evidence in patients with HF was inconclusive. In both patients with CAD and HF, we found evidence for a null effect of type D on cardiac and all-cause mortality.

BackgroundData on long-term cardiovascular outcomes in primary Sjogren's syndrome (PSS) are scarce. ObjectivesWe aim to investigate the long-term rate of incident heart failure (HF) and other adverse cardiovascular endpoints in patients with PSS compared with the general population and to investigate mortality in individuals with incident HF with or without a history of PSS. MethodsUsing Danish nationwide registries, PSS patients (diagnosed 1996-2018) without a history of other autoimmune diseases were each matched with four individuals from the general population by sex, age, and comorbidities. Multivariable Cox regression was used to estimate the rate of cardiovascular outcomes. In addition, the rate of death from any cause was compared between PSS patients with incident HF and four age- and sex-matched HF patients without PSS. ResultsIn total, 5092 patients with newly diagnosed PSS were matched with 20,368 individuals from the general population (median age 57 years, 87.3% women, median follow-up 7.4 years). The cumulative incidence of HF at 10 years was 4.0% for PSS patients and 2.8% for matched individuals. After adjustment, patients with PSS had a higher associated rate of incident HF (hazard ratios [HR] 1.42 [95% CI, 1.20-1.68]) and other cardiovascular outcomes, compared with the background population. PSS patients with incident HF had a similar rate of death from all-cause mortality compared with HF patients without PSS (HR 0.94 [0.74-1.19]). ConclusionsPatients with PSS had a higher associated rate of incident HF and other cardiovascular outcomes compared with the general population. In individuals with incident HF, a history of PSS was not associated with increased mortality.

Aims Optimal duration of dual antiplatelet therapy (DAPT) in patients with concomitant indication to oral anticoagulation (OAC) is still debated. Methods and results A systematic review was performed on electronic databases to search for randomized controlled trials comparing an abbreviated or prolonged (≥3 months) DAPT regimen in patients with OAC and they were analysed in the framework of standard and network meta-analyses. Co-primary endpoints were major or clinically relevant non-major bleedings (MCRB) and major bleeding, while the composite of major adverse cardiovascular events (MACE) was the key safety endpoint. Five studies and 7 665 patients (abbreviated DAPT n = 3 843; prolonged DAPT n = 3 822) were included. Both MCRB and major bleeding were lower with abbreviated DAPT [risk ratio (RR) 0.69 (0.52–0.91); P = 0.01 and 0.70 (0.52–0.95); P = 0.01, respectively] while MACE [RR: 0.96 (0.70–1.33); P = 0.6], all-cause death, cardiovascular death, stent thrombosis, or myocardial infarction did not differ. Network meta-analysis showed that peri-procedural DAPT had the highest probability to prevent MCRB and major bleeding (97.1 and 92.0% respectively) when compared with both short (4–6 weeks) and longer (≥3 months) DAPT regimens. Sensitivity analyses and meta-regressions showed consistency in different clinical scenarios and suggested a larger bleeding reduction with P2Y12 inhibitors vs. aspirin after DAPT discontinuation. Conclusion In patients undergoing PCI with concomitant OAC indication, an abbreviated DAPT regimen reduced MCRB and major bleeding without increasing MACE or other ischaemic events. Peri-procedural DAPT and P2Y12 inhibitor monotherapy after DAPT withdrawal appear to be the best strategies to optimize the bleeding and ischaemic risk tradeoff. Trial registration. PROSPERO CRD284001

Background Non-vitamin K antagonist oral anticoagulants (NOACs) are increasingly preferred over vitamin K antagonists (VKAs) in atrial fibrillation (AF) management. However, differences in oral anticoagulant (OAC) prescribing according to patient's age, patient's sex and physician's specialty may be present. Purpose To investigate the incident and prevalent use of OACs, NOACs and VKAs, stratified by age, sex and prescriber, and factors associated with the choice of OAC on a full-population scale. Methods Using two Belgian nationwide healthcare databases, AF patients ≥45 years old with ≥1 OAC prescription claim between January 1st, 2013 and December 31st, 2019 were identified. OAC use was investigated per half-year with a repeated cross-sectional design, based on medication prescription claims on a day-to-day basis. Incident use was defined as the first OAC use during the study period in OAC-naïve AF patients, whereas prevalent OAC use was defined as at least 1 OAC dispensing during a specific half-year. Factors influencing NOAC versus VKA initiation were identified by multivariable logistic regression models. Results Among 448,661 included OAC-treated AF patients (260,184 prevalent NOAC and 188,477 prevalent VKA users), 297,818 were newly-treated (232,739 incident NOAC and 65,079 incident VKA users). The mean age of incident NOAC and VKA users was 76±10 and 71±12 years, and 48% and 47% were female, respectively. Incident OAC use ranged from 45–49 to 42–44 users/10,000 persons between 2013–2019, whereas prevalent OAC use increased from 337 to 435 users/10,000 persons. Incident and prevalent NOAC use exceeded VKA use since 2013 and 2015 respectively, and NOACs represented 92% of incident and 81% of prevalent OAC users in 2019. Apixaban was the most frequently used NOAC since 2016. NOACs were significantly more prescribed by cardiologists and to older patients, whereas VKAs were more initiated in patients with cardiovascular, renal and hepatic comorbidities. Prevalent OAC use increased less in women than men (+25% versus +33% between 2013–2019) and female subjects had a 5% significantly lower odds of NOAC versus VKA initiation than men after multivariable adjustment. Conclusions Prevalent anticoagulant use increased with 29% in Belgium between 2013 and 2019. However, potential (N)OAC underuse among female AF patients was observed. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO)

Background Risk factors for bleeding complications during extracorporeal life support (ECLS) indicated for cardiac support remain poorly investigated. The aim is to develop and internally validate a prediction model to calculate the risk for bleeding complications in adult patients receiving veno-arterial (V-A) ECLS. Methods Data of the Extracorporeal Life Support Organization registry of adult patients undergoing V-A ECLS between 2010 and 2020 were analyzed. The primary outcome was bleeding complications recorded during V-A ECLS. Multivariable logistic regression with backward stepwise elimination was used to develop the prediction model. Performance of the model was tested by discriminative ability and calibration with receiver operator characteristic, area under the curve, and visual inspection of the calibration plot. Internal validation was performed to detect overfitting of the model. Results In total 28 767 adult patients were included, of which 29.0% developed bleeding complications. Sex, body mass index, surgical cannulation, pre-ECLS respiratory and hemodynamic variables, pre-ECLS support and interventions, and different type of diagnosis were included in the prediction model. This prediction model showed a predictive capability with an AUC of 0.66. Conclusion The model is based on the largest cohort of V-A ECLS patients and is the best available predictive model for bleeding events given the predictors that are available in V-A ECLS compared to current literature. The model can help in identifying patients at high risk for bleeding complications and will help in developing further research and decision-making in terms of anticoagulation management. External validation is warranted to extrapolate this model in the clinical setting.

In this Review, Santovito and Weber discuss the functional relevance of non-canonical features of microRNAs for cardiovascular homeostasis and pathophysiology, describing the role of atypical microRNA biogenesis and localization, RISC heterogeneity, and non-conventional regulatory functions, including direct protein interactions and transcriptional regulation in the nucleus and in mitochondria.Research showing that microRNAs (miRNAs) are versatile regulators of gene expression has instigated tremendous interest in cardiovascular research. The overwhelming majority of studies are predicated on the dogmatic notion that miRNAs regulate the expression of specific target mRNAs by inhibiting mRNA translation or promoting mRNA decay in the RNA-induced silencing complex (RISC). These efforts mostly identified and dissected contributions of multiple regulatory networks of miRNA-target mRNAs to cardiovascular pathogenesis. However, evidence from studies in the past decade indicates that miRNAs also operate beyond this canonical paradigm, featuring non-conventional regulatory functions and cellular localizations that have a pathophysiological role in cardiovascular disease. In this Review, we highlight the functional relevance of atypical miRNA biogenesis and localization as well as RISC heterogeneity. Moreover, we delineate remarkable non-canonical examples of miRNA functionality, including direct interactions with proteins beyond the Argonaute family and their role in transcriptional regulation in the nucleus and in mitochondria. We scrutinize the relevance of non-conventional biogenesis and non-canonical functions of miRNAs in cardiovascular homeostasis and pathology, and contextualize how uncovering these non-conventional properties can expand the scope of translational research in the cardiovascular field and beyond.

Background: Calcification, a key feature of advanced human atherosclerosis, is positively associated with vascular disease burden and adverse events. We showed that macrocalcification can be a stabilizing factor for carotid plaque molecular biology, due to inverse association with immune processes. Mast cells (MCs) are important contributors to plaque instability, but their relationship with macrocalcification is unexplored. With a hypothesis that MC activation negatively associates with carotid plaque macrocalcification, we aimed to investigate the link between MCs and carotid plaque vulnerability, and study MC role in plaque calcification via smooth muscle cells (SMCs).Methods: Pre-operative computed tomography angiographies of patients (n = 40) undergoing surgery for carotid stenosis were used to characterize plaque morphology. Plaque microarrays (n = 40 and n = 126) were used for bioinformatic deconvolution of immune cell populations. Tissue microarrays (n = 103) were used to histologi-cally validate the contribution of activated and resting MCs in plaques. Results: Activated MCs and their typical markers were negatively correlated with macrocalcification. The ratio of activated vs. resting MCs was increased in low-calcified plaques from symptomatic patients. There was no modulating effect of medication on MC ratios. In vitro experiments showed that SMC calcification attenuated MC activation, while both active and resting MCs stimulated SMC calcification and induced dedifferentiation towards a pro-inflammatory-, osteochondrocyte-like phenotype, without modulating their migro-proliferative function.Conclusions: Integrative analyses from human plaques showed that MC activation is inversely associated with macrocalcification and positively with parameters of plaque vulnerability. Mechanistically, MCs induce SMC osteogenic reprograming, while matrix calcification in turn attenuates MC activation, offering new therapeutic avenues for exploration.

Background High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD. Methods A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group. Results Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that >= 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE >= 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking. Conclusion Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Contains fulltext : 282329.pdf (Publisher’s version ) (Open Access) BACKGROUND: High-quality evidence from trials directly comparing single antiplatelet therapies in symptomatic peripheral arterial disease (PAD) to dual antiplatelet therapies or acetylsalicylic acid (ASA) plus low-dose rivaroxaban is lacking. Therefore, we conducted a network meta-analysis on the effectiveness of all antithrombotic regimens studied in PAD. METHODS: A systematic search was conducted to identify randomized controlled trials. The primary endpoints were major adverse cardiovascular events (MACE) and major bleedings. Secondary endpoints were major adverse limb events (MALE) and acute limb ischaemia (ALI). For each outcome, a frequentist network meta-analysis was used to compare relative risks (RRs) between medication and ASA. ASA was the universal comparator since a majority of studies used ASA as in the reference group. RESULTS: Twenty-four randomized controlled trials were identified including 48,759 patients. With regard to reducing MACE, clopidogrel [RR 0.78, 95% confidence interval (CI) 0.66-0.93], ticagrelor (RR 0.79, 95% CI 0.65-0.97), ASA plus ticagrelor (RR 0.79, 95% CI 0.64-0.97), and ASA plus low-dose rivaroxaban (RR 0.84, 95% CI 0.76-0.93) were more effective than ASA, and equally effective to one another. As compared to ASA, major bleedings occurred more frequently with vitamin K antagonists, rivaroxaban, ASA plus vitamin K antagonists, and ASA plus low-dose rivaroxaban. All regimens were similar to ASA concerning MALE, while ASA plus low-dose rivaroxaban was more effective in preventing ALI (RR 0.67, 95% CI 0.55-0.80). Subgroup analysis in patients undergoing peripheral revascularization revealed that ≥ 3 months after intervention, evidence of benefit regarding clopidogrel, ticagrelor, and ASA plus ticagrelor was lacking, while ASA plus low-dose rivaroxaban was more effective in preventing MACE (RR 0.87, 95% CI 0.78-0.97) and MALE (RR 0.89, 95% CI 0.81-0.97) compared to ASA. ASA plus clopidogrel was not superior to ASA in preventing MACE ≥ 3 months after revascularization. Evidence regarding antithrombotic treatment strategies within 3 months after a peripheral intervention was lacking. CONCLUSION: Clopidogrel, ticagrelor, ASA plus ticagrelor, and ASA plus low-dose rivaroxaban are superior to ASA monotherapy and equally effective to one another in preventing MACE in PAD. Of these four therapies, only ASA plus low-dose rivaroxaban provides a higher risk of major bleedings. More than 3 months after peripheral vascular intervention, ASA plus low-dose rivaroxaban is superior in preventing MACE and MALE compared to ASA but again at the cost of a higher risk of bleeding, while other treatment regimens show non-superiority. Based on the current evidence, clopidogrel may be considered the antithrombotic therapy of choice for most PAD patients, while in patients who underwent a peripheral vascular intervention, ASA plus low-dose rivaroxaban could be considered for the long-term (> 3 months) prevention of MACE and MALE.

Major bleeding is a common threat in patients requiring antiplatelet therapy. Timing and intensity with regard to resumption of antiplatelet therapy represent a major challenge in clinical practice. Knowledge of the patient's bleeding risk, defining transient/treatable and permanent/untreatable risk factors for bleeding, and weighing these against thrombotic risk are key to successful prevention of major adverse events. Shared decision-making involving various disciplines is essential to determine the optimal strategy. The present article addresses clinically relevant questions focusing on the most life-threatening or frequently occurring bleeding events, such as intracranial hemorrhage and gastrointestinal bleeding, and discusses the evidence for antiplatelet therapy resumption using individual risk assessment in high-risk cardiovascular disease patients.

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. © 2022 European Society of Cardiology.

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting.

Contains fulltext : 291889.pdf (Publisher’s version ) (Open Access) BACKGROUND: Angina without angiographic evidence of obstructive coronary artery disease (ANOCA) is a highly prevalent condition with insufficient pathophysiological knowledge and lack of evidence-based medical therapies. This affects ANOCA patients prognosis, their healthcare utilization and quality of life. In current guidelines, performing a coronary function test (CFT) is recommended to identify a specific vasomotor dysfunction endotype. The NetherLands registry of invasive Coronary vasomotor Function testing (NL-CFT) has been designed to collect data on ANOCA patients undergoing CFT in the Netherlands. METHODS: The NL-CFT is a web-based, prospective, observational registry including all consecutive ANOCA patients undergoing clinically indicated CFT in participating centers throughout the Netherlands. Data on medical history, procedural data and (patient reported) outcomes are gathered. The implementation of a common CFT protocol in all participating hospitals promotes an equal diagnostic strategy and ensures representation of the entire ANOCA population. A CFT is performed after ruling out obstructive coronary artery disease. It comprises of both acetylcholine vasoreactivity testing as well as bolus thermodilution assessment of microvascular function. Optionally, continuous thermodilution or Doppler flow measurements can be performed. Participating centers can perform research using own data, or pooled data will be made available upon specific request via a secure digital research environment, after approval of a steering committee. CONCLUSION: NL-CFT will be an important registry by enabling both observational and registry based (randomized) clinical trials in ANOCA patients undergoing CFT.

Decades of research have established atherosclerosis as an inflammatory disease. Only recently though, clinical trials provided proof-of-concept evidence for the efficacy of anti-inflammatory strategies with respect to cardiovascular events, thus offering a new paradigm for lowering residual vascular risk. Efforts to target the inflammasome-interleukin-1β-interleukin-6 pathway have been highly successful, but inter-individual variations in drug response, a lack of reduction in all-cause mortality, and a higher rate of infections also highlight the need for a second generation of anti-inflammatory agents targeting atherosclerosis-specific immune mechanisms while minimizing systemic side effects. CC-motif chemokine ligand 2/monocyte-chemoattractant protein-1 (CCL2/MCP-1) orchestrates inflammatory monocyte trafficking between the bone marrow, circulation, and atherosclerotic plaques by binding to its cognate receptor CCR2. Adding to a strong body of data from experimental atherosclerosis models, a coherent series of recent large-scale genetic and observational epidemiological studies along with data from human atherosclerotic plaques highlight the relevance and therapeutic potential of the CCL2-CCR2 axis in human atherosclerosis. Here, we summarize experimental and human data pinpointing the CCL2-CCR2 pathway as an emerging drug target in cardiovascular disease. Furthermore, we contextualize previous efforts to interfere with this pathway, scrutinize approaches of ligand targeting vs. receptor targeting, and discuss possible pathway-intrinsic opportunities and challenges related to pharmacological targeting of the CCL2-CCR2 axis in human atherosclerotic disease.

Left ventricular pseudoaneurysm (LVP) is a very rare, but potentially lethal mechanical complication of acute myocardial infarction (AMI). Despite representing a unique subset of cardiac rupture, it presents peculiar features that distinguish it from both ventricular free-wall rupture (FWR) and ventricular true aneurysm. LVP occurs in less than 0.5% of patients affected by AMI. However, LVP is generally burdened by high mortality, often related to false cavity rupture, leading to catastrophic and often irreversible consequences. The risk of rupture is inversely proportional to the timing from AMI onset, which also determines both the classification of LVP and drives the indication for treatment. Despite the lack of a current consensus on LVP management, urgent surgery is the treatment of choice for LVPs occurring within 3 months from AMI, especially if larger than 3 cm in diameter. A matter of debate, however, is represented by chronic LVPs, especially because the risk of rupture decreases progressively as time passes and left ventricular (LV) false cavity stabilizes. Surgical mortality rate remains not negligible (more than 20%), but these suboptimal results may be considered acceptable, especially considering the lethality associated with the occurrence of pseudoaneurysm rupture. Diagnostic workup is essential for anatomical characterization of LV rupture, which is mandatory to guide the decision on surgical approach and technique for pseudoaneurysm repair. Finally, for a subset of patients with anterior LVP and a well-defined fibrotic neck, and deemed at excessively high surgical risk, percutaneous closure of the cavity has been described with encouraging results.

Iron deficiency has been extensively researched and is associated with adverse outcomes in heart failure. However, to our knowledge, the temporal evolution of iron status has not been previously investigated in patients with acute coronary syndrome (ACS). Therefore, we aimed to explore the temporal pattern of repeatedly measured iron, ferritin, transferrin, and transferrin saturation (TSAT) in relation to prognosis post-ACS. BIOMArCS (BIOMarker study to identify the Acute risk of a Coronary Syndrome) is a prospective, multicenter, observational cohort study conducted in The Netherlands between 2008 and 2015. A total of 844 patients with post-ACS were enrolled and underwent high-frequency (median 17) blood sampling during 1 year follow-up. Biomarkers of iron status were measured batchwise in a central laboratory. We analyzed 3 patient subsets, including the case-cohort (n = 187). The primary endpoint (PE) was a composite of cardiovascular mortality and repeat nonfatal ACS, including unstable angina pectoris requiring revascularization. The association between iron status and the PE was analyzed using multivariable joint models. Mean age was 63 years; 78% were men, and >50% had iron deficiency at first sample in the case-cohort. After adjustment for a broad range of clinical variables, 1 SD decrease in log-iron was associated with a 2.2-fold greater risk of the PE (hazard ratio 2.19, 95% confidence interval 1.34 to 3.54, p = 0.002). Similarly, 1 SD decrease in log-TSAT was associated with a 78% increased risk of the PE (hazard ratio 1.78, 95% confidence interval 1.17 to 2.65, p = 0.006). Ferritin and transferrin were not associated with the PE. Repeated measurements of iron and TSAT predict risk of adverse outcomes in patients with post-ACS during 1 year follow-up. Trial Registration: The Netherlands Trial Register. Unique identifiers: NTR1698 and NTR1106. Registered at https://www.trialregister.nl/trial/1614 and https://www.trialregister.nl/trial/1073.

Aims Guidelines recommend the use of potent P2Y12 inhibitors over clopidogrel for the reduction of ischaemic events in patients with acute coronary syndrome (ACS). However, this comes at the expense of increased bleeding. A guided selection of P2Y12 inhibiting therapy has the potential to overcome this limitation. We aimed at evaluating the comparative safety and efficacy of guided vs. routine selection of potent P2Y12 inhibiting therapy in patients with ACS. Methods and results We performed a network meta-analysis of randomized controlled trials (RCTs) comparing different oral P2Y12 inhibitors currently recommended for the treatment of patients with ACS (clopidogrel, prasugrel, and ticagrelor). RCTs including a guided approach (i.e. platelet function or genetic testing) vs. standard selection of P2Y12 inhibitors among patients with ACS were also included. Incidence rate ratios (IRR) and associated 95% confidence intervals (CIs) were estimated. P-scores were used to estimate hierarchies of efficacy and safety. The primary efficacy endpoint was major adverse cardiovascular events (MACE) and the primary safety endpoint was all bleeding. A total of 61 898 patients from 15 RCTs were included. Clopidogrel was used as reference treatment. A guided approach was the only strategy associated with reduced MACE (IRR: 0.80, 95% CI: 0.65–0.98) without any significant trade-off in all bleeding (IRR: 1.22, 95% CI: 0.96–1.55). A guided approach and prasugrel were associated with reduced myocardial infarction. A guided approach, prasugrel, and ticagrelor were associated with reduced stent thrombosis. Ticagrelor was also associated with reduced total and cardiovascular mortality. Prasugrel was associated with increased major bleeding. Prasugrel and ticagrelor were associated with increased minor bleeding. The incidence of stroke did not differ between treatments. Conclusion In patients with an ACS, compared with routine selection of potent P2Y12 inhibiting therapy (prasugrel or ticagrelor), a guided selection of P2Y12 inhibiting therapy is associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided approach for the selection of P2Y12 inhibiting therapy in patients with ACS. Study registration number This study is registered in PROSPERO (CRD42021258603). Key Question A guided selection of P2Y12 inhibiting therapy using platelet function or genetic testing improves outcomes among patients undergoing percutaneous coronary intervention. Nevertheless, the comparative safety and efficacy of a guided versus routine selection of potent P2Y12-inhibiting therapy in acute coronary syndrome has not been explored. Key Finding In a comprehensive network meta-analysis including the totality of available evidence and using clopidogrel as treatment reference, a guided approach was the only strategy associated with reduced major adverse cardiovascular events without any significant trade-off in bleeding. Prasugrel and ticagrelor increased bleeding and only ticagrelor reduced mortality. Take Home Message A guided selection of P2Y12-inhibiting therapy represents the strategy associated with the most favourable balance between safety and efficacy. These findings support a broader adoption of guided P2Y12 inhibiting therapy in patients with acute coronary syndrome.

Assessment of right ventricular (RV) function is crucial for the evaluation of the dyspnoeic patient and/or with systemic venous congestion and provides powerful prognostic insights. It can be performed using different imaging modalities including standard and advanced echocardiographic techniques, cardiac magnetic resonance imaging, computed tomography, and radionuclide techniques, which should be used in a complementary fashion. Each modality has strengths and weaknesses based on which the choice of their use and in which combination may vary according to the different clinical scenarios as will be detailed in this review. The conclusions from multiple studies using different imaging techniques are concordant: RV function can be reliably assessed and is a critical predictor of clinical outcomes. ispartof: EUROPEAN HEART JOURNAL-CARDIOVASCULAR IMAGING vol:23 issue:7 pages:885-897 ispartof: location:England status: published

Kidney international 101(2), 256-273 (2022). doi:10.1016/j.kint.2021.10.025, Published by Elsevier, New York, NY

Chronic kidney disease (CKD) triggers the risk of developing uremic cardiomyopathy as characterized by cardiac hypertrophy, fibrosis and functional impairment. Traditionally, animal studies are used to reveal the underlying pathological mechanism, although variable CKD models, mouse strains and readouts may reveal diverse results. Here, we systematically reviewed 88 studies and performed meta-analyses of 52 to support finding suitable animal models for future experimental studies on pathological kidney-heart crosstalk during uremic cardiomyopathy. We compared different mouse strains and the direct effect of CKD on cardiac hypertrophy, fibrosis and cardiac function in "single hit" strategies as well as cardiac effects of kidney injury combined with additional cardiovascular risk factors in "multifactorial hit" strategies. In C57BL/6 mice, CKD was associated with a mild increase in cardiac hypertrophy and fibrosis and marginal systolic dysfunction. Studies revealed high variability in results, especially regarding hypertrophy and systolic function. Cardiac hypertrophy in CKD was more consistently observed in 129/Sv mice, which express two instead of one renin gene and more consistently develop increased blood pressure upon CKD induction. Overall, "multifactorial hit" models more consistently induced cardiac hypertrophy and fibrosis compared to "single hit" kidney injury models. Thus, genetic factors and additional cardiovascular risk factors can "prime" for susceptibility to organ damage, with increased blood pressure, cardiac hypertrophy and early cardiac fibrosis more consistently observed in 129/Sv compared to C57BL/6 strains.

The prevalence and public health burden of chronic heart failure (CHF) in Europe is steadily increasing mainly caused by the ageing population and prolonged survival of patients with CHF. Frequent hospitalizations, high morbidity and mortality rates, and enormous healthcare costs contribute to the health-related burden. However, multidisciplinary frameworks that emphasize effective long-term management and the psychological needs of the patients are sparse. The present position paper endorsed by the European Association of Preventive Cardiology (EAPC) provides a comprehensive overview on the scientific evidence of psychosocial aspects of heart failure (HF). In order to synthesize newly available information and reinforce best medical practice, information was gathered via literature reviews and consultations of experts. It covers the evidence for aetiological and prospective psychosocial risk factors and major underlying psycho-biological mechanisms. The paper elucidates the need to include psychosocial aspects in self-care concepts and critically reviews the current shortcomings of psychotherapeutic and psycho-pharmacological interventions. It also highlights the need for involvement of psychological support in device therapy for patients with HF and finally calls for better palliative care in the final stage of HF progression.

The residual risk of patients surviving until 1 year after acute coronary syndromes (ACS) is still high, despite secondary prevention. The cornerstone of treatment of patients with ACS is dual antiplatelet therapy (DAPT) consisting of low-dose aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) for 12 months, or less in those patients at higher risk for bleeding. To reduce the residual risk beyond 1 year in those patients not at high bleeding risk who tolerated DAPT and did not suffer an (ischaemic or bleeding) event would intuitively mean to prolong DAPT. However, prolonged DAPT always comes at the cost of more bleeding. Therefore, assessing both ischaemic and bleeding risk in these patients at 1 year after ACS is crucial. In addition, another antithrombotic treatment consisting of low-dose rivaroxaban combined with low-dose aspirin has been shown to reduce ischaemic events. In this review, we describe residual thrombotic risk at 1 year after ACS, evaluate the evidence for antithrombotic options beyond 1 year and provide a practical guide to determine which patients would benefit the most from these therapies.

A link between influenza infection and cardiovascular morbidity has been known for almost a century. This narrative review examined the cardiovascular complications associated with influenza and the potential mechanisms behind this relationship. The most common reported cardiovascular complications are cardiovascular death, myocardial infarction, and heart failure hospitalization. There are multiple proposed mechanisms driving the increased risk of cardiovascular complications. These mechanics involve influenza-specific effects such as direct cardiac infection and endothelial dysfunction leading to plaque destabilization and rupture, but also hypoxaemia and systemic inflammatory responses including increased metabolic demand, biomechanical stress, and hypercoagulability. The significance of the individual effects is unclear, and thus whether influenza directly or indirectly causes cardiovascular events is unknown. In conclusion, the risk of acute cardiovascular morbidity and mortality is elevated during influenza infection. The proposed underlying pathophysiological mechanisms support this association, but systemic responses to infection may drive this relationship.

Introduction: Dual antiplatelet therapy (DAPT) is standard treatment for patients with acute coronary syndrome (ACS). This includes lifelong aspirin combined with a P2Y(12) inhibitor for 1 year. The indication for one of the P2Y(12) inhibitors (clopidogrel, prasugrel, ticagrelor) is dependent on the treatment strategy; whether patients undergo coronary angiography or are treated medically only. Tailoring antiplatelet therapy to the risk profile of the individual patient is of specific importance to the older patient. Areas covered: In this review, we discuss dual antiplatelet therapy in elderly patients with ACS. We present the options to tailor antiplatelet therapy based on platelet function testing, CYP2C19 genotyping and patients' thrombotic and bleeding risk. Finally, we discuss alternatives for dual antiplatelet therapy. Expert opinion: DAPT in elderly patients with ACS should consist of aspirin with clopidogrel or ticagrelor. Weighing patients' thrombotic and bleeding risk, based on clinical judgment or with use of specific risk scores, is probably the most convenient method to individualize antiplatelet therapy; however, CYP2C19 genotyping can also be used. In elderly patients with an increased bleeding risk, clopidogrel is a safe and effective alternative to ticagrelor. An alternative to 12 months DAPT could be ticagrelor monotherapy after a short period of DAPT.

Psoriatic arthritis (PsA) is an inflammatory disease with a high prevalence of cardiovascular (CV) events due to traditional cardiovascular risk factors and increased systemic inflammation. In this review, our objectives were to (i) evaluate the cardiovascular events and risk factors and (ii) investigate the relationship between autonomic dysfunction and CV diseases in PsA. A systematic review of the literature was done on the Medline/PubMed, Scopus, and the Directory of Open Access Journals databases between January 2017 and July 2022. After screening and exclusions, 73 studies were included for the final review. Patients with PsA have a greater risk of CV diseases and increased traditional CV risk factors, including hypertension, diabetes mellitus, obesity, metabolic syndrome, and dyslipidemia. Although autonomic dysfunction is more common in PsA than in the general population, its relationship with increased CV diseases in these patients is still unclear. Limitations in explaining CV risk in these patient groups complicate patient assessment as cardiovascular risk factors are linked to the morbidity and mortality of PsA, and it is essential to improve an optimal screening and management strategy for CV disease. All CV risk scoring systems cannot fully assess the CV risk in these patients, so in addition to scoring systems, carotid ultrasound evaluation may be a part of the CV evaluation.

© 2022, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.We aimed to evaluate the impact of hormone replacement, melatonin, or exercise alone or their combination on oxidative damage and functional status of heart, brain, and aorta of ovariectomized (OVX) rats and to determine whether the signaling pathway is dependent on sirtuin-1 (SIRT1). Ovariectomized Sprague Dawley rats were orally given either a hormone replacement therapy (1 mg/kg/day,17β estradiol; HRT) or melatonin (4 mg/kg/day) or HRT + melatonin treatments or tap water, while each group was further divided into sedentary and exercise (30 min/5 days/week) groups. After the heart rate measurements and memory tests were performed, trunk blood was collected at the end of the 10th week to determine metabolic parameters in serum samples. Tissue samples of abdominal aorta, heart, and brain were taken for biochemical measurements and histopathological evaluation. Heart rates and memory performances of the OVX rats were not changed significantly by none of the applications. Melatonin treatment or its co-administration with HRT upregulated the expressions of IL-10 and SIRT1, reduced the expressions of IL-6 and TNF-α, and reduced DNA damage in the hearts and thoracic aortae of non-exercised rats. Co-administration of melatonin and HRT to exercised OVX rats reduced inflammatory response and upregulated SIRT1 expression in the aortic and cardiac tissues. The present study suggests that melatonin treatment, either alone or in combination with exercise and/or HRT, upregulates SIRT1 expression and alleviates oxidative injury and inflammation in the hearts and aortas of OVX rats. Melatonin should be considered in alleviating cardiovascular disease risk in postmenopausal women.

BackgroundActivated cardiac fibroblasts (CF) play a central role in cardiac fibrosis, a condition associated with most cardiovascular diseases. Conversion of quiescent into activated CF sustains heart integrity upon injury. However, permanence of CF in active state inflicts deleterious heart function effects. Mechanisms underlying this cell state conversion are still not fully disclosed, contributing to a limited target space and lack of effective anti-fibrotic therapies.Materials and methodsTo prioritize targets for drug development, we studied CF remodeling upon activation at transcriptomic and proteomic levels, using three different cell sources: primary adult CF (aHCF), primary fetal CF (fHCF), and induced pluripotent stem cells derived CF (hiPSC-CF).ResultsAll cell sources showed a convergent response upon activation, with clear morphological and molecular remodeling associated with cell-cell and cell-matrix interactions. Quantitative proteomic analysis identified known cardiac fibrosis markers, such as FN1, CCN2, and Serpine1, but also revealed targets not previously associated with this condition, including MRC2, IGFBP7, and NT5DC2.ConclusionExploring such targets to modulate CF phenotype represents a valuable opportunity for development of anti-fibrotic therapies. Also, we demonstrate that hiPSC-CF is a suitable cell source for preclinical research, displaying significantly lower basal activation level relative to primary cells, while being able to elicit a convergent response upon stimuli.

Cardiac rehabilitation (CR) has evolved as an important part of the treatment of patients with cardiovascular disease. However, to date, its full potential is fairly underutilised. This review discusses new developments in CR aimed at improving participation rates and long-term effectiveness in the general cardiac population. It consecutively highlights new or challenging target groups, new delivery modes and new care pathways for CR programmes. These new or challenging target groups include patients with atrial fibrillation, obesity and cardiovascular disease, chronic coronary syndromes, (advanced) chronic heart failure with or without intracardiac devices, women and frail elderly patients. Also, the current evidence regarding cardiac telerehabilitation and loyalty programmes is discussed as new delivery modes for CR. Finally, this paper discusses novel care pathways with the integration of CR in residual risk management and transmural care pathways. These new developments can help to make optimal use of the benefits of CR. Therefore we should seize the opportunities to reshape current CR programmes, broaden their applicability and incorporate them into or combine them with other cardiovascular care programmes/pathways.

Timing and causes of hospital mortality in adult patients undergoing veno-arterial extracorporeal membrane oxygenation (V-A ECMO) have been poorly described. Aim of the current review was to investigate the timing and causes of death of adult patients supported with V-A ECMO and subsequently define the "V-A ECMO gap," which represents the patients who are successfully weaned of ECMO but eventually die during hospital stay. A systematic search was performed using electronic MEDLINE and EMBASE databases through PubMed. Studies reporting on adult V-A ECMO patients from January 1993 to December 2020 were screened. The studies included in this review were studies that reported more than 10 adult, human patients, and no mechanical circulatory support other than V-A ECMO. Information extracted from each study included mainly mortality and causes of death on ECMO and after weaning. Complications and discharge rates were also extracted. Sixty studies with 9181 patients were included for analysis in this systematic review. Overall mortality was 38.0% (95% confidence intervals [CIs] 34.2%-41.9%) during V-A ECMO support (reported by 60 studies) and 15.3% (95% CI 11.1%-19.5%, reported by 57 studies) after weaning. Finally, 44.0% of patients (95% CI 39.8-52.2) were discharged from hospital (reported by 60 studies). Most common causes of death on ECMO were multiple organ failure, followed by cardiac failure and neurological causes. More than one-third of V-A ECMO patients die during ECMO support. Additionally, many of successfully weaned patients still decease during hospital stay, defining the "V-A ECMO gap." Underreporting and lack of uniformity in reporting of important parameters remains problematic in ECMO research. Future studies should uniformly define timing and causes of death in V-A ECMO patients to better understand the effectiveness and complications of this support.