Graphical Abstract
Graphical Abstract
Chain of events from dietary proteins, gut microbial metabolites, to chronic inflammatory diseases. Exogenous factors such as diet (proteins, lipids, and ...carbohydrates) and microbes interact in the intestinal mucosa as a host interface. This interaction induces gut microbe-dependent metabolites such as aromatic amino acids (AAAs) and regulates immune-inflammatory responses that may lead to chronic inflammatory disease phenotypes including coronary artery disease (CAD), arthritis, inflammatory bowel disease, etc. The novel findings of Nemet et al. (red boxes) contribute to the promising perspective of a road map for precision microbiome-dependent therapies in CAD (green box). Δ AAA, change in aromatic amino acids; Abx, antibiotics; CVD, cardiovascular disease; MACE, major adverse cardiovascular events.
The authors investigated the development of pulmonary hypertension (PH), predictors of PH regression, and its prognostic impact on short, mid-, and long-term outcomes in patients undergoing ...transcatheter aortic valve replacement (TAVR) for severe aortic stenosis (AS).
PH represents a common finding in patients with AS. Although TAVR is frequently associated with regression of PH, the predictors of reversible PH and its prognostic significance remain uncertain.
In this study, 617 consecutive patients undergoing TAVR between 2009 and 2015 were stratified per baseline tertiles of pulmonary artery systolic pressure (PASP) as follows: normal (PASP <34 mm Hg), mild-to-moderate (PASP ≥34 mm Hg and <46 mm Hg), and severe PASP elevation (PASP ≥46 mm Hg). After TAVR, 520 patients with PH at discharge were stratified according to the presence or absence of PASP reduction. Primary outcome was all-cause mortality at 30 days, 1 year, and long-term follow-up at a maximum of 5.9 years.
In patients with both mild-to-moderate and severe PH at baseline, PASP decreased significantly at discharge (ΔPASP 3.0 ± 9.3 mm Hg and 12.0 ± 10.0 mm Hg, respectively) and 1 year (ΔPASP 5.0 ± 9.7 mm Hg and 18.0 ± 14.0 mm Hg, respectively). At a median follow-up of 370 days (interquartile range IQR: 84 to 500 days), the risk of all-cause mortality was similar among baseline PASP groups at all time intervals evaluated. After TAVR, a significant regression of PH was observed in 46% of patients. Contrarily, patients with residual PH had a higher risk of all-cause mortality at 30 days (hazard ratio HR: 3.49, 95% confidence interval CI: 1.74 to 6.99; p < 0.001), 1 year (HR: 3.12, 95% CI: 2.06 to 4.72; p < 0.001), and long-term (HR: 2.47, 95% CI: 1.74 to 3.49; p < 0.001). Left ventricular ejection fraction (LVEF) >40% (odds ratio OR: 3.56, 95% CI: 2.24 to 5.65; p < 0.001), baseline PASP ≥46 mm Hg (OR: 3.26, 95% CI: 2.07 to 5.12; p < 0.001), absence of concomitant tricuspid regurgitation (TR) ≥ moderate (OR: 0.53, 95% CI: 0.34 to 0.84; p < 0.001), and logistic EuroSCORE <25% (OR: 1.59, 95% CI: 1.04 to 2.45; p = 0.03) were independent predictors of PASP reduction.
In most patients with PH and AS, TAVR is associated with a significant early and late reduction of PASP. Patients with reversible PH after TAVR are at lower risk of all-cause mortality at early, mid-, and long-term follow-up. Therefore, the presence of PH should not preclude treatment with TAVR.
During the last decade, the incidence and mortality rates of ST-elevation myocardial infarction (STEMI) has been steadily increasing in young women but not in men. Environmental variables that ...contribute to cardiovascular events in women remain ill-defined.
A total of 2199 consecutive patients presenting with acute ST-elevation myocardial infarction (STEMI, 25.8% women, mean age 62.6±12.4 years) were admitted at the Montreal Heart Institute between June 2010 and December 2014. Snow fall exceeding 2cm/day was identified as a positive predictor for STEMI admission rates in the overall population (RR 1.28, 95% CI 1.07-1.48, p = 0.005), with a significant effect being seen in men (RR 1.30, 95% CI 1.06-1.53, p = 0.01) but not in women (p = NS). An age-specific analysis revealed a significant increase in hospital admission rates for STEMI in younger women ≤55 years, (n = 104) during days with higher outside temperature (p = 0.004 vs men ≤55 years) and longer daylight hours (p = 0.0009 vs men ≤55 years). Accordingly, summer season, increased outside temperature and sunshine hours were identified as strong positive predictors for STEMI occurrence in women ≤55 years (RR 1.66, 95% CI 1.1-2.5, p = 0.012, RR 1.70, 95% CI 1.2-2.5, p = 0.007, and RR 1.67, 95% CI 1.2-2.5, p = 0.011, respectively), while an opposite trend was observed in men ≤55 years (RR for outside temperature 0.8, 95% CI 0.73-0.95, p = 0.01).
The impact of environmental variables on STEMI is age- and sex-dependent. Higher temperature may play an important role in triggering such acute events in young women.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNA) are important non-coding modulators controlling patterns of gene expression. However, profiling and validation of circulating miRNA levels related to adverse cardiovascular outcome ...has not been performed in patients with an acute coronary syndrome (ACS).
In a multicentre, prospective ACS cohort, 1002 out of 2168 patients presented with ST-segment elevation myocardial infarction (STEMI). Sixty-three STEMI patients experienced an adjudicated major cardiovascular event (MACE, defined as cardiac death or recurrent myocardial infarction) within 1 year of follow-up. From a miRNA profiling in a matched derivation case-control cohort, 14 miRNAs were selected for validation. Comparing 63 cases vs. 126 controls, 3 miRNAs were significantly differentially abundant. In patients with MACE, miR-26b-5p levels (P = 0.038) were decreased, whereas miR-320a (P = 0.047) and miR-660-5p (P = 0.01) levels were increased. MiR-26b-5p has been suggested to prevent adverse cardiomyocyte hypertrophy, whereas miR-320a promotes cardiomyocyte death and apoptosis, and miR-660-5p has been related to active platelet production. This suggests that miR-26b-5p, miR-320a, and miR-660-5p may reflect alterations of different pathophysiological pathways involved in clinical outcome after ACS. Consistently, these three miRNAs reliably discriminated cases from controls area under the receiver-operating characteristic curve (AUC) in age- and sex-adjusted Cox regression for miR-26b-5p = 0.707, miR-660-5p = 0.683, and miR-320a =0.672. Combination of the three miRNAs further increased AUC to 0.718. Importantly, addition of the three miRNAs to both, the Global Registry of Acute Coronary Events (GRACE) score and a clinical model increased AUC from 0.679 to 0.720 and 0.722 to 0.732, respectively, with a net reclassification improvement of 0.20 in both cases.
This is the first study performing profiling and validation of miRNAs that are associated with adverse cardiovascular outcome in patients with STEMI. MiR-26b-5p, miR-320a, and miR-660-5p discriminated for MACE and increased risk prediction when added to the GRACE score and a clinical model. These findings suggest that the release of specific miRNAs into circulation may reflect the activation of molecular pathways that impact on clinical outcome after STEMI.
This review gives an overview of sex-based differences in aortic valve stenosis, spanning from pathophysiological mechanisms and disease progression, clinical presentation, presence of comorbidities, ...and diagnostic assessment, to treatment and outcomes. In particular, sex-related differences in the degree of aortic valve calcification, the response of the left ventricle to pressure overload, as well as in the referral to procedures, with women being less frequently referred for surgical aortic valve replacement and experiencing longer waiting times for transcatheter procedures, will be discussed. Sex-related differences are also particularly evident in outcomes of patients with severe aortic stenosis undergoing surgical or transcatheter procedures. The apparent sex paradox seen in women undergoing transcatheter aortic valve implantation refers to the phenomenon of women experiencing higher rates of short-term mortality and bleeding events, but demonstrating improved long-term survival as compared to men. Women who undergo surgical aortic valve replacement have generally worse outcomes as compared to men, which is reflected by the inclusion of female sex in surgical risk calculation scores. Hence, a thorough understanding of sex-related differences in aortic valve stenosis is important to provide optimal and personalized patient care.
Abstract
Convergent experimental and clinical evidence have established the pathophysiological importance of pro-inflammatory pathways in coronary artery disease. Notably, the interest in treating ...inflammation in patients suffering acute myocardial infarction (AMI) is now expanding from its chronic aspects to the acute setting. Few large outcome trials have proven the benefits of anti-inflammatory therapies on cardiovascular outcomes by targeting the residual inflammatory risk (RIR), i.e. the smouldering ember of low-grade inflammation persisting in the late phase after AMI. However, these studies have also taught us about potential risks of anti-inflammatory therapy after AMI, particularly related to impaired host defence. Recently, numerous smaller-scale trials have addressed the concept of targeting a deleterious flare of excessive inflammation in the early phase after AMI. Targeting different pathways and implementing various treatment regimens, those trials have met with varied degrees of success. Promising results have come from those studies intervening early on the interleukin-1 and -6 pathways. Taking lessons from such past research may inform an optimized approach to target post-AMI inflammation, tailored to spare ‘The Good’ (repair and defence) while treating ‘The Bad’ (smouldering RIR) and capturing ‘The Ugly’ (flaming early burst of excess inflammation in the acute phase). Key constituents of such a strategy may read as follows: select patients with large pro-inflammatory burden (i.e. large AMI); initiate treatment early (e.g. ≤12 h post-AMI); implement a precisely targeted anti-inflammatory agent; follow through with a tapering treatment regimen. This approach warrants testing in rigorous clinical trials.
Graphical Abstract
Graphical Abstract
‘The Good’, ‘The Bad’, and ‘The Ugly’: Distinct facets of inflammation in acute myocardial infarction (AMI). The left panel (‘The Good’) shows the role of cytokines, T-cells, NKs, and macrophages in myocardial protection and healing. IL-10 and IL-2 reduce pro-inflammatory signals (e.g. TNFα, MCP-1, IL-8), extracellular matrix remodelling (MMP downregulation), while promoting Treg, Th2, and NK activation with subsequent macrophage polarization towards the M2 phenotype. The mid panel (‘The Bad’) represents the smouldering state of low-grade inflammation persisting in the late phase after AMI. Among the protagonist cellular players responsible for ‘The Bad’ are M1-polarized macrophages, foam cells, and PMNs. Induction of the NLRP3 inflammasome enhances production and secretion of IL-1α, IL-1β with subsequent enhancement of inflammatory signals via IL-6 production. These processes entertain the smouldering embers of inflammation, consequently entailing the residual inflammatory risk (RIR) that negatively affects patient outcome. The right panel focuses on ‘The Ugly’, flaming burst of excess inflammation in the early phase after AMI. PMN activation and monocytes recruitment occur upon plaque rupture and thrombosis that is further increased by NET formation. The ensuing oxidative burst contributes to damage amplification during this early phase. Cytokines which are also present in ‘The Bad’, namely IL-1 and IL-6, show a particularly excessive surge in the early phase after AMI, their damaging characteristics thus potentiated during this phase. AMI, acute myocardial infarction; CRP, C-reactive protein; IL, interleukin; MACE, major adverse cardiovascular events; MCP, monocyte chemoattractant protein; MMP, matrix metalloproteinase; NLRP, NOD-, LRR-, and pyrin domain-containing protein; NET, neutrophil extracellular trap; NK, natural killer cell; PAI1, plasminogen activator inhibitor 1; PMN, polymorphonuclear neutrophil; SAA, serum amyloid A; TIMPS, tissue inhibitors of metalloproteinases; TNF, tumour necrosis factor; Treg, regulatory T-cell.
Abstract
Aims
Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying ...pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping.
Methods and results
The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS.
Conclusions
The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC.
Trial registration
The study was registered at clinicalTrials.gov (NCT03129503).
Graphical Abstract
Aims
Patients suffering from cardiogenic shock (CS) have a high mortality and morbidity. The Impella percutaneous left-ventricular assist device (LVAD) decreases LV preload, increases cardiac output, ...and improves coronary blood flow. We aimed to review and meta-analyze available data comparing Impella versus intra-aortic pump (IABP) counterpulsation or medical treatment in CS due to acute myocardial infarction or post-cardiac arrest.
Methods and results
Study-level data were analyzed. Heterogeneity was assessed using the
I
2
statistic. Risk rates were calculated and obtained using a random-effects model (DerSimonian and Laird). Four studies were found suitable for the final analysis, including 588 patients. Primary endpoint was short-term mortality (in-hospital or 30-day mortality).
In a meta-analysis of four studies comparing Impella versus control, Impella was not associated with improved short-term mortality (in-hospital or 30-day mortality; RR 0.84; 95% CI 0.57–1.24;
p
= 0.38;
I
2
55%). Stroke risk was not increased (RR 1.00; 95% CI 0.36–2.81;
p
= 1.00;
I
2
2 0%), but risk for major bleeding (RR 3.11 95% CI 1.50–6.44;
p
= 0.002;
I
2
0%) and peripheral ischemia complications (RR 2.58; 95% CI 1.24–5.34;
p
= 0.01;
I
2
0%) were increased in the Impella group.
Conclusion
In patients suffering from severe CS due to AMI, the use of Impella is not associated with improved short-time survival but with higher complications rates compared to IABP and medical treatment. Better patient selection avoiding Impella implantation in futile situations or in possible lower risk CS might be necessary to elucidate possible advantages of Impella in future studies.
Quantitative flow ratio (QFR) is a computation of fractional flow reserve (FFR) based on invasive coronary angiographic images. Calculating QFR is less invasive than measuring FFR and may be ...associated with lower costs. Current evidence supports the call for an adequately powered randomised comparison of QFR and FFR for the evaluation of intermediate coronary stenosis. The aim of the FAVOR III Europe Japan trial is to investigate if a QFR-based diagnostic strategy yields a non-inferior 12-month clinical outcome compared with a standard FFR-guided strategy in the evaluation of patients with intermediary coronary stenosis. FAVOR III Europe Japan is an investigator-initiated, randomised, clinical outcome, non-inferiority trial scheduled to randomise 2,000 patients with either 1) stable angina pectoris and intermediate coronary stenosis, or 2) indications for functional assessment of at least 1 non-culprit lesion after acute myocardial infarction. Up to 40 international centres will randomise patients to either a QFR-based or a standard FFR-based diagnostic strategy. The primary endpoint of major adverse cardiovascular events is a composite of all-cause mortality, any myocardial infarction, and any unplanned coronary revascularisation at 12 months. QFR could emerge as an adenosine- and wire-free alternative to FFR, making the functional evaluation of intermediary coronary stenosis less invasive and more cost-effective.
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