Impact of respiratory infectious epidemics on STEMI incidence and care.

The effect of respiratory infectious diseases on STEMI incidence, but also STEMI care is not well understood. The Influenza 2017/2018 epidemic and the COVID-19 pandemic were chosen as observational periods to investigate the effect of respiratory virus diseases on these outcomes in a metropolitan area with an established STEMI network. We analyzed data on incidence and care during the COVID-19 pandemic, Influenza 2017/2018 epidemic and corresponding seasonal control periods. Three comparisons were performed: (1) COVID-19 pandemic group versus pandemic control group, (2) COVID-19 pandemic group versus Influenza 2017/2018 epidemic group and (3) Influenza 2017/2018 epidemic group versus epidemic control group. We used Student's t-test, Fisher's exact test and Chi square test for statistical analysis. 1455 patients were eligible. The daily STEMI incidence was 1.49 during the COVID-19 pandemic, 1.40 for the pandemic season control period, 1.22 during the Influenza 2017/2018 epidemic and 1.28 during the epidemic season control group. Median symptom-to-contact time was 180 min during the COVID-19 pandemic. In the pandemic season control group it was 90 min (p = 0.183), and in the Influenza 2017/2018 cohort it was 90 min, too (p = 0.216). Interval in the epidemic control group was 79 min (p = 0.733). The COVID-19 group had a door-to-balloon time of 49 min, corresponding intervals were 39 min for the pandemic season group (p = 0.038), 37 min for the Influenza 2017/2018 group (p = 0.421), and 38 min for the epidemic season control group (p = 0.429). In-hospital mortality was 6.1% for the COVID-19 group, 5.9% for the Influenza 2017/2018 group (p = 1.0), 11% and 11.2% for the season control groups. The respiratory virus diseases neither resulted in an overall treatment delay, nor did they cause an increase in STEMI mortality or incidence. The registry analysis demonstrated a prolonged door-to-balloon time during the COVID-19 pandemic.

Current status and needs for changes in critical care training: the voice of the young cardiologists.

AIMS: The implementation of the 2013 European Society of Cardiology (ESC) Core Curriculum guidelines for acute cardiovascular care (acc) training among European countries is unknown. We aimed to evaluate the current status of acc training among cardiology trainees and young cardiologists (<40 years) from ESC countries. METHODS AND RESULTS: The survey (March-July 2019) asked about details of cardiology training, self-confidence in acc technical and non-technical skills, access to training opportunities, and needs for further training in the field. Overall 614 young doctors, 31 (26-43) years old, 55% males were surveyed. Place and duration of acc training differed between countries and between centres in the same country. Although the majority of the respondents (91%) had completed their acc training, the average self-confidence to perform invasive procedures and to manage acc clinical scenarios was low-44% (27.3-70.4). The opportunities for simulation-based learning were scarce-18% (5.8-51.3), as it was previous leadership training (32%) and knowledge about key teamwork principles was poor (48%). The need for further acc training was high-81% (61.9-94.3). Male gender, higher level of training centres, professional qualifications of respondents, longer duration of acc/intensive care training, debriefings, and previous leadership training as well as knowledge about teamwork were related to higher self-confidence in all investigated aspects. CONCLUSIONS: The current cardiology training program is burdened by deficits in acc technical/non-technical skills, substantial variability in programs across ESC countries, and a clear gender-related disparity in outcomes. The forthcoming ESC Core Curriculum for General Cardiology is expected to address these deficiencies.

Droplet digital PCR of serum miR-499, miR-21 and miR-208a for the detection of functionally relevant coronary artery disease.

BACKGROUND: microRNAs (miRNAs) have shown promise as potential new biomarkers for myocardial injury and myocardial ischemia. New digital polymerase chain reaction (PCR) techniques allow for highly precise and reliable absolute direct quantification. METHODS: In this pilot study we used droplet digital PCR (ddPCR) to assess if miRNAs might be released into circulation in patients with functionally relevant coronary artery disease (CAD). Blood samples for measurement of high-sensitivity cardiac troponin I (hs-cTnI) and miRNAs were obtained before, immediately after peak stress, and 2 h after stress testing in a blinded manner in consecutive patients referred for rest/stress myocardial perfusion single-photon emission tomography/computer tomography (MPI-SPECT/CT). ddPCR was used to directly quantify the serum concentrations of miR-21, miR-208a, and miR-499 as potential markers of myocardial injury/ischemia. Functionally relevant CAD was determined by expert interpretation of MPI-SPECT/CT, coronary angiography and fractional flow reserve, if performed. RESULTS: Overall, 200 patients were included and functionally relevant CAD was detected in 85 of them (42%). Neither miR-21, miR-208a, nor miR-499 concentrations differed at rest, stress, or 2-h after stress when comparing patients with versus without functionally relevant CAD, while hs-cTnI concentrations were significantly higher in patients with functionally relevant CAD (P < 0.001). Exercise-induced changes in miRNA or hs-cTnI concentrations did not have diagnostic utility and were similar in patients with versus without functionally relevant CAD. CONCLUSION: miR-208a, miR-21 and miR-499 concentrations at rest, after exercise and exercise-induced changes do not provide additional clinical value regarding the detection of functionally relevant CAD.

Droplet digital PCR as a novel detection method for quantifying microRNAs in acute myocardial infarction.

BACKGROUND: micro-RNAs have shown promise as potential biomarkers for acute myocardial infarction and ischemia-reperfusion injury (I/R). Most recently droplet digital polymerase chain reaction (ddPCR) has been introduced as a more reliable and reproducible method for detecting micro-RNAs. AIMS: We aimed to demonstrate the improved technical performance and diagnostic potential of ddPCR by measuring micro-RNAs in ST-elevation myocardial infarction (STEMI). METHODS: A dilution series was performed in duplicate on synthetic Caenorrhabditis elegans-miR-39, comparing quantitative real-time PCR (qRT-PCR) and ddPCR. We used ddPCR and qRT-PCR to quantify the serum levels of miR-21, miR-208a and miR-499 between STEMI patients (n=24) and stable coronary artery disease (CAD) patients (n=20). In STEMI, I/R injury was assessed via measurement of ST-segment resolution. RESULTS: In the dilution series, ddPCR demonstrated superior coefficient of variation (12.1%vs.32.9%) and limit of detection (0.9325 vs.2.425copies/µl). In the patient cohort, ddPCR demonstrated greater differences in miR-21 levels (2190.5 vs. 484.7copies/µl; p=0.0004 for ddPCR and 136.4 vs. 122.8copies/µl; p=0.2273 for qRT-PCR) and in miR-208a (0 vs. 24.1copies/µl, p=0.0013 for ddPCR and 0 vs. 0copies/µl, p=0.0032 for qRT-PCR), with similar differences observed in miR-499 levels (9.4 vs. 81.5copies/µl, p<0.0001 for ddPCR and 0 vs. 19.41copies/µl, p<0.0001 for qRT-PCR). ddPCR also more accurately defined STEMI for all miRNAs (area under the curve (AUC) of 0.8021/0.7740/0.9063 for miR-21/208a/499 with ddPCR vs. AUC of 0.6083/0.6917/0.8417 with qRT-PCR). However, there was no association between miR-21/208a/499 levels and ischemia-reperfusion injury. CONCLUSION: ddPCR demonstrates superiority in both technical performance and diagnostic potential compared to qRT-PCR. Ultimately, this supports its use as a diagnostic method for quantifying micro-RNAs, particularly in large multi-center trials.

Circulating HtrA2 as a novel biomarker for mitochondrial induced cardiomyocyte apoptosis and ischemia-reperfusion injury in ST-segment elevation myocardial infarction.

BACKGROUND: Ischemia-reperfusion (I/R) injury in ST-segment elevation myocardial infarction (STEMI) significantly contributes to overall myocardial damage. As a consequence of I/R injury in the heart, the high-temperature requirement protein A2 (HtrA2) is released from the mitochondrial intermembrane space of cardiomyocytes to the cytoplasm, whereupon it induces apoptosis. METHODS: Serum was obtained from STEMI (n=37), non-ST-segment elevation myocardial infarction (NSTEMI) (n=20), stable coronary artery disease (CAD) (n=17) and patients with CAD excluded (n=9). In STEMI, I/R injury was assessed via measurement of ST-segment resolution. RESULTS: HtrA2 was significantly increased in STEMI compared to NSTEMI, stable CAD and patients with CAD excluded (981.3 (IQR: 543.5-1526.2)pg/mL vs. 494.5 (IQR: 413.8-607)pg/mL vs. 291 (IQR: 239-458.5)pg/mL vs. 692.2 (IQR: 276.6-964.7)pg/mL; p≤0.0001). STEMI patients with HtrA2 level of at least the median or above had a higher peak creatine kinase (CK) (p=0.0002) and cardiac troponin T levels (cTnT) (p=0.0019). Significantly more STEMI patients with HtrA2 levels of at least the median or above were identified as I/R injury (87% vs. 42%; p<0.0001). Serum HtrA2 demonstrated a superior area under a curve in a receiver operating characteristic analysis for predicting I/R injury compared to CK, creatine kinase myocardial-band (CK-MB) and cTnT levels (AUC=0.7105 vs. AUC=0.5632 vs. AUC=0.5660 vs. AUC=0.5407 respectively). CONCLUSION: HtrA2 shows promise as a novel potential biomarker for mitochondrial-induced cardiomyocyte apoptosis and may help to identify I/R injury after STEMI.

Asymptomatic atrial fibrillation and risk of stroke.

The incidence of atrial fibrillation rises with advancing age. About 10% of patients over 80 years suffer from atrial fibrillation, but episodes are often not recognized. However, about 25% of cryptogenic strokes are caused by asymptomatic atrial fibrillation showing a significant risk of thromboembolism by this condition. New insertable cardiac monitors or wearable sensors offer the opportunity of continuous rhythm monitoring over wider time spans. Thereby, they enable detection of asymptomatic atrial fibrillation episodes. Several lines of evidence point towards an association between duration of asymptomatic episodes and thromboembolic risk. However, definite data on optimal risk stratification and therapy is missing in this collective. Currently, oral anticoagulation should be initiated according to the CHA2DS2VASc Score. Given the better safety profile of direct oral anticoagulants these substances should be preferred. In patients with high bleeding risk and asymptomatic atrial fibrillation, catheter-based left appendage occlusion may represent a valuable alternative to oral anticoagulation.

Anticoagulation during and after acute coronary syndrome.

Current antithrombotic therapy in patients with acute coronary syndrome (ACS) comprises antiplatelet and anticoagulant therapy. Dual antiplatelet therapy composed of aspirin plus a third generation P2Y12 inhibitor (prasugrel or ticagrelor) represents the gold standard, while aspirin plus second generation P2Y12 inhibitor (clopidogrel) may be used as an alternative in the presence of contraindications for third generation P2Y12 inhibitors and/or a high risk of bleeding. Unfractionated heparin (UFH) has been the unchallenged mainstay in anticoagulation for ACS for many decades and is still widely used in patients with ACS treated interventionally. Novel alternative parenteral anticoagulant strategies include the low molecular weight heparin enoxaparin and the synthetic pentasaccharide fondaparinux. Both of these agents share advantages over UFH particularly in medically treated patients with ACS not scheduled for PCI. The direct parenteral factor IIa (thrombin) inhibitor bivalirudin, when used as sole anticoagulant in patients with ACS undergoing PCI, is as effective as the regimen of UFH plus GPIIb/IIIa inhibitor in NSTEMI and superior to the latter regimen in patients with STEMI. The novel approach of a long-term low dose factor Xa inhibition with rivaroxaban in the post ACS phase even further reduced cardiovascular mortality in a clinical trial but has yet to be established in daily clinical practice in the setting of third generation P2Y12 inhibitors. This review discusses currently clinically established anticoagulants for the treatment of ACS alongside with novel approaches such as rivaroxaban.

Oral anticoagulation with edoxaban. Focus on current phase III clinical development.

Edoxaban (the former DU176b) an orally available direct factor Xa inhibitor has been engineered from DX-9065a, which was one of the first parenteral Xa inhibitors. Edoxaban has a time to peak plasma concentrations of 1-2 hours and a half-life of approximately 10 hours after multiple doses. Edoxaban is the third new oral anticoagulant in the group of direct factor Xa inhibitors that has gained clinical approval for the prevention of venous thromboembolism after major orthopaedic surgery. Currently, edoxaban is assessed in late stage clinical development for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (ENGAGE AF-TIMI 48, NCT00781391) and for the treatment and prevention of venous thromboembolism in patients with acute deep vein thrombosis and/or pulmonary embolism (HOKUSAI VTE, NCT00986154). Both clinical phase III trials represent the largest single clinical studies in their entity so far with an enrolment of 21107 patients in ENGAGE AF-TIMI 48 and a planned enrolment of 7500 patients in HOKUSAI VTE. The pharmacological properties of edoxaban will be discussed along with the current late stage clinical development focusing on the prevention of stroke and venous thromboembolism.

Oral anticoagulation with edoxaban.

Edoxaban (the former DU176b) an orally available direct factor Xa inhibitor has been engineered from DX-9065a, which was one of the first parenteral Xa inhibitors. Edoxaban has a time to peak plasma concentrations of 1-2 hours and a half-life of approximately 10 hours after multiple doses. Edoxaban is the third new oral anticoagulant in the group of direct factor Xa inhibitors that has gained clinical approval for the prevention of venous thromboembolism after major orthopaedic surgery. Currently, edoxaban is assessed in late stage clinical development for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (ENGAGE AF-TIMI 48, NCT00781391) and for the treatment and prevention of venous thromboembolism in patients with acute deep vein thrombosis and/or pulmonary embolism (HOKUSAI VTE, NCT00986154).Both clinical phase III trials represent the largest single clinical studies in their entity so far with an enrolment of 21 107 patients in ENGAGE AF-TIMI 48 and a planned enrolment of 7500 patients in HOKUSAI VTE.The pharmacological properties of edoxaban will be discussed along with the current late stage clinical development focusing on the prevention of stroke and venous thromboembolism.

Opposing effects of monomeric and pentameric C-reactive protein on endothelial progenitor cells.

C-reactive protein (CRP) has been linked to the pathogenesis of atherosclerosis. The dissociation of native, pentameric (p)CRP to monomeric (m)CRP on the cell membrane of activated platelets has recently been demonstrated. The dissociation of pCRP to mCRP may explain local pro-inflammatory reactions at the site of developing atherosclerotic plaques. As a biomarker, pCRP predicts cardiovascular adverse events and so do reduced levels and function of circulating endothelial progenitor cells (EPCs). We hypothesised that mCRP and pCRP exert a differential effect on EPC function and differentiation. EPCs were treated with mCRP or pCRP for 72 h, respectively. Phenotypical characterisation was done by flow cytometry and immunofluorescence microscopy, while the effect of mCRP and pCRP on gene expression was examined by whole-genome gene expression analysis. The functional capacity of EPCs was determined by colony forming unit (CFU) assay and endothelial tube formation assay. Double staining for acetylated LDL and ulex lectin significantly decreased in cells treated with pCRP. The length of tubuli in a matrigel assay with HUVECs decreased significantly in response to pCRP, but not to mCRP. The number of CFUs increased after pCRP treatment. RNA expression profiling demonstrated that mCRP and pCRP cause highly contradictory gene regulation. Interferon-responsive genes (IFI44L, IFI44, IFI27, IFI 6, MX1, OAS2) were among the highly up-regulated genes after mCRP, but not after pCRP treatment. In conclusion, EPC phenotype, genotype and function were differentially affected by mCRP and pCRP, strongly arguing for differential roles of these two CRP conformations. The up-regulation of interferon-inducible genes in response to mCRP may constitute a mechanism for the local regulation of EPC function.

[Factor Xa-inhibition in interventional cardiology]. / Faktor-Xa-Inhibition in der interventionellen Kardiologie.

The recently established correlation between bleeding events and clinical outcomes in patients with coronary artery disease undergoing either non-invasive or invasive treatment for acute coronary syndromes (ACS) highlights the unmet need for safer anticoagulants that can be used in conjunction with dual or triple antiplatelet therapy. The central position of the coagulation factors IIa and Xa within the coagulation system account for their prominent role as targets for anticoagulants. Unfractionated heparin (UFH) achieves a variable indirect inhibition of both factors. The low molecular weight heparins (LMWH) show favourable pharmacokinetics over UFH and have a more pronounced activity against factor Xa as opposed to thrombin which may partially account for the benefits observed with LMWH in clinical trials. New agents that have been developed allow for a selective inhibition of factor Xa. Recently, exciting results have been reported with an indirect selective inhibitor of factor Xa in patients with ST-elevation myocardial infarction (STEMI) -acute coronary syndromes (ACS) and non-STEMI-ACS. In this article the pharmacology of the indirect selective factor Xa inhibitors Fondaparinux and Idraparinux will be discussed along with the direct selective factor Xa inhibitors DX-9065a and Otamixaban in the setting of interventional cardiology.

A novel functional role for the highly conserved alpha-subunit KVGFFKR motif distinct from integrin alphaIIbbeta3 activation processes.

BACKGROUND: The highly conserved integrin alpha-subunit membrane-proximal motif KVGFFKR plays a decisive role in modulating the activation of integrin alphaIIbbeta3. Previously, we have shown that a platelet permeable palmityl (pal)-peptide with this seven amino acid sequence can directly activate alphaIIbbeta3 leading to platelet aggregation. OBJECTIVES: To investigate further the role of the KVGFFKR motif in integrin alphaIIbbeta3 function. METHODS: We used two sequence-specific complementary model systems, palmityl pal-peptides in platelets, and mutant alphaIIbbeta3-expressing Chinese Hamster Ovary (CHO) cell lines. RESULTS: In platelets we show that the two phenylalanine amino acids in pal-KVGFFKR (pal-FF) peptide are critical for stimulating platelet aggregation. Pal-FF peptide treatment of platelets also gives rise to a tyrosine phosphorylation signal despite the presence of inhibitors of fibrinogen binding. In CHO cells, a double alanine substitution, alphaIIb(F992A, F993A)beta3, induces constitutive integrin activation but prevents actin stress fiber formation upon adhesion to fibrinogen, suggesting that alphaIIbbeta3-mediated cytoskeletal reorganization is also dependent on F992 and F993. This further highlights a critical role for the two phenylalanine residues in both of these alphaIIbbeta3-mediated processes. CONCLUSION: In addition to regulating integrin alphaIIbbeta3 activation state, the KVGFFKR motif also influences cytoskeletal reorganization. This activity is critically determined by F992 and F993 within the seven amino acid sequence.

Evidence for a differential functional regulation of the two beta(3)-integrins alpha(V)beta(3) and alpha(IIb)beta(3).

The functional regulation of integrins is a major determinant of cell adhesion, migration and tissue maintenance. The binding of cytoskeletal proteins to various sites of integrin cytoplasmic domains is a key mechanism of this functional regulation. Expression of recombinant integrin alpha(IIb)beta(3) and alpha(M)beta(2) lacking the GFFKR-region in CHO cells results in constitutively activated integrins. In contrast, CHO cells stably expressing either a GFFKR-deleted alpha(V(del))beta(3) or a FF to AA-substituted alpha(V(AA))beta(3) do not reveal a constitutively activated integrin. Adhesion to immobilized fibrinogen is strongly impaired in alpha(V(del))beta(3) or alpha(V(AA))beta(3)-expressing cells, whereas it is not impaired in alpha(IIb)beta(3) and alpha(M)beta(2), both lacking the GFFKR-region. In a parallel plate flow chamber assay, alpha(V)beta(3)-expressing cells adhere firmly to fibrinogen and spread even at shear rates of 15 to 20 dyn/cm(2), whereas alpha(V(del))beta(3) or alpha(V(AA))beta(3) cells are detached at 15 dyn/cm(2). Actin stress fiber formation and focal adhesion plaques containing alpha(V)beta(3) are observed in alpha(V)beta(3) cells but not in alpha(V(del))beta(3) or alpha(V(AA))beta(3)-expressing cells. As an additional manifestation of impaired outside-in signaling, phosphorylation of pp125(FAK) was reduced in these cells. In summary, we report that the GFFKR-region of the alpha(V)-cytoplasmic domain and in particular two phenylalanines are essential for integrin alpha(V)beta(3) function, especially for outside-in signaling. Our results suggest that the two beta(3)-integrins alpha(IIb)beta(3) and alpha(V)beta(3) are differentially regulated via their GFFKR-region.

[Inhibition of platelet aggregation for the secondary prevention after ACS: when clopidogrel instead of ASA, when clopidogrel and ASA?]. / Langzeit-Antiaggregation mit Clopidogrel statt ASS, Clopidogrel und ASS. Was ist wann indiziert bei akutem Koronarsyndrom?

Long-term inhibition of platelet aggregation is essential for the secondary prevention after acute coronary syndromes (ACS). Inhibition of platelet aggregation with acetylsalicylic acid (ASA) has been established as a safe and effective therapy in this indication already end of the eighties in the preceding century. A decade later, with the introduction of the thieno-pyridines, combined platelet aggregation inhibition became possible. This opened the door for new treatment strategies in interventional cardiology. The first substance, ticlopidine was more or less replaced by the newer substance clopidogrel, which has improved pharmacological properties and less side effects. Low dose ASA (75 mg/d) is still regarded as the standard therapy for secondary prevention after ACS. However, large clinical trials established clopidogrel as at least as effective and safe as ASA in this indication. Following PCI with bare metal stent implantation, a combined therapy of ASA and clopidogrel should be given for at least 4 weeks. After ACS with non-ST-elevation myocardial infarction the combined therapy with ASA and clopidogrel gives a better outcome than ASA alone. Recently published clinical trials show superiority of this strategy in patients with ST-elevation myocardial infarction, too. If a combined long-term platelet aggregation inhibition with ASA and clopidogrel will be safe and more effective for secondary prevention is discussed.

Inhibition of platelet activation and aggregation.

It has recently been established that platelets are involved at all stages of atherosclerotic disease. A major platelet mediated process is the acute vessel closure at the site of atherosclerotic plaque rupture and there is emerging evidence for platelet adhesion to endothelial cells in the early stage of atherosclerotic disease. This, through engagement of other cells, leads to the development of the atherosclerotic plaque. Beside dietary, cholesterol- and lipid-lowering, and other pharmaceutical approaches antiplatelet therapy plays an important part in the treatment of atherosclerosis and its multifarious clinical manifestations. Antiplatelet therapy and the currently approved substances for oral (acetylsalicylic acid, dipyridamole, cilostazol, ticlopidin and clopidogrel) and parenteral (acetylsalicylic acid, abciximab, eptifibatide and tirofiban) administration are discussed in the following section. Attention is given to each single agent and its mechanism of action. Differences in pharmacodynamic and pharmacokinetic properties are elucidated and outlook on future antiplatelet strategies is discussed.

Effect of drug intake prior to or after meals on serum theophylline concentrations: single-dose studies with Euphylong.

Three separate single-dose, randomized, cross-over studies in normal, healthy volunteers were performed to investigate the possible influence of drug intake in relation to concomitant food intake and of different dietary habits such as cold and hot evening meals on the bioavailability of theophylline from Euphylong. Euphylong is a new, pH- and rpm-independent theophylline formulation designed for once-daily administration in the evening. The results obtained show that the timing of drug intake, in relation to concomitant food intake, has no influence on the bioavailability of Euphylong. Under equicaloric conditions, a 10% decrease in AUC and a 20% decrease in Cmax is observed when Euphylong is administered after a hot evening meal compared with a cold evening meal. Viewed against the dramatic changes in bioavailability of up to 100%, which have been observed for certain other sustained-release theophylline formulations, these minor changes for Euphylong are negligible and without clinical relevance.