Cardiac Index by Transthoracic Echocardiography (CITE) study.

AIMS: Left ventricular ejection fraction (LVEF) is the most frequently used parameter in the assessment of heart failure (HF). Cardiac index (CI) is considered a potential alternative to LVEF despite limited evidence. We aimed to assess and compare the predictive accuracy of LVEF and echocardiographically-assessed CI in HF patients. METHODS AND RESULTS: A single-centre, retrospective cohort study was conducted in patients hospitalized for acute HF from 2010-2016. Cox proportional hazard models including either LVEF or CI were created to predict all cause death, cardiovascular (CV) death, or first HF-readmission. Of 334 patients included in the analysis, 58.7% exhibited HF with reduced LVEF (HFrEF). Left ventricular ejection fraction did not show correlation with any endpoint, while CI was predictive of HF-readmission in the entire cohort. Both the LVEF-based and CI-based models demonstrated moderate discriminative accuracy when predicting all-cause death, CV death, or HF-readmission. Left ventricular ejection fraction proved to be an independent predictor of CV mortality in HFrEF-patients, while CI was predictive of HF-readmission in the non-HFrEF group. CONCLUSIONS: Left ventricular ejection fraction seemed to be associated more closely with disease severity in HFrEF, and CI in the non-HFrEF group, in this real-life cohort of elderly HF patients. The LVEF-based and CI-based predictive models have clinically similar predictive accuracy for mortality and HF-readmission, thus CI may be a potential alternative to LVEF in the assessment of left ventricular function. Cardiac index may be an important new tool in the assessment of HF patients with midrange or preserved LVEF.

Alternative complement pathway activation during invasive coronary procedures in acute myocardial infarction and stable angina pectoris.

The effect of invasive percutaneous coronary procedures on complement activation has not been elucidated. We enrolled stable angina patients with elective percutaneous coronary intervention (SA-PCI, n=24), diagnostic coronary angiography (CA, n=52) and 23 patients with ST segment elevation myocardial infarction and primary PCI (STEMI-PCI). Complement activation products (C1rC1sC1inh, C3bBbP and SC5b-9) were measured on admission, 6 and 24h after coronary procedures. The alternative pathway product, C3bBbP significantly and reversibly increased 6h after elective PCI (baseline: 7.81AU/ml, 6h: 16.09AU/ml, 24h: 4.27AU/ml, p<0.01, n=23) and diagnostic angiography (baseline: 6.13AU/ml, 6h: 12.08AU/ml, 24h: 5.4AU/ml, p<0.01, n=52). Six hour C3bBbP values correlated with post-procedural CK, creatinine level and the applied contrast material volume (r=0.41, r=0.4, r=0.3, p<0.05, respectively). In STEMI-PCI, baseline C3bBbP level was higher, compared to SA-PCI or CA patients (11.33AU/ml vs. 7.81AU/ml or 6.13AU/ml, p<0.001). Similarly, the terminal complex (SC5b-9) level was already elevated at baseline compared to SA-PCI group (3.49AU/ml vs. 1.87AU/ml, p=0.011). Complement pathway products did not increase further after primary PCI. Elective coronary procedures induced transient alternative complement pathway activation, influenced by the applied contrast volume. In STEMI, the alternative complement pathway is promptly activated during the atherothrombotic event and PCI itself had no further detectable effect.

High on clopidogrel treatment platelet reactivity is frequent in acute and rare in elective stenting and can be functionally overcome by switch of therapy.

UNLABELLED: The benefit of adjusted antiplatelet therapy in patients with myocardial infarction after primary percutaneous coronary intervention is not well elucidated. We aimed to identify patients with high on treatment platelet reactivity and to gradually adjust antiplatelet therapy. MATERIALS AND METHODS: We enrolled 133 acute myocardial infarction and 67 stable angina patients undergoing intracoronary stenting into our study. Maximal aggregation was determined with light transmission aggregometry. Aggregation >50% induced by 5 µM ADP was indexed with high on-clopidogrel treatment platelet reactivity. In these cases 75 mg clopidogrel was doubled and control test was performed. Patients effectively inhibited with 150 mg clopidogrel were defined as clopidogrel pseudo non-responders. Patients with high platelet reactivity even on 150 mg clopidogrel were considered as clopidogrel real non-responders and were switched to ticlopidine. RESULTS: Aggregations (5ADP; p=0.046) and the ratio of real non-responders (p=0.013) were significantly higher in the myocardial infarction group. Most real non-responders were effectively treated with switch of therapy. The ratio of pseudo non-responders also tended to be higher in myocardial infarction. Platelet reactivity remained constant during follow-up; however, a new appearance of high platelet reactivity was observed at 6 and at 12 months. CONCLUSIONS: Patients with acute myocardial infarction undergoing percutaneous coronary intervention may benefit from prospective platelet function testing, because of higher platelet reactivity and much higher ratio of clopidogrel real non-response. Switch of therapy may effectively overcome clopidogrel non-response. A new appearance of high platelet reactivity with unknown clinical significance is observed in both groups among the patients on clopidogrel.

Elevated C1rC1sC1inh levels independently predict atherosclerotic coronary heart disease.

UNLABELLED: Clinical studies as well as animal models emphasized the importance of the complement system in the pathogenesis of coronary atherosclerosis and cardiovascular diseases. Our aim was to examine the extent and clinical implication of complement system activation in patients with stable atherosclerotic coronary heart disease (ACHD). Seventy-six patients with stable angina pectoris (SAP) scheduled for elective coronary angiography were enrolled into the study. Percutaneous coronary intervention (PCI) was performed in 24 patients, in 27 patients (NOPCI group) the coronary angiography showed significant stenosis and bypass surgery (CABG) or optimal medical therapy (OMT) were advised, whereas in 25 patients the coronary angiography was negative (NC group). 115 volunteers served as healthy controls (HC). In all individuals, the plasma level of several complement activation products - C1rC1sC1inh, C3bBbP and SC5b-9 - were determined on admission, strictly before the coronary angiography. In patients with angiographically proven ACHD (PCI and NOPCI groups), the baseline C1rC1sC1inh levels were significantly higher compared to NC group and HC (p<0.0001, for both comparisons). According to the multiple logistic regression analysis, high C1rC1sC1inh level proved to be an independent biomarker of coronary heart disease (p<0.026, OR: 65.3, CI: 1.628-2616.284). CONCLUSION: Activation of the classical complement pathway can be observed in angiographically proven coronary atherosclerosis. Elevated C1rC1sC1inh levels might represent an useful biomarker for coronary artery disease.

Very late drug-eluting stent thrombosis after nonsteroidal anti-inflammatory drug treatment despite dual antiplatelet therapy.

BACKGROUND: Drug-eluting coronary stent implantation emerged as a safe and effective therapeutic approach by preventing coronary restenosis and reducing the need for further revascularization. However, in contrast to bare metal stents, recent data suggest a unique underlying pathology, namely late coronary stent thrombosis and delayed endothelial healing. OBJECTIVE: To report a case of very late coronary stent thrombosis (834 days after implantation) requiring repeat urgent target-vessel revascularization. Importantly, six days before the acute coronary event, combined nonsteroidal anti-inflammatory drug therapy was initiated. RESULTS: Although a dual antiplatelet regimen was continuously maintained, aggregation measurements indicated only partial antiplatelet effect, which returned to the expected range when nonsteroidal anti-inflammatory drugs were omitted. CONCLUSIONS: The observation indicates that, even 834 days after drug-eluting stent implantation, effective combined antiplatelet therapy might be crucial in certain individuals and the possible impact of drug interactions should not be underestimated. Further efforts should focus on the challenging task of identifying patients or medical situations with prolonged, increased risk of stent thrombosis.

Analysis of platelet alpha2-adrenergic receptor activity in stable coronary artery disease patients on dual antiplatelet therapy.

Combined antiplatelet therapy reduces recurrent atherothrombotic events in stable coronary disease patients; however, high residual platelet reactivity measured ex vivo still raises concerns as a condition related to treatment failure. Alpha-2 adrenoceptor enhances platelet reactivity and might contribute to this phenomenon. For the present study, 121 stable angina patients on standard dual antiplatelet therapy (75 mg clopidogrel and 100 mg acetylsalicylic acid) were recruited. Born aggregometry was performed with adenosine diphosphate (ADP), collagen and epinephrine. To verify platelet adrenergic activity, potentiation by low-dose epinephrine and inhibition by selective alpha-2 receptor blocker atipamezole were determined. To assess the P2Y(12)-specific residual activity, cangrelor was used. Plasma norepinephrine, soluble CD40-ligand, high-sensitivity-C-reactive protein (hsCRP) - and in 24 subjects platelet P-selectin positivity were measured. Epinephrine - at very low concentration (10(-9)g/ml) - significantly potentiates (1.25 microM ADP: 26.5% vs. 43%; 5 microM ADP: 53% vs. 64.5%; collagen: 17% vs 42%, p < 0.001) while atipamezole inhibits ADP- and collagen-induced platelet aggregations (1.25 microM ADP: 26.5% vs. 23%; 5 microM ADP: 53% vs. 47%; collagen: 17% vs. 11%, p < 0.001). Patients with high adrenergic activity have significantly increased baseline ADP- and collagen-induced platelet aggregation. Based on cangrelor's efficacy, these patients have significantly more residual P2Y(12) activity as well. HsCRP and soluble CD40-ligand levels were similar. In conclusion, stable coronary heart disease patients with prominent adrenoceptor activity in vitro have significantly increased platelet aggregability and more functional P2Y(12) receptor, indicating poor inhibitory response to thienopyridines. Therefore, platelet adrenergic receptor represents a considerable, dynamic factor of high residual platelet reactivity and might contribute to cardiovascular events indicating failure of antiplatelet therapy.

Inverse correlation between coronary blood flow velocity and sICAM-1 level observed in ischemic heart disease patients.

Systemic factors and blood flow velocity related to atherosclerosis have been examined mainly separately or by in vitro studies. The aim of our study was to investigate the association between local coronary blood flow (corrected TIMI frame count, CTFC) and systemic atherosclerosis-related inflammatory parameters such as soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-6 (Il-6), high sensitivity C-reactive protein (hsCRP) and von Willebrand factor (vWF) in humans. We enrolled the following groups of ischemic heart disease (IHD) patients: patients with coronary stenosis and stable (CAD, n = 96) or unstable angina (ACS, n = 27), patients with documented myocardial ischemia and normal coronary angiogram (NEG, n = 68). Patient groups showed only marginal differences in CTFC or sICAM-1 levels. In contrast, when IHD patients were studied individually, general positive correlation was found between CTFC and sICAM-1 level (r = 0.33; in NEG r = 0.25; in CAD r = 0.37; in ACS r = 0.61), being the strongest in ACS. The relation was independent from age, gender, BMI, smoking, hypertension, diabetes, previous myocardial infarction, family history of IHD, medication, hsCRP, IL-6 and vWF levels. (odds ratio, OR = 6.4; CI 95%: 2.43-16.84; p < 0.05). Nevertheless, correlation between CTFC and IL-6, hsCRP, vWF levels was not found. These results indicate inverse correlation between coronary blood flow and adhesion molecule production independently from conventional cardiovascular risk factors and inflammatory markers.

Activation of poly(ADP-ribose) polymerase by myocardial ischemia and coronary reperfusion in human circulating leukocytes.

Reactive free radical and oxidant production leads to DNA damage during myocardial ischemia/reperfusion. Consequent overactivation of poly(ADP-ribose) polymerase (PARP) promotes cellular energy deficit and necrosis. We hypothesized that PARP is activated in circulating leukocytes in patients with myocardial infarction and reperfusion during primary percutaneous coronary intervention (PCI). In 15 patients with ST segment elevation acute myocardial infarction, before and after primary PCI and 24 and 96 h later, we determined serum hydrogen peroxide concentrations, plasma levels of the oxidative DNA adduct 8-hydroxy-2'-deoxyguanosine (8OHdG), tyrosine nitration, PARP activation, and translocation of apoptosis-inducing factor (AIF) in circulating leukocytes. Plasma 8OHdG levels and leukocyte tyrosine nitration were rapidly increased by PCI. Similarly, poly(ADP-ribose) content of the leukocytes increased in cells isolated just after PCI, indicating immediate PARP activation triggered by reperfusion of the myocardium. In contrast, serum hydrogen peroxide concentrations and the translocation of AIF gradually increased over time and were most pronounced at 96 h. Reperfusion-related oxidative/nitrosative stress triggers DNA damage, which leads to PARP activation in circulating leukocytes. Translocation of AIF and lipid peroxidation occurs at a later stage. These results represent the first direct demonstration of PARP activation in human myocardial infarction. Future work is required to test whether pharmacological inhibition of PARP may offer myocardial protection during primary PCI.

[Endothelial function and ischemic heart disease]. / Endothelfunkció és ischaemiás szívbetegség.

The original hypothesis of the development of human atherosclerosis and ischemic heart disease called "response-to-injury" suggested the loss of integrity of the endothelium as the first step of the process. The recent version of this hypothesis emphasizes the term of endothelial dysfunction, that can be triggered by any of the well known cardiovascular risk factors. The atherosclerotic process, starting with endothelial dysfunction is a slow grade inflammatory process, promoting the oxidation of the low density lipoprotein molecules, activation of cell adhesion molecules as well as various ligands and cytokines, and activating immunological processes resulting in the development of unstable atherosclerotic plaque, followed by plaque rupture and formation of atherothrombotic lesions. Among the laboratory methods used for the detection of endothelial dysfunction, the flow mediated vasodilation (FMD) is increasingly known. A novel method is the laser Doppler flowmetry, still adapted to routine clinical tests. Clinical experiments are currently running with the coronarographic evaluation of intravascular flow velocity (slow coronary flow phenomenon), and also with the isolation and clinical evaluation of the circulating endothelial cells in patients with ischemic heart disease.