An investigation into the relationship between platelet activation (platelet monocyte interaction & microparticles), inflammation and microvascular dysfunction in coronary artery disease

Introduction Inflammation and platelet activation play a pivotal role in the pathogenesis of acute coronary syndrome (ACS). Mounting evidence indicates that microparticles (MP) are potent pro-coagulant molecules modulating inflammatory processes. Aims The aim of my study was to investigate the intracoronary and systemic microparticle expression in patients with symptomatic coronary heart disease (CHD) and their relationship with markers of inflammation, platelet activation and microvascular dysfunction (MvD). Methods Forty eight patients with CHD (37 with ACS [23 patients with ST segment myocardial infarction (STEMI) and 14 with non-ST segment elevation myocardial infarction (NSTEMI)] and 11 with stable angina (SA) treated with percutaneous coronary intervention (PCI) were recruited. Blood samples were aspirated sequentially from the right atrium (RA) and the coronary (CO) artery (distal to the culprit lesion). AnnexinV+ MP (AnV+MP) from platelet poor plasma were measured using fluorescent monoclonal antibodies and flow cytometry. Markers of inflammation (hs-CRP, IL-6, TNF-α, serum amyloid antigen (SAA) and platelet activation (soluble p-selectin and platelet monocyte aggregates (PMA) were measured using ELISA. MvD was assessed by measuring the index of microvascular resistance (IMR) and coronary wedge pressure (Pw). Results The main novel findings of this study are the demonstration of: 1) differences between MP levels in patients with varying severity of CHD i.e. MP levels were overall higher in those with ACS (more specifically the highest MP levels were observed in the STEMI patients) compared with SA; 2. differential local and systemic AnV+ MP expression in human coronary artery disease; 3. differential local and systemic expression of inflammatory markers in ACS patients; 4. differential local and systemic expression of markers of platelet activation in ACS patients; 5. positive correlation between AnV+MP and markers of inflammation, platelet activation and myocardial necrosis in ACS patients both in the CO and RA; and 6. positive correlation between invasive markers of microvascular dysfunction and PMA in human coronary artery disease. Conclusions High levels of AnV+MP occur in the coronary artery of patients with ACS. Levels of AnV+MP correlate with severity of the ischaemic lesion since higher MPs were detected in the STEMI versus the NSTEMI and SA groups. Markers of platelet activation and inflammation in ACS patients, both at the site of the culprit lesion and in the systemic circulation, strongly correlated with total and cell specific AnV+MP. The interaction between activated platelets and monocytes with endothelial cells and the subsequent formation of AnV+MP and PMA during ACS would be compatible with a direct pathogenic link between inflammatory and prothrombotic pathways in the pathogenesis of ACS and myocardial necrosis. This may suggest a novel role for MPs as effectors of the inflammatory response and cellular injury in ACS. Our observations also support the hypothesis that PMA formation may be important determinants of platelet activation, inflammation and microvascular dysfunction in coronary artery disease. Whether these MP merely reflect the severity of the ischaemic lesion, and/or are active participants in the pathogenesis of ACS now warrants further study, since these could be important, novel therapeutic targets

The Impact of Stochasticity and Its Control on a Model of the Inflammatory Response

The dysregulation of inflammation, normally a self-limited response that initiates healing, is a critical component of many diseases. Treatment of inflammatory disease is hampered by an incomplete understanding of the complexities underlying the inflammatory response, motivating the application of systems and computational biology techniques in an effort to decipher this complexity and ultimately improve therapy. Many mathematical models of inflammation are based on systems of deterministic equations that do not account for the biological noise inherent at multiple scales, and consequently the effect of such noise in regulating inflammatory responses has not been studied widely. In this work, noise was added to a deterministic system of the inflammatory response in order to account for biological stochasticity. Our results demonstrate that the inflammatory response is highly dependent on the balance between the concentration of the pathogen and the level of biological noise introduced to the inflammatory network. In cases where the pro- and anti-inflammatory arms of the response do not mount the appropriate defense to the inflammatory stimulus, inflammation transitions to a different state compared to cases in which pro- and anti-inflammatory agents are elaborated adequately and in a timely manner. In this regard, our results show that noise can be both beneficial and detrimental for the inflammatory endpoint. By evaluating the parametric sensitivity of noise characteristics, we suggest that efficiency of inflammatory responses can be controlled. Interestingly, the time period on which parametric intervention can be introduced efficiently in the inflammatory system can be also adjusted by controlling noise. These findings represent a novel understanding of inflammatory systems dynamics and the potential role of stochasticity thereon

Congenital heart diseases: post-operative appearance on multi-detector CT—a pictorial essay

Echocardiography is considered as an initial imaging modality of choice in patients with congenital heart disease (CHD), and magnetic resonance (MR) imaging is preferred for detailed functional information. Multi-detector computed tomography (CT) plays an important role in clinical practice in assessing post-operative morphological and functional information of patients with complex CHD when echocardiography and MR imaging are not contributory. Radiologists should understand and become familiar with the complex morphology and physiology of CHD, as well as with various palliative and corrective surgical procedures performed in these patients, to obtain CT angiograms with diagnostic quality and promptly recognise imaging features of normal post-operative anatomy and complications of these complex surgeries

Generation of Functional CLL-Specific Cord Blood CTL Using CD40-Ligated CLL APC

PMCID: PMC3526610This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Doppler findings in a rare Coronary Artery Fistula

One of the primary forms of congenital anomalies of the coronary arteries is coronary artery fistula (CAF). It is defined as a direct communication between the coronary artery and any surrounding cardiac chamber or vascular structure, which bypasses the myocardial capillary bed. We present a newborn baby with a large coronary artery fistula connecting the left anterior descending (LAD) artery to the left ventricular (LV) apex. Associated cardiac abnormalities were found: a ventricular septal defect (diameter 4 mm), a patent foramen ovale as well as trivial tricuspid and mitral regurgitation. Here we demonstrate the echocardiograms of an extremely rare form of CAF diagnosed within the first days of postnatal life

A dose escalation and pharmacokinetic study of biweekly pegylated liposomal doxorubicin, paclitaxel and gemcitabine in patients with advanced solid tumours

To determine the maximum tolerated doses (MTDs) and dose-limiting toxicities (DLTs) of pegylated liposomal doxorubicin (PLD), paclitaxel (PCX) and gemcitabine (GEM) combination administered biweekly in patients with advanced solid tumours. Twenty-two patients with advanced-stage solid tumours were treated with escalated doses of PLD on day 1 and PCX plus GEM on day 2 (starting doses: 10, 100 and 800 mg m−2, respectively) every 2 weeks. DLTs and pharmacokinetic (PK) parameters of all drugs were determined during the first cycle of treatment. All but six (73%) patients had previously received at least one chemotherapy regimen. The DLT dose level was reached at PLD 12 mg m−2, PCX 110 mg m−2 and GEM 1000 mg m−2 with neutropaenia being the dose-limiting event. Of the 86 chemotherapy cycles delivered, grade 3 and 4 neutropaenia occurred in 20% with no cases of febrile neutropaenia. Non-haematological toxicities were mild. The recommended MTDs are PLD 12 mg m−2, PCX 100 mg m−2 and GEM 1000 mg m−2 administered every 2 weeks. The PK data revealed no obvious drug interactions. Biweekly administration of PLD, PCX and GEM is a well-tolerated chemotherapy regimen, which merits further evaluation in various types of solid tumours

Serial analysis of circulating tumor cells in metastatic breast cancer receiving first-line chemotherapy

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. Methods: Serial CTC data from 469 patients (2,202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs (bCTC), combined CTC status at baseline to the end of cycle 1 (cCTC), and tCTC. Akaike Information Criterion (AIC) was used to select the model that best predicted PFS and OS. Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (tCTCneg, 56.9% ), low (tCTClo, 23.7%), intermediate (tCTCmid, 14.5%), or high (tCTChi, 4.9%). Patients with tCTClo, tCTCmid and tCTChi patterns had statistically significant inferior PFS and OS compared to those with tCTCneg (P<.001). AIC indicated that the tCTC model best predicted PFS and OS when compared to bCTC and cCTC models. Validation studies in an independent cohort of 1,856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. Conclusions: We identified four novel prognostic groups in MBC based on similarities in CTC trajectory patterns during chemotherapy. Prognostic groups included patients with very poor outcome (tCTCmid+tCTChi, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be utilized for fine-tuning of CTC-based risk-stratification strategies to guide future prospective clinical trials in MBC

Visualization of the intracavitary blood flow in systemic ventricles of Fontan patients by contrast echocardiography using particle image velocimetry

<p>Abstract</p> <p>Background</p> <p>Flow patterns in univentricular hearts may have clinical value. Therefore, it is our objective to asses and characterize vortex flow patterns with Fontan circulation in comparison with healthy controls.</p> <p>Methods</p> <p>Twenty-three patients (8 Fontan and 15 normal patients) underwent echocardiography with intravenous contrast agent (Sonovue^®) administration. Dedicated software was used to perform particle image velocimetry (PIV) and to visualize intracavitary flow in the systemic ventricles of the patients. Vortex parameters including vortex depth, length, width, and sphericity index were measured. Vortex pulsatility parameters including relative strength, vortex relative strength, and vortex pulsation correlation were also measured.</p> <p>Results</p> <p>The data from this study show that it is feasible to perform particle velocimetry in Fontan patients. Vortex length (VL) was significantly lower (0.51 ± 0.09 vs 0.65 ± 0.12, <it>P </it>= 0.010) and vortex width (VW) (0.32 ± 0.06 vs 0.27 ± 0.04, <it>p </it>= 0.014), vortex pulsation correlation (VPC) (0.26 ± 0.25 vs -0.22 ± 0.87, <it>p </it>= 0.05) were significantly higher in Fontan patients. Sphericity index (SI) (1.66 ± 0.48 vs 2.42 ± 0.62, <it>p </it>= 0.005), relative strength (RS) (0.77 ± 0.33 vs 1.90 ± 0.47, <it>p </it>= 0.0001), vortex relative strength (VRS) (0.18 ± 0.13 vs 0.43 ± 0.14, <it>p </it>= 0.0001) were significantly lower in the Fontan patients group.</p> <p>Conclusions</p> <p>PIV using contrast echocardiography is feasible in Fontan patients. Fontan patients had aberrant flow patterns as compared to normal hearts in terms of position, shape and sphericity of the main vortices. The vortex from the Fontan group was consistently shorter, wider and rounder than in controls. Whether vortex characteristics are related with clinical outcome is subject to further investigation.</p

Nomenclature for Pediatric and Congenital Cardiac Care: Unification of Clinical and Administrative Nomenclature – The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the Eleventh Revision of the International Classification of Diseases (ICD-11)

Substantial progress has been made in the standardization of nomenclature for paediatric and congenital cardiac care. In 1936, Maude Abbott published her Atlas of Congenital Cardiac Disease, which was the first formal attempt to classify congenital heart disease. The International Paediatric and Congenital Cardiac Code ( IPCCC ) is now utilized worldwide and has most recently become the paediatric and congenital cardiac component of the Eleventh Revision of the International Classification of Diseases ( ICD-11 ). The most recent publication of the IPCCC was in 2017. This manuscript provides an updated 2021 version of the IPCCC . The International Society for Nomenclature of Paediatric and Congenital Heart Disease ( ISNPCHD ), in collaboration with the World Health Organization (WHO), developed the paediatric and congenital cardiac nomenclature that is now within the eleventh version of the International Classification of Diseases (ICD-11). This unification of IPCCC and ICD-11 is the IPCCC ICD-11 Nomenclature and is the first time that the clinical nomenclature for paediatric and congenital cardiac care and the administrative nomenclature for paediatric and congenital cardiac care are harmonized. The resultant congenital cardiac component of ICD-11 was increased from 29 congenital cardiac codes in ICD-9 and 73 congenital cardiac codes in ICD-10 to 318 codes submitted by ISNPCHD through 2018 for incorporation into ICD-11. After these 318 terms were incorporated into ICD-11 in 2018, the WHO ICD-11 team added an additional 49 terms, some of which are acceptable legacy terms from ICD-10, while others provide greater granularity than the ISNPCHD thought was originally acceptable. Thus, the total number of paediatric and congenital cardiac terms in ICD-11 is 367. In this manuscript, we describe and review the terminology, hierarchy, and definitions of the IPCCC ICD-11 Nomenclature . This article, therefore, presents a global system of nomenclature for paediatric and congenital cardiac care that unifies clinical and administrative nomenclature. The members of ISNPCHD realize that the nomenclature published in this manuscript will continue to evolve. The version of the IPCCC that was published in 2017 has evolved and changed, and it is now replaced by this 2021 version. In the future, ISNPCHD will again publish updated versions of IPCCC , as IPCCC continues to evolve