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1.
Physiol Meas ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32197256

RESUMO

AIMS: The visual appearance of coronary thrombi may be clinically informative in ST elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (pPCI). However, subjective assessment is poorly reproducible and cannot provide an objective basis for treatment decisions or patient stratification. We have assessed the feasibility of a novel reflectance spectroscopy technique to systematically characterize coronary artery thrombi retrieved by aspiration during pPCI in patients with STEMI, and the clinical utility for predicting distal microvascular obstruction. METHODS AND RESULTS: Patients with STEMI treated with pPCI and thrombus aspiration (n=288) were recruited from the Oxford Acute Myocardial Infarction (OxAMI) Study. Of these, 158 patients underwent cardiac magnetic resonance imaging within 48 hours for assessment of microvascular obstruction (MVO). Coronary thrombi were imaged by reflectance spectroscopy across wavelengths 500 to 800 nm. Spectral data were analysed using function fitting and multivariate models. The coefficient "cred" determined from the fitting procedure correlated with the visually-assessed colour of thrombi ("red" or "white") and with MVO. When applied to a reduced data set, consisting of spectra from 20 patients with the largest MVO and from 20 propensity-score-matched patients with no MVO, three multivariate analysis methods were able to discriminate spectra of thrombi from patients without MVO and with the largest MVO. CONCLUSIONS: Reflectance spectral analysis of coronary thrombus provides new insights into the pathology of STEMI, with potential clinical implications for emergency patient care. Further studies are warranted for validation as a point-of-care stratification tool in predicting the degree of microvascular injury and clinical outcomes in STEMI.

2.
J Cardiovasc Magn Reson ; 22(1): 3, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31915031

RESUMO

BACKGROUND: Myocardial recovery after primary percutaneous coronary intervention in acute myocardial infarction is variable and the extent and severity of injury are difficult to predict. We sought to investigate the role of cardiovascular magnetic resonance T1 mapping in the determination of myocardial injury very early after treatment of ST-segment elevation myocardial infarction (STEMI). METHODS: STEMI patients underwent 3 T cardiovascular magnetic resonance (CMR), within 3 h of primary percutaneous intervention (PPCI). T1 mapping determined the extent (area-at-risk as %left ventricle, AAR) and severity (average T1 values of AAR) of acute myocardial injury, and related these to late gadolinium enhancement (LGE), and microvascular obstruction (MVO). The characteristics of myocardial injury within 3 h was compared with changes at 24-h to predict final infarct size. RESULTS: Forty patients were included in this study. Patients with average T1 values of AAR ≥1400 ms within 3 h of PPCI had larger LGE at 24-h (33% ±14 vs. 18% ±10, P = 0.003) and at 6-months (27% ±9 vs. 12% ±9; P < 0.001), higher incidence and larger extent of MVO (85% vs. 40%, P = 0.016) & [4.0 (0.5-9.5)% vs. 0 (0-3.0)%, P = 0.025]. The average T1 value was an independent predictor of acute LGE (ß 0.61, 95%CI 0.13 to 1.09; P = 0.015), extent of MVO (ß 0.22, 95%CI 0.03 to 0.41, P = 0.028) and final infarct size (ß 0.63, 95%CI 0.21 to 1.05; P = 0.005). Receiver-operating-characteristic analysis showed that T1 value of AAR obtained within 3-h, but not at 24-h, predicted large infarct size (LGE > 9.5%) with 100% positive predictive value at the optimal cut-off of 1400 ms (area-under-the-curve, AUC 0.88, P = 0.006). CONCLUSION: Hyper-acute T1 values of the AAR (within 3 h post PPCI, but not 24 h) predict a larger extent of MVO and infarct size at both 24 h and 6 months follow-up. Delayed CMR scanning for 24 h could not substitute the significant value of hyper-acute average T1 in determining infarct characteristics.

3.
Eur Heart J ; 2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31834357

RESUMO

AIMS: ST-elevation myocardial infarction is associated with high levels of cardiac sympathetic drive and release of the co-transmitter neuropeptide Y (NPY). We hypothesized that despite beta-blockade, NPY promotes arrhythmogenesis via ventricular myocyte receptors. METHODS AND RESULTS: In 78 patients treated with primary percutaneous coronary intervention, sustained ventricular tachycardia (VT) or fibrillation (VF) occurred in 6 (7.7%) within 48 h. These patients had significantly (P < 0.05) higher venous NPY levels despite the absence of classical risk factors including late presentation, larger infarct size, and beta-blocker usage. Receiver operating curve identified an NPY threshold of 27.3 pg/mL with a sensitivity of 0.83 and a specificity of 0.71. RT-qPCR demonstrated the presence of NPY mRNA in both human and rat stellate ganglia. In the isolated Langendorff perfused rat heart, prolonged (10 Hz, 2 min) stimulation of the stellate ganglia caused significant NPY release. Despite maximal beta-blockade with metoprolol (10 µmol/L), optical mapping of ventricular voltage and calcium (using RH237 and Rhod2) demonstrated an increase in magnitude and shortening in duration of the calcium transient and a significant lowering of ventricular fibrillation threshold. These effects were prevented by the Y1 receptor antagonist BIBO3304 (1 µmol/L). Neuropeptide Y (250 nmol/L) significantly increased the incidence of VT/VF (60% vs. 10%) during experimental ST-elevation ischaemia and reperfusion compared to control, and this could also be prevented by BIBO3304. CONCLUSIONS: The co-transmitter NPY is released during sympathetic stimulation and acts as a novel arrhythmic trigger. Drugs inhibiting the Y1 receptor work synergistically with beta-blockade as a new anti-arrhythmic therapy.

4.
EuroIntervention ; 2019 Dec 24.
Artigo em Inglês | MEDLINE | ID: mdl-31854300

RESUMO

AIMS: Assessment of microvascular function in patients with ST-elevation acute myocardial infarction (STEMI) may be useful to determine treatment strategy. The possible role of pressure-bounded coronary flow reserve (pb-CFR) in this setting has not been determined. METHODS AND RESULTS: Thermodilution-pressure-wire assessment of the infarct-related artery was performed in 148 STEMI patients before stenting and/or at completion of primary percutaneous coronary intervention (PPCI). The extent of the myocardial injury was assessed with cardiovascular magnetic resonance imaging at 48-hours and 6-months after STEMI. Post-PPCI pb-CFR was impaired (<2) and normal (>2) in 69.9% and 9.0% of the cases respectively. In the remaining 21.1% of the patients, pb-CFR was "indeterminate". In this cohort, pb-CFR correlated poorly with thermodilution-derived coronary flow reserve (k=0.03, p=0.39). The index of microcirculatory resistance (IMR) was significantly different across the pb-CFR subgroups. Similarly, significant differences were observed in microvascular obstruction (MVO), myocardium area-at-risk and 48-hours infarct-size (IS). A trend towards lower 6-month IS was observed in patients with high (>2) post-PPCI pb-CFR. Nevertheless, pb-CFR was inferior to IMR in predicting MVO and the extent of IS. CONCLUSIONS: Pb-CFR can identify microvascular dysfunction in patients after STEMI and provided superior diagnostic performance compared to thermodilution-derived CFR in predicting MVO. However, IMR was superior to both pb-CFR and thermodilution-derived CFR and consequently, IMR was the most accurate in predicting all of the studied CMR endpoints of myocardial injury after PPCI.

5.
BMJ ; 367: l6055, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748235

RESUMO

OBJECTIVE: To determine the relation between age and troponin level and its prognostic implication. DESIGN: Retrospective cohort study. SETTING: Five cardiovascular centres in the UK National Institute for Health Research Health Informatics Collaborative (UK-NIHR HIC). PARTICIPANTS: 257 948 consecutive patients undergoing troponin testing for any clinical reason between 2010 and 2017. MAIN OUTCOME MEASURE: All cause mortality. RESULTS: 257 948 patients had troponin measured during the study period. Analyses on troponin were performed using the peak troponin level, which was the highest troponin level measured during the patient's hospital stay. Troponin levels were standardised as a multiple of each laboratory's 99th centile of the upper limit of normal (ULN). During a median follow-up of 1198 days (interquartile range 514-1866 days), 55 850 (21.7%) deaths occurred. A positive troponin result (that is, higher than the upper limit of normal) signified a 3.2 higher mortality hazard (95% confidence interval 3.1 to 3.2) over three years. Mortality varied noticeably with age, with a hazard ratio of 10.6 (8.5 to 13.3) in 18-29 year olds and 1.5 (1.4 to 1.6) in those older than 90. A positive troponin result was associated with an approximately 15 percentage points higher absolute three year mortality across all age groups. The excess mortality with a positive troponin result was heavily concentrated in the first few weeks. Results were analysed using multivariable adjusted restricted cubic spline Cox regression. A direct relation was seen between troponin level and mortality in patients without acute coronary syndrome (ACS, n=120 049), whereas an inverted U shaped relation was found in patients with ACS (n=14 468), with a paradoxical decline in mortality at peak troponin levels >70×ULN. In the group with ACS, the inverted U shaped relation persisted after multivariable adjustment in those who were managed invasively; however, a direct positive relation was found between troponin level and mortality in patients managed non-invasively. CONCLUSIONS: A positive troponin result was associated with a clinically important increased mortality, regardless of age, even if the level was only slightly above normal. The excess mortality with a raised troponin was heavily concentrated in the first few weeks. STUDY REGISTRATION: ClinicalTrials.gov NCT03507309.


Assuntos
Envelhecimento/sangue , Doenças Cardiovasculares , Troponina/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/terapia , Estudos de Coortes , Tratamento Conservador/estatística & dados numéricos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mortalidade , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Fatores de Risco , Reino Unido/epidemiologia
6.
Cardiovasc Res ; 2019 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-31584065

RESUMO

INTRODUCTION: Genome Wide Association studies have consistently identified an association between coronary artery disease (CAD) and a locus on chromosome 10 containing a single gene, JCAD (formerly KIAA1462). However, little is known about the mechanism by which JCAD could influence the development of atherosclerosis. METHODS AND RESULTS: Vascular function was quantified in subjects with CAD by flow mediated dilatation [FMD] and vasorelaxation responses in isolated blood vessel segments. The JCAD risk allele identified by GWAS was associated with reduced FMD and reduced endothelial-dependent relaxations. To study the impact of loss of Jcad on atherosclerosis, Jcad-/- mice were crossed to an ApoE-/- background and fed a high fat diet from 6 to16 weeks of age. Loss of Jcad did not affect blood pressure or heart rate. However, Jcad-/-ApoE-/- mice developed significantly less atherosclerosis in the aortic root and the inner curvature of the aortic arch. En-face analysis revealed a striking reduction in pro-inflammatory adhesion molecules at sites of disturbed flow on the endothelial cell layer of Jcad-/- mice. Loss of Jcad lead to a reduced recovery perfusion in response to hind limb ischemia, a model of altered in vivo flow. Knock down of JCAD using siRNA in primary human aortic endothelial cells significantly reduced the response to acute onset of flow, as evidenced by reduced phosphorylation of NF-КB, eNOS and Akt. CONCLUSION: The novel CAD gene JCAD promotes atherosclerotic plaque formation via a role in the endothelial cell shear stress mechanotransduction pathway. TRANSLATIONAL PERSPECTIVE: We reveal that JCAD is a novel coronary artery disease susceptibility gene which determines atherosclerosis progression via a role in the endothelial cell shear stress mechanotransduction pathway. Identifying this new role for JCAD in atherosclerotic plaque progression highlights the importance of new coronary artery disease genes that mediate blood flow mechanotransduction in the pathogenesis of coronary artery disease. These genes are potential novel targets for treatments to reduce atherosclerotic plaque formation, independent of established risk factors and biological mechanisms.

8.
Eur Heart J ; 40(43): 3529-3543, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31504423

RESUMO

BACKGROUND: Coronary inflammation induces dynamic changes in the balance between water and lipid content in perivascular adipose tissue (PVAT), as captured by perivascular Fat Attenuation Index (FAI) in standard coronary CT angiography (CCTA). However, inflammation is not the only process involved in atherogenesis and we hypothesized that additional radiomic signatures of adverse fibrotic and microvascular PVAT remodelling, may further improve cardiac risk prediction. METHODS AND RESULTS: We present a new artificial intelligence-powered method to predict cardiac risk by analysing the radiomic profile of coronary PVAT, developed and validated in patient cohorts acquired in three different studies. In Study 1, adipose tissue biopsies were obtained from 167 patients undergoing cardiac surgery, and the expression of genes representing inflammation, fibrosis and vascularity was linked with the radiomic features extracted from tissue CT images. Adipose tissue wavelet-transformed mean attenuation (captured by FAI) was the most sensitive radiomic feature in describing tissue inflammation (TNFA expression), while features of radiomic texture were related to adipose tissue fibrosis (COL1A1 expression) and vascularity (CD31 expression). In Study 2, we analysed 1391 coronary PVAT radiomic features in 101 patients who experienced major adverse cardiac events (MACE) within 5 years of having a CCTA and 101 matched controls, training and validating a machine learning (random forest) algorithm (fat radiomic profile, FRP) to discriminate cases from controls (C-statistic 0.77 [95%CI: 0.62-0.93] in the external validation set). The coronary FRP signature was then tested in 1575 consecutive eligible participants in the SCOT-HEART trial, where it significantly improved MACE prediction beyond traditional risk stratification that included risk factors, coronary calcium score, coronary stenosis, and high-risk plaque features on CCTA (Δ[C-statistic] = 0.126, P < 0.001). In Study 3, FRP was significantly higher in 44 patients presenting with acute myocardial infarction compared with 44 matched controls, but unlike FAI, remained unchanged 6 months after the index event, confirming that FRP detects persistent PVAT changes not captured by FAI. CONCLUSION: The CCTA-based radiomic profiling of coronary artery PVAT detects perivascular structural remodelling associated with coronary artery disease, beyond inflammation. A new artificial intelligence (AI)-powered imaging biomarker (FRP) leads to a striking improvement of cardiac risk prediction over and above the current state-of-the-art.

9.
Sci Transl Med ; 11(510)2019 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534019

RESUMO

Obesity is associated with changes in the secretome of adipose tissue (AT), which affects the vasculature through endocrine and paracrine mechanisms. Wingless-related integration site 5A (WNT5A) and secreted frizzled-related protein 5 (SFRP5), adipokines that regulate noncanonical Wnt signaling, are dysregulated in obesity. We hypothesized that WNT5A released from AT exerts endocrine and paracrine effects on the arterial wall through noncanonical RAC1-mediated Wnt signaling. In a cohort of 1004 humans with atherosclerosis, obesity was associated with increased WNT5A bioavailability in the circulation and the AT, higher expression of WNT5A receptors Frizzled 2 and Frizzled 5 in the human arterial wall, and increased vascular oxidative stress due to activation of NADPH oxidases. Plasma concentration of WNT5A was elevated in patients with coronary artery disease compared to matched controls and was independently associated with calcified coronary plaque progression. We further demonstrated that WNT5A induces arterial oxidative stress and redox-sensitive migration of vascular smooth muscle cells via Frizzled 2-mediated activation of a previously uncharacterized pathway involving the deubiquitinating enzyme ubiquitin-specific protease 17 (USP17) and the GTPase RAC1. Our study identifies WNT5A and its downstream vascular signaling as a link between obesity and vascular disease pathogenesis, with translational implications in humans.

11.
Cell Rep ; 28(1): 218-230.e7, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31269442

RESUMO

Classical activation of macrophages (M(LPS+IFNγ)) elicits the expression of inducible nitric oxide synthase (iNOS), generating large amounts of NO and inhibiting mitochondrial respiration. Upregulation of glycolysis and a disrupted tricarboxylic acid (TCA) cycle underpin this switch to a pro-inflammatory phenotype. We show that the NOS cofactor tetrahydrobiopterin (BH4) modulates IL-1ß production and key aspects of metabolic remodeling in activated murine macrophages via NO production. Using two complementary genetic models, we reveal that NO modulates levels of the essential TCA cycle metabolites citrate and succinate, as well as the inflammatory mediator itaconate. Furthermore, NO regulates macrophage respiratory function via changes in the abundance of critical N-module subunits in Complex I. However, NO-deficient cells can still upregulate glycolysis despite changes in the abundance of glycolytic intermediates and proteins involved in glucose metabolism. Our findings reveal a fundamental role for iNOS-derived NO in regulating metabolic remodeling and cytokine production in the pro-inflammatory macrophage.

12.
J Clin Invest ; 129(8): 3374-3386, 2019 07 22.
Artigo em Inglês | MEDLINE | ID: mdl-31329158

RESUMO

Oxidative stress plays an important role in aging-related neurodegeneration. This study used littermates of WT and Nox2-knockout (Nox2KO) mice plus endothelial cell-specific human Nox2 overexpression-transgenic (HuNox2Tg) mice to investigate Nox2-derived ROS in brain aging. Compared with young WT mice (3-4 months), aging WT mice (20-22 months) had obvious metabolic disorders and loss of locomotor activity. Aging WT brains had high levels of angiotensin II (Ang II) and ROS production; activation of ERK1/2, p53, and γH2AX; and losses of capillaries and neurons. However, these abnormalities were markedly reduced in aging Nox2KO brains. HuNox2Tg brains at middle age (11-12 months) already had high levels of ROS production and activation of stress signaling pathways similar to those found in aging WT brains. The mechanism of Ang II-induced endothelial Nox2 activation in capillary damage was examined using primary brain microvascular endothelial cells. The clinical significance of Nox2-derived ROS in aging-related loss of cerebral capillaries and neurons was investigated using postmortem midbrain tissues of young (25-38 years) and elderly (61-85 years) adults. In conclusion, Nox2 activation is an important mechanism in aging-related cerebral capillary rarefaction and reduced brain function, with the possibility of a key role for endothelial cells.

13.
mBio ; 10(3)2019 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-31239374

RESUMO

HBsAg and HBeAg have gained traction as biomarkers of control and clearance during chronic hepatitis B virus infection (CHB). Improved understanding of the clearance correlates of these proteins could help inform improvements in patient-stratified care and advance insights into the underlying mechanisms of disease control, thus underpinning new cure strategies. We collected electronic clinical data via an electronic pipeline supported by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC), adopting an unbiased approach to the generation of a robust longitudinal data set for adults testing HBsAg positive from a large UK teaching hospital over a 6-year period (2011 to 2016 inclusive). Of 553 individuals with CHB, longitudinal data were available for 319, representing >107,000 weeks of clinical follow-up. Among these 319 individuals, 13 (4%) cleared HBsAg completely. Among these 13, the HBsAg clearance rate in individuals on nucleos(t)ide analogue (NA) therapy (n = 4 [31%]; median clearance time,150 weeks) was similar to that in individuals not on NA therapy (n = 9 [69%]; median clearance time, 157 weeks). Those who cleared HBsAg were significantly older and less likely to be on NA therapy than nonclearers (P = 0.003 and P = 0.001, respectively). Chinese ethnicity was associated with HBeAg positivity (P = 0.025). HBeAg clearance occurred in individuals both on NA therapy (n = 24; median time, 49 weeks) and off NA therapy (n = 19; median time, 52 weeks). Improved insights into the dynamics of these biomarkers can underpin better prognostication and patient-stratified care. Our systematized approach to data collection paves the way for scaling up efforts to harness clinical data to address research questions and support improvements in clinical care.IMPORTANCE Advances in the diagnosis, monitoring, and treatment of hepatitis B virus (HBV) infection are urgently required if we are to meet international targets for elimination by the year 2030. Here we demonstrate how routine clinical data can be harnessed through an unbiased electronic pipeline, showcasing the significant potential for amassing large clinical data sets that can help to inform advances in patient care and provide insights that may help to inform new cure strategies. Our cohort from a large UK hospital includes adults from diverse ethnic groups that have previously been underrepresented in the literature. By tracking two protein biomarkers that are used to monitor chronic HBV infection, we provide new insights into the timelines of HBV clearance, both on and off treatment. These results contribute to improvements in individualized clinical care and may provide important clues into the immune events that underpin disease control.


Assuntos
Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/sangue , Adolescente , Adulto , Idoso , Antivirais/uso terapêutico , Biomarcadores/sangue , Criança , Estudos de Coortes , Feminino , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Hospitais/estatística & dados numéricos , Humanos , Estudos Longitudinais , Masculino , Informática Médica , Pessoa de Meia-Idade , Reino Unido , Adulto Jovem
14.
Cardiovasc Revasc Med ; 20(9): 768-774, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31208837

RESUMO

BACKGROUND: Patients with ST-elevation Myocardial Infarction treated by primary percutaneous coronary intervention (PPCI) experience drastic hemodynamic systemic changes (i.e., blood pressure) during the different phases of the procedure. Optical coherence tomography is often used to unveil the underlying cause of STEMI (pre-PCI) and to optimize stent implantation (post-PCI). The impact of blood pressure variability on coronary lumen remains uncertain. This study aimed to investigate the relationship between blood pressure variability, before and after PCI, and coronary arterial lumen dimensions of the infarct-related artery. METHODS: We measured systolic, diastolic and mean arterial blood pressure (SBP, DBP, and MAP; respectively) at pre- and post-PCI. Frequency-domain optical coherence tomography (FD-OCT) imaging was performed at the same time points. Offline quantitative image analyses were performed to assess the average and minimum lumen area (LA). Δ blood pressure (after and before the PCI) was then calculated. RESULTS: A total of 14 ST-segment elevation myocardial infarction (STEMI) patients were included. 84.2% of enrolled patients were male with a mean age of (58 ±â€¯10.7 years). Roughly two-thirds (57.8%) had hypertension. The mean SBP was (112.6 mm Hg ±â€¯16.1) and (117.2 mm Hg ±â€¯20.9), pre- and post-stenting, respectively; the range of the observed SBP differences (between pre- and post-PCI) went from -25 to +23 mm Hg. Pre- and post-stenting mean average LA were (7.1 ±â€¯2.5 mm2 and 6.8 ±â€¯2.3 mm2; respectively). There were poor correlations between ΔSBP and Δ mean minimum LA. A similar pattern was observed with ΔDBP and ΔMAP. CONCLUSION: Despite significant hemodynamic variability, the difference in lumen cross-sectional area, between pre- and post-coronary artery stenting was minimal. This study supports the use of OCT lumen areas to inform clinical decisions during PPCI.

15.
Am J Cardiol ; 124(3): 381-388, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31174836

RESUMO

Despite frequent percutaneous coronary intervention (PCI) in calcified vessels of older patients, rotational atherectomy (RA) has not been endorsed in patients with severe aortic stenosis (AS) due to safety concerns and lack of data. We explored periprocedural safety and mortality in severe AS patients undergoing RA. Prospective anonymized clinical, echocardiographic, procedural and outcome data of patients undergoing RA PCI between January 2012 and July 2018 were retrospectively extracted from the institutional coronary database. Patients with severe AS undergoing RA PCI were 1:1 propensity matched with patients undergoing RA PCI in the absence of AS. Outcomes of interest were RA related periprocedural complications, 30-day and 1-year mortality. A prespecified subgroup analysis examined the influence of transcatheter aortic valve replacement on mortality following RA PCI. A total of 544 patients underwent RA PCI; 478 without AS and 66 with AS. Propensity matching yielded 35 matched pairs with improved balance in covariates of interest and no significant differences in baseline characteristics postmatching. In the matched cohort (n = 70) slow flow/no-reflow, coronary dissection, perforation, and hemodynamic instability were rare and not significantly different. Survival analyses revealed significantly higher 30-day (Log-Rank p = 0.02) and 1-year mortality (Log rank p = 0.02, HR 5.24 [95% CI 1.13 to 24.28]) in the severe AS group; driven by a fivefold increase in the hazard of death among patients who did not undergo transcatheter aortic valve replacement HR 4.98 [95% CI 1.03 to 24.1]. In conclusion, our study of 70 patients undergoing radial RA PCI suggests that it can be safely performed in patients with severe AS. Long-term outcomes after RA in patients with severe AS are determined by the presence of the valve disease and other co-morbidities.


Assuntos
Estenose da Valva Aórtica/complicações , Aterectomia Coronária/métodos , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/cirurgia , Idoso , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/mortalidade , Estenose da Valva Aórtica/cirurgia , Doença da Artéria Coronariana/mortalidade , Feminino , Seguimentos , Humanos , Masculino , Análise por Pareamento , Fenômeno de não Refluxo/etiologia , Artéria Radial , Estudos Retrospectivos , Índice de Gravidade de Doença , Substituição da Valva Aórtica Transcateter
16.
Int J Cardiol ; 292: 25-31, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043319

RESUMO

BACKGROUND: Dual quantitative coronary angiography (QCA) has been recently tested for assessment of intracoronary thrombus volume in experimental models. The present study aimed to validate dual QCA in vivo for the assessment of thrombus burden by exploring the correlations between dual QCA-thrombus volume and optical coherence tomography (OCT)-derived indices of thrombotic burden. METHODS AND RESULTS: Fifty-one patients with ACS and angiographic evidence of thrombus undergoing OCT of the culprit lesion before stenting were included. Dual QCA-thrombus volume was calculated as difference between edge-detection and video-densitometry area functions along the target segment. Culprit lesion was categorized using the Ambrose's and AHA/ACC angiographic classifications. Thrombus volume (mean thrombus area × thrombus length), thrombus burden [(mean thrombus area/mean lumen area) x100] and Prati thrombus score (number of quadrants with thrombus) were measured by OCT, and the presence of plaque rupture (PR) or intact fibrous cap (IFC) was assessed. Dual QCA-thrombus volume correlated significantly with OCT-thrombus volume (R = 0.791), thrombus burden (R = 0.767) and Prati thrombus score (R = 0.600) (all p < 0.001). Dual-QCA thrombus volume was significantly higher in patients with PR compared with those with IFC (3.48 mm3 [1.45-11.26] vs. 1.69 mm3 [0.09-5.02], p = 0.013). Compared with IFC, PR showed higher prevalence of eccentric type II Ambrose lesion (41.7% vs. 7.4%, p = 0.004), complex B2/C lesion (87.5% vs. 55.6%, p = 0.012), and heavy calcification (29.2% vs. 3.7%, p = 0.013). CONCLUSIONS: Dual QCA analysis appears to be a promising tool for quantification of intracoronary thrombus in vivo. This novel methodology may be useful to guide intracoronary thrombus removal during percutaneous coronary intervention and to aid prognostic stratification in patients with ACS.

17.
PLoS One ; 14(4): e0216315, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31022288

RESUMO

[This corrects the article DOI: 10.1371/journal.pone.0214361.].

18.
Proc Natl Acad Sci U S A ; 116(16): 8038-8047, 2019 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-30944221

RESUMO

Abdominal aortic aneurysm (AAA) is an inflammatory vascular disease with high mortality and limited treatment options. How blood lipids regulate AAA development is unknown. Here lipidomics and genetic models demonstrate a central role for procoagulant enzymatically oxidized phospholipids (eoxPL) in regulating AAA. Specifically, through activating coagulation, eoxPL either promoted or inhibited AAA depending on tissue localization. Ang II administration to ApoE -/- mice increased intravascular coagulation during AAA development. Lipidomics revealed large numbers of eoxPL formed within mouse and human AAA lesions. Deletion of eoxPL-generating enzymes (Alox12 or Alox15) or administration of the factor Xa inhibitor rivaroxaban significantly reduced AAA. Alox-deficient mice displayed constitutively dysregulated hemostasis, including a consumptive coagulopathy, characterized by compensatory increase in prothrombotic aminophospholipids (aPL) in circulating cell membranes. Intravenously administered procoagulant PL caused clotting factor activation and depletion, induced a bleeding defect, and significantly reduced AAA development. These data suggest that Alox deletion reduces AAA through diverting coagulation away from the vessel wall due to eoxPL deficiency, instead activating clotting factor consumption and depletion in the circulation. In mouse whole blood, ∼44 eoxPL molecular species formed within minutes of clot initiation. These were significantly elevated with ApoE -/- deletion, and many were absent in Alox -/- mice, identifying specific eoxPL that modulate AAA. Correlation networks demonstrated eoxPL belonged to subfamilies defined by oxylipin composition. Thus, procoagulant PL regulate AAA development through complex interactions with clotting factors. Modulation of the delicate balance between bleeding and thrombosis within either the vessel wall or circulation was revealed that can either drive or prevent disease development.

19.
PLoS One ; 14(4): e0214361, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30970015

RESUMO

Quantifying the value of investment in medical research can inform decision-making on the prioritisation of research programmes. Existing methodologies to estimate the rate of return of medical research are inappropriate for early-phase translational research due to censoring of health benefits and time lags. A strategy to improve the process of translational research for patient benefit has been initiated as part of the UK National Institute for Health Research (NIHR) investment in Biomedical Research Centres (BRCs) in England. By providing a platform for partnership between universities, NHS trusts and industry, successful BRCs should reduce time lags within translational research whilst also providing an impetus for local economic growth through industry collaboration. We present a novel contribution in the assessment of early-phase biomedical research by estimating the impact of the Oxford Biomedical Research Centre (OxBRC) on income and job creation following the initial NIHR investment. We adopt a macroeconomic assessment approach using Input-Output Analysis to estimate the value of medical research in terms of income and job creation during the early pathway towards translational biomedical research. Inter-industry linkages are assessed by building a model economy for the South East England region to estimate the return on investment of the OxBRC. The results from the input-output model estimate that the return on investment in biomedical research within the OxBRC is 46%. Each £1 invested in the OxBRC generates an additional £0.46 through income and job creation alone. Multiplicative employment effects following a marginal investment in the OxBRC of £98m during the period 2007-2017 result in an estimated additional 196 full time equivalent positions being created within the local economy on top of direct employment within OxBRC. Results from input-output analyses can be used to inform the prioritisation of biomedical research programmes when compared against national minimum thresholds of investment.


Assuntos
Pesquisa Biomédica/economia , Análise Custo-Benefício/economia , Gastos em Saúde , Pesquisa Médica Translacional/economia , Humanos , Modelos Econômicos , Anos de Vida Ajustados por Qualidade de Vida , Medicina Estatal/economia , Reino Unido
20.
Eur Heart J ; 40(24): 1920-1929, 2019 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-30859228

RESUMO

AIMS: The co-transmitter neuropeptide-Y (NPY) is released during high sympathetic drive, including ST-elevation myocardial infarction (STEMI), and can be a potent vasoconstrictor. We hypothesized that myocardial NPY levels correlate with reperfusion and subsequent recovery following primary percutaneous coronary intervention (PPCI), and sought to determine if and how NPY constricts the coronary microvasculature. METHODS AND RESULTS: Peripheral venous NPY levels were significantly higher in patients with STEMI (n = 45) compared to acute coronary syndromes/stable angina ( n = 48) or with normal coronary arteries (NC, n = 16). Overall coronary sinus (CS) and peripheral venous NPY levels were significantly positively correlated (r = 0.79). STEMI patients with the highest CS NPY levels had significantly lower coronary flow reserve, and higher index of microvascular resistance measured with a coronary flow wire. After 2 days they also had significantly higher levels of myocardial oedema and microvascular obstruction on cardiac magnetic resonance imaging, and significantly lower ejection fractions and ventricular dilatation 6 months later. NPY (100-250 nM) caused significant vasoconstriction of rat microvascular coronary arteries via increasing vascular smooth muscle calcium waves, and also significantly increased coronary vascular resistance and infarct size in Langendorff hearts. These effects were blocked by the Y1 receptor antagonist BIBO3304 (1 µM). Immunohistochemistry of the human coronary microvasculature demonstrated the presence of vascular smooth muscle Y1 receptors. CONCLUSION: High CS NPY levels immediately after reperfusion correlate with microvascular dysfunction, greater myocardial injury, and reduced ejection fraction 6 months after STEMI. NPY constricts the coronary microcirculation via the Y1 receptor, and antagonists may be a useful PPCI adjunct therapy.

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