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1.
Heart ; 107(23): 1881-1888, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34544804

RESUMO

BACKGROUND AND AIM: Although the diagnostic usefulness of high-sensitivity cardiac troponin T (hs-cTnT) is well established in ST-segment elevation myocardial infarction (STEMI), its prognostic relevance in risk stratification of patients with STEMI remains obscure. This study sought to determine the prognostic value of pre-reperfusion (admission) and post-reperfusion (12-hour) hs-cTnT in patients with STEMI treated with primary percutaneous coronary intervention (PPCI). METHODS: Retrospective observational longitudinal study including consecutive patients with STEMI treated with PPCI at a university hospital in the northeast of England. hs-cTnT was measured at admission to the catheterisation laboratory and 12 hours after PPCI. Clinical, procedural and laboratory data were prospectively collected during patient hospitalisation (June 2010-December 2014). Mortality data were obtained from the UK Office of National Statistics. The study endpoints were in-hospital and overall mortality. RESULTS: A total of 3113 patients were included. Median follow-up was 53 months. Admission hs-cTnT >515 ng/L (fourth quartile) was independently associated with in-hospital mortality (HR=2.53 per highest to lower quartiles; 95% CI: 1.32 to 4.85; p=0.005) after multivariable adjustment for a clinical model of mortality prediction. Likewise, admission hs-cTnT >515 ng/L independently predicted overall mortality (HR=1.27 per highest to lower quartiles; 95% CI: 1.02 to 1.59; p=0.029). Admission hs-cTnT correctly reclassified risk for in-hospital death (net reclassification index (NRI)=0.588, p<0.001) and overall mortality (NRI=0.178, p=0.001). Conversely, 12-hour hs-cTnT was not independently associated with mortality. CONCLUSION: Admission, but not 12-hour post-reperfusion, hs-cTnT predicts mortality and improves risk stratification in the PPCI era. These results support a prognostic role for admission hs-cTnT while challenge the cost-effectiveness of routine 12-hour hs-cTnT measurements in patients with STEMI.

2.
Mech Ageing Dev ; 198: 111540, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34237321

RESUMO

Ageing is the biggest risk factor for impaired cardiovascular health, with cardiovascular disease being the cause of death in 40 % of individuals over 65 years old. Ageing is associated with an increased prevalence of atherosclerosis, coronary artery stenosis and subsequent myocardial infarction, thoracic aortic aneurysm, valvular heart disease and heart failure. An accumulation of senescence and increased inflammation, caused by the senescence-associated secretory phenotype, have been implicated in the aetiology and progression of these age-associated diseases. Recently it has been demonstrated that compounds targeting components of anti-apoptotic pathways expressed by senescent cells can preferentially induce senescence cells to apoptosis and have been termed senolytics. In this review, we discuss the evidence demonstrating that senescence contributes to cardiovascular disease, with a particular focus on studies that indicate the promise of senotherapy. Based on these data we suggest novel indications for senolytics as a treatment of cardiovascular diseases which have yet to be studied in the context of senotherapy. Finally, while the potential benefits are encouraging, several complications may result from senolytic treatment. We, therefore, consider these challenges in the context of the cardiovascular system.

3.
ACS Appl Mater Interfaces ; 13(24): 27868-27879, 2021 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-34110781

RESUMO

We demonstrate that a novel functionalized interface, where molecularly imprinted polymer nanoparticles (nanoMIPs) are attached to screen-printed graphite electrodes (SPEs), can be utilized for the thermal detection of the cardiac biomarker troponin I (cTnI). The ultrasensitive detection of the unique protein cTnI can be utilized for the early diagnosis of myocardial infraction (i.e., heart attacks), resulting in considerably lower patient mortality and morbidity. Our developed platform presents an innovative route to develop accurate, low-cost, and disposable sensors for the diagnosis of cardiovascular diseases, specifically myocardial infraction. A reproducible and advantageous solid-phase approach was utilized to synthesize high-affinity nanoMIPs (average size = 71 nm) for cTnI, which served as synthetic receptors in a thermal sensing platform. To assess the performance and commercial potential of the sensor platform, various approaches were used to immobilize nanoMIPs onto thermocouples or SPEs: dip coating, drop casting, and a covalent approach relying on electrografting with an organic coupling reaction. Characterization of the nanoMIP-functionalized surfaces was performed with electrochemical impedance spectroscopy, atomic force microscopy, and scanning electron microscopy. Measurements from an in-house designed thermal setup revealed that covalent functionalization of nanoMIPs onto SPEs led to the most reproducible sensing capabilities. The proof of application was provided by measuring buffered solutions spiked with cTnI, which demonstrated that through monitoring changes in heat transfer at the solid-liquid interface, we can measure concentrations as low as 10 pg L-1, resulting in the most sensitive test of this type. Furthermore, preliminary data are presented for a prototype platform, which can detect cTnI with shorter measurement times and smaller sample volumes. The excellent sensor performance, versatility of the nanoMIPs, and reproducible and low-cost nature of the SPEs demonstrate that this sensor platform technology has a clear commercial route with high potential to contribute to sustainable healthcare.


Assuntos
Polímeros Molecularmente Impressos/química , Nanopartículas/química , Troponina I/análise , Biomarcadores/análise , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodos , Eletrodos , Grafite/química , Temperatura
4.
Front Immunol ; 12: 605857, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34046028

RESUMO

Aims: Latent cytomegalovirus (CMV) infection is associated with adverse cardiovascular outcomes. Virus-specific CX3CR1+ effector memory T-cells may be instrumental in this process due to their pro-inflammatory properties. We investigated the role of CX3CR1 (fractalkine receptor) in CMV-related lymphocyte kinetics and cardiac remodeling in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (pPCI). Methods and Results: We retrospectively analysed lymphocyte count, troponin, and survival in 4874 STEMI/pPCI patients, evaluated lymphocyte kinetics during reperfusion in a prospective cohort, and obtained sequential cardiac MRI (cMRI) to assess remodeling. Pre-reperfusion lymphopenia independently predicted mortality at 7.5 years. Prior to reperfusion, CCR7+ T-lymphocytes appeared to be depleted. After reperfusion, T-lymphocytes expressing CX3CR1 were depleted predominantly in CMV-seropositive patients. During ischaemia/reperfusion, a drop in CX3CR1+ T-lymphocytes was significantly linked with microvascular obstruction in CMV+ patients, suggesting increased fractalkine-receptor interaction. At 12 weeks, CMV+ patients displayed adverse LV remodeling. Conclusion: We show that lymphopenia occurs before and after reperfusion in STEMI by different mechanisms and predicts long-term outcome. In CMV+ patients, increased fractalkine induction and sequestration of CX3CR1+ T-cells may contribute to adverse remodeling, suggesting a pro-inflammatory pathomechanism which presents a novel therapeutic target.


Assuntos
Receptor 1 de Quimiocina CX3C/genética , Infecções por Citomegalovirus/complicações , Linfócitos/metabolismo , Infarto do Miocárdio/complicações , Infarto do Miocárdio/metabolismo , Remodelação Ventricular , Idoso , Biomarcadores , Receptor 1 de Quimiocina CX3C/metabolismo , Citomegalovirus , Infecções por Citomegalovirus/virologia , Feminino , Testes de Função Cardíaca , Humanos , Imunofenotipagem , Linfócitos/imunologia , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/mortalidade , Receptores CCR7/metabolismo , Remodelação Ventricular/genética , Remodelação Ventricular/imunologia
5.
FASEB J ; 35(5): e21604, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33913566

RESUMO

Myocardial infarction leads to a rapid innate immune response that is ultimately required for repair of damaged heart tissue. We therefore examined circulating monocyte dynamics immediately after reperfusion of the culprit coronary vessel in STEMI patients to determine whether this correlated with level of cardiac injury. A mouse model of cardiac ischemia/reperfusion injury was subsequently used to establish the degree of monocyte margination to the coronary vasculature that could potentially contribute to the drop in circulating monocytes. We retrospectively analyzed blood samples from 51 STEMI patients to assess the number of non-classical (NC), classical, and intermediate monocytes immediately following primary percutaneous coronary intervention. Classical and intermediate monocytes showed minimal change. On the other hand, circulating numbers of NC monocytes fell by approximately 50% at 90 minutes post-reperfusion. This rapid decrease in NC monocytes was greatest in patients with the largest infarct size (P < .05) and correlated inversely with left ventricular function (r = 0.41, P = .04). The early fall in NC monocytes post-reperfusion was confirmed in a second prospective study of 13 STEMI patients. Furthermore, in a mouse cardiac ischemia model, there was significant monocyte adhesion to coronary vessel endothelium at 2 hours post-reperfusion pointing to a specific and rapid vessel margination response to cardiac injury. In conclusion, rapid depletion of NC monocytes from the circulation in STEMI patients following coronary artery reperfusion correlates with the level of acute cardiac injury and involves rapid margination to the coronary vasculature.


Assuntos
Traumatismos Cardíacos/sangue , Traumatismos Cardíacos/patologia , Monócitos/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/complicações , Animais , Feminino , Traumatismos Cardíacos/etiologia , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Estudos Prospectivos , Estudos Retrospectivos
6.
Front Immunol ; 12: 584538, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679735

RESUMO

The cardiovascular and immune systems undergo profound and intertwined alterations with aging. Recent studies have reported that an accumulation of memory and terminally differentiated T cells in elderly subjects can fuel myocardial aging and boost the progression of heart diseases. Nevertheless, it remains unclear whether the immunological senescence profile is sufficient to cause age-related cardiac deterioration or merely acts as an amplifier of previous tissue-intrinsic damage. Herein, we sought to decompose the causality in this cardio-immune crosstalk by studying young mice harboring a senescent-like expanded CD4+ T cell compartment. Thus, immunodeficient NSG-DR1 mice expressing HLA-DRB1*01:01 were transplanted with human CD4+ T cells purified from matching donors that rapidly engrafted and expanded in the recipients without causing xenograft reactions. In the donor subjects, the CD4+ T cell compartment was primarily composed of naïve cells defined as CCR7+CD45RO-. However, when transplanted into young lymphocyte-deficient mice, CD4+ T cells underwent homeostatic expansion, upregulated expression of PD-1 receptor and strongly shifted towards effector/memory (CCR7- CD45RO+) and terminally-differentiated phenotypes (CCR7-CD45RO-), as typically seen in elderly. Differentiated CD4+ T cells also infiltrated the myocardium of recipient mice at comparable levels to what is observed during physiological aging. In addition, young mice harboring an expanded CD4+ T cell compartment showed increased numbers of infiltrating monocytes, macrophages and dendritic cells in the heart. Bulk mRNA sequencing analyses further confirmed that expanding T-cells promote myocardial inflammaging, marked by a distinct age-related transcriptomic signature. Altogether, these data indicate that exaggerated CD4+ T-cell expansion and differentiation, a hallmark of the aging immune system, is sufficient to promote myocardial alterations compatible with inflammaging in juvenile healthy mice.


Assuntos
Envelhecimento/imunologia , Linfócitos T CD4-Positivos/imunologia , Diferenciação Celular/imunologia , Cardiopatias/imunologia , Memória Imunológica/imunologia , Miocárdio/imunologia , Envelhecimento/genética , Animais , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular/genética , Células Cultivadas , Expressão Gênica/imunologia , Cadeias HLA-DRB1/genética , Cadeias HLA-DRB1/imunologia , Cadeias HLA-DRB1/metabolismo , Cardiopatias/genética , Cardiopatias/metabolismo , Humanos , Memória Imunológica/genética , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , RNA-Seq/métodos , Transplante Heterólogo
7.
Arterioscler Thromb Vasc Biol ; 41(3): 1047-1061, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33504179

RESUMO

Shortened telomeres have been linked to numerous chronic diseases, most importantly coronary artery disease, but the underlying mechanisms remain ill defined. Loss-of-function mutations and deletions in telomerase both accelerate telomere shortening but do not necessarily lead to a clinical phenotype associated with atherosclerosis, questioning the causal role of telomere length in cardiac pathology. The differential extranuclear functions of the 2 main components of telomerase, telomerase reverse transcriptase and telomerase RNA component, offer important clues about the complex relationship between telomere length and cardiovascular pathology. In this review, we critically discuss relevant preclinical models, genetic disorders, and clinical studies to elucidate the impact of telomerase in cardiovascular disease and its potential role as a therapeutic target. We suggest that the antioxidative function of mitochondrial telomerase reverse transcriptase might be atheroprotective, making it a potential target for clinical trials. Graphic Abstract: A graphic abstract is available for this article.


Assuntos
Doenças Cardiovasculares/enzimologia , Doenças Cardiovasculares/terapia , Telomerase/metabolismo , Animais , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Ensaios Clínicos como Assunto , Medicamentos de Ervas Chinesas/uso terapêutico , Exercício Físico , Estudo de Associação Genômica Ampla , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Leucócitos/enzimologia , Camundongos , Modelos Cardiovasculares , Mutação , RNA/genética , Telomerase/sangue , Telomerase/genética , Homeostase do Telômero/fisiologia , Encurtamento do Telômero/fisiologia
8.
Aging Cell ; 19(10): e13249, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32996233

RESUMO

A key component of cardiac ischemia-reperfusion injury (IRI) is the increased generation of reactive oxygen species, leading to enhanced inflammation and tissue dysfunction in patients following intervention for myocardial infarction. In this study, we hypothesized that oxidative stress, due to ischemia-reperfusion, induces senescence which contributes to the pathophysiology of cardiac IRI. We demonstrate that IRI induces cellular senescence in both cardiomyocytes and interstitial cell populations and treatment with the senolytic drug navitoclax after ischemia-reperfusion improves left ventricular function, increases myocardial vascularization, and decreases scar size. SWATH-MS-based proteomics revealed that biological processes associated with fibrosis and inflammation that were increased following ischemia-reperfusion were attenuated upon senescent cell clearance. Furthermore, navitoclax treatment reduced the expression of pro-inflammatory, profibrotic, and anti-angiogenic cytokines, including interferon gamma-induced protein-10, TGF-ß3, interleukin-11, interleukin-16, and fractalkine. Our study provides proof-of-concept evidence that cellular senescence contributes to impaired heart function and adverse remodeling following cardiac ischemia-reperfusion. We also establish that post-IRI the SASP plays a considerable role in the inflammatory response. Subsequently, senolytic treatment, at a clinically feasible time-point, attenuates multiple components of this response and improves clinically important parameters. Thus, cellular senescence represents a potential novel therapeutic avenue to improve patient outcomes following cardiac ischemia-reperfusion.


Assuntos
Senescência Celular/fisiologia , Traumatismo por Reperfusão/metabolismo , Feminino , Humanos , Masculino
9.
JMIR Res Protoc ; 9(9): e19456, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32965237

RESUMO

BACKGROUND: Inflammation plays a key role in the pathophysiology of coronary heart disease (CHD) and its acute manifestation, acute coronary syndrome (ACS). Aging is associated with a decline of the immune system, a process known as immunosenescence. This is characterized by an increase in highly proinflammatory T cells that are involved in CHD progression, plaque destabilization, and myocardial ischemia-reperfusion injury. Telomere dysfunction has been implicated in immunosenescence of T lymphocytes. Telomerase is the enzyme responsible for maintaining telomeres during cell divisions. It has a protective effect on cells under oxidative stress and helps regulate flow-mediated dilation in microvasculature. OBJECTIVE: The TACTIC (Telomerase ACTivator to reverse Immunosenescence in Acute Coronary Syndrome) trial will investigate whether a telomerase activator, TA-65MD, can reduce the proportion of senescent T cells in patients with ACS with confirmed CHD. It will also assess the effect of TA-65MD on decreasing telomere shortening, reducing oxidative stress, and improving endothelial function. METHODS: The study was designed as a single-center, randomized, double-blind, parallel-group, placebo-controlled phase II trial. Recruitment started in January 2019. A total of 90 patients, aged 65 years or older, with treated ACS who have had CHD confirmed by angiography will be enrolled. They will be randomized to one of two groups: TA-65MD oral therapy (8 mg twice daily) or placebo taken for 12 months. The primary outcome is the effect on immunosenescence determined by a decrease in the proportion of CD8+ TEMRA (T effector memory cells re-expressing CD45RA [CD45 expressing exon A]) cells at 12 months. Secondary outcomes include leukocyte telomere length, endothelial function, cardiac function as measured by echocardiography and NT-proBNP (N-terminal fragment of the prohormone brain-type natriuretic peptide), systemic inflammation, oxidative stress, and telomerase activity. RESULTS: The study received National Health Service (NHS) ethics approval on August 9, 2018; Medicines and Healthcare products Regulatory Agency approval on October 19, 2018; and NHS Health Research Authority approval on October 22, 2018. The trial began recruiting participants in January 2019 and completed recruitment in March 2020; the trial is due to report results in 2021. CONCLUSIONS: This pilot trial in older patients with CHD will explore outcomes not previously investigated outside in vitro or preclinical models. The robust design ensures that bias has been minimized. Should the results indicate reduced frequency of immunosenescent CD8+ T cells as well as improvements in telomere length and endothelial function, we will plan a larger, multicenter trial in patients to determine if TA-65MD is beneficial in the treatment of CHD in elderly patients. TRIAL REGISTRATION: ISRCTN Registry ISRCTN16613292; http://www.isrctn.com/ISRCTN16613292 and European Union Drug Regulating Authorities Clinical Trials Database (EudraCT), European Union Clinical Trials Register 2017-002876-26; https://tinyurl.com/y4m2so8g. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/19456.

10.
Clin Sci (Lond) ; 134(17): 2243-2262, 2020 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-32880386

RESUMO

In the elderly population, pathological inflammation has been associated with ageing-associated diseases. The term 'inflammageing', which was used for the first time by Franceschi and co-workers in 2000, is associated with the chronic, low-grade, subclinical inflammatory processes coupled to biological ageing. The source of these inflammatory processes is debated. The senescence-associated secretory phenotype (SASP) has been proposed as the main origin of inflammageing. The SASP is characterised by the release of inflammatory cytokines, elevated activation of the NLRP3 inflammasome, altered regulation of acetylcholine (ACh) nicotinic receptors, and abnormal NAD+ metabolism. Therefore, SASP may be 'druggable' by small molecule therapeutics targeting those emerging molecular targets. It has been shown that inflammageing is a hallmark of various cardiovascular diseases, including atherosclerosis, hypertension, and adverse cardiac remodelling. Therefore, the pathomechanism involving SASP activation via the NLRP3 inflammasome; modulation of NLRP3 via α7 nicotinic ACh receptors; and modulation by senolytics targeting other proteins have gained a lot of interest within cardiovascular research and drug development communities. In this review, which offers a unique view from both clinical and preclinical target-based drug discovery perspectives, we have focused on cardiovascular inflammageing and its molecular mechanisms. We have outlined the mechanistic links between inflammageing, SASP, interleukin (IL)-1ß, NLRP3 inflammasome, nicotinic ACh receptors, and molecular targets of senolytic drugs in the context of cardiovascular diseases. We have addressed the 'druggability' of NLRP3 and nicotinic α7 receptors by small molecules, as these proteins represent novel and exciting targets for therapeutic interventions targeting inflammageing in the cardiovascular system and beyond.


Assuntos
Envelhecimento , Inflamação/patologia , Terapia de Alvo Molecular , Animais , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo
11.
Mech Ageing Dev ; 190: 111321, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32735896

RESUMO

Decline in immune system function (immunosenescence) has been implicated in several age-related disorders. However, little is known about whether alteration in T-cell senescence, a process underlying immunological ageing, is related to muscle health in very old adults (aged ≥85 years). Utilising data from the Newcastle 85+ Study, we aimed to (a) derive and characterise immunosenescence profiles by clustering 13 baseline immunosenescence-related biomarkers of lymphocyte compartments in 657 participants; (b) explore the association between the profiles and 5-year change in muscle strength (grip strength) and physical performance (Timed Up-and-Go test), and (c) determine whether immunosenescence profiles predict 3-year incident sarcopenia. Two distinct clusters were identified; Cluster 1 ('Senescent-like phenotype', n = 421), and Cluster 2 ('Less senescent-like phenotype', n = 236) in individuals with complete biomarker data. Although Cluster 1 was characterised by T-cell senescence (e.g., higher frequency of CD4 and CD8 senescence-like effector memory cells), and elements of the immune risk profile (lower CD4/CD8 ratio, CMV+), it was not associated with change in muscle function over time, or with prevalent or incident sarcopenia. Future studies will determine whether more in-depth characterisation or change in T-cell phenotypes predict the decline in muscle health in late adulthood.


Assuntos
Envelhecimento , Linfócitos T CD4-Positivos , Linfócitos T CD8-Positivos , Imunossenescência/fisiologia , Força Muscular , Sarcopenia , Idoso de 80 Anos ou mais , Envelhecimento/imunologia , Envelhecimento/patologia , Biomarcadores/análise , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Senescência Celular/imunologia , Feminino , Humanos , Masculino , Desempenho Físico Funcional , Sarcopenia/epidemiologia , Sarcopenia/imunologia , Sarcopenia/fisiopatologia , Reino Unido/epidemiologia
12.
Hellenic J Cardiol ; 61(6): 381-395, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32534109

RESUMO

The novel coronavirus disease 2019 (COVID-19) pandemic has already caused more than 300,000 deaths worldwide. Several studies have elucidated the central role of cardiovascular complications in the disease course. Herein, we provide a concise review of current knowledge regarding the involvement of cardiovascular system in the pathogenesis and prognosis of COVID-19. We summarize data from 21 studies involving in total more than 21,000 patients from Asia, Europe, and the USA indicating that severe disease is associated with the presence of myocardial injury, heart failure, and arrhythmias. Additionally, we present the clinical and laboratory differences between recovered and deceased patients highlighting the importance of cardiac manifestations. For the infected patients, underlying cardiovascular comorbidities and particularly existing cardiovascular disease seem to predispose to the development of cardiovascular complications, which are in turn associated with higher mortality rates. We provide mechanistic insights into the underlying mechanisms including direct myocardial damage by the virus and the consequences of the hyperinflammatory syndrome developed later in the disease course. Finally, we summarize current knowledge on therapeutic modalities and recommendations by scientific societies and experts regarding the cardiovascular management of patients with COVID-19.


Assuntos
COVID-19 , Doenças Cardiovasculares , Sistema Cardiovascular , SARS-CoV-2/patogenicidade , COVID-19/complicações , COVID-19/diagnóstico , COVID-19/mortalidade , COVID-19/fisiopatologia , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Doenças Cardiovasculares/virologia , Sistema Cardiovascular/imunologia , Sistema Cardiovascular/fisiopatologia , Sistema Cardiovascular/virologia , Comorbidade , Gerenciamento Clínico , Humanos , Mortalidade , Prognóstico
13.
Int J Cardiol Heart Vasc ; 28: 100526, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32435689

RESUMO

Background: The aim of this clinical research was to investigate the effects of Pressure-controlled intermittent Coronary Sinus Occlusion (PiCSO) on infarct size at 5 days after primary percutaneous coronary intervention (pPCI) in patients with ST-segment elevation myocardial infarction (STEMI). Methods and results: This comparative study was carried out in four UK hospitals. Forty-five patients with anterior STEMI presenting within 12 h of symptom onset received pPCI plus PiCSO (initiated after reperfusion; n = 45) and were compared with a propensity score-matched control cohort from INFUSE-AMI (n = 80). Infarct size (% of LV mass, median [interquartile range]) measured by cardiac magnetic resonance (CMR) at day 5 was significantly lower in the PiCSO group (14.3% [95% CI 9.2-19.4%] vs. 21.2% [95% CI 18.0-24.4%]; p = 0.023). There were no major adverse cardiac events (MACE) related to the PiCSO intervention. Conclusions: PiCSO, as an adjunct to pPCI, was associated with a lower infarct size at 5 days after anterior STEMI in a propensity score-matched population.

14.
Br J Clin Pharmacol ; 86(7): 1387-1397, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32067256

RESUMO

AIMS: Following a favourable pilot trial using a single bolus of ciclosporin, it has been unclear why 2 large studies (CYCLE and CIRCUS) failed to prevent reperfusion injury and reduce infarct size in STEMI (ST elevation myocardial infarction). The purpose of this study was to assess the effect of ciclosporin on myocardial injury, left ventricular remodelling and lymphocyte kinetics in patients with acute STEMI undergoing primary percutaneous coronary intervention. METHODS: In this double-blind, single centre trial, we randomly assigned 52 acute STEMI patients with an onset of pain of <6 hours and blocked culprit artery to a single bolus of ciclosporin (n = 26) or placebo (n = 26, control group) prior to reperfusion by stent percutaneous coronary intervention. The primary endpoint was infarct size at 12 weeks. RESULTS: Mean infarct size at 12 weeks was identical in both groups (9.1% [standard deviation= 7.0] vs 9.1% [standard deviation = 7.0], P = .99; 95% confidence interval for difference: -4.0 to 4.1). CD3 T-lymphocytes dropped to similar levels at 90 minutes (867 vs 852 cells/µL, control vs ciclosporin) and increased to 1454 vs 1650 cells/µL at 24 hours. CONCLUSION: In our pilot trial, a single ciclosporin bolus did not affect infarct size or left ventricular remodelling, matching the results from CYCLE and CIRCUS. Our study suggests that ciclosporin does either not reach ischaemic cardiomyocytes, or requires earlier application during first medical contact. Finally, 1 bolus of ciclosporin is not sufficient to inhibit CD4 T-lymphocyte proliferation during remodelling. We therefore believe that further studies are warranted. (Evaluating the effectiveness of intravenous Ciclosporin on reducing reperfusion injury in pAtients undergoing PRImary percutaneous coronary intervention [CAPRI]; NCT02390674).


Assuntos
Ciclosporina , Infarto do Miocárdio , Ciclosporina/uso terapêutico , Método Duplo-Cego , Humanos , Cinética , Linfócitos , Imageamento por Ressonância Magnética , Infarto do Miocárdio/tratamento farmacológico , Resultado do Tratamento , Remodelação Ventricular
15.
NPJ Aging Mech Dis ; 6: 3, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31993214

RESUMO

Cytomegalovirus (CMV) seropositivity in adults has been linked to increased cardiovascular disease burden. Phenotypically, CMV infection leads to an inflated CD8 T-lymphocyte compartment. We employed a 8-colour flow cytometric protocol to analyse circulating T cells in 597 octogenarians from the same birth cohort together with NT-proBNP measurements and followed all participants over 7 years. We found that, independent of CMV serostatus, a high number of CD27-CD28+ CD8 EMRA T-lymphocytes (TEMRA) protected from all-cause death after adjusting for known risk factors, such as heart failure, frailty or cancer (Hazard ratio 0.66 for highest vs lowest tertile; confidence interval 0.51-0.86). In addition, CD27-CD28+ CD8 EMRA T-lymphocytes protected from both, non-cardiovascular (hazard ratio 0.59) and cardiovascular death (hazard ratio 0.65). In aged mice treated with the senolytic navitoclax, in which we have previously shown a rejuvenated cardiac phenotype, CD8 effector memory cells are decreased, further indicating that alterations in T cell subpopulations are associated with cardiovascular ageing. Future studies are required to show whether targeting immunosenescence will lead to enhanced life- or healthspan.

16.
Clin Chem ; 66(1): 247-256, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672851

RESUMO

BACKGROUND: Failed myocardial reperfusion occurs in approximately 50% of patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (PPCI). It manifests as microvascular obstruction (MVO) on cardiac magnetic resonance (CMR) imaging. Although prognostically important, MVO is not routinely screened for. Our aim was to investigate the kinetics of circulating short noncoding ribonucleic acids [microRNAs (miRNAs)] following PPCI and their association with MVO in STEMI patients. METHODS: Screening of 2083 miRNAs in plasma from STEMI patients with (n = 6) and without (n = 6) MVO was performed by next-generation sequencing. Two candidate miRNAs were selected and quantified at 13 time points within 3 h postreperfusion in 20 STEMI patients by reverse transcription and quantitative PCR. Subsequently, these 2 miRNAs were measured in a "validation" STEMI cohort (n = 50) that had CMR imaging performed at baseline and 3 months post-PPCI to evaluate their association with MVO. RESULTS: miR-1 and miR-133b were rapidly released following PPCI in a monophasic or biphasic pattern. Both miRNAs were enriched in circulating microparticles. A second miR-1 peak (90-180 min postreperfusion) seemed to be associated with a higher index of microvascular resistance. In addition, miR-1 and miR-133b levels at 90 min post-PPCI were approximately 3-fold (P = 0.001) and 4.4-fold (P = 0.008) higher in patients with MVO, respectively. Finally, miR-1 was significantly increased in a subgroup of patients with worse left ventricular (LV) functional recovery 3 months post-PPCI. CONCLUSIONS: miR-1 and miR-133b levels increase within 3 h of PPCI. They are positively associated with MVO and worse LV functional recovery post-PPCI.


Assuntos
MicroRNA Circulante/metabolismo , Reperfusão Miocárdica/métodos , Biomarcadores/sangue , Humanos , Cinética , Imagem Cinética por Ressonância Magnética , MicroRNAs/sangue , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Função Ventricular Esquerda/fisiologia
17.
Kardiol Pol ; 77(10): 908-917, 2019 10 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553327

RESUMO

Little attention is paid to the coronary microvasculature when treating acute myocardial infarction (MI). Microvascular obstruction (MVO) contributes to ischemia-reperfusion injury, which hampers distal blood flow to the myocardium despite recanalization of the culprit epicardial vessel. One of the mechanisms behind reperfusion injury is MVO due to persistent vasoconstrictor tone during reperfusion. Arginine vasopressin (AVP) is a hormone with prominent vasoactive effects on the coronary microvessels. Its levels are elevated as part of a stress response triggered by MI, which was shown to exert vasoconstrictive effects on the coronary arteries in preclinical models, mainly in the nonepicardial vessels of the microcirculation. Circulating AVP levels are up to 100­fold higher in MI and do not immediately decrease to baseline levels on reperfusion. This results in the so called coronary slow flow phenomenon and mediates ischemia-reperfusion injury. Recently, the C­terminal fragment of preprovasopressin, copeptin, has emerged as a surrogate biomarker for AVP, as it is more stable in the circulation. Multiple studies have shown the predictive value of both AVP and copeptin with regards to long­term prognoses of MI patients. We propose that both AVP and copeptin have more than just a predictive value but also play a role in the pathophysiology of adverse outcome post­MI. Therefore, the treatment of choice for MI should not only focus on the epicardial vessel but also on targeting MVO that might pre­exist or might directly follow reperfusion. This mandates a clinical trial with an AVP­receptor antagonist in patients with acute MI undergoing reperfusion therapy.


Assuntos
Arginina Vasopressina , Infarto do Miocárdio/enzimologia , Reperfusão Miocárdica , Animais , Humanos
18.
Aging Cell ; 18(3): e12945, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30920115

RESUMO

Cardiovascular disease is the leading cause of death in individuals over 60 years old. Aging is associated with an increased prevalence of coronary artery disease and a poorer prognosis following acute myocardial infarction (MI). With age, senescent cells accumulate in tissues, including the heart, and contribute to age-related pathologies. However, the role of senescence in recovery following MI has not been investigated. In this study, we demonstrate that treatment of aged mice with the senolytic drug, navitoclax, eliminates senescent cardiomyocytes and attenuates profibrotic protein expression in aged mice. Importantly, clearance of senescent cells improved myocardial remodelling and diastolic function as well as overall survival following MI. These data provide proof-of-concept evidence that senescent cells are major contributors to impaired function and increased mortality following MI and that senolytics are a potential new therapeutic avenue for MI.


Assuntos
Envelhecimento/efeitos dos fármacos , Compostos de Anilina/farmacologia , Antineoplásicos/farmacologia , Senescência Celular/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Sulfonamidas/farmacologia , Doença Aguda , Compostos de Anilina/administração & dosagem , Animais , Antineoplásicos/administração & dosagem , Sobrevivência Celular/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Sulfonamidas/administração & dosagem
20.
Thromb Haemost ; 118(7): 1257-1269, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29890520

RESUMO

BACKGROUND: Cardiac-enriched micro ribonucleic acids (miRNAs) are released into the circulation following ST-elevation myocardial infarction (STEMI). Lack of standardized approaches for reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) data normalization and presence of RT-qPCR inhibitors (e.g. heparin) in patient blood samples have prevented reproducible miRNA quantification in this cohort and subsequent translation of these biomarkers to clinical practice. MATERIALS AND METHODS: Using a RT-qPCR miRNA screening platform, we identified and validated an endogenous circulating miRNA as a normalization control. In addition, we assessed the effects of in vivo and in vitro anticoagulant drugs administration (heparin and bivalirudin) on three RT-qPCR normalization strategies (global miRNA mean, exogenous spike-in control [cel-miR-39] and endogenous miRNA control). Finally, we evaluated the effect of heparin and its in vitro inhibition with heparinase on the quantification of cardiac-enriched miRNAs in STEMI patients. RESULTS: miR-425-5p was validated as an endogenous miRNA control. Heparin administration in vitro and in vivo inhibited all RT-qPCR normalization strategies. In contrast, bivalirudin had no effects on cel-miR-39 or miR-425-5p quantification. In vitro RNA sample treatment with 0.3 U of heparinase overcame heparin-induced over-estimation of cardiac-enriched miRNA levels and improved their correlation with high-sensitivity troponin T. CONCLUSION: miRNA quantification in STEMI patients receiving heparin is jeopardized by its effect on all RT-qPCR normalization approaches. Use of samples from bivalirudin-treated patients or in vitro treatment of heparin-contaminated samples with heparinase are suitable alternatives for miRNA quantification in this cohort. Finally, we reinforce the evidence that cardiac-enriched miRNAs early after myocardial reperfusion reflect the severity of cardiac injury.


Assuntos
Anticoagulantes/efeitos adversos , MicroRNA Circulante/genética , Heparina Liase/metabolismo , Heparina/efeitos adversos , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Infarto do Miocárdio com Supradesnível do Segmento ST/genética , Idoso , Anticoagulantes/sangue , MicroRNA Circulante/sangue , Feminino , Marcadores Genéticos , Heparina/sangue , Hirudinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Intervenção Coronária Percutânea , Reação em Cadeia da Polimerase em Tempo Real/normas , Proteínas Recombinantes/sangue , Reprodutibilidade dos Testes , Reação em Cadeia da Polimerase Via Transcriptase Reversa/normas , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Fatores de Tempo , Resultado do Tratamento
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