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1.
ESC Heart Fail ; 2020 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-32686334

RESUMO

AIMS: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that cannot be attributed to a culprit lesion in coronary arteries. Cardiac overstimulation by catecholamines in the setting of stress is implicated in the pathogenesis of TS. While catecholamine-induced alterations in cardiac contractility have been studied as part of the causal pathway in TS, the importance of catecholamine-mediated tachycardia has not been studied. Our aim was to explore whether the reduction in heart rate, either by pharmacological suppression of the sinoatrial node with ivabradine or by surgical induction of third-degree atrioventricular block, prevents isoprenaline-induced TS-like akinesia in an experimental animal model. METHODS AND RESULTS: We used 142 female Sprague-Dawley rats in two separate protocols. The TS-like phenotype was induced by an intraperitoneal bolus dose of isoprenaline (ISO) 50 mg/kg. In the first protocol, we randomized 54 rats to ivabradine 10 min before ISO (IVAB1), ivabradine 10 min after ISO (IVAB2), or saline 10 min before ISO (CONTROL). In the second protocol, we randomized 88 rats to surgically induced complete heart block (CHB) or sham operation (CTRL) 10 min before the administration of ISO. All drugs were administered intraperitoneally. We recorded heart rate and blood pressure invasively in the right carotid artery. Cardiac morphology and function were evaluated by high-resolution echocardiography (VisualSonics 770 VEVO, Toronto, Ontario, Canada) 90 min after ISO injection. IVAB1 and IVAB2 rats had significantly lower heart rate and less pronounced TS-like cardiac dysfunction than CONTROL. CHB rats had a lower (54%) heart rate, and no animal developed left ventricular akinesia. In the first protocol, the CONTROL group had a median degree of akinesia of 10.2 [inter-quartile range (IQR) 0.0-18.6]. The IVAB1 group showed a median of akinesia of 0% (IQR 0.0-0.0, P < 0.001 vs. CONTROL). In the IVAB2 group, 5% had TS-like dysfunction (P = 0.001). Ejection fraction was higher in both the IVAB1 (92%, IQR 89-95) and IVAB2 groups (93%, IQR 87-96) than in the CONTROL group (78%, IQR 63-87, P < 0.05). In the second protocol, the median degree of akinesia in the CTRL group was 21.9% (IQR 8.9-24.6). In the CHB group, no rat developed akinesia (median 0%; IQR 0.0-0.0, P < 0.001 vs. CONTROL). Ejection fraction was higher in the CHB group (90%, IQR 87-92) than in the CTRL group (51%, IQR 87-92, P < 0.05). CONCLUSIONS: Isoprenaline-induced TS-like cardiac dysfunction can be prevented by lowering heart rate. Tachycardia may be an important part of the causal pathway in TS.

2.
J Am Coll Cardiol ; 75(22): 2785-2799, 2020 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-32498806

RESUMO

BACKGROUND: Intracoronary pressure wire measurement of fractional flow reserve (FFR) provides decision-making guidance during percutaneous coronary intervention (PCI). However, limited data exist on the effect of FFR on long-term clinical outcomes in patients with stable angina pectoris. OBJECTIVES: The purpose of this study was to determine the association between the usage of FFR and all-cause mortality in patients with stable angina undergoing PCI. METHODS: Data was used from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) on all patients undergoing PCI (with or without FFR guidance) for stable angina pectoris in Sweden between January 2005 and March 2016. The primary endpoint was all-cause mortality, and the secondary endpoints were stent thrombosis (ST) or restenosis and peri-procedural complications. The primary model was multilevel Cox proportional hazards regression adjusted with Kernel-based propensity score matching. RESULTS: In total, 23,860 patients underwent PCI for stable angina pectoris; of these, FFR guidance was used in 3,367. After a median follow-up of 4.7 years (range 0 to 11.2 years), the FFR group had lower adjusted risk estimates for all-cause mortality (hazard ratio: 0.81; 95% confidence interval [CI]: 0.73 to 0.89; p < 0.001), and ST and restenosis (hazard ratio: 0.74; 95% CI: 0.57 to 0.96; p = 0.022). The number of peri-procedural complications did not differ between the groups (adjusted odds ratio: 0.96; 95% CI: 0.77 to 1.19; p = 0.697). CONCLUSIONS: In this observational study, the use of FFR was associated with a lower risk of long-term mortality, ST, and restenosis in patients undergoing PCI for stable angina pectoris. This study supports the current European and American guidelines for the use of FFR during PCI and shows that intracoronary pressure wire guidance confers prognostic benefit in patients with stable angina pectoris.

3.
ESC Heart Fail ; 7(4): 1534-1546, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32424988

RESUMO

AIMS: In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. METHODS AND RESULTS: MPO, MPO-related biomarkers, and echocardiography were assessed in 86 patients, 4-8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all-cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e' was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m2 (38;52). Controls were 60 (57;62) years old (vs. patients; P < 0.001), 24% were female (P = 0.005), and left ventricular EF was 63% (59;66; P = 0.790). MPO was increased in HFpEF compared with controls, 101 (81;132) vs. 86 (74;101 ng/mL, P = 0.015), as was uric acid 369 (314;439) vs. 289 (252;328 µmol/L, P < 0.001), calprotectin, asymmetric dimethyl arginine (ADMA), and symmetric dimethyl arginine (SDMA), while arginine was decreased. MPO correlated with uric acid (r = 0.26; P = 0.016). In patients with E/e' > 14, uric acid and SDMA were elevated (421 vs. 344 µM, P = 0.012; 0.54 vs. 0.47 µM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P < 0.001) and ADMA/SDMA (1.36 vs. 1.17; P = 0.002) were decreased in HFpEF patients, suggesting reduced NO availability and increased enzymatic clearance of ADMA, respectively. Uric acid independently predicted the endpoint [hazard ratio (HR) 3.76 (95% CI 1.19-11.85; P = 0.024)] but not MPO [HR 1.48 (95% CI 0.70-3.14; P = 0.304)] or the other biomarkers. CONCLUSIONS: In HFpEF, MPO-dependent oxidative stress reflected by uric acid and calprotectin is increased, and SDMA is associated with diastolic dysfunction and uric acid with outcome. This suggests microvascular neutrophil involvement mirroring endothelial dysfunction, a central component of the HFpEF syndrome and a potential treatment target.

4.
Expert Opin Drug Saf ; 19(3): 281-294, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32064957

RESUMO

Introduction: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity. Echocardiography is the method of choice because of its widespread availability, low cost, and absence of radiation exposure. Cardiac magnetic resonance imaging can provide better reliability, reproducibility, and accuracy in the detection of drug-induced myocardial dysfunction. In addition, it enables assessment of myocardial edema, fibrosis, and necrosis. Cardiac serologic biomarkers such as troponins and B-type natriuretic peptides are used in combination with imaging during drug development. This article provides a general overview of each imaging modality and practical guidance for early detection and monitoring of cardiotoxicity.Areas covered: Cardiovascular imaging modalities and cardiac biomarkers for monitoring of cardiac function and early detection of drug-induced myocardial dysfunction in drug development.Expert opinion: Some new drugs especially in the oncology field, can cause myocardial dysfunction. Depending on the strength of pre-clinical or clinical data, CV imaging modalities and cardiac biomarkers play an important role in the early detection and mitigation plans for such drugs during their development.

5.
Heart ; 106(5): 342-349, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31911501

RESUMO

OBJECTIVE: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. We aimed to derive HFpEF phenotype-based groups ('phenogroups') based on clinical and echocardiogram data using machine learning, and to compare clinical characteristics, proteomics and outcomes across the phenogroups. METHODS: We applied model-based clustering to 32 echocardiogram and 11 clinical and laboratory variables collected in stable condition from 320 HFpEF outpatients in the Karolinska-Rennes cohort study (56% female, median 78 years (IQR: 71-83)). Baseline proteomics and the composite end point of all-cause mortality or heart failure (HF) hospitalisation were used in secondary analyses. RESULTS: We identified six phenogroups, for which significant differences in the prevalence of concomitant atrial fibrillation (AF), anaemia and kidney disease were observed (p<0.05). Fifteen out of 86 plasma proteins differed between phenogroups (false discovery rate, FDR<0.05), including biomarkers of HF, AF and kidney function. The composite end point was significantly different between phenogroups (log-rank p<0.001), at short-term (100 days), mid-term (18 months) and longer-term follow-up (1000 days). Phenogroup 2 was older, with poorer diastolic and right ventricular function and higher burden of risk factors as AF (85%), hypertension (83%) and chronic obstructive pulmonary disease (30%). In this group a third experienced the primary outcome to 100 days, and two-thirds to 18 months (HR (95% CI) versus phenogroups 1, 3, 4, 5, 6: 1.5 (0.8-2.9); 5.7 (2.6-12.8); 2.9 (1.5-5.6); 2.7 (1.6-4.6); 2.1 (1.2-3.9)). CONCLUSIONS: Using machine learning we identified distinct HFpEF phenogroups with differential characteristics and outcomes, as well as differential levels of inflammatory and cardiovascular proteins.

6.
Vasc Health Risk Manag ; 15: 375-384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31695398

RESUMO

Background: Survivors of myocardial infarction (MI) are at high risk of new major adverse cardiovascular events (MACE). Coronary flow reserve (CFR) is a strong and independent predictor of MACE. Understanding the prevalence of impaired CFR in this patient group and identifying risk markers for impaired CFR are important steps in the development of personalized and targeted treatment for high-risk individuals with prior MI. Methods: PROFLOW is a prospective, exploratory, cross-sectional open study. We used information from the SCAAR (Swedish Coronary Angiography and Angioplasty Registry) to identify high-risk patients with a history of type-1 MI. We measured CFR non-invasively in a left anterior descending artery (LAD) using transthoracic Doppler echocardiography. Coronary flow velocity was measured at rest and at maximal flow after induction of hyperemia by intravenous infusion of adenosine (140 µg/kg/min). Independent predictors of CFR were assessed with multiple linear regression. Results: We included 619 patients. The median age was 69 (IQR 65-73), and 114 (18.4%) were women. Almost one-half of the patients, 285 (46.0%) had the multi-vessel disease, and 147 (23.7%) were incompletely revascularized. The majority were on optimal standard treatment eg ASA (93.1%), statins (90.0%), ACEI/ARB (82.6%) and beta-blockers (80.8%). The majority, 547 (88.4%) had no angina pectoris, and 572 (92.2%) were in NYHA class I. Evaluation of CFR was possible in 611 (98.7%) patients. Mean CFR was 2.74 (±0.79 (mean ± SD)). A substantial number of patients (39.7%) had CFR ≤2.5. In a multiple linear regression model age, dyslipidemia, smoking, hypertension, body mass index, incomplete revascularization, and treatment with angiotensin receptor blockers were independent predictors of CFR. Conclusion: In this high-risk group of patients with prior MI, the prevalence of impaired CFR was high. Further risk stratification with CFR in addition to traditional cardiovascular risk factors may improve predictive accuracy for future MACE in this patient population.


Assuntos
Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Ecocardiografia Doppler , Reserva Fracionada de Fluxo Miocárdico , Infarto do Miocárdio/diagnóstico por imagem , Adenosina/administração & dosagem , Idoso , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/fisiopatologia , Doença da Artéria Coronariana/terapia , Vasos Coronários/fisiopatologia , Estudos Transversais , Feminino , Humanos , Hiperemia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/epidemiologia , Infarto do Miocárdio/fisiopatologia , Infarto do Miocárdio/terapia , Valor Preditivo dos Testes , Prevalência , Prognóstico , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Prevenção Secundária , Suécia/epidemiologia , Vasodilatadores/administração & dosagem
7.
Am J Physiol Endocrinol Metab ; 317(6): E1063-E1069, 2019 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-31593502

RESUMO

A high-fat diet (HFD) can rapidly recruit neutrophils to insulin target tissues and within days induce microvascular insulin resistance (IR). Myeloperoxidase (MPO) is highly enriched in neutrophils, can inhibit nitric oxide-mediated vasorelaxation in vitro and is associated with increased cardiovascular disease risk. AZD5904 irreversibly inhibits MPO and in human clinical trials. MPO knockout, or chemical inhibition, blunts HFD-induced metabolic IR in mice. Whether MPO affects microvascular IR or muscle metabolic insulin sensitivity in vivo is unknown. We used contrast-enhanced ultrasound and the euglycemic insulin clamp to test whether inhibiting MPO could prevent the development or reverse established HFD-induced metabolic and/or microvascular IR in Sprague-Dawley rats. Two weeks of HFD feeding blocked insulin-mediated skeletal muscle capillary recruitment, inhibited glucose utilization, and insulin signaling to muscle. Continuous subcutaneous AZD5904 infusion during the 2 wk selectively blocked HFD's microvascular effect. Furthermore, AZD5904 infusion during the last 2 of 4 wk of HFD feeding restored microvascular insulin sensitivity but not metabolic IR. We conclude that inhibiting MPO selectively improves vascular IR. This selective microvascular effect may connote a therapeutic potential for MPO inhibition in the prevention of vascular disease/dysfunction seen in IR humans.


Assuntos
Aorta/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Resistência à Insulina , Microvasos/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Peroxidase/antagonistas & inibidores , Animais , Aorta/metabolismo , Velocidade do Fluxo Sanguíneo/efeitos dos fármacos , Dieta Hiperlipídica , Técnica Clamp de Glucose , Masculino , Microcirculação/efeitos dos fármacos , Microvasos/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/efeitos dos fármacos , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Óxido Nítrico Sintase Tipo III/efeitos dos fármacos , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Ratos Sprague-Dawley
9.
Am J Cardiol ; 124(10): 1584-1589, 2019 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-31575425

RESUMO

Heart failure with preserved ejection fraction (HFpEF) is frequently accompanied by co-morbidities and a systemic proinflammatory state, resulting in coronary microvascular dysfunction (CMD), as well as myocardial fibrosis. The purpose of this study is to examine the relation between myocardial perfusion reserve (MPR) and diffuse myocardial fibrosis in patients with HFpEF using cardiovascular magnetic resonance. A single center study was performed in 19 patients with clinical HFpEF and 15 healthy control subjects who underwent quantitative first-pass perfusion imaging to calculate global MPR. T1 mapping was used to assess fibrosis and to calculate extracellular volume. Spiral cine displacement encoded stimulated echo was used to calculate myocardial strain. Comprehensive 2D echocardiograms with speckle tracking, cardiopulmonary exercise testing, and brain natriuretic peptide levels were also obtained. In patients with HFpEF, mean left ventricular EF was 61% ± 9% and left ventricular mass index 45 ± 12 g/m2. Compared with controls, HFpEF patients had reduced global MPR (2.29 ± 0.64 vs 3.38 ± 0.76, p = 0.002) and VO2 max (16.5 ± 6.8 vs 30.9 ± 7.7 ml/kg min, p <0.001) whereas extracellular volume (0.29 ± 0.04 vs 0.25 ± 0.04, p = 0.02), pulmonary artery systolic pressure (35.4 ± 13.7 vs 22.3 ± 5.4 mm Hg, p = 0.004), and average E/e' (15.0 ± 7.6 vs 8.6 ± 2.0, p = 0.005) were increased. Displacement encoded stimulated echo peak systolic circumferential strain (p = 0.60) as well as echocardiographic derived global longitudinal strain (p = 0.07) were similar between both groups. The prevalence of CMD, defined as global MPR <2.5, in the HFpEF group was 69%. In conclusion, HFpEF patients have a high prevalence of CMD and diffuse fibrosis. These parameters may be useful clinical end points for future therapeutic trials.


Assuntos
Cardiomiopatias/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Circulação Coronária/fisiologia , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/fisiopatologia , Imagem Cinética por Ressonância Magnética/métodos , Volume Sistólico/fisiologia , Idoso , Cardiomiopatias/epidemiologia , Cardiomiopatias/fisiopatologia , Comorbidade , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/fisiopatologia , Feminino , Fibrose/diagnóstico , Fibrose/epidemiologia , Fibrose/fisiopatologia , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/epidemiologia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Incidência , Masculino , Microcirculação/fisiologia , Pessoa de Meia-Idade , Miocárdio/patologia , Prevalência , Estados Unidos/epidemiologia , Função Ventricular Esquerda
10.
J Mol Cell Cardiol ; 137: 1-8, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31533023

RESUMO

AIMS: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. MATERIALS AND METHODS: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. RESULTS: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. CONCLUSIONS: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events.

11.
Atherosclerosis ; 287: 122-133, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31260875

RESUMO

BACKGROUND AND AIMS: Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects. METHODS: AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro. RESULTS: α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983 decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages. CONCLUSIONS: This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/-mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans.

12.
J Am Coll Cardiol ; 73(23): 2946-2957, 2019 06 18.
Artigo em Inglês | MEDLINE | ID: mdl-31196451

RESUMO

BACKGROUND: Genetic variants currently known to affect coronary artery disease (CAD) risk explain less than one-quarter of disease heritability. The heritability contribution of gene regulatory networks (GRNs) in CAD, which are modulated by both genetic and environmental factors, is unknown. OBJECTIVES: This study sought to determine the heritability contributions of single nucleotide polymorphisms affecting gene expression (eSNPs) in GRNs causally linked to CAD. METHODS: Seven vascular and metabolic tissues collected in 2 independent genetics-of-gene-expression studies of patients with CAD were used to identify eSNPs and to infer coexpression networks. To construct GRNs with causal relations to CAD, the prior information of eSNPs in the coexpression networks was used in a Bayesian algorithm. Narrow-sense CAD heritability conferred by the GRNs was calculated from individual-level genotype data from 9 European genome-wide association studies (GWAS) (13,612 cases, 13,758 control cases). RESULTS: The authors identified and replicated 28 independent GRNs active in CAD. The genetic variation in these networks contributed to 10.0% of CAD heritability beyond the 22% attributable to risk loci identified by GWAS. GRNs in the atherosclerotic arterial wall (n = 7) and subcutaneous or visceral abdominal fat (n = 9) were most strongly implicated, jointly explaining 8.2% of CAD heritability. In all, these 28 GRNs (each contributing to >0.2% of CAD heritability) comprised 24 to 841 genes, whereof 1 to 28 genes had strong regulatory effects (key disease drivers) and harbored many relevant functions previously associated with CAD. The gene activity in these 28 GRNs also displayed strong associations with genetic and phenotypic cardiometabolic disease variations both in humans and mice, indicative of their pivotal roles as mediators of gene-environmental interactions in CAD. CONCLUSIONS: GRNs capture a major portion of genetic variance and contribute to heritability beyond that of genetic loci currently known to affect CAD risk. These networks provide a framework to identify novel risk genes/pathways and study molecular interactions within and across disease-relevant tissues leading to CAD.


Assuntos
Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/genética , Redes Reguladoras de Genes/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Tecido Adiposo/patologia , Tecido Adiposo/fisiologia , Animais , Doença da Artéria Coronariana/diagnóstico , Endotélio Vascular/patologia , Endotélio Vascular/fisiologia , Feminino , Humanos , Masculino , Camundongos , Camundongos Transgênicos , Suécia/epidemiologia
13.
Database (Oxford) ; 20192019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30951143

RESUMO

Single-cell RNA sequencing is an increasingly used method to measure gene expression at the single cell level and build cell-type atlases of tissues. Hundreds of single-cell sequencing datasets have already been published. However, studies are frequently deposited as raw data, a format difficult to access for biological researchers due to the need for data processing using complex computational pipelines. We have implemented an online database, PanglaoDB, accessible through a user-friendly interface that can be used to explore published mouse and human single cell RNA sequencing studies. PanglaoDB contains pre-processed and pre-computed analyses from more than 1054 single-cell experiments covering most major single cell platforms and protocols, based on more than 4 million cells from a wide range of tissues and organs. The online interface allows users to query and explore cell types, genetic pathways and regulatory networks. In addition, we have established a community-curated cell-type marker compendium, containing more than 6000 gene-cell-type associations, as a resource for automatic annotation of cell types.


Assuntos
Bases de Dados de Ácidos Nucleicos , RNA-Seq , RNA/biossíntese , RNA/genética , Animais , Humanos , Camundongos
14.
Nat Commun ; 10(1): 871, 2019 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-30787295

RESUMO

Chemically modified mRNA is an efficient, biocompatible modality for therapeutic protein expression. We report a first-time-in-human study of this modality, aiming to evaluate safety and potential therapeutic effects. Men with type 2 diabetes mellitus (T2DM) received intradermal injections of modified mRNA encoding vascular endothelial growth factor A (VEGF-A) or buffered saline placebo (ethical obligations precluded use of a non-translatable mRNA control) at randomized sites on the forearm. The only causally treatment-related adverse events were mild injection-site reactions. Skin microdialysis revealed elevated VEGF-A protein levels at mRNA-treated sites versus placebo-treated sites from about 4-24 hours post-administration. Enhancements in basal skin blood flow at 4 hours and 7 days post-administration were detected using laser Doppler fluximetry and imaging. Intradermal VEGF-A mRNA was well tolerated and led to local functional VEGF-A protein expression and transient skin blood flow enhancement in men with T2DM. VEGF-A mRNA may have therapeutic potential for regenerative angiogenesis.


Assuntos
Diabetes Mellitus Tipo 2/terapia , Neovascularização Fisiológica/fisiologia , RNA Mensageiro/efeitos adversos , RNA Mensageiro/uso terapêutico , Pele/irrigação sanguínea , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Terapia Genética , Humanos , Injeções Intradérmicas , Masculino , Pessoa de Meia-Idade , Placebos/administração & dosagem , RNA Mensageiro/genética , Fluxo Sanguíneo Regional/genética
15.
Cardiovasc Diabetol ; 18(1): 16, 2019 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-30732594

RESUMO

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) is the first class of anti-diabetes treatment that reduces mortality and risk for hospitalization due to heart failure. In clinical studies it has been shown that SGLT2i's promote a general shift to fasting state metabolism characterized by reduced body weight and blood glucose, increase in glucagon/insulin ratio and modest increase in blood ketone levels. Therefore, we investigated the connection between metabolic changes and cardiovascular function in the ob/ob-/- mice; a rodent model of early diabetes with specific focus on coronary microvascular function. Due to leptin deficiency these mice develop metabolic syndrome/diabetes and hepatic steatosis. They also develop cardiac contractile and microvascular dysfunction and are thus a promising model for translational studies of cardiometabolic diseases. We investigated whether this mouse model responded in a human-like manner to empagliflozin treatment in terms of metabolic parameters and tested the hypothesis that it could exert direct effects on coronary microvascular function and contractile performance. METHODS: Lean, ob/ob-/- untreated and ob/ob-/- treated with SGLT2i were followed for 10 weeks. Coronary flow velocity reserve (CFVR) and fractional area change (FAC) were monitored with non-invasive Doppler ultrasound imaging. Food intake, urinary glucose excursion and glucose control via HbA1c measurements were followed throughout the study. Liver steatosis was assessed by histology and metabolic parameters determined at the end of the study. RESULTS: Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob-/- animals resulted in a switch to a more catabolic state as observed in clinical studies: blood cholesterol and HbA1c were decreased whereas glucagon/insulin ratio and ketone levels were increased. SGLT2i treatment reduced liver triglyceride, steatosis and alanine aminotransferase, an indicator for liver dysfunction. L-Arginine/ADMA ratio, a marker for endothelial function was increased. SGLT2i treatment improved both cardiac contractile function and coronary microvascular function as indicated by improvement of FAC and CFVR, respectively. CONCLUSIONS: Sodium-glucose cotransporter 2 inhibitors treatment of ob/ob-/- mice mimics major clinical findings regarding metabolism and cardiovascular improvements and is thus a useful translational model. We demonstrate that SGLT2 inhibition improves coronary microvascular function and contractile performance, two measures with strong predictive values in humans for CV outcome, alongside with the known metabolic changes in a preclinical model for prediabetes and heart failure.


Assuntos
Compostos Benzidrílicos/farmacologia , Doença da Artéria Coronariana/prevenção & controle , Circulação Coronária/efeitos dos fármacos , Angiopatias Diabéticas/prevenção & controle , Cardiomiopatias Diabéticas/prevenção & controle , Glucosídeos/farmacologia , Microcirculação/efeitos dos fármacos , Contração Miocárdica/efeitos dos fármacos , Obesidade/complicações , Estado Pré-Diabético/tratamento farmacológico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Biomarcadores/sangue , Biomarcadores/urina , Doença da Artéria Coronariana/etiologia , Doença da Artéria Coronariana/metabolismo , Doença da Artéria Coronariana/fisiopatologia , Angiopatias Diabéticas/etiologia , Angiopatias Diabéticas/metabolismo , Angiopatias Diabéticas/fisiopatologia , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/fisiopatologia , Modelos Animais de Doenças , Metabolismo Energético/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Obesidade/metabolismo , Estado Pré-Diabético/complicações , Estado Pré-Diabético/metabolismo , Transportador 2 de Glucose-Sódio/metabolismo
16.
Br J Clin Pharmacol ; 85(4): 762-770, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30618054

RESUMO

AIMS: Myeloperoxidase activity can contribute to impaired vascular endothelial function and fibrosis in chronic inflammation-related cardiovascular disease. Here, we investigated the safety, tolerability and pharmacokinetics of the myeloperoxidase inhibitor, AZD4831. METHODS: In this randomized, single-blind, placebo-controlled, phase I, first-in-human study, healthy men in five sequential cohorts were randomized 3:1 to receive a single oral dose of AZD4831 (5, 15, 45, 135 or 405 mg) or placebo, after overnight fasting. After at least 7 days' washout, one cohort additionally received AZD4831 45 mg after a high-calorie meal. RESULTS: Forty men participated in the study (eight per cohort: AZD4831, n = 6; placebo, n = 2). AZD4831 distributed rapidly into plasma, with a half-life of 38.2-50.0 hours. The area under the plasma concentration-time curve (AUC) increased proportionally with dose (AUC0-∝ slope estimate 1.060; 95% confidence interval [CI] 0.9943, 1.127). Increases in maximum plasma concentration were slightly more than dose proportional (slope estimate 1.201; 95% CI 1.071, 1.332). Food intake reduced AZD4831 absorption rate but did not substantially affect overall exposure or plasma half-life (n = 4). Serum uric acid concentrations decreased by 71.77 (95% CI 29.15, 114.39) and 84.42 (58.90, 109.94) µmol L-1 with AZD4831 135 mg and 405 mg, respectively. Maculopapular rash (moderate intensity) occurred in 4/30 participants receiving AZD4831 (13.3%). No other safety concerns were identified. CONCLUSIONS: AZD4831 was generally well tolerated, rapidly absorbed, had a long plasma half-life and lowered uric acid concentrations after single oral doses in healthy men. These findings support the further clinical development of AZD4831.


Assuntos
Inibidores Enzimáticos/administração & dosagem , Peroxidase/antagonistas & inibidores , Ácido Úrico/sangue , Administração Oral , Adulto , Área Sob a Curva , Doenças Cardiovasculares/prevenção & controle , Esquema de Medicação , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/farmacocinética , Meia-Vida , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Placebos , Método Simples-Cego , Adulto Jovem
17.
Int J Cardiol ; 281: 99-104, 2019 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-30638749

RESUMO

BACKGROUND: Takotsubo syndrome (TS) is an acute cardiac syndrome characterized by regional myocardial akinesia that is not caused by coronary artery occlusion. Exogenous as well as endogenous excess catecholamines can induce TS. The aim of this study was to explore the effects of pharmacological cardio-simulative and cardio-depressing drugs on the development of isoprenaline-induced takotsubo-like cardiac dysfunction, a rat model of TS. METHODS: We randomized 295 rats into twelve groups. The animals were randomized to pre-treatment with either a low or high dose of metoprolol, propranolol, ICI 118551 (beta2-receptor antagonists), milrinone (phosphodiesterase inhibitor), levosimendan or saline (control) before induction of TS with isoprenaline. In one additional group, high dose of milrinone was administered alone. We measured invasively blood pressure and heart rate over a period of 90 min. Cardiac function and morphology were evaluated with high-resolution echocardiography. RESULTS: Milrinone alone induced apical ballooning similar to isoprenaline. Pretreatment with propranolol and metoprolol but not with ICI 118551 attenuated takotsubo-like akinesia in a dose-dependent manner. Pretreatment with metoprolol decreased mortality. Pretreatment with levosimendan resulted in higher incidence of apical ballooning while pretreatment with milrinone did not change the degree of akinesia. CONCLUSION: The phosphodiesterase inhibitor milrinone induces takotsubo-like dysfunction in the absence of exogenous catecholamines. This finding challenges the concept that high levels of circulating catecholamines or excessive stimulation of adrenergic receptors are necessary for the development of takotsubo syndrome. Our study provides experimental evidence for the concept of avoidance of inotropes and that selective beta1-blockade may be beneficial in the treatment of TS-patients.


Assuntos
Agonistas Adrenérgicos beta/toxicidade , Antagonistas Adrenérgicos beta/administração & dosagem , Cardiotônicos/administração & dosagem , Isoproterenol/toxicidade , Cardiomiopatia de Takotsubo/induzido quimicamente , Cardiomiopatia de Takotsubo/tratamento farmacológico , Animais , Relação Dose-Resposta a Droga , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Cardiomiopatia de Takotsubo/diagnóstico por imagem , Resultado do Tratamento
18.
Clin Physiol Funct Imaging ; 39(1): 15-21, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29761608

RESUMO

Renal denervation (RDN) is a potential modality in the treatment of patients with resistant hypertension (RH) and has shown beneficial effect on a variety of cardiovascular surrogate markers. Coronary flow reserve, as assessed by transthoracic Doppler echocardiography (TDE-CFR) is impaired in patients with hypertension and is an independent predictor of cardiac morbidity. However, data on the effect of RDN on TDE-CFR are scarce. The main objective of this study was to assess the effect of RDN on TDE-CFR. Twenty-six consecutive patients with RH (9 female and 17 male; mean age 62 ± 8 years; mean number of antihypertensive drugs 4·2 ± 1·6) underwent bilateral RDN. CFR was assessed at baseline and 6 months after intervention. Mean flow velocity was measured in the left anterior descending artery by transthoracic Doppler echocardiography at baseline and during adenosine infusion (TDE-CFR). Systolic office blood pressure was reduced at follow-up (174 ± 24 versus 162 ± 27 mmHG; P = 0·01). Mean systolic ambulatory blood pressure decreased from 151 ± 21 to 147 ± 18 (P = 0·17). TDE-CFR remained unchanged 6 months after intervention (2·7 ± 0·6 versus 2·7 ± 0·7; P = 0·67). In conclusion, renal denervation was not associated with any changes in regard to coronary flow reserve at 6-month follow-up.


Assuntos
Pressão Sanguínea , Circulação Coronária , Hipertensão/cirurgia , Rim/irrigação sanguínea , Artéria Renal/inervação , Simpatectomia/métodos , Idoso , Anti-Hipertensivos/uso terapêutico , Velocidade do Fluxo Sanguíneo , Pressão Sanguínea/efeitos dos fármacos , Resistência a Medicamentos , Ecocardiografia Doppler , Feminino , Humanos , Hipertensão/diagnóstico por imagem , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Simpatectomia/efeitos adversos , Fatores de Tempo , Resultado do Tratamento
19.
J Hypertens ; 37(1): 65-72, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30063646

RESUMO

OBJECTIVES: Cardiac magnetic resonance (CMR) provides a unique approach to the characterization of hypertensive heart disease (HHD), enabling the measurement of left ventricular mass and expansion of extracellular volume (ECV). Combining plasma biomarkers with CMR could provide potential insights into the pathophysiological mechanisms in ventricular remodelling. METHODS: In this study, we estimated correlations between plasma biomarkers and CMR parameters of HHD. Patients with a history of hypertension with or without left ventricular hypertrophy (LVH) and healthy volunteers (17 hypertensive non-LVH, 13 hypertensive LVH and 11 controls) underwent CMR on a Siemens 1.5T Avanto. T1 mapping was performed before (native T1) and serially after injection of 0.15 mmol/kg gadolinium-DTPA. Mean ECV and left ventricular mass index (LVMI) were determined. Blood samples were obtained and analysed using the Olink CVD 92-plex biomarker panel. RESULTS: Individual groups were compared on the basis of 91 plasma biomarkers using partial least squares discriminant analysis (PLS-DA). ECV and LVMI were correlated with the 91 distinct plasma biomarkers via orthogonal projection to latent structures by partial least square (OPLS) analysis. A two-dimensional PLS-DA explained 49% of the differences between the three groups. OPLS analysis showed that four plasma biomarkers were significantly correlated to both ECV and LVMI, eight were significantly correlated with LVMI only and 11 were significantly correlated to ECV only. CONCLUSION: ECV and LVMI correlate differentially in plasma biomarker patterns. Top predictors of ECV consisted of well established biomarkers of systemic inflammation and metabolic function.


Assuntos
Coração/diagnóstico por imagem , Hipertensão , Hipertrofia Ventricular Esquerda , Imagem por Ressonância Magnética , Biomarcadores/sangue , Humanos , Hipertensão/sangue , Hipertensão/epidemiologia , Hipertensão/metabolismo , Hipertensão/patologia , Hipertrofia Ventricular Esquerda/diagnóstico por imagem , Hipertrofia Ventricular Esquerda/patologia , Inflamação , Miocárdio/patologia
20.
Eur Heart J ; 39(37): 3439-3450, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30165580

RESUMO

Aims: To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results: This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). Conclusions: PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.


Assuntos
Vasos Coronários/fisiopatologia , Insuficiência Cardíaca Diastólica , Microvasos/fisiopatologia , Idoso , Idoso de 80 Anos ou mais , Ecocardiografia Doppler , Feminino , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Insuficiência Cardíaca Diastólica/epidemiologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos
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