RESUMO
BACKGROUND: Data regarding clinical outcomes after optical coherence tomography (OCT)-guided percutaneous coronary intervention (PCI) as compared with angiography-guided PCI are limited. METHODS: In this prospective, randomized, single-blind trial, we randomly assigned patients with medication-treated diabetes or complex coronary-artery lesions to undergo OCT-guided PCI or angiography-guided PCI. A final blinded OCT procedure was performed in patients in the angiography group. The two primary efficacy end points were the minimum stent area after PCI as assessed with OCT and target-vessel failure at 2 years, defined as a composite of death from cardiac causes, target-vessel myocardial infarction, or ischemia-driven target-vessel revascularization. Safety was also assessed. RESULTS: The trial was conducted at 80 sites in 18 countries. A total of 2487 patients underwent randomization: 1233 patients were assigned to undergo OCT-guided PCI, and 1254 to undergo angiography-guided PCI. The minimum stent area after PCI was 5.72±2.04 mm2 in the OCT group and 5.36±1.87 mm2 in the angiography group (mean difference, 0.36 mm2; 95% confidence interval [CI], 0.21 to 0.51; P<0.001). Target-vessel failure within 2 years occurred in 88 patients in the OCT group and in 99 patients in the angiography group (Kaplan-Meier estimates, 7.4% and 8.2%, respectively; hazard ratio, 0.90; 95% CI, 0.67 to 1.19; P = 0.45). OCT-related adverse events occurred in 1 patient in the OCT group and in 2 patients in the angiography group. Stent thrombosis within 2 years occurred in 6 patients (0.5%) in the OCT group and in 17 patients (1.4%) in the angiography group. CONCLUSIONS: Among patients undergoing PCI, OCT guidance resulted in a larger minimum stent area than angiography guidance, but there was no apparent between-group difference in the percentage of patients with target-vessel failure at 2 years. (Funded by Abbott; ILUMIEN IV: OPTIMAL PCI ClinicalTrials.gov number, NCT03507777.).
Assuntos
Angiografia Coronária , Doença da Artéria Coronariana , Intervenção Coronária Percutânea , Tomografia de Coerência Óptica , Humanos , Angiografia Coronária/efeitos adversos , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/terapia , Doença da Artéria Coronariana/etiologia , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/métodos , Estudos Prospectivos , Método Simples-Cego , Tomografia de Coerência Óptica/métodos , Resultado do Tratamento , Diabetes Mellitus , Implante de Prótese Vascular/métodos , StentsRESUMO
BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).
Assuntos
Doenças Cardiovasculares , Fatores de Risco de Doenças Cardíacas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/mortalidade , Diabetes Mellitus , Fatores de Risco , Fumar/efeitos adversos , InternacionalidadeRESUMO
BACKGROUND: Chronic kidney disease represents one of the strongest risk factors for cardiovascular diseases, and particularly for heart failure. Despite improved pharmaceutical treatments, mortality remains high. Recently, experimental studies demonstrated that mosaic loss of Y chromosome (LOY) associates with cardiac fibrosis in male mice. Since diffuse cardiac fibrosis is the common denominator for progression of all forms of heart failure, we determined the association of LOY on mortality and cardiovascular disease outcomes in patients with chronic kidney disease. METHODS: LOY was quantified in men with stable chronic kidney disease (CARE for HOMe study [XXX], n=279) and dialysis patients (4D study, n=544). The association between LOY and mortality, combined cardiovascular and heart failure-specific end points, and echocardiographic measures was assessed. RESULTS: In CARE for HOMe, the frequency of LOY increased with age. LOY >17% was associated with increased mortality (heart rate, 2.58 [95% CI, 1.33-5.03]) and risk for cardiac decompensation or death (heart rate, 2.30 [95% CI, 1.23-4.27]). Patients with LOY >17% showed a significant decline of ejection fraction and an increase of E/E' within 5 years. Consistently, in the 4D study, LOY >17% was significantly associated with increased mortality (heart rate, 2.76 [95% CI, 1.83-4.16]), higher risk of death due to heart failure and sudden cardiac death (heart rate, 4.11 [95% CI, 2.09-8.08]), but not atherosclerotic events. Patients with LOY >17% showed significantly higher plasma levels of soluble interleukin 1 receptor-like 1, a biomarker for myocardial fibrosis. Mechanistically, intermediate monocytes from patients with LOY >17% showed significantly higher C-C chemokine receptor type 2 expression and higher plasma levels of the C-C chemokine receptor type 2 chemokine (C-C motif) ligand 2, which may have contributed to increased heart failure events. CONCLUSIONS: LOY identifies male patients with chronic kidney disease at high risk for mortality and heart failure events.
RESUMO
BACKGROUND: About half of patients with severe aortic stenosis present with concomitant coronary artery disease. The optimal timing of percutaneous coronary intervention (PCI) and transcatheter aortic valve implantation (TAVI) in patients with severe aortic stenosis and concomitant coronary artery disease remains unknown. STUDY DESIGN: The TAVI PCI trial is a prospective, international, multicenter, randomized, two-arm, open-label study planning to enroll a total of 986 patients. It is designed to investigate whether the strategy "angiography-guided complete revascularization after (within 1-45 days) TAVI" is non-inferior to the strategy "angiography-guided complete revascularization before (within 1-45 days) TAVI" using the Edwards SAPIEN 3 or 3 Ultra Transcatheter Heart Valve™ in patients with severe aortic stenosis and concomitant coronary artery disease. Patients are randomized in a 1:1 ratio to one of the two treatment strategies. The primary end point is a composite of all-cause death, non-fatal myocardial infarction, ischemia-driven revascularization, rehospitalization (valve- or procedure-related including heart failure), or life-threatening/disabling or major bleeding at 1 year. CONCLUSIONS: The TAVI PCI trial tests the hypothesis that the strategy "PCI after TAVI" is non-inferior to the strategy "PCI before TAVI" in patients with severe aortic stenosis and concomitant coronary artery disease.
RESUMO
BACKGROUND: Complete revascularization is associated with improved outcomes in patients with myocardial infarction and multivessel coronary artery disease. Quantitative flow ratio (QFR) represents an emerging angiography-based tool for functional lesion assessment. The present study investigated the prognostic impact of QFR-consistent complete revascularization in patients with myocardial infarction and multivessel disease. METHODS: A total of 792 patients with myocardial infarction and multivessel disease were enrolled in the analysis. Post-hoc QFR analyses of 1,320 nonculprit vessels were performed by investigators blinded to clinical outcomes. The primary endpoint was a composite of all-cause death, nonculprit vessel related nonfatal myocardial infarction, and ischemia-driven revascularization at 2 years after index myocardial infarction. Patients were stratified into a QFR-consistent PCI group (n = 646) and a QFR-inconsistent PCI group (n = 146), based on whether the intervention was congruent with the QFR-determined functional significance of the nonculprit lesions. RESULTS: The primary endpoint occurred in a total of 22 patients (3.4%) in the QFR-consistent PCI group and in 27 patients (18.5%) in the QFR-inconsistent group (HR 0.17, 95% CI 0.10-0.30, P < .001).The difference in the primary endpoint was driven by reduced rates of nonfatal myocardial infarction (2.0% vs. 15.1%; HR 0.13, 95% CI 0.06-0.25; P < .001) and ischemia-driven revascularization (1.2% vs. 5.5%; HR 0.21, 95% CI 0.08-0.57; P = .001) in the QFR-consistent PCI group. CONCLUSIONS: Among patients with myocardial infarction and multivessel disease, a QFR-consistent complete revascularization was associated with a reduced risk of all-cause mortality, nonfatal myocardial infarction, and ischemia-driven revascularization. These findings underline the value of angiography-based functional lesion assessment for personalized revascularization strategies.
RESUMO
BACKGROUND: The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). METHODS: NAPKON-HAP is a multi-centered prospective observational study with a long-term follow-up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. RESULTS: Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. CONCLUSION: NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.
Assuntos
COVID-19 , Humanos , COVID-19/epidemiologia , SARS-CoV-2 , Pandemias/prevenção & controle , Qualidade de Vida , Alemanha/epidemiologia , Estudos Observacionais como AssuntoRESUMO
AIMS: Mosaic loss of Y chromosome (LOY) in blood cells is the most common acquired mutation, increases with age, and is related to cardiovascular disease. Loss of Y chromosome induces cardiac fibrosis in murine experiments mimicking the consequences of aortic valve stenosis, the prototypical age-related disease. Cardiac fibrosis is the major determinant of mortality even after transcatheter aortic valve replacement (TAVR). It was hypothesized that LOY affects long-term outcome in men undergoing TAVR. METHODS AND RESULTS: Using digital PCR in DNA of peripheral blood cells, LOY (Y/X ratio) was assessed by targeting a 6 bp sequence difference between AMELX and AMELY genes using TaqMan. The genetic signature of monocytes lacking the Y chromosome was deciphered by scRNAseq. In 362 men with advanced aortic valve stenosis undergoing successful TAVR, LOY ranged from -4% to 83.4%, and was >10% in 48% of patients. Three-year mortality increased with LOY. Receiver operating characteristic (ROC) curve analysis revealed an optimal cut-off of LOY >17% to predict mortality. In multivariate analysis, LOY remained a significant (P < 0.001) independent predictor of death during follow-up. scRNAseq disclosed a pro-fibrotic gene signature with LOY monocytes displaying increased expression of transforming growth factor (TGF) ß-associated signaling, while expression of TGFß-inhibiting pathways was down-regulated. CONCLUSION: This is the first study to demonstrate that LOY in blood cells is associated with profoundly impaired long-term survival even after successful TAVR. Mechanistically, the pro-fibrotic gene signature sensitizing the patient-derived circulating LOY monocytes for the TGFß signaling pathways supports a prominent role of cardiac fibrosis in contributing to the effects of LOY observed in men undergoing TAVR.
Assuntos
Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Humanos , Masculino , Animais , Camundongos , Substituição da Valva Aórtica Transcateter/métodos , Cromossomos Humanos Y , Monócitos , Mosaicismo , Estenose da Valva Aórtica/genética , Estenose da Valva Aórtica/cirurgia , Fibrose , Valva Aórtica/cirurgia , Resultado do Tratamento , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: In one-third of patients with acute coronary syndrome (ACS), thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, 'plaque erosion'). Recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets. METHODS AND RESULTS: Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO-ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of the TLR2 ligand: hyaluronic acid. CONCLUSION: The current study provides first in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid. Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS.
Assuntos
Síndrome Coronariana Aguda , Placa Aterosclerótica , Trombose , Humanos , Síndrome Coronariana Aguda/complicações , Ácido Hialurônico , Receptor 2 Toll-Like , Neutrófilos , Metaloproteinase 9 da Matriz , Células Endoteliais/metabolismo , Placa Aterosclerótica/patologia , Fibrose , Trombose/complicações , Tomografia de Coerência Óptica/métodos , Angiografia CoronáriaRESUMO
AIMS: Rupture of the fibrous cap (RFC) and erosion of an intact fibrous cap (IFC) are the two predominant mechanisms causing acute coronary syndromes (ACS). It is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response. The prospective, translational OPTIcal-COherence Tomography in Acute Coronary Syndrome study programme investigates the impact of the culprit lesion phenotype on inflammatory profiles and prognosis in ACS patients. METHODS AND RESULTS: This analysis included 398 consecutive ACS patients, of which 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE+)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE+ than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1ß. Circulating plasma levels of interleukin-1ß decreased from baseline to 3 months following IFC-ACS (P < 0.001) but remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE+ (P = 0.01) but persisted high in those with MACE+. CONCLUSION: This study demonstrates a distinct inflammatory response and a lower risk of MACE+ following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis generating data for personalized anti-inflammatory therapeutic allocation to ACS patients, a strategy that merits evaluation in future clinical trials.
Assuntos
Síndrome Coronariana Aguda , Placa Aterosclerótica , Humanos , Síndrome Coronariana Aguda/terapia , Interleucina-1beta/metabolismo , Estudos Prospectivos , Interleucina-6 , Proteômica , Ruptura Espontânea/complicações , Placa Aterosclerótica/patologia , Fibrose , Tomografia de Coerência Óptica/métodos , Angiografia Coronária/métodos , Vasos Coronários/patologiaRESUMO
BACKGROUND: D-dimer testing is known to have a high sensitivity at simultaneously low specificity, resulting in nonspecific elevations in a variety of conditions. METHODS: This retrospective study sought to assess diagnostic and prognostic features of D-dimers in cancer patients referred to the emergency department for suspected pulmonary embolism (PE) and deep vein thrombosis (DVT). In total, 526 patients with a final adjudicated diagnosis of PE (n = 83) and DVT (n = 69) were enrolled, whereas 374 patients served as the comparative group, in which venous thromboembolism (VTE) has been excluded. RESULTS: For the identification of VTE, D-dimers yielded the highest positive predictive value of 96% (95% confidence interval (CI), 85-99) at concentrations of 9.9 mg/L and a negative predictive value of 100% at .6 mg/L (95% CI, 97-100). At the established rule-out cut-off level of .5 mg/L, D-dimers were found to be very sensitive (100%) at a moderate specificity of nearly 65%. Using an optimised cut-off value of 4.9 mg/L increased the specificity to 95% for the detection of life-threatening VTE at the cost of moderate sensitivities (64%). During a median follow-up of 30 months, D-dimers positively correlated with the reoccurrence of VTE (p = .0299) and mortality in both cancer patients with VTE (p < .0001) and without VTE (p = .0008). CONCLUSIONS: Although D-dimer testing in cancer patients is discouraged by current guidelines, very high concentrations above the 10-fold upper reference limit contain diagnostic and prognostic information and might be helpful in risk assessment, while low concentrations remain useful for ruling out VTE.
Assuntos
Neoplasias , Tromboembolia Venosa , Humanos , Tromboembolia Venosa/diagnóstico , Prognóstico , Estudos Retrospectivos , Produtos de Degradação da Fibrina e do Fibrinogênio , Valor Preditivo dos TestesRESUMO
BACKGROUND: Cancer is a well-known risk factor for venous thromboembolism (VTE). A combined strategy of D-dimer testing and clinical pre-test probability is usually used to exclude VTE. However, its effectiveness is diminished in cancer patients due to reduced specificity, ultimately leading to a decreased clinical utility. This review article seeks to provide a comprehensive summary of how to interpret D-dimer testing in cancer patients. METHODS: In accordance with PRISMA standards, literature pertaining to the diagnostic and prognostic significance of D-dimer testing in cancer patients was carefully chosen from reputable sources such as PubMed and the Cochrane databases. RESULTS: D-dimers have not only a diagnostic value in ruling out VTE but can also serve as an aid for rule-in if their values exceed 10-times the upper limit of normal. This threshold allows a diagnosis of VTE in cancer patients with a positive predictive value of more than 80%. Moreover, elevated D-dimers carry important prognostic information and are associated with VTE reoccurrence. A gradual increase in risk for all-cause death suggests that VTE is also an indicator of biologically more aggressive cancer types and advanced cancer stages. Considering the lack of standardization for D-dimer assays, it is essential for clinicians to carefully consider the variations in assay performance and the specific test characteristics of their institution. CONCLUSIONS: Standardizing D-dimer assays and developing modified pretest probability models specifically for cancer patients, along with adjusted cut-off values for D-dimer testing, could significantly enhance the accuracy and effectiveness of VTE diagnosis in this population.
Assuntos
Produtos de Degradação da Fibrina e do Fibrinogênio , Neoplasias , Humanos , Neoplasias/sangue , Neoplasias/complicações , Neoplasias/diagnóstico , Valor Preditivo dos Testes , Fatores de Risco , Tromboembolia Venosa/sangue , Tromboembolia Venosa/diagnóstico , Tromboembolia Venosa/prevenção & controle , Bioensaio/normas , Sensibilidade e EspecificidadeRESUMO
Randomized trials suggest benefits for fractional flow reserve (FFR)-guided vs. angiography-guided treatment strategies in well-defined and selected patient cohorts with acute coronary syndromes (ACS). The long-term prognostic value of FFR measurement in unselected all-comer ACS patients, however, remains unknown. This subanalysis of the Fractional FLOw Reserve In cardiovascular DiseAses (FLORIDA) study sought to investigate the long-term effects of FFR in the management of lesions in patients with acute coronary syndrome (ACS). FLORIDA was an observational all-comer cohort study performed in Germany, that was population-based and unselected. Patients enrolled into the anonymized InGef Research Database presenting with ACS and undergoing coronary angiography between January 2014 and December 2015 were included in the analysis. Patients were stratified into either the FFR-guided or the angiography-guided treatment arm, based on the treatment received. A matched cohort study design was used. The primary endpoint was all-cause mortality. The secondary endpoint was major adverse cardiovascular events (MACE), a composite of death, non-fatal myocardial infarction (MI), and repeat revascularization. Follow-up time was 3 years. Rates of 3-year mortality were 10.2 and 14.0% in the FFR-guided and the angiography-guided treatment arms (p = 0.04), corresponding to a 27% relative risk reduction for FFR in ACS patients. Rates of MACE were similar in both arms (47.7 vs. 51.5%, p = 0.14), including similar rates of non-fatal MI (27.7 vs. 25.4%, p = 0.47) and revascularization (9.9 vs. 12.1%, p = 0.17). In this large, all-comer observational study of ACS patients, FFR-guided revascularization was associated with a lower mortality at 3 years. This finding encourages the routine use of FFR to guide lesion revascularization in patients presenting with ACS.
Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Reserva Fracionada de Fluxo Miocárdico , Infarto do Miocárdio , Intervenção Coronária Percutânea , Humanos , Síndrome Coronariana Aguda/diagnóstico , Síndrome Coronariana Aguda/terapia , Síndrome Coronariana Aguda/complicações , Prognóstico , Estudos de Coortes , Florida , Angiografia Coronária/efeitos adversos , Intervenção Coronária Percutânea/efeitos adversos , Doença da Artéria Coronariana/terapia , Resultado do TratamentoRESUMO
AIMS: Atherosclerotic cardiovascular disease (ACVD) is a major cause of mortality and morbidity worldwide, and increased low-density lipoproteins (LDLs) play a critical role in development and progression of atherosclerosis. Here, we examined for the first time gut immunomodulatory effects of the microbiota-derived metabolite propionic acid (PA) on intestinal cholesterol metabolism. METHODS AND RESULTS: Using both human and animal model studies, we demonstrate that treatment with PA reduces blood total and LDL cholesterol levels. In apolipoprotein E-/- (Apoe-/-) mice fed a high-fat diet (HFD), PA reduced intestinal cholesterol absorption and aortic atherosclerotic lesion area. Further, PA increased regulatory T-cell numbers and interleukin (IL)-10 levels in the intestinal microenvironment, which in turn suppressed the expression of Niemann-Pick C1-like 1 (Npc1l1), a major intestinal cholesterol transporter. Blockade of IL-10 receptor signalling attenuated the PA-related reduction in total and LDL cholesterol and augmented atherosclerotic lesion severity in the HFD-fed Apoe-/- mice. To translate these preclinical findings to humans, we conducted a randomized, double-blinded, placebo-controlled human study (clinical trial no. NCT03590496). Oral supplementation with 500 mg of PA twice daily over the course of 8 weeks significantly reduced LDL [-15.9 mg/dL (-8.1%) vs. -1.6 mg/dL (-0.5%), P = 0.016], total [-19.6 mg/dL (-7.3%) vs. -5.3 mg/dL (-1.7%), P = 0.014] and non-high-density lipoprotein cholesterol levels [PA vs. placebo: -18.9 mg/dL (-9.1%) vs. -0.6 mg/dL (-0.5%), P = 0.002] in subjects with elevated baseline LDL cholesterol levels. CONCLUSION: Our findings reveal a novel immune-mediated pathway linking the gut microbiota-derived metabolite PA with intestinal Npc1l1 expression and cholesterol homeostasis. The results highlight the gut immune system as a potential therapeutic target to control dyslipidaemia that may introduce a new avenue for prevention of ACVDs.
Assuntos
Aterosclerose , Propionatos , Animais , Apolipoproteínas E/metabolismo , Aterosclerose/etiologia , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Humanos , Absorção Intestinal , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Propionatos/farmacologia , Propionatos/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The current systematic review aims to provide novel insights into the distinct pathological features of acute coronary syndrome (ACS) with intact fibrous cap, also known as 'plaque erosion'. A more detailed understanding of its underlying pathomechanisms provides the basis for future personalized therapeutic approaches to ACS. RECENT FINDINGS: In the past years, a mounting proportion of evidence point towards the concept of plaque erosion being responsible for more than one-third of all cases of ACS and representing an autonomous ACS-causing entity driven by biomechanical forces, immunological alternations and systemic elevation of inflammatory mediators. First pilot studies proved a therapeutic paradigm shift from primary PCI at the ACS-causing culprit lesion to systemic therapies in patients with ACS caused by plaque erosion. SUMMARY: This review provides the current status of the broad basic and clinical studies focused to the topic of plaque erosion: a new ACS-causing pathophysiology with different pathological aspects providing appropriate implications for personalized therapies in ACS.
Assuntos
Síndrome Coronariana Aguda , Intervenção Coronária Percutânea , Placa Aterosclerótica , Síndrome Coronariana Aguda/diagnóstico , Humanos , Placa Aterosclerótica/diagnóstico , Ruptura Espontânea , Tomografia de Coerência ÓpticaRESUMO
AIMS: Acute coronary syndromes with intact fibrous cap (IFC-ACS), i.e. caused by coronary plaque erosion, account for approximately one-third of ACS. However, the underlying pathophysiological mechanisms as compared with ACS caused by plaque rupture (RFC-ACS) remain largely undefined. The prospective translational OPTICO-ACS study programme investigates for the first time the microenvironment of ACS-causing culprit lesions (CL) with intact fibrous cap by molecular high-resolution intracoronary imaging and simultaneous local immunological phenotyping. METHODS AND RESULTS: The CL of 170 consecutive ACS patients were investigated by optical coherence tomography (OCT) and simultaneous immunophenotyping by flow cytometric analysis as well as by effector molecule concentration measurements across the culprit lesion gradient (ratio local/systemic levels). Within the study cohort, IFC caused 24.6% of ACS while RFC-ACS caused 75.4% as determined and validated by two independent OCT core laboratories. The IFC-CL were characterized by lower lipid content, less calcification, a thicker overlying fibrous cap, and largely localized near a coronary bifurcation as compared with RFC-CL. The microenvironment of IFC-ACS lesions demonstrated selective enrichment in both CD4+ and CD8+ T-lymphocytes (+8.1% and +11.2%, respectively, both P < 0.05) as compared with RFC-ACS lesions. T-cell-associated extracellular circulating microvesicles (MV) were more pronounced in IFC-ACS lesions and a significantly higher amount of CD8+ T-lymphocytes was detectable in thrombi aspirated from IFC-culprit sites. Furthermore, IFC-ACS lesions showed increased levels of the T-cell effector molecules granzyme A (+22.4%), perforin (+58.8%), and granulysin (+75.4%) as compared with RFC plaques (P < 0.005). Endothelial cells subjected to culture in disturbed laminar flow conditions, i.e. to simulate coronary flow near a bifurcation, demonstrated an enhanced adhesion of CD8+T cells. Finally, both CD8+T cells and their cytotoxic effector molecules caused endothelial cell death, a key potential pathophysiological mechanism in IFC-ACS. CONCLUSIONS: The OPTICO-ACS study emphasizes a novel mechanism in the pathogenesis of IFC-ACS, favouring participation of the adaptive immune system, particularly CD4+ and CD8+ T-cells and their effector molecules. The different immune signatures identified in this study advance the understanding of coronary plaque progression and may provide a basis for future development of personalized therapeutic approaches to ACS with IFC. TRIAL REGISTRATION: The study was registered at clinicalTrials.gov (NCT03129503).
Assuntos
Síndrome Coronariana Aguda , Doença da Artéria Coronariana , Placa Aterosclerótica , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Células Endoteliais , Humanos , Placa Aterosclerótica/diagnóstico por imagem , Estudos Prospectivos , Ruptura Espontânea , Tomografia de Coerência ÓpticaRESUMO
BACKGROUND: The relevance of blood lipid concentrations to long-term incidence of cardiovascular disease and the relevance of lipid-lowering therapy for cardiovascular disease outcomes is unclear. We investigated the cardiovascular disease risk associated with the full spectrum of bloodstream non-HDL cholesterol concentrations. We also created an easy-to-use tool to estimate the long-term probabilities for a cardiovascular disease event associated with non-HDL cholesterol and modelled its risk reduction by lipid-lowering treatment. METHODS: In this risk-evaluation and risk-modelling study, we used Multinational Cardiovascular Risk Consortium data from 19 countries across Europe, Australia, and North America. Individuals without prevalent cardiovascular disease at baseline and with robust available data on cardiovascular disease outcomes were included. The primary composite endpoint of atherosclerotic cardiovascular disease was defined as the occurrence of the coronary heart disease event or ischaemic stroke. Sex-specific multivariable analyses were computed using non-HDL cholesterol categories according to the European guideline thresholds, adjusted for age, sex, cohort, and classical modifiable cardiovascular risk factors. In a derivation and validation design, we created a tool to estimate the probabilities of a cardiovascular disease event by the age of 75 years, dependent on age, sex, and risk factors, and the associated modelled risk reduction, assuming a 50% reduction of non-HDL cholesterol. FINDINGS: Of the 524â444 individuals in the 44 cohorts in the Consortium database, we identified 398â846 individuals belonging to 38 cohorts (184â055 [48·7%] women; median age 51·0 years [IQR 40·7-59·7]). 199â415 individuals were included in the derivation cohort (91â786 [48·4%] women) and 199â431 (92â269 [49·1%] women) in the validation cohort. During a maximum follow-up of 43·6 years (median 13·5 years, IQR 7·0-20·1), 54â542 cardiovascular endpoints occurred. Incidence curve analyses showed progressively higher 30-year cardiovascular disease event-rates for increasing non-HDL cholesterol categories (from 7·7% for non-HDL cholesterol <2·6 mmol/L to 33·7% for ≥5·7 mmol/L in women and from 12·8% to 43·6% in men; p<0·0001). Multivariable adjusted Cox models with non-HDL cholesterol lower than 2·6 mmol/L as reference showed an increase in the association between non-HDL cholesterol concentration and cardiovascular disease for both sexes (from hazard ratio 1·1, 95% CI 1·0-1·3 for non-HDL cholesterol 2·6 to <3·7 mmol/L to 1·9, 1·6-2·2 for ≥5·7 mmol/L in women and from 1·1, 1·0-1·3 to 2·3, 2·0-2·5 in men). The derived tool allowed the estimation of cardiovascular disease event probabilities specific for non-HDL cholesterol with high comparability between the derivation and validation cohorts as reflected by smooth calibration curves analyses and a root mean square error lower than 1% for the estimated probabilities of cardiovascular disease. A 50% reduction of non-HDL cholesterol concentrations was associated with reduced risk of a cardiovascular disease event by the age of 75 years, and this risk reduction was greater the earlier cholesterol concentrations were reduced. INTERPRETATION: Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. We provide a simple tool for individual long-term risk assessment and the potential benefit of early lipid-lowering intervention. These data could be useful for physician-patient communication about primary prevention strategies. FUNDING: EU Framework Programme, UK Medical Research Council, and German Centre for Cardiovascular Research.
Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/epidemiologia , LDL-Colesterol/sangue , Medição de Risco/métodos , Adulto , Idoso , Austrália/epidemiologia , Europa (Continente)/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Estados Unidos/epidemiologiaRESUMO
Targeted quantitative mass spectrometry metabolite profiling is the workhorse of metabolomics research. Robust and reproducible data are essential for confidence in analytical results and are particularly important with large-scale studies. Commercial kits are now available which use carefully calibrated and validated internal and external standards to provide such reliability. However, they are still subject to processing and technical errors in their use and should be subject to a laboratory's routine quality assurance and quality control measures to maintain confidence in the results. We discuss important systematic and random measurement errors when using these kits and suggest measures to detect and quantify them. We demonstrate how wider analysis of the entire data set alongside standard analyses of quality control samples can be used to identify outliers and quantify systematic trends to improve downstream analysis. Finally, we present the MeTaQuaC software which implements the above concepts and methods for Biocrates kits and other target data sets and creates a comprehensive quality control report containing rich visualization and informative scores and summary statistics. Preliminary unsupervised multivariate analysis methods are also included to provide rapid insight into study variables and groups. MeTaQuaC is provided as an open source R package under a permissive MIT license and includes detailed user documentation.
Assuntos
Espectrometria de Massas/métodos , Metabolômica/métodos , Metabolômica/normas , Controle de Qualidade , SoftwareRESUMO
BACKGROUND: Quantitative flow ratio (QFR) has recently been introduced as a novel, less-invasive, adenosine-free measure for functional coronary lesion assessment. Whether reference vessel dimensions affect functional lesion assessment is uncertain. METHODS: A total of 436 patients with 516 interrogated coronary vessels by means of FFR were included in the study. Patients were dichotomized according to the median reference vessel diameter (group 1: ≤2.8 mm and group 2: >2.8 mm). QFR analyses were performed offline at the institution's core laboratories. RESULTS: Reference vessel diameter was 2.5 [2.3-2.7] mm in group 1 and 3.3 [3.0-3.6] mm in group 2. Diameter stenosis (41.4 [36.4-47.6] % vs. 41.4 [36.4-45.7] %, p = .20) did not differ among groups. Median FFR values were lower in group 1 (0.87 [0.81-0.92]) as compared with group 2 (0.89 [0.84-0.93], p = .001). Consistently, QFR values were lower in group 1 (0.88 [0.82-0.92]) than in group 2 (0.91 [0.85-0.94], p = .001). The proportions of functionally significant coronary lesions as defined by FFR ≤0.80 were 24.1% and 14.2% in groups 1 and 2 (p = .005), and as defined by cQFR ≤0.80 20.4% and 11.8% (p = 0.009), respectively. In ROC analysis for an FFR ≤.80, the AUC was 0.89 (95% CI 0.85-0.93, p < .001) in group 1 and 0.81 (95% CI 0.76-0.86, p < .001) in group 2. CONCLUSIONS: These results suggest that QFR measurements are accurate irrespective of the reference vessel diameter. Future studies are needed to elucidate the higher percentage of functionally significant lesions observed in small vessels despite a similar angiographic lesion severity.
Assuntos
Cateterismo Cardíaco , Angiografia Coronária , Doença da Artéria Coronariana/diagnóstico por imagem , Vasos Coronários/diagnóstico por imagem , Reserva Fracionada de Fluxo Miocárdico , Idoso , Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/fisiopatologia , Vasos Coronários/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Reprodutibilidade dos TestesRESUMO
OBJECTIVES: We sought to compare the procedural and clinical performance of dual- versus single-catheter strategy for transradial coronary angiography. BACKGROUND: The radial artery (RA) is recommended as the vascular access of choice in patients undergoing coronary angiography and intervention. The procedural and clinical performance of dual- versus single-catheter strategy in patients undergoing transradial coronary angiography remains a matter of debate. METHODS: This is a study-level meta-analysis of randomized trials. The primary outcome was procedure time. The main secondary outcome was fluoroscopy time. Other outcomes of interest were contrast volume, crossover to other catheter strategy and RA spasm. RESULTS: A total of 2,062 patients (978 randomly assigned to dual-catheter and 1,084 to single-catheter strategy) included in seven trials were available for the quantitative synthesis. A dual-catheter strategy was associated with procedure time (standardized mean difference [95% confidence intervals (CI)], 0.55 [-0.69, 1.78]; p = .32), fluoroscopy time (-0.36 [-2.39, 1.67]; p = .68) and contrast volume (-0.93 [-3.79, 1.94]; p = .44) comparable to a single-catheter strategy. The risk for crossover was lower (risk ratio [95% CI], 0.14 [0.03, 0.70]; p = .025) while the risk for RA spasm was higher (1.81 [1.54, 2.12]; p < .001) among patients assigned to dual- versus single-catheter strategy. CONCLUSIONS: This meta-analysis provides evidence for a comparable procedural performance of either dual- or single-catheter strategy for transradial coronary angiography. The fewer crossovers with dual-catheter strategy occur at the expense of more frequent radial artery spasm.
Assuntos
Cateterismo Cardíaco , Cateterismo Periférico , Angiografia Coronária , Artéria Radial , Idoso , Arteriopatias Oclusivas/etiologia , Arteriopatias Oclusivas/fisiopatologia , Cateterismo Cardíaco/efeitos adversos , Cateterismo Cardíaco/instrumentação , Cateteres Cardíacos , Cateterismo Periférico/efeitos adversos , Cateterismo Periférico/instrumentação , Angiografia Coronária/efeitos adversos , Angiografia Coronária/instrumentação , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Punções , Artéria Radial/lesões , Artéria Radial/fisiopatologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Fatores de Tempo , Lesões do Sistema Vascular/etiologia , Lesões do Sistema Vascular/fisiopatologia , VasoconstriçãoRESUMO
OBJECTIVES: This study sought to investigate the relation between left ventricular end-diastolic pressure (LVEDP) and outcomes in patients undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS). BACKGROUND: Risk stratification in ACS patients is important. Data on the role of LVEDP in the prognostication of ACS patients are scarce. METHODS: A total of 1,410 patients undergoing PCI for ACS and with available data on LVEDP were divided according to LVEDP tertiles (lowest tertile: ≤13 mmHg, intermediate tertile: 14-20 mmHg, and highest tertile: >20 mmHg). The primary endpoint was all-cause mortality at a median follow-up of 246 [28-848] days. RESULTS: Median LVEDP was 16 (11-22) mmHg. All-cause mortality was 2.8%, 4.5%, and 15.0% in the lowest, the intermediate, and the highest LVEDP tertile groups (p < .001), respectively. Belonging to the highest LVEDP tertile was associated with an increased risk of all-cause mortality (adjusted hazard ratio [HR] = 2.66, 95% confidence interval [CI] [1.30, 5.47], p = .008). By receiver operating characteristic curve analysis, the optimal cut-off value for predicting all-cause mortality was 20 mmHg (sensitivity 68.3%, specificity 72.5%). There was no differential effect of LVEDP on mortality in patients with and without LV dysfunction (interaction p = .23) or ST-elevation myocardial infarction as index ACS event (interaction p = .86). CONCLUSIONS: In patients undergoing PCI for ACS, LVEDP was independently related with mortality. Hence, LVEDP should be incorporated into early risk stratification and clinical decision making of ACS patients.