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BACKGROUND: The initial derivation of cardiac power output (CPO) included the difference between mean arterial pressure (MAP) and right atrial pressure (RAP) in the numerator, before multiplying by cardiac output (CO). We hypothesized that the inclusion of RAP (CPO-RAP) would enhance the prognostic performance of this parameter in those with an elevated RAP. METHODS AND RESULTS: We obtained patient-level data from the ESCAPE trial via the Biolincc database. Participants with full final hemodynamics were included in the analysis. The CPO-RAP was calculated as [(MAP - RAP)â¯×â¯CO)]/451 Watts (W), and the CPO was calculated as (MAPâ¯×â¯CO)/451. The primary outcome was freedom from left ventricular assist device, heart transplant, or death at 6 months. Included participants (nâ¯=â¯157) were a median of 58 years of age (interquartile range [IQR] 49-67 years), 27% were women, and 59% had ischemic cardiomyopathy. The median CPO was 0.70 W (IQR 0.50-0.90 W), and the median CPO-RAP was 0.62 W (IQR 0.47-0.79 W). In univariable logistic regressions, the CPO was not associated with the primary outcome (odds ratio 0.32, 95% confidence interval 0.08-1.29, Pâ¯=â¯.11), but the CPO-RAP was (odds ratio 0.10, 95% confidence interval 0.02-0.54, P < .01). In Kaplan-Meier analyses, there were no significant difference in outcomes with CPO (76% vs 64%, Pâ¯=â¯.08), but for CPO-RAP, there were significant differences in outcomes (81% vs 63%, Pâ¯=â¯.01). When further delineating CPO-RAP by RAP above or below the median, there was no significant difference in the outcome for participants with a RAP 8 or less (94% vs 79%, Pâ¯=â¯.07), but a significant difference in participants with a RAP of more than 8 mm Hg (66% vs 45%, P < .05). CONCLUSIONS: The inclusion of RAP resulted in a significant association with the primary outcome; CPO alone was not.
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Insuficiência Cardíaca , Coração Auxiliar , Idoso , Pressão Atrial , Débito Cardíaco , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Atherosclerosis is the predominant cause of coronary artery disease. The last several decades have witnessed significant advances in lipid-lowering therapies, which comprise a central component of atherosclerotic cardiovascular disease prevention. In addition to cardiovascular risk reduction with dyslipidemia management, some lipid-based therapies show promise at the level of the atherosclerotic plaque itself through mechanisms governing lipid accumulation, plaque stability, local inflammation, endothelial dysfunction, and thrombogenicity. The capacity of lipid-lowering therapies to modify atherosclerotic plaque burden, size, composition, and vulnerability should correlate with their ability to reduce disease progression. This review discusses plaque characteristics, diagnostic modalities to evaluate these characteristics, and how they are altered by current and emerging lipid-lowering therapies, all in human coronary artery disease.
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AIMS: The TOPCAT trial showed no benefit for spironolactone in heart failure patients with preserved ejection fraction (HFpEF). Post-hoc, spironolactone helped participants from the Americas, but not Eastern Europe. Determining which patients with HFpEF could respond like TOPCAT's responders should help guide their care. We aimed to develop a TOPCAT Trial Score (TS) as a composite metric to identify such patients. METHODS AND RESULTS: From the TOPCAT individual-level data, we calculated a TS of age, body mass index, systolic blood pressure, heart rate, creatinine, potassium, glucose, left ventricular ejection fraction, and left atrial volume for each participant as a weighted distance in multidimensional space from the theoretical perfectly average Americas participant. Logistic regression was used to measure TS and spironolactone as predictors of TOPCAT's primary outcome. The relationship between TS and the H2 FPEF score was also determined in TOPCAT and a registry cohort of real-world patients in the U.S. with HFpEF. A bimodal distribution of TS separated American (n = 1766) and Eastern European (n = 1,677) participants. Those with lower TS showed no significant response to spironolactone. Spironolactone's benefit rose with rising TS [ßinteraction = -0.28 (P < 0.01)]. Significantly more American participants had benefit from spironolactone based on higher TS (> 1.14), in addition to higher likelihood of HFpEF based on higher H2 FPEF scores (≥3). The cohort of real-world patients with HFpEF had even higher TS than American TOPCAT participants. CONCLUSIONS: Patients with HFpEF can be quantified by the TS to capture the likelihood of benefit from spironolactone.
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Insuficiência Cardíaca , Espironolactona , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Antagonistas de Receptores de Mineralocorticoides , Volume Sistólico , Resultado do Tratamento , Função Ventricular EsquerdaRESUMO
OBJECTIVE: To rapidly exclude severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection using artificial intelligence applied to the electrocardiogram (ECG). METHODS: A global, volunteer consortium from 4 continents identified patients with ECGs obtained around the time of polymerase chain reaction-confirmed COVID-19 diagnosis and age- and sex-matched controls from the same sites. Clinical characteristics, polymerase chain reaction results, and raw electrocardiographic data were collected. A convolutional neural network was trained using 26,153 ECGs (33.2% COVID positive), validated with 3826 ECGs (33.3% positive), and tested on 7870 ECGs not included in other sets (32.7% positive). Performance under different prevalence values was tested by adding control ECGs from a single high-volume site. RESULTS: The area under the curve for detection of acute COVID-19 infection in the test group was 0.767 (95% CI, 0.756 to 0.778; sensitivity, 98%; specificity, 10%; positive predictive value, 37%; negative predictive value, 91%). To more accurately reflect a real-world population, 50,905 normal controls were added to adjust the COVID prevalence to approximately 5% (2657/58,555), resulting in an area under the curve of 0.780 (95% CI, 0.771 to 0.790) with a specificity of 12.1% and a negative predictive value of 99.2%. CONCLUSION: Infection with SARS-CoV-2 results in electrocardiographic changes that permit the artificial intelligence-enhanced ECG to be used as a rapid screening test with a high negative predictive value (99.2%). This may permit the development of electrocardiography-based tools to rapidly screen individuals for pandemic control.
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Inteligência Artificial , COVID-19/diagnóstico , Eletrocardiografia , Estudos de Casos e Controles , Humanos , Valor Preditivo dos Testes , Sensibilidade e EspecificidadeRESUMO
BACKGROUND: Tetralogy of Fallot is a congenital heart defect diagnosed in infancy. Assessment of right ventricular size and function is important for evaluation of patients with tetralogy of Fallot, but these quantitative measures are challenging by echocardiography. This study evaluates a semi-automated software (EchoInsight®, Epsilon Imaging) by comparing its measures to manual measures in children with tetralogy of Fallot. METHODS: Echocardiographic measurements were performed using manual techniques and semi-automated software. Right ventricular measurements included end-diastolic and end-systolic area, fractional area change, chamber dimensions, and tricuspid annular plane systolic excursion. Reliability, correlation, and agreement between manual and semi-automated measures were assessed. RESULTS: Echocardiograms for 46 patients were analysed. Intra- and inter-observer reliabilities for semi-automated measures were good with intraclass correlation coefficients all over 0.95 and 0.85, respectively. There was high correlation between manual and semi-automated methods for areas and dimensions (r = 0.91-0.98). Tricuspid annular plane systolic excursion measures and fractional area change also correlated, albeit less strongly. The semi-automated measurements of end-systolic and end-diastolic area were a 20 and 47% higher than manual methods, respectively.The semi-automated method yielded a relative 52% lower fractional area change compared to the manual method. CONCLUSIONS: The semi-automated software generates quantitative right ventricular measures in children with tetralogy of Fallot with good reliability and good correlation with manual methods for all measures, but with significant difference between manual and semi-automated techniques for area and functional measures. The specific right ventricular geometry in tetralogy of Fallot children may be why, compared to normal anatomy, greater differences were observed between the two techniques.
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Tetralogia de Fallot , Disfunção Ventricular Direita , Criança , Diástole , Ecocardiografia , Ventrículos do Coração/diagnóstico por imagem , Humanos , Reprodutibilidade dos Testes , Tetralogia de Fallot/diagnóstico por imagem , Disfunção Ventricular Direita/diagnóstico por imagem , Função Ventricular DireitaRESUMO
AIMS: Aortic pulsatility index (API), calculated as (systolic-diastolic blood pressure)/pulmonary capillary wedge pressure (PCWP), is a novel haemodynamic measurement representing both cardiac filling pressures and contractility. We hypothesized that API would better predict clinical outcomes than traditional haemodynamic metrics of cardiac function. METHODS AND RESULTS: The Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial individual-level data were used. Routine haemodynamic measurements, including Fick cardiac index (CI), and the advanced haemodynamic metrics of API, cardiac power output (CPO), and pulmonary artery pulsatility index (PAPI) were calculated after final haemodynamic-monitored optimization. The primary outcome was a composite endpoint of death or need for orthotopic heart transplant (OHT) or left ventricular assist device (LVAD) at 6 months. A total of 433 participants were enrolled in the ESCAPE trial of which 145 had final haemodynamic data. Final API measurements predicted the primary outcome, OR 0.47 (95% CI 0.32-0.70, P < 0.001), while CI, CPO, and PAPI did not. Receiver operator characteristic analyses of final advanced haemodynamic measurements indicated API best predicted the primary outcome with a cutoff of 2.9 (sensitivity 76.2%, specificity 55.3%, correctly classified 61.4%, area-under-the-curve 0.71), compared with CPO, CI, and PAPI. Kaplan-Meier analyses indicated API ≥ 2.9 was associated with greater freedom from the primary outcome (83.5%), compared with API < 2.9 (58.4%), P = 0.001. While PAPI was also significantly associated, CI and CPO were not. CONCLUSIONS: The novel haemodynamic measurement API better predicted clinical outcomes in the ESCAPE trial when compared with traditional invasive haemodynamic metrics of cardiac function.
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Insuficiência Cardíaca , Coração Auxiliar , Cateterismo de Swan-Ganz , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/terapia , Humanos , Artéria Pulmonar/diagnóstico por imagem , Pressão Propulsora PulmonarRESUMO
BACKGROUND: Chronic activation of the innate immune system drives inflammation and contributes directly to atherosclerosis. We previously showed that macrophages in the atherogenic plaque undergo RIPK3 (receptor-interacting serine/threonine-protein kinase 3)-MLKL (mixed lineage kinase domain-like protein)-dependent programmed necroptosis in response to sterile ligands such as oxidized low-density lipoprotein and damage-associated molecular patterns and that necroptosis is active in advanced atherosclerotic plaques. Upstream of the RIPK3-MLKL necroptotic machinery lies RIPK1 (receptor-interacting serine/threonine-protein kinase 1), which acts as a master switch that controls whether the cell undergoes NF-κB (nuclear factor κ-light-chain-enhancer of activated B cells)-dependent inflammation, caspase-dependent apoptosis, or necroptosis in response to extracellular stimuli. We therefore set out to investigate the role of RIPK1 in the development of atherosclerosis, which is driven largely by NF-κB-dependent inflammation at early stages. We hypothesize that, unlike RIPK3 and MLKL, RIPK1 primarily drives NF-κB-dependent inflammation in early atherogenic lesions, and knocking down RIPK1 will reduce inflammatory cell activation and protect against the progression of atherosclerosis. METHODS: We examined expression of RIPK1 protein and mRNA in both human and mouse atherosclerotic lesions, and used loss-of-function approaches in vitro in macrophages and endothelial cells to measure inflammatory responses. We administered weekly injections of RIPK1 antisense oligonucleotides to Apoe-/- mice fed a cholesterol-rich (Western) diet for 8 weeks. RESULTS: We find that RIPK1 expression is abundant in early-stage atherosclerotic lesions in both humans and mice. Treatment with RIPK1 antisense oligonucleotides led to a reduction in aortic sinus and en face lesion areas (47.2% or 58.8% decrease relative to control, P<0.01) and plasma inflammatory cytokines (IL-1α [interleukin 1α], IL-17A [interleukin 17A], P<0.05) in comparison with controls. RIPK1 knockdown in macrophages decreased inflammatory genes (NF-κB, TNFα [tumor necrosis factor α], IL-1α) and in vivo lipopolysaccharide- and atherogenic diet-induced NF-κB activation. In endothelial cells, knockdown of RIPK1 prevented NF-κB translocation to the nucleus in response to TNFα, where accordingly there was a reduction in gene expression of IL1B, E-selectin, and monocyte attachment. CONCLUSIONS: We identify RIPK1 as a central driver of inflammation in atherosclerosis by its ability to activate the NF-κB pathway and promote inflammatory cytokine release. Given the high levels of RIPK1 expression in human atherosclerotic lesions, our study suggests RIPK1 as a future therapeutic target to reduce residual inflammation in patients at high risk of coronary artery disease.
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Aterosclerose/metabolismo , Inativação Gênica/fisiologia , Mediadores da Inflamação/metabolismo , NF-kappa B/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/biossíntese , Animais , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol na Dieta/administração & dosagem , Colesterol na Dieta/efeitos adversos , Feminino , Expressão Gênica , Células Endoteliais da Veia Umbilical Humana , Humanos , Inflamação/genética , Inflamação/metabolismo , Inflamação/patologia , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/antagonistas & inibidores , NF-kappa B/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/genéticaRESUMO
BACKGROUND: The role of donor-derived cell-free DNA (dd-cfDNA) in screening for cardiac allograft vasculopathy (CAV) is unknown. We hypothesized that dd-cfDNA correlates with CAV, markers of inflammation, and angiogenesis in stable heart transplant (HT) recipients. METHODS: Sixty-five HT recipients ≥2 years post-transplant, without recent rejection, were stratified by high (≥0.12%) versus low levels (<0.12%) of dd-cfDNA. A targeted amplification, next-generation sequencing assay (AlloSure® ; CareDx, Inc.) was used to detect dd-cfDNA. Peripheral blood inflammatory and angiogenesis markers were assessed using a multiplex immunoassay system (Bioplex® ). RESULTS: Of 65 patients, 58 patients had a known CAV status and were included. Thirty had high levels of dd-cfDNA (≥0.12%), and 28 had low levels (<0.12%). CAV was present in 63% of patients with high dd-cfDNA vs. 35% with low dd-cfDNA (p = .047). Donor-specific antibodies were present in 25% of patients with high dd-cfDNA vs. 3.8% in those with low dd-cfDNA (p = .03). There were no differences in rejection episodes, inflammatory, or angiogenesis markers. Importantly, dd-cfDNA levels were not different when stratified by time post-transplant. CONCLUSIONS: Higher dd-cfDNA levels were associated with CAV in stable chronic HT recipients. Further studies are warranted to investigate a possible association between dd-cfDNA levels and CAV severity and whether dd-cfDNA can predict CAV progression.
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Ácidos Nucleicos Livres , Transplante de Coração , Transplante de Rim , Aloenxertos , Rejeição de Enxerto/diagnóstico , Rejeição de Enxerto/etiologia , Transplante de Coração/efeitos adversos , Humanos , Doadores de TecidosRESUMO
BACKGROUND: High sensitivity cardiac troponin-T (hs-TnT) has been associated with mortality in patients hospitalized with COVID-19. We aimed to determine if hs-TnT levels and their timing are independent predictors of adverse events in these patients. DESIGN: Retrospective chart review was performed for all patients hospitalized at our institution between 23 March 2020 and 13 April 2020 who were found to be COVID-19-positive. Clinical, demographic, and laboratory variables including initial and peak hs-TnT were recorded. Univariable and multivariable analyses were completed for a primary composite endpoint of in-hospital death, intubation, need for critical care, or cardiac arrest. RESULTS: In the 276 patients analysed, initial hs-TnT above the median (≥17 ng/L) was associated with increased length of stay, need for vasoactive medications, and death, along with the composite endpoint (OR 3.92, p < 0.001). Multivariable analysis demonstrated that elevated initial hs-TnT was independently associated with the primary endpoint (OR 2.92, p = 0.01). Late-peaking hs-TnT (OR 2.19 for each additional day until peak, p < 0.001) was also independently associated with the composite endpoint. CONCLUSIONS: In patients hospitalized with COVID-19, hs-TnT identifies patients at high risk for adverse in-hospital events, and trends of hs-TnT over time, particularly during the first day, provide additional prognostic information.
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Biomarcadores/sangue , COVID-19/sangue , Troponina T/sangue , Idoso , Idoso de 80 Anos ou mais , COVID-19/epidemiologia , COVID-19/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Valor Preditivo dos Testes , Prognóstico , Estudos Retrospectivos , Medição de Risco/métodos , Medição de Risco/estatística & dados numéricos , Fatores de Risco , SARS-CoV-2/fisiologia , Sensibilidade e EspecificidadeRESUMO
NEW FINDINGS: What is the central question of this study? Are circulating monocyte markers correlated with their derived macrophage polarization patterns and coronary artery disease severity? What is the main finding and its importance? There was an inverse relationship between circulating CD16+ monocytes (high) and M2 macrophages (low) that marked coronary disease severity, and the differences in polarization of macrophages were seen despite a week of cell culture ex vivo. This study highlights the importance, and potential prognostic implications, of circulating monocyte and descendant macrophage phenotypes in coronary artery disease. ABSTRACT: Monocytes and macrophages are central to atherosclerosis, but how they combine to mark progression of human coronary artery disease (CAD) is unclear. We tested whether patients' monocyte subtypes paired with their derived macrophage profiles were correlated with extent of CAD. Peripheral blood was collected from 40 patients undergoing cardiac catheterization, and patients were categorized as having no significant CAD, single vessel disease or multivessel disease according to the number of affected coronary arteries. Mononuclear cells were measured for the monocyte markers CD14 and CD16 by flow cytometry, and separate monocytes were cultured into macrophages over 7 days and measured for the polarization markers CD86 and CD206. At baseline, patients with a greater CAD burden were older, with higher rates of statin, ß-blocker and antiplatelet drug use, whereas other characteristics were similar across the spectrum of coronary disease. CD16+ (both intermediate and non-classical) monocytes were elevated in patients with single vessel and multivessel disease compared with those without significant CAD (P < 0.05), whereas regulatory M2 macrophages (CD206+ ) were decreased in patients with single vessel and multivessel disease (P < 0.001). An inverse relationship between paired CD16+ monocytes and M2 macrophages marked CAD severity. On multivariable linear regression, CAD severity was associated, along with age and traditional cardiovascular risk factors, with CD16+ monocytes (directly) and M2 macrophages (inversely). Circulating monocytes may influence downstream polarization of lesional macrophages, and these measures of monocyte and macrophage subtypes hold potential as biomarkers in CAD.
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Biomarcadores/metabolismo , Doença da Artéria Coronariana/metabolismo , Macrófagos/metabolismo , Monócitos/metabolismo , Idoso , Antígenos CD/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: Evaluating the applicability of a clinical trial to a specific patient is difficult. A novel framework, the Trial Score, was created to quantify the generalizability of a trial's result based on participants' baseline characteristics and not on the trial's inclusion and exclusion criteria. METHODS: For each Systolic Blood Pressure Intervention Trial (SPRINT) participant, the Euclidean distance in six-dimensional space from the theoretical "average" participant was calculated to produce an individual Trial Score that incorporates multiple distinct continuous-variable baseline characteristics. We prospectively defined the "data-rich," "data-limited," and "data-free" zones as Trial Scores < 90th percentile, the 90th-97.5th percentile, and >97.5th percentile, respectively. Trial Scores were then calculated for National Health and Nutrition Examination Survey participants to map data zones of the general population. Individual participant data from the Action to Control Cardiovascular Risk in Diabetes blood pressure trial (ACCORD-BP) was used to test if participants further from the average SPRINT participant behave differently than the overall SPRINT results. RESULTS: The National Health and Nutrition Examination Survey cohort and the ACCORD-BP trial demonstrate large percentages of participants in SPRINT's data-free and data-limited zones. Time-to-event rates seen with intensive and standard blood pressure control in SPRINT were the same as ACCORD-BP participants within SPRINT's data-rich zone (hazard ratio 0.97, p = 0.84 and hazard ratio 0.95, p = 0.70). However, these rates were significantly different than those of ACCORD-BP participants outside SPRINT's data-rich zone (hazard ratio 0.64, p < 0.01 and hazard ratio 0.77, p < 0.01). CONCLUSIONS: ACCORD-BP participants with SPRINT Trial Scores in the 90th percentile or below have similar event rates to SPRINT participants in both the intensive and standard blood pressure groups. Quantifying the difference between an individual patient and the average clinical trial participant holds promise as a tool to more precisely determine applicability of a specific trial to individual patients.
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Anti-Hipertensivos/uso terapêutico , Pressão Sanguínea/efeitos dos fármacos , Definição da Elegibilidade , Medicina Baseada em Evidências , Hipertensão/tratamento farmacológico , Seleção de Pacientes , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Fatores Etários , Idoso , Biomarcadores/sangue , Glicemia/metabolismo , Índice de Massa Corporal , Colesterol/sangue , Tomada de Decisão Clínica , Comorbidade , Creatinina/sangue , Feminino , Nível de Saúde , Humanos , Hipertensão/diagnóstico , Hipertensão/epidemiologia , Hipertensão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Inquéritos Nutricionais , Estudos Prospectivos , Fatores de Risco , Resultado do Tratamento , Estados Unidos/epidemiologiaRESUMO
Monocyte chemoattractant protein-1 (MCP-1) stimulates the migration of monocytes to inflammatory sites, leading to the progression of many diseases. Recently, we described a monocyte-targeting peptide amphiphile micelle (MCP-1 PAM) incorporated with the chemokine receptor CCR2 binding motif of MCP-1, which has a high affinity for monocytes in atherosclerotic plaques. We further report here the biomimetic components of MCP-1 PAMs and the influence of the nanoparticle upon binding to monocytes. We report that MCP-1 PAMs have enhanced secondary structure compared to the MCP-1 peptide. As a result, MCP-1 PAMs displayed improved binding and chemoattractant properties to monocytes, which upregulated the inflammatory signaling pathways responsible for monocyte migration. Interestingly, when MCP-1 PAMs were incubated in the presence of prostate cancer cells in vitro, the particle displayed anticancer efficacy by reducing CCR2 expression. Given that monocytes play an important role in tumor cell migration and invasion, our results demonstrate that PAMs can improve the native biofunctional properties of the peptide and may be used as an effective inhibitor to prevent chemokine-receptor interactions that promote disease progression.
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Systemic inflammation promotes cardiovascular disease. Inflammatory connective tissue diseases (CTD) like lupus and rheumatoid arthritis associate with cardiovascular risk, but it is unknown whether particular groups of patients have enhanced propensity for atherosclerotic cardiovascular disease (ASCVD) associated with their CTD. Analysis of aggregate health record data at a large U.S. academic center identified CTD and ASCVD status for 287,467 African American and white adults. ASCVD prevalence in those with CTD was 29.7% for African Americans and 14.7% for white patients with prevalence ratios, compared to those without CTD, of 3.1 and 1.8, respectively. When different types of CTD were analyzed individually (rheumatoid arthritis; lupus; scleroderma; Sjögren Syndrome; dermatomyositis/polymyositis; unspecified/mixed CTD; other inflammatory arthropathy), increased ASCVD rates were found in nearly all subsets, always with higher prevalence ratios in African Americans. The prevalence ratio of ASCVD was particularly high in young African Americans. Furthermore, individuals lacking traditional cardiovascular risk factors had more ASCVD if they had CTD (prevalence ratio 2.9). Multivariate analysis confirmed a positive interaction between CTD and African-American race and a negative interaction between CTD and age. The factors driving the observed disproportionate CTD-associated ASCVD in African Americans, young adults, and those without traditional risk factors warrant further study.
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Aterosclerose/epidemiologia , Doenças do Tecido Conjuntivo/complicações , Adolescente , Adulto , Negro ou Afro-Americano , Fatores Etários , Idoso , Aterosclerose/etnologia , Aterosclerose/etiologia , Doenças do Tecido Conjuntivo/epidemiologia , Doenças do Tecido Conjuntivo/etnologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prevalência , Fatores de Risco , Fatores Sexuais , População Branca , Adulto JovemRESUMO
Atherosclerosis is a multifactorial inflammatory disease that can progress silently for decades and result in myocardial infarction, stroke, and death. Diagnostic imaging technologies have made great strides to define the degree of atherosclerotic plaque burden through the severity of arterial stenosis. However, current technologies cannot differentiate more lethal "vulnerable plaques," and are not sensitive enough for preventive medicine. Imaging early molecular markers and quantifying the extent of disease progression continues to be a major challenge in the field. To this end, monocyte-targeting, peptide amphiphile micelles (PAMs) are engineered through the incorporation of the chemokine receptor CCR2-binding motif of monocyte chemoattractant protein-1 (MCP-1) and MCP-1 PAMs are evaluated preclinically as diagnostic tools for atherosclerosis. Monocyte-targeting is desirable as the influx of monocytes is a marker of early lesions, accumulation of monocytes is linked to atherosclerosis progression, and rupture-prone plaques have higher numbers of monocytes. MCP-1 PAMs bind to monocytes in vitro, and MCP-1 PAMs detect and discriminate between early- and late-stage atherosclerotic aortas. Moreover, MCP-1 PAMs are found to be eliminated via renal clearance and the mononuclear phagocyte system (MPS) without adverse side effects. Thus, MCP-1 PAMs are a promising new class of diagnostic agents capable of monitoring the progression of atherosclerosis.
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Aterosclerose/diagnóstico , Quimiocina CCL2/metabolismo , Monócitos/metabolismo , Sequência de Aminoácidos , Animais , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Aterosclerose/patologia , Sítios de Ligação , Quimiocina CCL2/química , Quimiocina CCL2/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Macrófagos , Camundongos Transgênicos , Micelas , Dados de Sequência Molecular , Patologia Molecular/métodos , Receptores CCR2/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/farmacocinética , Distribuição TecidualRESUMO
The organization of the plasma membrane is both highly complex and highly dynamic. One manifestation of this dynamic complexity is the lateral mobility of proteins within the plane of the membrane, which is often an important determinant of intermolecular protein-binding interactions, downstream signal transduction, and local membrane mechanics. The mode of membrane protein mobility can range from random Brownian motion to immobility and from confined or restricted motion to actively directed motion. Several methods can be used to distinguish among the various modes of protein mobility, including fluorescence recovery after photobleaching, single-particle tracking, fluorescence correlation spectroscopy, and variations of these techniques. Here, we present both a brief overview of these methods and examples of their use to elucidate the dynamics of membrane proteins in mammalian cells-first in erythrocytes, then in erythroblasts and other cells in the hematopoietic lineage, and finally in non-hematopoietic cells. This multisystem analysis shows that the cytoskeleton frequently governs modes of membrane protein motion by stably anchoring the proteins through direct-binding interactions, by restricting protein diffusion through steric interactions, or by facilitating directed protein motion. Together, these studies have begun to delineate mechanisms by which membrane protein dynamics influence signaling sequelae and membrane mechanical properties, which, in turn, govern cell function.