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1.
J Am Coll Cardiol ; 74(9): 1177-1186, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31466614

RESUMO

BACKGROUND: Patients with acute coronary syndrome (ACS) and history of coronary artery bypass grafting (CABG) are at high risk for recurrent cardiovascular events and death. OBJECTIVES: This study sought to determine the clinical benefit of adding alirocumab to statins in ACS patients with prior CABG in a pre-specified analysis of ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab). METHODS: Patients (n = 18,924) 1 to 12 months post-ACS with elevated atherogenic lipoprotein levels despite high-intensity statin therapy were randomized to alirocumab or placebo subcutaneously every 2 weeks. Median follow-up was 2.8 years. The primary composite endpoint of major adverse cardiovascular events (MACE) comprised coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. Patients were categorized by CABG status: no CABG (n = 16,896); index CABG after qualifying ACS, but before randomization (n = 1,025); or CABG before the qualifying ACS (n = 1,003). RESULTS: In each CABG category, hazard ratios (95% confidence intervals) for MACE (no CABG 0.86 [0.78 to 0.95], index CABG 0.85 [0.54 to 1.35], prior CABG 0.77 [0.61 to 0.98]) and death (0.88 [0.75 to 1.03], 0.85 [0.46 to 1.59], 0.67 [0.44 to 1.01], respectively) were consistent with the overall trial results (0.85 [0.78 to 0.93] and 0.85 [0.73 to 0.98], respectively). Absolute risk reductions (95% confidence intervals) differed across CABG categories for MACE (no CABG 1.3% [0.5% to 2.2%], index CABG 0.9% [-2.3% to 4.0%], prior CABG 6.4% [0.9% to 12.0%]) and for death (0.4% [-0.1% to 1.0%], 0.5% [-1.9% to 2.9%], and 3.6% [0.0% to 7.2%]). CONCLUSIONS: Among patients with recent ACS and elevated atherogenic lipoproteins despite intensive statin therapy, alirocumab was associated with large absolute reductions in MACE and death in those with CABG preceding the ACS event. (ODYSSEY OUTCOMES: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).

2.
Circulation ; 140(2): 103-112, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31117810

RESUMO

BACKGROUND: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. METHODS: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. RESULTS: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths ( P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events ( P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined with achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). CONCLUSIONS: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01663402.

3.
Eur Heart J ; 40(33): 2801-2809, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31121022

RESUMO

AIMS : The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin-kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. METHODS AND RESULTS : Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77-0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77-0.99; P = 0.032) and Type 2 (0.77, 0.61-0.97; P = 0.025), but not Type 4 MI. CONCLUSION : After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.

4.
J Am Coll Cardiol ; 74(9): 1167-1176, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-30898609

RESUMO

BACKGROUND: Patients with acute coronary syndrome (ACS) and concomitant noncoronary atherosclerosis have a high risk of major adverse cardiovascular events (MACEs) and death. The impact of lipid lowering by proprotein convertase subtilisin-kexin type 9 inhibition in such patients is undetermined. OBJECTIVES: This pre-specified analysis from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) determined whether polyvascular disease influenced risks of MACEs and death and their modification by alirocumab in patients with recent ACS and dyslipidemia despite intensive statin therapy. METHODS: Patients were randomized to alirocumab or placebo 1 to 12 months after ACS. The primary MACEs endpoint was the composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. All-cause death was a secondary endpoint. RESULTS: Median follow-up was 2.8 years. Of 18,924 patients, 17,370 had monovascular (coronary) disease, 1,405 had polyvascular disease in 2 beds (coronary and peripheral artery or cerebrovascular), and 149 had polyvascular disease in 3 beds (coronary, peripheral artery, cerebrovascular). With placebo, the incidence of MACEs by respective vascular categories was 10.0%, 22.2%, and 39.7%. With alirocumab, the corresponding absolute risk reduction was 1.4% (95% confidence interval [CI]: 0.6% to 2.3%), 1.9% (95% CI: -2.4% to 6.2%), and 13.0% (95% CI: -2.0% to 28.0%). With placebo, the incidence of death by respective vascular categories was 3.5%, 10.0%, and 21.8%; the absolute risk reduction with alirocumab was 0.4% (95% CI: -0.1% to 1.0%), 1.3% (95% CI: -1.8% to 4.3%), and 16.2% (95% CI: 5.5% to 26.8%). CONCLUSIONS: In patients with recent ACS and dyslipidemia despite intensive statin therapy, polyvascular disease is associated with high risks of MACEs and death. The large absolute reductions in those risks with alirocumab are a potential benefit for these patients. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]: NCT01663402).

5.
J Am Coll Cardiol ; 2018 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-30428396

RESUMO

BACKGROUND: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, added to high-intensity or maximum tolerated statin treatment, after acute coronary syndrome (ACS) in 18,924 patients. Alirocumab reduced the first occurrence of the primary composite endpoint and was associated with fewer all-cause deaths. OBJECTIVES: This pre-specified analysis determined the extent to which alirocumab reduced total (first and subsequent) nonfatal cardiovascular events and all-cause deaths in ODYSSEY OUTCOMES. METHODS: Hazard functions for total nonfatal cardiovascular events (myocardial infarction, stroke, ischemia-driven coronary revascularization, and hospitalization for unstable angina or heart failure) and death were jointly estimated, linked by a shared frailty accounting for patient risk heterogeneity and correlated within-patient nonfatal events. An association parameter also quantified the strength of the linkage between risk of nonfatal events and death. The model provides accurate relative estimates of nonfatal event risk if nonfatal events are associated with increased risk for death. RESULTS: With 3,064 first and 5,425 total events, 190 fewer first and 385 fewer total nonfatal cardiovascular events or deaths were observed with alirocumab compared with placebo. Alirocumab reduced total nonfatal cardiovascular events (hazard ratio 0.87, 95% confidence interval 0.82 to 0.93) and death (hazard ratio 0.83, 95% confidence interval 0.71 to 0.97) in the presence of a strong association between nonfatal and fatal event risk. CONCLUSIONS: In patients with ACS, the total number of nonfatal cardiovascular events and deaths prevented with alirocumab was twice the number of first events prevented. Consequently, total event reduction is a more comprehensive metric to capture the totality of alirocumab clinical efficacy after ACS.

6.
N Engl J Med ; 379(22): 2097-2107, 2018 11 29.
Artigo em Inglês | MEDLINE | ID: mdl-30403574

RESUMO

BACKGROUND: Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS: We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-high-density lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS: The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS: Among patients who had a previous acute coronary syndrome and who were receiving high-intensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo. (Funded by Sanofi and Regeneron Pharmaceuticals; ODYSSEY OUTCOMES ClinicalTrials.gov number, NCT01663402 .).

7.
J Clin Lipidol ; 11(4): 986-997, 2017 Jul - Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28693998

RESUMO

BACKGROUND: Nonadherence to cardiovascular medications, including daily, oral statin therapy, negatively impacts outcomes in patients requiring low-density lipoprotein cholesterol (LDL-C)-lowering therapy. The proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab also reduces LDL-C, but has a different mode of administration (subcutaneous injection). OBJECTIVE: The objective of the study was to assess long-term adherence to alirocumab 75 or 150 mg, given every 2 weeks, in phase III trials of patients with sub-optimally controlled hypercholesterolemia. METHODS: Data were pooled from 6 ODYSSEY trials (n = 4212) with double-blind treatment durations of 52 to 104 weeks. Adherence was reported as percentage of days receiving injections according to dosing schedule and categorized into 100% adherence, below-planned dosing, above-planned dosing, and both below- and above-planned dosing. Overall adherence was calculated as 100 - (percentage of days with below-planned dosing + percentage of days with above-planned dosing). Safety of alirocumab and effect on LDL-C levels were also evaluated. RESULTS: Adherence was analyzed for 4197 patients (n = 2786 alirocumab; n = 1411 control). Mean overall adherence was high (alirocumab 98.0%; control 97.8%). Among patients receiving alirocumab, 45.7% were 100% adherent, 20.4% had below-planned dosing, 2.9% had above-planned dosing, and 31.1% had both below- and above-planned dosing. Mean percentage reduction in LDL-C (baseline to Week 52) was 45.8% to 61.9%, depending on alirocumab dose, and was comparable across adherence categories. Treatment-emergent adverse events leading to alirocumab discontinuation were infrequent and included myalgia and injection-site reactions (<1% each). CONCLUSIONS: Alirocumab injections were associated with a high level of adherence over ≥1 year. Infrequent below- or above-planned dosing had minimal impact on LDL-C reductions.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Pró-Proteína Convertase 9/antagonistas & inibidores , Inibidores de Proteases/uso terapêutico , Cooperação e Adesão ao Tratamento/estatística & dados numéricos , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacologia , LDL-Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Inibidores de Proteases/efeitos adversos , Inibidores de Proteases/farmacologia , Segurança , Fatores de Tempo
8.
Cardiovasc Drugs Ther ; 31(4): 445-458, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28735360

RESUMO

PURPOSE: The need for novel approaches to cardiovascular drug development served as the impetus to convene an open meeting of experts from the pharmaceutical industry and academia to assess the challenges and develop solutions for drug discovery in cardiovascular disease. METHODS: The Novel Cardiovascular Therapeutics Summit first reviewed recent examples of ongoing or recently completed programs translating basic science observations to targeted drug development, highlighting successes (protein convertase sutilisin/kexin type 9 [PCSK9] and neprilysin inhibition) and targets still under evaluation (cholesteryl ester transfer protein [CETP] inhibition), with the hope of gleaning key lessons to successful drug development in the current era. Participants then reviewed the use of innovative approaches being explored to facilitate rapid and more cost-efficient evaluations of drug candidates in a short timeframe. RESULTS: We summarize observations gleaned from this summit and offer insight into future cardiovascular drug development. CONCLUSIONS: The rapid development in genetic and high-throughput drug evaluation technologies, coupled with new approaches to rapidly evaluate potential cardiovascular therapies with in vitro techniques, offer opportunities to identify new drug targets for cardiovascular disease, study new therapies with better efficiency and higher throughput in the preclinical setting, and more rapidly bring the most promising therapies to human testing. However, there must be a critical interface between industry and academia to guide the future of cardiovascular drug development. The shared interest among academic institutions and pharmaceutical companies in developing promising therapies to address unmet clinical needs for patients with cardiovascular disease underlies and guides innovation and discovery platforms that are significantly altering the landscape of cardiovascular drug development.


Assuntos
Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Desenho de Drogas , Animais , Fármacos Cardiovasculares/farmacologia , Doenças Cardiovasculares/fisiopatologia , Descoberta de Drogas/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Indústria Farmacêutica , Humanos
9.
Cytometry B Clin Cytom ; 78(5): 329-37, 2010 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-20544836

RESUMO

OBJECTIVE: Quantitative measures are needed to identify diabetic patients at higher risk for CV events. Cell-derived microparticles (MPs) are submicron membrane vesicles released from activated cells that are indicative of cell damage. Progenitor cells (PCs) including proangiogenic cells (PACs), often termed endothelial progenitor cells (EPCs), are mediators of reparative capacity. We examined whether the relationship of MPs to PCs/PACs could be used as an improved and clinically feasible index of vascular pathology. METHODS AND RESULTS: Plasma samples were collected from patients with early-stage (ES, Diagnosis < 1 year) and long-term (LT, Diagnosis > 5 years,) Type 2 diabetes and compared with age related healthy subjects (H). PC and MP subtypes were measured by a combination of flow cytometry and ELISA-based methods. The ratio of procoagulant MPs/CD34(+) PCs proved a valuable index to distinguish between subject groups (P = 0.01). This index of compromised vascular function was highest in the LT group despite intensive statin therapy and was more informative than a range of soluble protein biomarkers. CONCLUSIONS: This is the first report of a relationship between MPs and PCs in Type 2 diabetes. This ratio may provide a quantitative and clinically feasible measurement of vascular dysfunction and cardiovascular risk in patients with diabetes. © 2010 International Clinical Cytometry Society.


Assuntos
Micropartículas Derivadas de Células/patologia , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/patologia , Endotélio Vascular/patologia , Células-Tronco/patologia , Adulto , Idoso , Antígenos CD34/análise , Antígenos CD34/metabolismo , Pressão Sanguínea/efeitos dos fármacos , Micropartículas Derivadas de Células/efeitos dos fármacos , Colesterol/sangue , Estudos de Coortes , Diabetes Mellitus Tipo 2/tratamento farmacológico , Angiopatias Diabéticas/tratamento farmacológico , Endotélio Vascular/efeitos dos fármacos , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Masculino , Pessoa de Meia-Idade , Células-Tronco/efeitos dos fármacos
10.
Aging Cell ; 7(4): 599-604, 2008 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-18489728

RESUMO

Significant advances in the past decade have revealed that a large number of highly plastic stem cells are maintained in humans through adulthood and are present even in older adults. These findings are notable in light of the reduced capacity for repair and regeneration in older tissues. The apparent dichotomy can be reconciled through an appreciation of the age-associated changes in the microenvironmental pathways that govern adult stem cell plasticity and differentiation patterns. Specifically, the recent identification of the age-related loss of the local platelet-derived growth factor signals that promote the induction of cardiac myocytes from Oct-3/4+ bone marrow stem cells, rather than impairment in the stem cells themselves, provides a template for understanding and targeting the environmental pathways underlying the regenerative capacity of older tissues and organs. It is projected that this paradigm extends to the overall regulation of adult stem cell biology, shifting the balance from tissue generation during development and maturation to the prevention of untoward stem cell differentiation with aging.


Assuntos
Envelhecimento/fisiologia , Meio Ambiente , Células-Tronco/citologia , Células-Tronco Adultas/citologia , Animais , Células da Medula Óssea/citologia , Diferenciação Celular , Humanos
11.
J Mol Cell Cardiol ; 45(4): 582-92, 2008 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-18396293

RESUMO

The discovery of extracardiac progenitor cells and resident cardiac stem cells in recent years has led to a great deal of interest in the development of therapeutic strategies that target these endogenous cell sources for promotion of cardiovascular repair mechanisms in the diseased heart. Cardiovascular risk increases with age and among many factors, the age-associated decline in cardiac and vascular regenerative capacity may contribute to the progressive deterioration of cardiovascular health. Thus, understanding the mechanisms which underlie the dysregulation of cardiac stem and progenitor cells may lead to the identification of novel targets and approaches to reverse this decline. In this review, we outline the current knowledge about cardiac stem and progenitor cells, their contribution to cardiovascular regenerative processes and factors that may affect their decreased function in aging individuals. Moreover, we describe the therapeutic strategies that are currently being tested in clinical trials as well as potential new avenues of investigation for the future.


Assuntos
Envelhecimento , Doenças Cardiovasculares/terapia , Miocárdio , Transplante de Células-Tronco/métodos , Células-Tronco , Fatores Etários , Animais , Humanos , Fatores de Risco
12.
Expert Opin Ther Targets ; 11(11): 1385-99, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18028005

RESUMO

Vascular dysfunction underlies the pathophysiology of a wide range of diseases, including atherosclerosis, diabetes and arthritis. Angiogenic function is progressively impaired with increasing age and, therefore, has been linked to the increased risk of many of these diseases among older people. Elucidating the cellular and molecular angiogenic pathways that become dysregulated with age will lead to the identification of novel targets for the restoration of vascular repair mechanisms in the older population. This review examines the regulation of postnatal angiogenesis in vascular disease, the changes observed in ageing and highlights potential therapeutic targets, including endothelial progenitor cell-based strategies for the promotion of angiogenic pathways that are impaired with age.


Assuntos
Envelhecimento/fisiologia , Inibidores da Angiogênese/farmacologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Idoso , Sistemas de Liberação de Medicamentos , Endotélio Vascular/metabolismo , Humanos , Neovascularização Patológica/fisiopatologia , Fatores de Risco , Regulação para Cima , Doenças Vasculares/tratamento farmacológico , Doenças Vasculares/fisiopatologia
13.
Circ Res ; 100(8): 1116-27, 2007 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-17463327

RESUMO

It is well established that cardiovascular repair mechanisms become progressively impaired with age and that advanced age is itself a significant risk factor for cardiovascular disease. Although therapeutic developments have improved the prognosis for those with cardiovascular disease, mortality rates have nevertheless remained virtually unchanged in the last twenty years. Clearly, there is a need for alternative strategies for the treatment of cardiovascular disease. In recent years, the idea that the heart is capable of regeneration has raised the possibility that cell-based therapies may provide such an alternative to conventional treatments. Cells that have the potential to generate cardiomyocytes and vascular cells have been identified in both the adult heart and peripheral tissues, and in vivo experiments suggest that these cardiovascular stem cells and cardiovascular progenitor cells, including endothelial progenitor cells, are capable of replacing damaged myocardium and vascular tissues. Despite these findings, the endogenous actions of cardiovascular stem cells and cardiovascular progenitor cells appear to be insufficient to protect against cardiovascular disease in older individuals. Because recent evidence suggests that cardiovascular stem cells and cardiovascular progenitor cells are subject to age-associated changes that impair their function, these changes may contribute to the dysregulation of endogenous cardiovascular repair mechanisms in the aging heart and vasculature. Here we present the evidence for the impact of aging on cardiovascular stem cell/cardiovascular progenitor cell function and its potential importance in the increased severity of cardiovascular pathophysiology observed in the geriatric population.


Assuntos
Envelhecimento/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Regeneração/fisiologia , Células-Tronco/fisiologia , Envelhecimento/patologia , Animais , Doenças Cardiovasculares/patologia , Doenças Cardiovasculares/fisiopatologia , Sistema Cardiovascular/citologia , Sistema Cardiovascular/patologia , Senescência Celular/fisiologia , Humanos , Células-Tronco/citologia
14.
Circ Res ; 100(1): e1-11, 2007 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-17122441

RESUMO

The mechanisms that govern the capacity of the bone marrow stem cells to generate cardiac myocytes are still unknown. Herein we demonstrate that the cardiomyogenic potential of bone marrow-derived Oct3/4(+)/cKit(+/-)/CXCR4(+/-)/CD34(-)/Sca1(-) cells is governed by age-dependent paracrine/juxtacrine platelet-derived growth factor (PDGF) pathways. Specifically, bone marrow cell cultures from both 3- and 18-month-old mice formed aggregates of Oct3/4(+) cells circumscribed by PDGFRalpha(+)/Oct3/4(-)/Sca1(+) cells. In young (3-month) bone marrow cell cultures, induction of PDGF-AB preceded the induction of cardiac genes and was required for the generation of cardiomyogenesis. Indeed, in old (18-month) cultures, diminished PDGF-B induction was associated with impaired cardiomyogenic potential, despite having Oct3/4 levels similar to those in the young cells. Importantly, supplementation with PDGF-AB specifically restored the cardiac differentiation capacity of the old bone marrow cells. Together these results demonstrate that, regardless of age, the bone marrow niche contains Oct3/4 stem cells that are capable of differentiating into cardiac myocytes. Moreover, this differentiation is governed by age-dependent PDGF-AB-mediated paracrine/juxtacrine pathways that may be essential in the translation of bone marrow cell-mediated cardiomyogenesis.


Assuntos
Células da Medula Óssea/citologia , Diferenciação Celular/fisiologia , Senescência Celular/fisiologia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/metabolismo , Fator 3 de Transcrição de Octâmero/metabolismo , Proteínas de Transporte de Cátions Orgânicos/metabolismo , Comunicação Parácrina/fisiologia , Animais , Células da Medula Óssea/metabolismo , Agregação Celular , Células Cultivadas , Ligantes , Camundongos , Miócitos Cardíacos/fisiologia , Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/metabolismo , Transdução de Sinais/fisiologia , Esferoides Celulares/citologia , Células-Tronco/citologia
15.
Physiol Genomics ; 26(3): 202-8, 2006 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-16705020

RESUMO

Functional proteomic strategies offer unique advantages over current molecular array approaches, as the epitopes identified can directly provide bioactive peptides for investigational and/or translational applications. The vascular endothelium is well suited to proteomic assessment by in vivo phage display, but extensive enrichment and sequencing steps limit its application for high throughput molecular profiling. To overcome these limitations we developed a quantitative PCR (Q-PCR) strategy to allow the rapid quantification of in vivo phage binding. Primers were designed for distinct clones selected from a defined phage pool to probe for age-associated changes in cardiac vascular epitopes. Sensitivity and specificity of the primer sets were tested and confirmed in vitro. Q-PCR quantification of phage in vivo confirmed the preferential homing of all phage clones to the young rather than old cardiac vasculature and demonstrated a close correlation with phage measurements previously determined using traditional bacterial-based titration methods. This Q-PCR approach provides quantification of phage within hours of phage injection and may therefore be used for rapid, high throughput analysis of binding of defined phage sequences both in vivo and in vitro, complementing nonbiased phage approaches for the proteomic mapping of vascular beds and other tissues.


Assuntos
Biblioteca de Peptídeos , Reação em Cadeia da Polimerase/métodos , Proteômica/métodos , Envelhecimento , Motivos de Aminoácidos , Sequência de Aminoácidos , Animais , Vasos Coronários/metabolismo , Primers do DNA/genética , Imuno-Histoquímica , Camundongos , Dados de Sequência Molecular , Miócitos Cardíacos/metabolismo , Fragmentos de Peptídeos/análise , Fragmentos de Peptídeos/genética , Reprodutibilidade dos Testes , Homologia de Sequência de Aminoácidos
16.
Am Heart Hosp J ; 4(2): 95-7, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16687953

RESUMO

Realizing the promise of therapeutic cardiac regeneration requires the targeting of accessible cell sources to promote neomyogenesis for the injured heart. After initial trials with cardiac myocytes and skeletal muscle progenitor cells (myoblasts), the rapid advances of stem cell technology have established the feasibility of endogenous stem cells to serve as donor cells for cellular cardiomyoplasty. In particular, bone marrow-derived stem cells have a great potential for clinical application due to their extracardiac locale and capacity to give rise to functional cardiac myocytes. The recent identification of resident cardiac stem cells also offers the opportunity to regenerate the infarcted myocardium, using the cells from the heart for ex vivo expansion or as targets for in vivo induction. To this end, future advances in cellular cardiomyoplasty may likely be based on therapies stimulating the trophic/cellular interactions that direct exogenous/endogenous stem cell-mediated cardiac regeneration.


Assuntos
Coração/fisiologia , Miocárdio/citologia , Miócitos Cardíacos/transplante , Regeneração , Transplante de Células-Tronco , Animais , Doenças Cardiovasculares/cirurgia , Diferenciação Celular , Humanos , Mioblastos Cardíacos/classificação , Mioblastos Cardíacos/transplante , Engenharia Tecidual/tendências
17.
FASEB J ; 20(6): 717-9, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16461331

RESUMO

Microenvironmental cues mediate postnatal neovascularization via modulation of endothelial cell and bone marrow-derived endothelial progenitor cell (EPC) activity. Numerous signals regulate the activity of both of these cell types in response to vascular injury, which suggests that parallel mechanisms regulate angiogenesis in the vascular beds of both the heart and bone marrow. To identify mediators of such shared pathways, in vivo bone marrow/cardiac phage display biopanning was performed and led to the identification of tenascin-C as a candidate protein. Functionally, tenascin-C inhibits cardiac endothelial cell spreading and enhances migration in response to angiogenic growth factors. Analysis of human coronary thrombi revealed tenascin-C protein expression colocalized with the endothelial cell/EPC marker Tie-2 in intrathrombi vascular channels. Immunostains in the rodent heart demonstrated that tenascin-C also colocalizes with EPCs homing to sites of cardiac angiogenic induction. To determine the importance of tenascin-C in cardiac neovascularization, we used an established cardiac transplantation model and showed that unlike wild-type mice, tenascin-C-/- mice fail to vascularize cardiac allografts. This demonstrates for the first time that tenascin-C is essential for postnatal cardiac angiogenic function. Together, our data highlight the role of tenascin-C as a microenvironmental regulator of cardiac endothelial/EPC activity.


Assuntos
Vasos Coronários/crescimento & desenvolvimento , Endotélio Vascular/fisiologia , Neovascularização Fisiológica/fisiologia , Tenascina/metabolismo , Envelhecimento , Animais , Células da Medula Óssea/metabolismo , Adesão Celular , Movimento Celular , Regulação da Expressão Gênica , Humanos , Camundongos , Camundongos Knockout , Miocárdio/metabolismo , Fenótipo , Ratos , Ratos Endogâmicos F344 , Tenascina/genética , Trombose/metabolismo
18.
Physiol Genomics ; 24(3): 191-7, 2006 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-16352696

RESUMO

Aging is associated with shifts in autocrine and paracrine pathways in the cardiac vasculature that may contribute to the risk of cardiovascular disease in older persons. To elucidate the molecular basis of these changes in vivo, phage-display biopanning of 3- and 18-mo-old mouse hearts was performed that identified peptide epitopes with homology to brain-derived neurotrophic factor (BDNF) in old but not young phage pools. Quantification of cardiac phage binding by titration and immunostaining after injection with BDNF-like phage identified a twofold increased density of the BDNF receptor, truncated Trk B, in the aging hearts. Studies focused on the receptor ligand using a rat model of transient myocardial ischemia revealed increases in cardiac BDNF associated with local mononuclear infiltrates in 24- but not 4-mo-old rats. To investigate these changes, both 4- and 24-mo-old rat hearts were treated with intramyocardial injections of BDNF (or PBS control), demonstrating significant inflammatory increases with activated macrophage (ED1+) in BDNF-treated aging hearts compared with aging controls and similarly treated young hearts. Additional studies with permanent coronary occlusion following intramyocardial growth factor pretreatment revealed that BDNF significantly increased the extent of myocardial injury in older rat hearts (BDNF 35 +/- 10% vs. PBS 16.2 +/- 7.9% left ventricular injury; P < 0.05) without affecting younger hearts (BDNF 15 +/- 5.1% vs. PBS 14.5 +/- 6.0% left ventricular injury). Overall, these studies suggest that age-associated changes in BDNF-Trk B pathways may predispose the aging heart to increased injury after acute myocardial infarction and potentially contribute to the enhanced severity of cardiovascular disease in older individuals.


Assuntos
Envelhecimento/metabolismo , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Inflamação/metabolismo , Miocárdio/metabolismo , Animais , Feminino , Camundongos , Infarto do Miocárdio/metabolismo , Miocárdio/enzimologia , Biblioteca de Peptídeos , Ratos , Receptor beta de Fator de Crescimento Derivado de Plaquetas/metabolismo , Receptor trkB/metabolismo , Receptores do Fator de Necrose Tumoral/metabolismo
19.
Am J Physiol Heart Circ Physiol ; 290(4): H1387-92, 2006 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-16339836

RESUMO

Diabetes mellitus is associated with an increased risk of vascular disease, with significant alterations in systemic endothelial progenitor cells (EPCs) and peripheral vascular function. To identify the contribution of the different vascular compartments in the diabetic impairment of vascularization, we employed streptozotocin- and control-treated 3-mo-old C57Bl/6 mice in an isogeneic pinnal cardiac allograft model, revealing a significant delay in vascularization of wild-type cardiac tissue transplanted into diabetic mice. To investigate the basis of this impairment, the function of diabetic bone marrow cells was tested by transplantation of bone marrow cells isolated from diabetic and control mice into intact, unirradiated 18-mo-old C57Bl/6 mice, which have impaired function of both EPCs and peripheral endothelial cells. Importantly, cells derived from control, but not diabetic, bone marrow integrated into transplanted cardiac allografts. To assess the contribution of diabetic changes in the local vasculature, diabetic mice were treated with pinnal injections of platelet-derived growth factor (PDGF)-AB, which promotes cardiac angiogenesis in wild-type mice. However, whereas PDGF-AB enhanced allograft function in control mice, the activity of the cardiac transplants in the PDGF-AB-treated diabetic mice was significantly decreased. To decipher the potential interactions between systemic bone marrow-derived cells and local vascular pathways, diabetic mice were transplanted with wild-type bone marrow cells with or without PDGF-AB pinnal pretreatment, resulting in improved allograft function and donor cell recruitment only in the combination treatment arm. Overall, these studies show that the diabetic impairment in cardiac angiogenesis can be reversed by targeting the synergism between local trophic pathways and systemic cell function.


Assuntos
Transplante de Medula Óssea/métodos , Angiopatias Diabéticas/fisiopatologia , Angiopatias Diabéticas/terapia , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/cirurgia , Fator de Crescimento Derivado de Plaquetas/administração & dosagem , Animais , Angiopatias Diabéticas/induzido quimicamente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Estreptozocina , Resultado do Tratamento
20.
Exp Gerontol ; 41(1): 63-8, 2006 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16337354

RESUMO

Recent studies have demonstrated that targeting of an age-associated impairment in platelet-derived growth factor (PDGF-AB) pathways could reduce histological measures of myocardial infarction in aging rat hearts. To facilitate preclinical developments of this approach, non-invasive measures of cardiac function were investigated in a 24-month-old rat myocardial infarction model employing intramyocardial PDGF-AB (100 ng) or vehicle control pretreatment. Electrocardiographic recordings post-coronary occlusion revealed ST segment elevation-myocardial injury patterns in both groups, which was confirmed histologically 2 weeks later by Masson's trichrome stains (PDGF-AB, 14.6+/-2.8% of left ventricular area (LVA) vs. control, 27.9+/-9.2%; P<0.05). Echocardiographic fractional shortening (FS) measurements revealed greater preservation of cardiac function in PDGF-AB-treated hearts compared with controls (PDGF-AB FS: 27.3+/-3.7% vs. control--16.7+/-4.1% (ANOVA P=0.005) vs. sham operation--34.5+/-6.7%), with a significant inverse relationship between FS and extent of myocardial injury (m=-0.68; r=-0.84). Notably, exercise testing did not correlate with myocardial injury. These findings provide an important functional foundation in preclinical translations of PDGF-AB-based cardioprotective treatment strategies. Moreover, demonstration of respective roles of electrocardiography and echocardiography in the confirmation and correlation of myocardial injury in the aging rat heart may serve to facilitate both PDGF-AB-based and other age-targeted approaches in large animal models of aging and cardiovascular disease.


Assuntos
Envelhecimento/fisiologia , Cardiotônicos/uso terapêutico , Infarto do Miocárdio/prevenção & controle , Fator de Crescimento Derivado de Plaquetas/uso terapêutico , Animais , Modelos Animais de Doenças , Ecocardiografia Transesofagiana , Eletrocardiografia , Teste de Esforço , Feminino , Coração/fisiopatologia , Infarto do Miocárdio/diagnóstico por imagem , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Endogâmicos F344 , Proteínas Recombinantes/uso terapêutico
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