RESUMO
Orthotopic liver transplantation (OLT) is a viable treatment option for end-stage liver disease. Significant perioperative stress is placed on the cardiovascular system because of hemodynamic changes and the length of the operation. Diagnosis and treatment of cardiovascular disease before OLT are imperative to ensure favorable outcomes. Considerable variability exists among practitioners caring for these patients. Institutions tailor their protocols on the basis of local and historical practices, the preferences of the cardiologists, and the OLT team, and algorithms are not often revised or updated on the basis of the available evidence. In collaboration with cardiology and hepatology experts from leading OLT centers, we sought to examine the diagnostic cardiovascular workup of OLT candidates, including a review of the available literature on the diagnostic modalities used to screen cardiovascular disease before OLT. We advocate an emphasis on noninvasive methods to assess cardiovascular risk with reserved use of invasive risk stratification in select patients.
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PURPOSE OF THE REVIEW: Results from epidemiological studies suggest that vitamin D (VD) deficiency (VDD) may be a cause of hypertension (HTN). However, the results of randomized clinical trials (RCTs) designed to address the impact of VD supplementation on reducing blood pressure (BP) remain equivocal. To determine whether VD might serve as a beneficial treatment option for a specific subset of hypertensive patients, we performed a stratified analysis of RCT data and addressed problems associated with some methodological issues. RECENT FINDINGS: HTN is caused by multiple factors. VDD may be one of the factors contributing to the development of this disorder. There are more than 70 RCTs that examined the impact of VD supplementation on BP. These RCTs can be classified into four groups based on their respective study populations, including participants who are (1) VD-sufficient and normotensive, (2) VD-deficient and normotensive, (3) VD-sufficient and hypertensive, and (4) VD-deficient and hypertensive. Our evaluation of these studies demonstrates that VD supplementation is ineffective when used to reduce BP in VD-sufficient normotensive subjects. VD supplementation for five years or more may reduce the risk of developing HTN specifically among those with VDD. Interestingly, findings from 12 RCTs indicate that daily or weekly supplementation, as opposed to large bolus dosing, results in the reduction of BP in VD-deficient hypertensive patients. Our ongoing research focused on elucidating the mechanisms of VDD-induced HTN will ultimately provide evidence to support the development of etiology-specific prevention and treatment strategies focused on HTN in the VD-deficient population.
Assuntos
Hipertensão , Deficiência de Vitamina D , Suplementos Nutricionais , Humanos , Hipertensão/complicações , Hipertensão/tratamento farmacológico , Vitamina D/uso terapêutico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
OBJECTIVE: Stroke is a major cause of death and disability in the United States. Current acute stroke therapy consists of clot-dissolving drugs, catheter-based interventions and physical rehabilitation. To date, there are no therapies that directly enhance neuronal survival after a stroke. Previous work from our lab demonstrated that Interleukin-15 (IL-15) peptide could rescue cardiomyocytes subjected to hypoxia. We sought to extend these findings to cortical neurons since IL-15 has been implicated to have an important role in neuronal homeostasis. METHODS: We have evaluated the effect of IL-15 peptide on primary cortical neurons derived from embryonic rats in vitro under conditions of anoxia and glucose deprivation, and in vivo following middle cerebral artery occlusion. RESULTS: IL-15 administration rescued neuronal cells subjected to anoxia coupled with glucose deprivation (AGD), as well as with reoxygenation. A hallmark of stroke is the ischemic microenvironment and associated oxidative stress, which results in DNA damage and ER stress, both of which contribute to neuronal cell damage and death. The expression of anoxia, ER stress, and DNA damage factors/markers was evaluated via western blot and correlated with the cellular survival effects of IL-15 in vitro. In addition, IL-15 effect of alleviating ER stress and increasing cell survival was also observed in vivo. INTERPRETATION: Our data indicate, for the first time, that administration of the pleiotropic factor IL-15 reduces neuronal cell death during AGD, which correlates with modulation of multiple cellular stress pathways.
Assuntos
Isquemia Encefálica , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/tratamento farmacológico , Sobrevivência Celular , Células Cultivadas , Glucose , Infarto da Artéria Cerebral Média , Interleucina-15 , Neurônios , RatosRESUMO
Obstructive sleep apnea (OSA) is characterized by recurrent complete and partial upper airway obstructive events, resulting in intermittent hypoxemia, autonomic fluctuation, and sleep fragmentation. Approximately 34% and 17% of middle-aged men and women, respectively, meet the diagnostic criteria for OSA. Sleep disturbances are common and underdiagnosed among middle-aged and older adults, and the prevalence varies by race/ethnicity, sex, and obesity status. OSA prevalence is as high as 40% to 80% in patients with hypertension, heart failure, coronary artery disease, pulmonary hypertension, atrial fibrillation, and stroke. Despite its high prevalence in patients with heart disease and the vulnerability of cardiac patients to OSA-related stressors and adverse cardiovascular outcomes, OSA is often underrecognized and undertreated in cardiovascular practice. We recommend screening for OSA in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable. In patients with tachy-brady syndrome or ventricular tachycardia or survivors of sudden cardiac death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea. All patients with OSA should be considered for treatment, including behavioral modifications and weight loss as indicated. Continuous positive airway pressure should be offered to patients with severe OSA, whereas oral appliances can be considered for those with mild to moderate OSA or for continuous positive airway pressure-intolerant patients. Follow-up sleep testing should be performed to assess the effectiveness of treatment.
Assuntos
Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/etiologia , Comorbidade , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Programas de Rastreamento , Vigilância em Saúde Pública , Pesquisa/tendências , Medição de Risco , Fatores de Risco , Apneia Obstrutiva do Sono/diagnóstico , Apneia Obstrutiva do Sono/etiologia , Avaliação de SintomasRESUMO
A young man with a history of early-onset coronary disease presented with an ST-elevation myocardial infarction at the age of 38. He subsequently had recurrent in-stent restenosis requiring repeating interventions and ultimately bypass surgery. After 4 years, he presents with systemic symptoms, new skin lesions and a femoral artery pseudoaneurysm. He is diagnosed with Behçet syndrome, a rare systemic vasculitis characterised by the triad of oral aphthous ulcers, genital ulcers and ocular involvement. Behçet is not associated with premature coronary disease but can have a variety of cardiac complications. Additionally, pathergy, an exaggerated inflammatory response to local injury, is characteristic. We hypothesise that in retrospect, subclinical inflammation and a vascular pathergy likely predisposed him to his cardiac and vascular complications. Here, we review risk factors and presentation of premature coronary artery disease and review the literature on the cardiovascular complications of Behçet syndrome.
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Síndrome de Behçet/complicações , Doenças Cardiovasculares , Doença da Artéria Coronariana , Reestenose Coronária , Stents/efeitos adversos , Adulto , Cateterismo Cardíaco , Humanos , Masculino , Procedimentos Cirúrgicos VascularesRESUMO
Interleukin-15 is a pleotropic factor, capable of modulating metabolism, survival, proliferation, and differentiation in many different cell types. The rationale behind this study relates to previous work demonstrating that IL-15 is a major factor present in stem cell extracts, which protects cardiomyocytes subjected to hypoxic stress in vitro. The objective of this current study was to assess whether administration of IL-15 peptide will also show protective effects in vivo. The data indicate that administration of IL-15 reduces cell death, increases vascularity, decreases scar size, and significantly improves left ventricular ejection fraction in a mouse model of myocardial infarction.
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Fármacos Cardiovasculares/farmacologia , Interleucina-15/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Miócitos Cardíacos/efeitos dos fármacos , Volume Sistólico/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Morte Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miócitos Cardíacos/patologia , Neovascularização Fisiológica/efeitos dos fármacos , Recuperação de Função FisiológicaRESUMO
A growing body of evidence has demonstrated that pulmonary arterial capacitance (PAC) is the strongest hemodynamic predictor of clinical outcomes across a wide spectrum of cardiovascular disease, including pulmonary hypertension and heart failure. We hypothesized that a ratio of right ventricular stroke volume (RVOT VTI) to the associated peak arterial systolic pressure (PASP) could function as a reliable non-invasive surrogate for PAC. We performed a prospective study of patients undergoing simultaneous transthoracic echocardiography and right heart catheterization (RHC) for various clinical indications. Measurements of the RVOT VTI/PASP ratio from echocardiographic measurements were compared against PAC calculated from RHC measurements. Correlation coefficients and Bland-Altman analysis compared the RVOT VTI/PASP ratio with PAC. Forty-five subjects were enrolled, 38% were female and mean age was 54 years (SD 13 years). The reason for referral to RHC was most commonly post-heart transplant surveillance (40%), followed by heart failure (22%), and pulmonary hypertension (18%). Pre-capillary pulmonary hypertension was present in 18%, isolated post-capillary pulmonary hypertension was present in 13%, and combined pre-and post-capillary pulmonary hypertension was present in 29%. The RVOT VTI/PASP ratio was obtainable in the majority of patients (78%), and Pearson's correlation demonstrated moderately-strong association between PAC and the RVOT VTI/PASP ratio, r = 0.75 (P < 0.001). Bland-Altman analysis demonstrated good agreement between measurements without suggestion of systematic bias and a mean difference in standardized units of - 0.133. In a diverse population of patients and hemodynamic profiles, we validated that the ratio of RVOT VTI/PASP to be a reliably-obtained non-invasive marker associated with PAC.
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Pressão Arterial , Ecocardiografia Doppler , Hipertensão Pulmonar/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , Circulação Pulmonar , Volume Sistólico , Capacitância Vascular , Função Ventricular Direita , Adulto , Idoso , Cateterismo Cardíaco , Feminino , Humanos , Hipertensão Pulmonar/fisiopatologia , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Artéria Pulmonar/fisiopatologiaAssuntos
Doenças Cardiovasculares , Gerenciamento Clínico , Guias de Prática Clínica como Assunto , Apneia Obstrutiva do Sono , Doenças Cardiovasculares/epidemiologia , Doenças Cardiovasculares/etiologia , Doenças Cardiovasculares/terapia , Terapia Cognitivo-Comportamental/métodos , Humanos , Morbidade/tendências , Respiração com Pressão Positiva/métodos , Fatores de Risco , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/epidemiologia , Apneia Obstrutiva do Sono/terapia , Taxa de Sobrevida/tendências , Estados Unidos/epidemiologiaRESUMO
Cell-based strategies for the treatment of ischemic diseases are at the forefront of tissue engineering and regenerative medicine. Cell therapies purportedly can play a key role in the neovascularization of ischemic tissue; however, low survival and poor cell engraftment with the host vasculature following implantation limits their potential to treat ischemic diseases. To overcome these limitations, we previously developed a growth factor sequestering hyaluronic acid (HyA)-based hydrogel that enhanced transplanted mouse cardiosphere-derived cell survival and formation of vasculature that anastomosed with host vessels. In this work, we examined the mechanism by which HyA hydrogels presenting transforming growth factor beta-1 (TGF-ß1) promoted proliferation of more clinically relevant human cardiosphere-derived cells (hCDC), and their formation of vascular-like networks in vitro. We observed hCDC proliferation and enhanced formation of vascular-like networks occurred in the presence of TGF-ß1. Furthermore, production of nitric oxide (NO), VEGF, and a host of angiogenic factors were increased in the presence of TGF-ß1. This response was dependent on the co-activity of CD105 (Endoglin) with the TGF-ßR2 receptor, demonstrating its role in the process of angiogenic differentiation and vascular organization of hCDC. These results demonstrated that hCDC form vascular-like networks in vitro, and that the induction of vascular networks by hCDC within growth factor sequestering HyA hydrogels was mediated by TGF-ß1/CD105 signaling.
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Endoglina/metabolismo , Células Endoteliais , Ácido Hialurônico/química , Hidrogéis , Neovascularização Fisiológica , Esferoides Celulares/citologia , Fator de Crescimento Transformador beta1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Terapia Baseada em Transplante de Células e Tecidos/instrumentação , Terapia Baseada em Transplante de Células e Tecidos/métodos , Células Cultivadas , Composição de Medicamentos/métodos , Células Endoteliais/citologia , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Humanos , Hidrogéis/química , Hidrogéis/metabolismo , Miocárdio/citologia , Miocárdio/metabolismo , Miócitos Cardíacos/citologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Transdução de Sinais/efeitos dos fármacos , Esferoides Celulares/efeitos dos fármacos , Esferoides Celulares/metabolismo , Alicerces Teciduais/químicaRESUMO
When challenged by hemodynamic stress, aging hearts respond differently to young hearts. Preclinical models of heart disease should take into account the effects of age. However, in the transverse aortic constriction (TAC) model of pressure-overload cardiomyopathy, the larger aorta of aging mice has not previously been taken into account. First, we studied the aortic size in mice, and found that the aortic cross-sectional area (CSA) is 28% larger in aging mice than in young adult mice (P=0.001). We then performed TAC to make the same proportional reduction in CSA in young and aging mice. This produced the same pressure gradient across the constriction and the same rise in B-type natriuretic peptide expression. Young mice showed acute deterioration in systolic function assessed by pressure-volume loops, progressive LV remodeling on echocardiography, and a 50% mortality at 12 weeks post-TAC. In contrast, aging mice showed no acute deterioration in systolic function, much less ventricular remodeling and were protected from death. Aging mice also showed significantly increased levels of matrix metalloproteinase-3 (MMP-3; 3.2 fold increase, P<0.001) and MMP-12 (1.5-fold increase, P<0.001), which were not seen in young mice. Expression of tissue inhibitor of MMP-1 (TIMP-1) increased 8.6-fold in aging hearts vs 4.3-fold in young hearts (P<0.01). In conclusion, following size-appropriate TAC, aging mice exhibit less LV remodeling and lower mortality than young adult mice. This is associated with induction of protective ECM changes.
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Pesquisa Biomédica/métodos , Bioimpressão/métodos , Impressão Tridimensional , Animais , Pesquisa Biomédica/instrumentação , Bioimpressão/instrumentação , Prótese Vascular , Desenho Assistido por Computador , Difusão de Inovações , Próteses Valvulares Cardíacas , Humanos , Dispositivos Lab-On-A-Chip , Modelos Anatômicos , Modelos Cardiovasculares , Modelagem Computacional Específica para o Paciente , Impressão Tridimensional/instrumentação , Desenho de PróteseRESUMO
BACKGROUND: Computed tomography angiography (CTA) is the test of choice for pre-procedure imaging of transcatheter aortic valve replacement (TAVR) candidates. The iodinated contrast required, however, increases the risk of renal dysfunction in patients with pre-existing renal failure. Ferumoxytol is a magnetic resonance imaging (MRI) contrast agent that can be used with renal failure. Its long vascular resonance time allows gated MRA sequences that approach CTA in image quality. We present respiratory and cardiac gated MRA enabled by ferumoxytol that can be post-processed in an analogous fashion to CTA. METHODS: Seven patients with renal failure presenting for TAVR were imaged with respiratory and cardiac gated MRA at 3T using ferumoxtyol for contrast. Aortic annulus, root and peripheral access dimensions were calculated in a fashion identical to that used for CTA. Of these, 6 patients underwent a TAVR procedure and 5 had intraoperative valve assessment with transesophageal echocardiograph (TEE) using standard clinical protocols that employed both two- and three-dimensional techniques. RESULTS: Good correlation between MRA aortic annulus measurements and those from TEE were shown in 5 patients with mean annulus area of 392.4mm2 (290-470 range) versus 374.1mm2 (285-440 range), with a pairwise correlation coefficient of 0.92, p=0.029. All patients received Sapien valve implants (one 20mm, three 23mm, and two 26mm valves). Access decisions were guided by MRA with no complications. Annulus sizing resulted in no greater than trace/mild aortic regurgitation in all patients. CONCLUSIONS: Ferumoxytol MRA is a safe alternative to CTA in patients with renal failure for pre-TAVR analysis of the aortic root and peripheral access.
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Valva Aórtica/diagnóstico por imagem , Óxido Ferroso-Férrico/farmacologia , Doenças das Valvas Cardíacas/diagnóstico , Angiografia por Ressonância Magnética/métodos , Insuficiência Renal/complicações , Substituição da Valva Aórtica Transcateter , Idoso , Idoso de 80 Anos ou mais , Valva Aórtica/cirurgia , Feminino , Doenças das Valvas Cardíacas/complicações , Doenças das Valvas Cardíacas/cirurgia , Humanos , Imageamento Tridimensional , Masculino , Pessoa de Meia-Idade , Período Pré-Operatório , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The objective of this study was to measure myocardial blood flow (MBF) in humans using 99mTc-tetrofosmin and dynamic single-photon emission computed tomography (SPECT). METHODS: Dynamic SPECT using 99mTc-tetrofosmin and dynamic positron emission tomography (PET) was performed on a group of 16 patients. The SPECT data were reconstructed using a 4D-spatiotemporal iterative reconstruction method. The data corresponding to 9 patients were used to determine the flow-extraction curve for 99mTc-tefrofosmin while data from the remaining 7 patients were used for method validation. The nonlinear tracer correction parameters A and B for 99mTc-tefrofosmin were estimated for the 9 patients by fitting the flow-extraction curve [Formula: see text] for K 1 values estimated with 99mTc-tefrofosmin using SPECT and MBF values estimated with 13N-NH3 using PET. These parameters were then used to calculate MBF and coronary flow reserve (CFR) in three coronary territories (LAD, RCA, and LCX) using SPECT for an independent cohort of 7 patients. The results were then compared with that estimated with 13N-NH3 PET. The flow-dependent permeability surface-area product (PS) for 99mTc-tefrofosmin was also estimated. RESULTS: The estimated flow-extraction parameters for 99mTc-tefrofosmin were found to be A = 0.91 ± 0.11, B = 0.34 ± 0.20 (R 2 = 0.49). The range of MBF in LAD, RCA, and LCX was 0.44-3.81 mL/min/g. The MBF between PET and SPECT in the group of independent cohort of 7 patients showed statistically significant correlation, r = 0.71 (P < .001). However, the corresponding CFR correlation was moderate r = 0.39 yet statistically significant (P = .037). The PS for 99mTc-tefrofosmin was (0.019 ± 0.10)*MBF + (0.32 ± 0.16). CONCLUSIONS: Dynamic cardiac SPECT using 99mTc-tetrofosmin and a clinical two-headed SPECT/CT scanner can be a useful tool for estimation of MBF.
Assuntos
Velocidade do Fluxo Sanguíneo , Doença da Artéria Coronariana/diagnóstico por imagem , Doença da Artéria Coronariana/fisiopatologia , Circulação Coronária/fisiologia , Imagem de Perfusão do Miocárdio/métodos , Compostos Organofosforados , Compostos de Organotecnécio , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Vasos Coronários/diagnóstico por imagem , Vasos Coronários/fisiopatologia , Humanos , Aumento da Imagem/métodos , Interpretação de Imagem Assistida por Computador/métodos , Pessoa de Meia-Idade , Compostos Radiofarmacêuticos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
A critical design parameter for the function of synthetic extracellular matrices is to synchronize the gradual cell-mediated degradation of the matrix with the endogenous secretion of natural extracellular matrix (ECM) (e.g., creeping substitution). In hyaluronic acid (HyA)-based hydrogel matrices, we have investigated the effects of peptide crosslinkers with different matrix metalloproteinases (MMP) sensitivities on network degradation and neovascularization in vivo. The HyA hydrogel matrices consisted of cell adhesive peptides, heparin for both the presentation of exogenous and sequestration of endogenously synthesized growth factors, and MMP cleavable peptide linkages (i.e., QPQGLAK, GPLGMHGK, and GPLGLSLGK). Sca1(+)/CD45(-)/CD34(+)/CD44(+) cardiac progenitor cells (CPCs) cultured in the matrices with the slowly degradable QPQGLAK hydrogels supported the highest production of MMP-2, MMP-9, MMP-13, VEGF165, and a range of angiogenesis related proteins. Hydrogels with QPQGLAK crosslinks supported prolonged retention of these proteins via heparin within the matrix, stimulating rapid vascular development, and anastomosis with the host vasculature when implanted in the murine hindlimb.
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Materiais Biocompatíveis/metabolismo , Ácido Hialurônico/metabolismo , Hidrogel de Polietilenoglicol-Dimetacrilato/metabolismo , Metaloproteinase 13 da Matriz/metabolismo , Transplante de Células-Tronco , Animais , Materiais Biocompatíveis/química , Adesão Celular , Proliferação de Células , Células Cultivadas , Ácido Hialurônico/química , Hidrogel de Polietilenoglicol-Dimetacrilato/química , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Metaloproteinase 13 da Matriz/química , Camundongos , Camundongos Endogâmicos C57BL , Miocárdio/citologia , Neovascularização Fisiológica , Peptídeos/química , Peptídeos/metabolismo , Transplante de Células-Tronco/métodos , Células-Tronco/citologia , Células-Tronco/metabolismo , Alicerces Teciduais/químicaRESUMO
BACKGROUND: Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects. METHODS AND RESULTS: We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well-established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities. CONCLUSIONS: Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes.
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Doença da Artéria Coronariana/enzimologia , Células Progenitoras Endoteliais/enzimologia , Células Progenitoras Endoteliais/transplante , Infarto do Miocárdio/cirurgia , Neovascularização Fisiológica , Óxido Nítrico Sintase Tipo III/metabolismo , Óxido Nítrico/metabolismo , Transplante de Células-Tronco/métodos , Adulto , Idoso , Animais , Estudos de Casos e Controles , Movimento Celular , Células Cultivadas , Técnicas de Cocultura , Doença da Artéria Coronariana/diagnóstico , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Camundongos SCID , Pessoa de Meia-Idade , Infarto do Miocárdio/enzimologia , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Óxido Nítrico Sintase Tipo III/genética , Fenótipo , Interferência de RNA , Recuperação de Função Fisiológica , Regeneração , Transdução de Sinais , Fatores de Tempo , Transdução Genética , TransfecçãoRESUMO
BACKGROUND: We previously reported the generation of a reporter line of human embryonic stem cells (hESCs) with enhanced green fluorescent protein (eGFP) expression driven by the α-myosin heavy chain (αMHC) promoter. The GFP+/αMHC+ cells derived from this cell line behave as multipotent, human myocardial precursors (hMPs) in vitro. In this study, we evaluated the therapeutic effects of GFP+/αMHC+ cells isolated from the reporter line in a mouse model of myocardial infarction (MI). METHODS: MI was generated in immunodeficient mice. hMPs were injected into murine infarcted hearts under ultrasound guidance at 3 days post-MI. Human fetal skin fibroblasts (hFFs) were injected as control. Cardiac function was evaluated by echocardiography. Infarct size, angiogenesis, apoptosis, cell fate, and teratoma formation were analyzed by immunohistochemical staining. RESULTS: Compared with control, hMPs resulted in improvement of cardiac function post-MI with smaller infarct size, induced endogenous angiogenesis, and reduced apoptosis of host cardiomyocytes at the peri-infarct zone at 28 days post-MI. CONCLUSION: Intramyocardial injection of hMPs improved cardiac function post-MI. The engraftment rate of these cells in the myocardium post-MI was low, suggesting that the majority of effect occurs via paracrine mechanisms.
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Terapia Baseada em Transplante de Células e Tecidos/métodos , Células-Tronco Embrionárias/transplante , Células-Tronco Multipotentes/transplante , Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Animais , Apoptose/fisiologia , Células Cultivadas , Ecocardiografia , Feminino , Proteínas de Fluorescência Verde/genética , Coração/fisiopatologia , Testes de Função Cardíaca , Humanos , Camundongos , Camundongos SCID , Neovascularização FisiológicaRESUMO
Heart failure is increasing at an alarming rate, making it a worldwide epidemic. As the population ages and life expectancy increases, this trend is not likely to change. Myocardial infarction (MI)-induced adverse left ventricular (LV) remodeling is responsible for nearly 70% of heart failure cases. The adverse remodeling process involves an extension of the border zone (BZ) adjacent to an MI, which is normally perfused but shows myofiber contractile dysfunction. To improve patient-specific modeling of cardiac mechanics, we sought to create a finite element model of the human LV with BZ and MI morphologies integrated directly from delayed-enhancement magnetic resonance (DE-MR) images. Instead of separating the LV into discrete regions (e.g., the MI, BZ, and remote regions) with each having a homogeneous myocardial material property, we assumed a functional relation between the DE-MR image pixel intensity and myocardial stiffness and contractility--we considered a linear variation of material properties as a function of DE-MR image pixel intensity, which is known to improve the accuracy of the model's response. The finite element model was then calibrated using measurements obtained from the same patient--namely, 3D strain measurements-using complementary spatial modulation of magnetization magnetic resonance (CSPAMM-MR) images. This led to an average circumferential strain error of 8.9% across all American Heart Association (AHA) segments. We demonstrate the utility of our method for quantifying smooth regional variations in myocardial contractility using cardiac DE-MR and CSPAMM-MR images acquired from a 78-yr-old woman who experienced an MI approximately 1 yr prior. We found a remote myocardial diastolic stiffness of C(0) = 0.102 kPa, and a remote myocardial contractility of T(max) = 146.9 kPa, which are both in the range of previously published normal human values. Moreover, we found a normalized pixel intensity range of 30% for the BZ, which is consistent with the literature. Based on these regional myocardial material properties, we used our finite element model to compute patient-specific diastolic and systolic LV myofiber stress distributions, which cannot be measured directly. One of the main driving forces for adverse LV remodeling is assumed to be an abnormally high level of ventricular wall stress, and many existing and new treatments for heart failure fundamentally attempt to normalize LV wall stress. Thus, our noninvasive method for estimating smooth regional variations in myocardial contractility should be valuable for optimizing new surgical or medical strategies to limit the chronic evolution from infarction to heart failure.
Assuntos
Imageamento por Ressonância Magnética , Contração Miocárdica , Infarto do Miocárdio/fisiopatologia , Modelagem Computacional Específica para o Paciente , Disfunção Ventricular Esquerda/fisiopatologia , Idoso , Feminino , Análise de Elementos Finitos , Humanos , Infarto do Miocárdio/diagnósticoRESUMO
Injection of various stem cells has been tested with the hopes of improving cardiac function after a myocardial infarction (MI). However, there is continued controversy as to which cell type is best for repair. Due to technical differences in cell isolation, processing, delivery, and cardiac functional assessment by various investigators, it has been difficult to directly compare the results of different cells. Using same techniques to evaluate the efficacy of different cell types, we have separately delivered bone marrow cells (BMCs), cardiospheres (CSs), CS-derived Sca-1(+)/CD45(-) cells, human embryonic stem cell-derived cardiomyocytes, and BMC extract into infarcted murine myocardium and found that all of these treatments reduce infarct size and improve cardiac function post-MI similarly without one regimen being superior to another. The beneficial effects appear to be via paracrine influences. Different progenitors lead to improved cardiac function post-MI, but it is premature to hype any specific cell type at this time.
Assuntos
Transplante de Medula Óssea/métodos , Infarto do Miocárdio , Miócitos Cardíacos/fisiologia , Transplante de Células-Tronco/métodos , Células-Tronco , Animais , Humanos , Camundongos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/terapia , Células-Tronco/classificação , Células-Tronco/metabolismo , Resultado do TratamentoRESUMO
Growth factors are critical for regulating and inducing various stem cell functions. To study the effects of growth factor delivery kinetics and presentation on stem cell fate, we developed a series of heparin-containing hyaluronic acid (HyA)-based hydrogels with various degrees of growth factor affinity and retention. To characterize this system, we investigated the effect of heparin molecular weight, fractionation, and relative concentration on the loading efficiency and retention kinetics of TGFß1 as a model growth factor. At equal concentrations, high MW heparin both loaded and retained the greatest amount of TGFß1, and had the slowest release kinetics, primarily due to the higher affinity with TGFß1 compared to low MW or unfractionated heparin. Subsequently, we tested the effect of TGFß1, presented from various heparin-containing matrices, to differentiate a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs) into endothelial cells and form vascular-like networks in vitro. High MW heparin HyA hydrogels stimulated more robust differentiation of CPCs into endothelial cells, which formed vascular-like networks within the hydrogel. This observation was attributed to the ability of high MW heparin HyA hydrogels to sequester endogenously synthesized angiogenic factors within the matrix. These results demonstrate the importance of molecular weight, fractionation, and concentration of heparin on presentation of heparin-binding growth factors and their effect on stem cell differentiation and lineage specification.
Assuntos
Heparina/farmacologia , Ácido Hialurônico/farmacologia , Hidrogéis/farmacologia , Células-Tronco/efeitos dos fármacos , Fator de Crescimento Transformador beta1/farmacologia , Animais , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Heparina/química , Ácido Hialurônico/química , Hidrogéis/química , Cinética , Camundongos , Peso Molecular , Células-Tronco/citologia , Fator de Crescimento Transformador beta1/químicaRESUMO
We have generated a bioinspired tunable system of hyaluronic acid (HyA)-based hydrogels for Matrix-Assisted Cell Transplantation (MACT). With this material, we have independently evaluated matrix parameters such as adhesion peptide density, mechanical properties, and growth factor sequestering capacity, to engineer an environment that imbues donor cells with a milieu that promotes survival and engraftment with host tissues after transplantation. Using a versatile population of Sca-1(+)/CD45(-) cardiac progenitor cells (CPCs), we demonstrated that the addition of heparin in the HyA hydrogels was necessary to coordinate the presentation of TGFß1 and to support the trophic functions of the CPCs via endothelial cell differentiation and vascular like tubular network formation. Presentation of exogenous TGFß1 by binding with heparin improved differentiated CPC function by sequestering additional endogenously-produced angiogenic factors. Finally, we demonstrated that TGFß1 and heparin-containing HyA hydrogels can promote CPC survival when implanted subcutaneously into murine hind-limbs and encouraged their participation in the ensuing neovascular response, which included blood vessels that had anastomosed with the host's blood vessels.