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1.
Clin Res Cardiol ; 2019 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-31401672

RESUMO

AIMS: In the placebo-controlled, double-blind BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) 2 trial, intracoronary autologous bone marrow cell (BMC) transfer did not improve recovery of left ventricular ejection fraction (LVEF) at 6 months in patients with ST-elevation myocardial infarction (STEMI) and moderately reduced LVEF. Regional myocardial perfusion as determined by adenosine stress perfusion cardiac magnetic resonance imaging (S-CMR) may be more sensitive than global LVEF in detecting BMC treatment effects. Here, we sought to evaluate (i) the changes of myocardial perfusion in the infarct area over time (ii) the effects of BMC therapy on infarct perfusion, and (iii) the relation of infarct perfusion to LVEF recovery at 6 months. METHODS AND RESULTS: In 51 patients from BOOST-2 (placebo, n = 10; BMC, n = 41), S-CMR was performed 5.1 ± 2.9 days after PCI (before placebo/BMC treatment) and after 6 months. Infarct perfusion improved from baseline to 6 months in the overall patient cohort as reflected by the semi-quantitative parameters, perfusion defect-infarct size ratio (change from 0.54 ± 0.20 to 0.43 ± 0.22; P = 0.006) and perfusion defect-upslope ratio (0.54 ± 0.23 to 0.68 ± 0.22; P < 0.001), irrespective of randomised treatment. Perfusion defect-upslope ratio at baseline correlated with LVEF recovery (r = 0.62; P < 0.001) after 6 months, with a threshold of 0.54 providing the best sensitivity (79%) and specificity (74%) (area under the curve, 0.79; 95% confidence interval, 0.67-0.92). CONCLUSION: Infarct perfusion improves from baseline to 6 months and predicts LVEF recovery in STEMI patients undergoing early PCI. Intracoronary BMC therapy did not enhance infarct perfusion in the BOOST-2 trial.

2.
Eur Heart J ; 38(39): 2936-2943, 2017 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-28431003

RESUMO

Aims: Intracoronary infusion of autologous nucleated bone marrow cells (BMCs) enhanced the recovery of left ventricular ejection fraction (LVEF) after ST-segment elevation myocardial infarction (STEMI) in the randomised-controlled, open-label BOOST trial. We reassessed the therapeutic potential of nucleated BMCs in the randomised placebo-controlled, double-blind BOOST-2 trial conducted in 10 centres in Germany and Norway. Methods and results: Using a multiple arm design, we investigated the dose-response relationship and explored whether γ-irradiation which eliminates the clonogenic potential of stem and progenitor cells has an impact on BMC efficacy. Between 9 March 2006 and 16 July 2013, 153 patients with large STEMI were randomly assigned to receive a single intracoronary infusion of placebo (control group), high-dose (hi)BMCs, low-dose (lo)BMCs, irradiated hiBMCs, or irradiated loBMCs 8.1 ± 2.6 days after percutaneous coronary intervention (PCI) in addition to guideline-recommended medical treatment. Change in LVEF from baseline (before cell infusion) to 6 months as determined by MRI was the primary endpoint. The trial is registered at Current Controlled Trials (ISRCTN17457407). Baseline LVEF was 45.0 ± 8.5% in the overall population. At 6 months, LVEF had increased by 3.3 percentage points in the control group and 4.3 percentage points in the hiBMC group. The estimated treatment effect was 1.0 percentage points (95% confidence interval, -2.6 to 4.7; P = 0.57). The treatment effect of loBMCs was 0.5 percentage points (-3.0 to 4.1; P = 0.76). Likewise, irradiated BMCs did not have significant treatment effects. BMC transfer was safe and not associated with adverse clinical events. Conclusion: The BOOST-2 trial does not support the use of nucleated BMCs in patients with STEMI and moderately reduced LVEF treated according to current standards of early PCI and drug therapy.


Assuntos
Transplante de Medula Óssea/métodos , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Células da Medula Óssea/efeitos da radiação , Método Duplo-Cego , Feminino , Raios gama , Humanos , Infusões Intralesionais , Angiografia por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea , Transplante de Células-Tronco/métodos , Células-Tronco/efeitos da radiação , Transplante Autólogo , Resultado do Tratamento , Função Ventricular Esquerda/fisiologia
3.
Cell Transplant ; 26(1): 157-170, 2017 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-27539827

RESUMO

Cardiac cell replacement therapy is a promising therapy to improve cardiac function in heart failure. Persistence, structural and functional maturation, and integration of transplanted cardiomyocytes into recipients' hearts are crucial for a safe and efficient replacement of lost cells. We studied histology, electrophysiology, and quantity of intramyocardially transplanted rat neonatal cardiomyocytes (NCMs) and performed a detailed functional study with repeated invasive (pressure-volume catheter) and noninvasive (echocardiography) analyses of infarcted female rat hearts including pharmacological stress before and 3 weeks after intramyocardial injection of 5 × 106 (low NCM) or 25 × 106 (high NCM) syngeneic male NCMs or medium as placebo (Ctrl). Quantitative real-time polymerase chain reaction (PCR) for Y-chromosome confirmed a fivefold higher persisting male cell number in high NCM versus low NCM after 3 weeks. Sharp electrode measurements within viable slices of recipient hearts demonstrated that transplanted NCMs integrate into host myocardium and mature to an almost adult phenotype, which might be facilitated through gap junctions between host myocardium and transplanted NCMs as indicated by connexin43 in histology. Ejection fraction of recipient hearts was severely impaired after ligation of left anterior descending (LAD; pressure-volume catheter: 39.2 ± 3.6%, echocardiography: 39.9 ± 1.4%). Repeated analyses revealed a significant further decline within 3 weeks in Ctrl and a dose-dependent stabilization in cell-treated groups. Consistently, stabilized cardiac function/morphology in cell-treated groups was seen in stroke volume, cardiac output, ventricle length, and wall thickness. Our findings confirm that cardiac cell replacement is a promising therapy for ischemic heart disease since immature cardiomyocytes persist, integrate, and mature after intramyocardial transplantation, and they dose-dependently stabilize cardiac function after myocardial infarction.


Assuntos
Infarto do Miocárdio/terapia , Miócitos Cardíacos/citologia , Miócitos Cardíacos/transplante , Animais , Animais Recém-Nascidos , Débito Cardíaco/fisiologia , Conexina 43/metabolismo , Ecocardiografia , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Volume Sistólico/fisiologia
4.
J Clin Monit Comput ; 31(2): 353-360, 2017 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26886899

RESUMO

To compare stroke volumes (SV) in small hearts assessed by real-time three-dimensional echocardiography (3DE) with SV measured by transpulmonary thermodilution (TPTD) and continuous pulse contour analysis (PC) under various hemodynamic conditions. In thirteen anesthetized piglets (range 3.6-7.1 kg) SV were measured by 3DE, TPTD and PC at baseline and during phenylephrine and esmolol administration. 3DE and TPTD measurements were done successively while SV calculated by PC was documented at the time of 3DE. 3DE and TPTD showed a good correlation (r2 = 0.74) and a bias of -1.3 ml (limits of agreement -4.1 to 1.5 ml). While TPTD measured higher SV than 3DE, both methods tracked SV changes with a concordance rate of 91 %. PC and 3DE showed a lower correlation coefficient of r2 = 0.57 and a bias of -2.1 ml (limits of agreement -5.9 to 1.8 ml). Inter- and intra-observer variability of SV measured by 3DE was good with a mean bias <5 %. SV3DE showed a small variance and tracked acute small changes in SV in acceptable concordance with TPTD. PC measured SV with a higher variance and mean difference compared to 3DE. In an experimental setting 3DE has the possibility to offer non-invasive assessments of ventricular volumes volume changes. To determine whether 3DE could be used for SV assessment in a clinical routine our results need confirmation in a clinical setting.


Assuntos
Ecocardiografia Tridimensional/métodos , Coração/fisiologia , Volume Sistólico , Termodiluição/métodos , Animais , Feminino , Frequência Cardíaca , Hemodinâmica , Modelos Animais , Variações Dependentes do Observador , Pediatria , Fenilefrina/administração & dosagem , Propanolaminas/administração & dosagem , Reprodutibilidade dos Testes , Suínos , Sístole , Fatores de Tempo , Disfunção Ventricular Esquerda , Função Ventricular Esquerda
5.
PLoS One ; 11(10): e0165397, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27776179

RESUMO

BACKGROUND: Pressure-volume loops (PVL) provide vital information regarding ventricular performance and pathophysiology in cardiac disease. Unfortunately, acquisition of PVL by conductance technology is not feasible in neonates and small children due to the available human catheter size and resulting invasiveness. The aim of the study was to validate the accuracy of PVL in small hearts using volume data obtained by real-time three-dimensional echocardiography (3DE) and simultaneously acquired pressure data. METHODS: In 17 piglets (weight range: 3.6-8.0 kg) left ventricular PVL were generated by 3DE and simultaneous recordings of ventricular pressure using a mini pressure wire (PVL3D). PVL3D were compared to conductance catheter measurements (PVLCond) under various hemodynamic conditions (baseline, alpha-adrenergic stimulation with phenylephrine, beta-adrenoreceptor-blockage using esmolol). In order to validate the accuracy of 3D volumetric data, cardiac magnetic resonance imaging (CMR) was performed in another 8 piglets. RESULTS: Correlation between CMR- and 3DE-derived volumes was good (enddiastolic volume: mean bias -0.03ml ±1.34ml). Computation of PVL3D in small hearts was feasible and comparable to results obtained by conductance technology. Bland-Altman analysis showed a low bias between PVL3D and PVLCond. Systolic and diastolic parameters were closely associated (Intraclass-Correlation Coefficient for: systolic myocardial elastance 0.95, arterial elastance 0.93, diastolic relaxation constant tau 0.90, indexed end-diastolic volume 0.98). Hemodynamic changes under different conditions were well detected by both methods (ICC 0.82 to 0.98). Inter- and intra-observer coefficients of variation were below 5% for all parameters. CONCLUSIONS: PVL3D generated from 3DE combined with mini pressure wire represent a novel, feasible and reliable method to assess different hemodynamic conditions of cardiac function in hearts comparable to neonate and infant size. This methodology may be integrated into clinical practice and cardiac catheterization programs and has the capability to contribute to clinical decision making even in small hearts.


Assuntos
Ecocardiografia/métodos , Ventrículos do Coração , Animais , Imagem por Ressonância Magnética , Pressão , Suínos
7.
Am J Physiol Heart Circ Physiol ; 307(10): H1478-86, 2014 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-25217654

RESUMO

Large animal studies are an important step toward clinical translation of novel therapeutic approaches. We aimed to establish an ischemic heart failure (HF) model with a larger myocardial infarction (MI) relative to previous studies, and characterize the functional and structural features of this model. An MI was induced by occluding the proximal left anterior descending artery (LAD; n = 15) or the proximal left circumflex artery (LCx; n = 6) in Yorkshire pigs. Three pigs with sham procedures were also included. All pigs underwent hemodynamic and echocardiographic assessments before MI, at 1 mo, and 3 mo after MI. Analyses of left ventricular (LV) myocardial mechanics by means of strains and torsion were performed using speckle-tracking echocardiography and compared between the groups. The proximal LAD MI approach induced larger infarct sizes (14.2 ± 3.2% vs. 10.6 ± 1.9%, P = 0.03), depressed systolic function (LV ejection fraction; 39.8 ± 7.5% vs. 54.1 ± 4.6%, P < 0.001), and more LV remodeling (end-systolic volume index; 82 ± 25 ml/m(2) vs. 51 ± 18 ml/m(2), P = 0.02, LAD vs. LCx, respectively) compared with the LCx MI approach without compromising the survival rate. At the papillary muscle level, echocardiographic strain analysis revealed no differences in radial and circumferential strain between LAD and LCx MIs. However, in contrast with the LCx MI, the LAD MI resulted in significantly decreased longitudinal strain. The proximal LAD MI model induces more LV remodeling and depressed LV function relative to the LCx MI model. Location of MI significantly impacts the severity of HF, thus careful consideration is required when choosing an MI model for preclinical HF studies.


Assuntos
Oclusão Coronária/complicações , Insuficiência Cardíaca/etiologia , Infarto do Miocárdio/etiologia , Animais , Angiografia Coronária , Oclusão Coronária/diagnóstico , Oclusão Coronária/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia Doppler em Cores , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Contração Miocárdica , Infarto do Miocárdio/diagnóstico , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Índice de Gravidade de Doença , Estresse Mecânico , Volume Sistólico , Suínos , Fatores de Tempo , Função Ventricular Esquerda , Remodelação Ventricular
9.
Cardiovasc Res ; 100(3): 432-40, 2013 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-24042016

RESUMO

AIMS: Induced pluripotent stem cell-derived cardiomyocytes (iPSCM) are regarded as promising cell type for cardiac cell replacement therapy. We investigated long-term electrophysiological integration and maturation of transplanted iPSCM, which are essential for therapeutic benefit. METHODS AND RESULTS: Murine iPSCM expressing enhanced green fluorescent protein and a puromycin resistance under control of the α-myosin heavy chain promoter were purified by antibiotic selection and injected into adult mouse hearts. After 6-12 days, 3-6 weeks, or 6-8 months, viable slices of recipient hearts were prepared. Slices were focally stimulated by a unipolar electrode placed in host tissue, and intracellular action potentials (APs) were recorded with glass microelectrodes in transplanted cells and neighbouring host tissue within the slices. Persistence and electrical integration of transplanted iPSCM into recipient hearts could be demonstrated at all time points. Quality of coupling improved, as indicated by a maximal stimulation frequency without conduction blocks of 5.77 ± 0.54 Hz at 6-12 days, 8.98 ± 0.38 Hz at 3-6 weeks and 10.82 ± 1.07 Hz at 6-8 months after transplantation. AP properties of iPSCM became more mature from 6-12 days to 6-8 months after transplantation, but still differed significantly from those of host APs. CONCLUSION: Transplanted iPSCM can persist in the long term and integrate electrically into host tissue, supporting their potential for cell replacement therapy. Quality of electrical integration improves between 6-12 days and 6-8 months after transplantation, and there are signs of an electrophysiological maturation. However, even after 6-8 months, AP properties of transplanted iPSCM differ from those of recipient cardiomyocytes.


Assuntos
Diferenciação Celular , Células-Tronco Pluripotentes Induzidas/transplante , Miócitos Cardíacos/transplante , Potenciais de Ação , Animais , Linhagem Celular , Sobrevivência Celular , Proteínas de Fluorescência Verde/biossíntese , Proteínas de Fluorescência Verde/genética , Células-Tronco Pluripotentes Induzidas/metabolismo , Masculino , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Miócitos Cardíacos/metabolismo , Cadeias Pesadas de Miosina/genética , Regiões Promotoras Genéticas , Fatores de Tempo , Transfecção , Miosinas Ventriculares/genética
10.
Circulation ; 128(5): 512-23, 2013 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-23804254

RESUMO

BACKGROUND: Pulmonary arterial hypertension (PAH) is characterized by dysregulated proliferation of pulmonary artery smooth muscle cells leading to (mal)adaptive vascular remodeling. In the systemic circulation, vascular injury is associated with downregulation of sarcoplasmic reticulum Ca(2+)-ATPase 2a (SERCA2a) and alterations in Ca(2+) homeostasis in vascular smooth muscle cells that stimulate proliferation. We, therefore, hypothesized that downregulation of SERCA2a is permissive for pulmonary vascular remodeling and the development of PAH. METHODS AND RESULTS: SERCA2a expression was decreased significantly in remodeled pulmonary arteries from patients with PAH and the rat monocrotaline model of PAH in comparison with controls. In human pulmonary artery smooth muscle cells in vitro, SERCA2a overexpression by gene transfer decreased proliferation and migration significantly by inhibiting NFAT/STAT3. Overexpresion of SERCA2a in human pulmonary artery endothelial cells in vitro increased endothelial nitric oxide synthase expression and activation. In monocrotaline rats with established PAH, gene transfer of SERCA2a via intratracheal delivery of aerosolized adeno-associated virus serotype 1 (AAV1) carrying the human SERCA2a gene (AAV1.SERCA2a) decreased pulmonary artery pressure, vascular remodeling, right ventricular hypertrophy, and fibrosis in comparison with monocrotaline-PAH rats treated with a control AAV1 carrying ß-galactosidase or saline. In a prevention protocol, aerosolized AAV1.SERCA2a delivered at the time of monocrotaline administration limited adverse hemodynamic profiles and indices of pulmonary and cardiac remodeling in comparison with rats administered AAV1 carrying ß-galactosidase or saline. CONCLUSIONS: Downregulation of SERCA2a plays a critical role in modulating the vascular and right ventricular pathophenotype associated with PAH. Selective pulmonary SERCA2a gene transfer may offer benefit as a therapeutic intervention in PAH.


Assuntos
Hipertensão Pulmonar/terapia , Monocrotalina/toxicidade , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/uso terapêutico , Animais , Células Cultivadas , Modelos Animais de Doenças , Regulação para Baixo/efeitos dos fármacos , Regulação para Baixo/genética , Hipertensão Pulmonar Primária Familiar , Técnicas de Transferência de Genes , Células HEK293 , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/enzimologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/efeitos dos fármacos , Miócitos de Músculo Liso/metabolismo , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/biossíntese , Resultado do Tratamento
11.
PLoS One ; 8(5): e59656, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23700403

RESUMO

AIMS: Mammalian myocardium has a finite but limited capacity to regenerate. Experimentally stimulating proliferation of cardiomyocytes with extracellular regeneration factors like periostin enhances cardiac repair in rodents. The aim of this study was to develop a safe method for delivering regeneration factors to the heart and to test the functional and structural effects of periostin peptide treatment in a large animal model of myocardial infarction (MI). METHODS AND RESULTS: We developed a controlled release system to deliver recombinant periostin peptide into the pericardial space. A single application of this method was performed two days after experimental MI in swine. Animals were randomly assigned to receive either saline or periostin peptide. Experimental groups were compared at baseline, day 2, 1 month and 3 months. Treatment with periostin peptide increased the EF from 31% to 41% and decreased by 22% the infarct size within 12 weeks. Periostin peptide-treated animals had newly formed myocardium strips within the infarct scar, leading to locally improved myocardial function. In addition the capillary density was increased in animals receiving periostin. However, periostin peptide treatment increased myocardial fibrosis in the remote region at one week and 12 weeks post-treatment. CONCLUSION: Our study shows that myocardial regeneration through targeted peptides is possible. However, in the case of periostin the effects on cardiac fibrosis may limit its clinical application as a viable therapeutic strategy.


Assuntos
Moléculas de Adesão Celular/farmacologia , Coração/fisiopatologia , Infarto do Miocárdio/fisiopatologia , Regeneração , Indutores da Angiogênese/administração & dosagem , Indutores da Angiogênese/efeitos adversos , Indutores da Angiogênese/farmacologia , Animais , Moléculas de Adesão Celular/administração & dosagem , Moléculas de Adesão Celular/efeitos adversos , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Sistemas de Liberação de Medicamentos , Feminino , Fibrose/induzido quimicamente , Esponja de Gelatina Absorvível , Coração/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/fisiologia , Miofibroblastos , Sus scrofa , Função Ventricular Esquerda/efeitos dos fármacos
12.
Int J Cardiol ; 164(2): 170-8, 2013 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-21764470

RESUMO

BACKGROUND: Treatment of heart failure patients with aldosterone antagonists has been shown to reduce the occurrence of sudden cardiac death. Therefore we aimed at determining the consequences of chronic exposure to aldosterone and the aldosterone antagonists eplerenone and spironolactone on the electrophysiological properties of the heart in a rat model. METHODS AND RESULTS: Male Wistar rats were chronically treated (4weeks) with aldosterone (ALD) via an osmotic minipump. Spironolactone (SPI) or eplerenone (EPL) was administered with the rat chow. ALD treated animals developed left ventricular hypertrophy, prolonged QT-intervals, a higher rate of ventricular premature beats and non-sustained ventricular tachycardia despite normal blood pressure values. Spironolactone and eplerenone were both able to inhibit the alterations. Left-ventricular mRNA expressions of Kv4.2 and Kv4.3 (Ito), Kv1.5 (IKur), Kir2.1 and Kir2.3 (IK1) and of Cav1.2 (L-type Ca(2+) channel) were significantly down-regulated in ALD. Correspondingly, the protein expressions of subunits Kv1.5, Kir2.3 and Cav1.2 were significantly decreased. A diminished calcineurin activity and mRNA expression of the Aß subunit of calcineurin were found in ALD, which was insensitive to aldosterone antagonists. CONCLUSIONS: Chronic aldosterone-overload induces blood pressure independent structural and electrical remodeling of the myocardium resulting in an increased risk for malignant ventricular arrhythmias.


Assuntos
Aldosterona/toxicidade , Hipertensão/fisiopatologia , Taquicardia Ventricular/induzido quimicamente , Taquicardia Ventricular/fisiopatologia , Remodelação Ventricular/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Animais , Masculino , Ratos , Ratos Wistar
13.
Cardiovasc Ther ; 31(2): 76-83, 2013 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22279967

RESUMO

For the past 40 years, beta-blockers have been widely used in cardiovascular medicine, reducing morbidity as well as mortality. Beta-blockers are currently used in a number of cardiovascular conditions such as systolic heart failure, postmyocardial infarction, and in prevention and treatment of arrhythmias. They are not recommended as the first line antihypertensive therapy, particularly in the elderly, unless there are specific indications. Despite the benefits of beta-blockers, tolerability concerns in patients with co-morbidities have limited their use. Some of these problems were overcome with the discovery of cardioselective beta-blockers. The third generation beta-blockers have additional properties of vasodilatation and advantages in terms of minimizing the adverse effects of beta-blockers. Some of the advantages include improvement of insulin resistance, decrease in cholesterol as well as alleviation of erectile dysfunction. Acute treatment with beta-blockers modifies local muscular metabolic properties and impairs endurance exercise capacity whereas the influence of chronic is debated controversially.


Assuntos
Antagonistas Adrenérgicos beta/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Doenças Cardiovasculares/tratamento farmacológico , Tolerância ao Exercício/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Antagonistas Adrenérgicos beta/efeitos adversos , Animais , Fármacos Cardiovasculares/efeitos adversos , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Comorbidade , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Recuperação de Função Fisiológica , Medição de Risco , Resultado do Tratamento
14.
Circ Heart Fail ; 6(2): 310-7, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-23271792

RESUMO

BACKGROUND: Heart failure is characterized by impaired function and disturbed Ca2+ homeostasis. Transgenic increases in inhibitor-1 activity have been shown to improve Ca2 cycling and preserve cardiac performance in the failing heart. The aim of this study was to evaluate the effect of activating the inhibitor (I-1c) of protein phosphatase 1 (I-1) through gene transfer on cardiac function in a porcine model of heart failure induced by myocardial infarction. METHODS AND RESULTS: Myocardial infarction was created by a percutaneous, permanent left anterior descending artery occlusion in Yorkshire Landrace swine (n=16). One month after myocardial infarction, pigs underwent intracoronary delivery of either recombinant adeno-associated virus type 9 carrying I-1c (n=8) or saline (n=6) as control. One month after myocardial infarction was created, animals exhibited severe heart failure demonstrated by decreased ejection fraction (46.4±7.0% versus sham 69.7±8.5%) and impaired (dP/dt)max and (dP/dt)min. Intracoronary injection of AAV9.I-1c prevented further deterioration of cardiac function and led to a decrease in scar size. CONCLUSIONS: In this preclinical model of heart failure, overexpression of I-1c by intracoronary in vivo gene transfer preserved cardiac function and reduced the scar size.


Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Terapia Genética/métodos , Vetores Genéticos , Insuficiência Cardíaca/terapia , Contração Miocárdica , Miocárdio/enzimologia , Proteína Fosfatase 1/biossíntese , Função Ventricular Esquerda , Remodelação Ventricular , Animais , Modelos Animais de Doenças , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/genética , Insuficiência Cardíaca/fisiopatologia , Humanos , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Proteína Fosfatase 1/genética , Recuperação de Função Fisiológica , Volume Sistólico , Suínos , Fatores de Tempo , Disfunção Ventricular Esquerda/enzimologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia , Disfunção Ventricular Esquerda/terapia , Pressão Ventricular
15.
Can J Physiol Pharmacol ; 90(12): 1591-8, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23210438

RESUMO

NOS-activation in erythrocytes (eryNOS) is impaired in patients suffering from type 2 diabetes. We investigated the effect of physical exercise on eryNOS activation and whether 6 week hypoxia interval training may alter this process. Male patients with diabetes mellitus type 2 (NIDDM, n = 12; age, 61.3 ± 8.4 years; BMI, 29.8 ± 3.7 kg/m(2)) underwent physical exercise training before and after 6 week hypoxia interval training. Training was conducted 4 times per week for 90 min at 15.4-12.7 Vol% of inspired oxygen. Vital parameters were recorded. Before hypoxia intervention, eryNOS phosphorylation at serine(1177) decreased significantly during exercise (basal 17.4 ± 12.0 compared with exercise 8.4 ± 9.2 arbitrary grey values (arGV); P < 0.05). After 6 weeks of hypoxia intervention, eryNOS-pSer(1177) (2.2 ± 2.5 arGV) was significantly lower at baseline. Ergometry showed an increase (7.6 ± 3.0 arGV; P < 0.05) followed by a decrease to almost baseline levels after 30 min (3.8 ± 1.5 arGV). Maximal exercise capacity and O(2)-uptake ([Formula: see text] max) increased significantly. The effects were independent from exercise-induced elevation of blood pressure. Exercise-dependent eryNOS phosphorylation at serine(1177) was increased similar to that described for the endothelium in diabetic patients. EryNOS dysregulation was partially restored after intermittent hypoxia training.


Assuntos
Pressão Sanguínea/fisiologia , Diabetes Mellitus Tipo 2/enzimologia , Eritrócitos/enzimologia , Exercício/fisiologia , Hipóxia/enzimologia , Óxido Nítrico Sintase/sangue , Aptidão Física/fisiologia , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Eritrócitos/metabolismo , Humanos , Hipóxia/sangue , Hipóxia/metabolismo , Masculino , Pessoa de Meia-Idade , Oxigênio/metabolismo , Consumo de Oxigênio , Fosforilação
16.
Echocardiography ; 29(9): 1091-5, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22672366

RESUMO

BACKGROUND: Accurate left ventricular stroke volume (LVSV) measurement is clinically important in patients presenting with acute myocardial infarction. Three-dimensional echocardiography (3DE) is expected to overcome limitations of two-dimensional echocardiography (2DE). However, inaccuracy in volumetry by 3DE has often been reported hindering further clinical application. This study aimed at comparing agreement and correlation with the thermodilution method (TDM) between 2DE and 3DE measurement of LVSV. METHODS: Swine model of myocardial infarction was created and LVSV was measured by 3DE by subtracting end-systolic from end-diastolic volume (3DE-method). Pulsed Doppler ultrasound and left ventricular outlet tract area were used to measure LVSV by 2DE (2DE-method). TDM was performed by the Swan-Ganz catheter. Bland-Altman analysis followed by assessment of intraclass correlation coefficient (ICC) were performed between 2DE-method and TDM as well as 3DE-method and TDM. RESULTS: A total of 25 comparisons revealed a significant overestimation of LVSV by the 2DE-method (bias = 6.5 mL; 95% confidence interval [CI], 3.9-9.0 mL; P < 0.0001), whereas there was no significant bias by the 3DE-method (bias =-1.6; 95% CI, -4.3 to 1.1 mL; P = 0.22). The ICC between 2DE and TDM was 0.49 (95% CI, 0.14-0.74) whereas ICC between 3DE and TDM was 0.75 (95% CI, 0.51-0.88). CONCLUSIONS: This study elucidated that LVSV is better estimated by 3DE-method compared to the conventional 2DE-method. This investigation will provide a more accurate, quick and noninvasive way of LVSV and cardiac output assessment at bedside by further application of 3DE.


Assuntos
Ecocardiografia Tridimensional/métodos , Ecocardiografia/métodos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/diagnóstico por imagem , Volume Sistólico , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/etiologia , Animais , Humanos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Suínos , Termodiluição/métodos
17.
Am J Physiol Heart Circ Physiol ; 302(7): H1423-8, 2012 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-22307667

RESUMO

Among the various cardiac contractility parameters, left ventricular (LV) ejection fraction (EF) and maximum dP/dt (dP/dt(max)) are the simplest and most used. However, these parameters are often reported together, and it is not clear if they are complementary or redundant. We sought to compare the discriminative value of EF and dP/dt(max) in assessing systolic dysfunction after myocardial infarction (MI) in swine. A total of 220 measurements were obtained. All measurements included LV volumes and EF analysis by left ventriculography, invasive ventricular pressure tracings, and echocardiography. Baseline measurements were performed in 132 pigs, and 88 measurements were obtained at different time points after MI creation. Receiver operator characteristic (ROC) curves to distinguish the presence or absence of an MI revealed a good predictive value for EF [area under the curve (AUC): 0.998] but not by dP/dt(max) (AUC: 0.69, P < 0.001 vs. EF). Dividing dP/dt(max) by LV end-diastolic pressure and heart rate (HR) significantly increased the AUC to 0.87 (P < 0.001 vs. dP/dt(max) and P < 0.001 vs. EF). In naïve pigs, the coefficient of variation of dP/dt(max) was twice than that of EF (22.5% vs. 9.5%, respectively). Furthermore, in n = 19 pigs, dP/dt(max) increased after MI. However, echocardiographic strain analysis of 23 pigs with EF ranging only from 36% to 40% after MI revealed significant correlations between dP/dt(max) and strain parameters in the noninfarcted area (circumferential strain: r = 0.42, P = 0.05; radial strain: r = 0.71, P < 0.001). In conclusion, EF is a more accurate measure of systolic dysfunction than dP/dt(max) in a swine model of MI. Despite the variability of dP/dt(max) both in naïve pigs and after MI, it may sensitively reflect the small changes of myocardial contractility.


Assuntos
Infarto do Miocárdio/fisiopatologia , Volume Sistólico/fisiologia , Disfunção Ventricular Esquerda/fisiopatologia , Pressão Ventricular/fisiologia , Animais , Área Sob a Curva , Pressão Sanguínea/fisiologia , Volume Cardíaco/fisiologia , Diástole/fisiologia , Frequência Cardíaca/fisiologia , Contração Miocárdica/fisiologia , Curva ROC , Suínos , Ultrassonografia , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/diagnóstico por imagem
18.
Int J Cardiovasc Imaging ; 28(7): 1671-81, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22231467

RESUMO

The aim of this study was to reveal the temporal and spatial changes of strain parameters during the progression of chronic coronary ischemia. Fourteen pigs received occluder implantation to create gradual ischemia (CI), while six pigs underwent a sham surgery (Control). Six pigs after myocardial infarction were also studied (MI). Strain analysis was performed using a speckle-tracking algorithm. Eleven of the 14 animals with occluder implantation had total occlusion of the left anterior descending artery with collaterals at 1 month (early occlusion group), whereas three pigs had occlusion at 3 months (late occlusion group). Both radial strain (RS) and circumferential strain (CS) of ischemic area deteriorated at 1 month in the early occlusion group and remained at the same level throughout the remaining 2 months of the experiment. In the late occlusion group, RS gradually declined, while CS took the same course as Control until the 2 month time point. Thereafter, both metrics reached the same level as the early occlusion group at the time of occlusion. Interestingly, RS in the remote area decreased moderately, whereas CS remained normal in CI pigs. The comparison between CI and MI revealed preserved CS at the ischemic area in CI pigs. Both RS and CS deteriorate by the time total coronary occlusion was established and remain at the same level thereafter. Altered RS in the remote area may be an indicator of remodeling in the non-ischemic area, whereas CS may be useful for distinguishing between transmural and non-transmural scar.


Assuntos
Contração Miocárdica , Infarto do Miocárdio/fisiopatologia , Isquemia Miocárdica/fisiopatologia , Função Ventricular Esquerda , Algoritmos , Animais , Fenômenos Biomecânicos , Doença Crônica , Modelos Animais de Doenças , Progressão da Doença , Ecocardiografia Doppler , Hemodinâmica , Interpretação de Imagem Assistida por Computador , Infarto do Miocárdio/diagnóstico por imagem , Isquemia Miocárdica/diagnóstico por imagem , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Estresse Mecânico , Volume Sistólico , Suínos , Fatores de Tempo , Pressão Ventricular
19.
Mol Ther ; 20(3): 565-71, 2012 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22215018

RESUMO

SERCA2a gene therapy improves contractile and energetic function of failing hearts and has been shown to be associated with benefits in clinical outcomes, symptoms, functional status, biomarkers, and cardiac structure in a phase 2 clinical trial. In an effort to enhance the efficiency and homogeneity of gene uptake in cardiac tissue, we examined the effects of nitroglycerin (NTG) in a porcine model following AAV1.SERCA2a gene delivery. Three groups of Göttingen minipigs were assessed: (i) group A: control intracoronary (IC) AAV1.SERCA2a (n = 6); (ii) group B: a single bolus IC injection of NTG (50 µg) immediately before administration of intravenous (IV) AAV1.SERCA2a (n = 6); and (iii) group C: continuous IV NTG (1 µg/kg/minute) during the 10 minutes of AAV1.SERCA2a infusion (n = 6). We found that simultaneous IV infusion of NTG and AAV1.SERCA2a resulted in increased viral transduction efficiency, both in terms of messenger RNA (mRNA) as well as SERCA2a protein levels in the whole left ventricle (LV) compared to control animals. On the other hand, IC NTG pretreatment did not result in enhanced gene transfer efficiency, mRNA or protein levels when compared to control animals. Importantly, the transgene expression was restricted to the heart tissue. In conclusion, we have demonstrated that IV infusion of NTG significantly improves cardiac gene transfer efficiency in porcine hearts.


Assuntos
Dependovirus/genética , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Miocárdio/metabolismo , Nitroglicerina/administração & dosagem , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/genética , Animais , Células Cultivadas , Circulação Coronária/efeitos dos fármacos , Expressão Gênica , Hemodinâmica/efeitos dos fármacos , Infusões Intra-Arteriais , Infusões Intravenosas , Masculino , Miócitos Cardíacos/metabolismo , Nitroglicerina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Suínos , Transdução Genética
20.
Mol Ther ; 20(1): 73-83, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21915102

RESUMO

Adeno-associated virus (AAV)-based vectors are promising gene delivery vehicles for human gene transfer. One significant obstacle to AAV-based gene therapy is the high prevalence of neutralizing antibodies in humans. Until now, it was thought that, except for nonhuman primates, pre-existing neutralizing antibodies are not a problem in small or large animal models for gene therapy. Here, we demonstrate that sera of several animal models of cardiovascular diseases harbor pre-existing antibodies against the cardiotropic AAV serotypes AAV1, AAV6, and AAV9 and against AAV2. The neutralizing antibody titers vary widely both between species and between serotypes. Of all species tested, rats displayed the lowest levels of neutralizing antibodies. Surprisingly, naive mice obtained directly from commercial vendors harbored neutralizing antibodies. Of the large animal models tested, the neutralization of AAV6 transduction by dog sera was especially pronounced. Sera of sheep and rabbits showed modest neutralization of AAV transduction whereas porcine sera strongly inhibited transduction by all AAV serotypes and displayed the largest variation between individual animals. Importantly, neutralizing antibody titers as low as 1/4 completely prevented in vivo transduction by AAV9 in rats. Our results suggest that prescreening of animals for neutralizing antibodies will be important for future gene transfer experiments in these animal models.


Assuntos
Anticorpos Neutralizantes/sangue , Anticorpos Neutralizantes/imunologia , Dependovirus/imunologia , Animais , Anticorpos Neutralizantes/isolamento & purificação , Dependovirus/classificação , Cães , Técnicas de Transferência de Genes , Vetores Genéticos/imunologia , Células HEK293 , Humanos , Masculino , Camundongos , Testes de Neutralização , Coelhos , Ratos , Ratos Sprague-Dawley , Sorotipagem , Ovinos/imunologia , Suínos/imunologia , Transdução Genética
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