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1.
Cardiovasc Res ; 81(2): 319-27, 2009 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-19015135

RESUMO

AIMS: Clinical studies suggest that intake of omega-3 polyunsaturated fatty acids (omega-3 PUFA) may lower the incidence of heart failure. Dietary supplementation with omega-3 PUFA exerts metabolic and anti-inflammatory effects that could prevent left ventricle (LV) pathology; however, it is unclear whether these effects occur at clinically relevant doses and whether there are differences between omega-3 PUFA from fish [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and vegetable sources [alpha-linolenic acid (ALA)]. METHODS AND RESULTS: We assessed the development of LV remodelling and pathology in rats subjected to aortic banding treated with omega-3 PUFA over a dose range that spanned the intake of humans taking omega-3 PUFA supplements. Rats were fed a standard food or diets supplemented with EPA+DHA or ALA at 0.7, 2.3, or 7% of energy intake. Without supplementation, aortic banding increased LV mass and end-systolic and -diastolic volumes. ALA supplementation had little effect on LV remodelling and dysfunction. In contrast, EPA+DHA dose-dependently increased EPA and DHA, decreased arachidonic acid in cardiac membrane phospholipids, and prevented the increase in LV end-diastolic and -systolic volumes. EPA+DHA resulted in a dose-dependent increase in the anti-inflammatory adipokine adiponectin, and there was a strong correlation between the prevention of LV chamber enlargement and plasma levels of adiponectin (r = -0.78). Supplementation with EPA+DHA had anti-aggregatory and anti-inflammatory effects as evidenced by decreases in urinary thromboxane B(2) and serum tumour necrosis factor-alpha. CONCLUSION: Dietary supplementation with omega-3 PUFA derived from fish, but not from vegetable sources, increased plasma adiponectin, suppressed inflammation, and prevented cardiac remodelling and dysfunction under pressure overload conditions.


Assuntos
Ácidos Graxos Ômega-3/administração & dosagem , Hipertensão/complicações , Inflamação/prevenção & controle , Óleo de Semente do Linho/administração & dosagem , Remodelação Ventricular/efeitos dos fármacos , Adenilato Quinase/metabolismo , Adiponectina/sangue , Animais , Fator Natriurético Atrial/genética , Relação Dose-Resposta a Droga , Hipertrofia Ventricular Esquerda/prevenção & controle , Masculino , Contração Miocárdica/efeitos dos fármacos , Cadeias Pesadas de Miosina/genética , Fosfolipídeos/análise , RNA Mensageiro/análise , Ratos , Ratos Wistar , Tromboxano B2/urina , Fator de Necrose Tumoral alfa/sangue , Função Ventricular Esquerda/efeitos dos fármacos
2.
Cardiology ; 112(4): 294-302, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-18832825

RESUMO

OBJECTIVES: beta-Blockers are standard therapy for patients with heart failure (HF). This study compared the effects of chronic monotherapy with 2 different beta(1)-selective adrenoceptor blockers, namely atenolol and metoprolol succinate, on left ventricular (LV) function and remodeling in dogs with coronary microembolization-induced HF [LV ejection fraction (EF) 30-40%]. METHODS: Twenty HF dogs were randomized to 3 months of therapy with atenolol (50 mg once daily, n = 6), metoprolol succinate (100 mg, once daily, n = 7) or to no therapy (control, n = 7). LV EF and volumes were measured before initiating therapy and after 3 months of therapy. The change (Delta) in EF and volumes between measurements before and after therapy was calculated and compared among study groups. RESULTS: In controls, EF decreased and end-systolic volume increased. Atenolol prevented the decrease in EF and the increase in ESV. In contrast, metoprolol succinate significantly increased EF and decreased end-systolic volume. DeltaEF was significantly higher and Deltaend-systolic volume significantly lower in metoprolol succinate-treated dogs compared to atenolol-treated dogs (EF: 6.0 +/- 0.86% vs. 0.8 +/- 0.85%, p < 0.05; end-systolic volume: -4.3 +/- 0.81 ml vs. -1 +/- 0.52 ml, p <0.05). CONCLUSIONS: In HF dogs, chronic therapy with atenolol does not elicit the same LV function and remodeling benefits as those achieved with metoprolol succinate.


Assuntos
Antagonistas Adrenérgicos beta/farmacologia , Atenolol/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Metoprolol/farmacologia , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Antagonistas Adrenérgicos beta/administração & dosagem , Animais , Atenolol/administração & dosagem , Modelos Animais de Doenças , Cães , Quimioterapia Combinada , Metoprolol/administração & dosagem , Distribuição Aleatória , Resultado do Tratamento
3.
Am J Physiol Heart Circ Physiol ; 295(6): H2475-82, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18952719

RESUMO

In anemic patients with heart failure (HF), erythropoietin-type drugs can elicit clinical improvement. This study examined the effects of chronic monotherapy with darbepoetin-alpha (DARB) on left ventricular (LV) function and remodeling in nonanemic dogs with advanced HF. HF [LV ejection fraction (EF) approximately 25%] was produced in 14 dogs by intracoronary microembolizations. Dogs were randomized to once a week subcutaneous injection of DARB (1.0 microg/kg, n=7) or to no therapy (HF, n=7). All procedures were performed during cardiac catheterization under general anesthesia and under sterile conditions. LV end-diastolic volume (EDV), end-systolic volume (ESV), and EF were measured before the initiation of therapy and at the end of 3 mo of therapy. mRNA and protein expression of caspase-3, hypoxia inducible factor-1alpha, and the bone marrow-derived stem cell marker c-Kit were determined in LV tissue. In HF dogs, EDV and ESV increased and EF decreased after 3 mo of followup. Treatment with DARB prevented the increase in EDV, decreased ESV, and increased EF. DARB therapy also normalized the expression of HIF-1alpha and active caspase-3 and enhanced the expression of c-Kit. We conclude that chronic monotherapy with DARB prevents progressive LV dysfunction and dilation in nonanemic dogs with advanced HF. These results suggest that DARB elicits beneficial effects in HF that are independent of the presence of anemia.


Assuntos
Cardiotônicos/farmacologia , Eritropoetina/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , Disfunção Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos , Anemia/tratamento farmacológico , Anemia/etiologia , Animais , Células da Medula Óssea/patologia , Cardiotônicos/administração & dosagem , Caspase 3/genética , Caspase 3/metabolismo , Darbepoetina alfa , Modelos Animais de Doenças , Progressão da Doença , Cães , Eritropoetina/administração & dosagem , Eritropoetina/farmacologia , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Hematínicos/farmacologia , Células-Tronco Hematopoéticas/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Injeções Subcutâneas , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas Proto-Oncogênicas c-kit/genética , Proteínas Proto-Oncogênicas c-kit/metabolismo , RNA Mensageiro/metabolismo , Volume Sistólico/efeitos dos fármacos , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/patologia , Disfunção Ventricular Esquerda/fisiopatologia
4.
Am J Physiol Heart Circ Physiol ; 295(5): H2098-105, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18820029

RESUMO

When recovering from heart failure (HF), the myocardium displays a marked plasticity and can regain normal gene expression and function; however, recovery of substrate oxidation capacity has not been explored. We tested whether cardiac functional recovery is matched by normalization of energy substrate utilization during post-HF recovery. HF was induced in dogs by pacing the left ventricle (LV) at 210-240 beats/min for 4 wk. Tachycardia was discontinued, and the heart was allowed to recover. An additional group was studied in HF, and healthy dogs served as controls (n = 8/group). Cardiac free fatty acids (FFAs) and glucose oxidation were measured with [3H]oleate and [14C]glucose. At 10 days of recovery, hemodynamic parameters returned to control values; however, the contractile response to dobutamine remained depressed, LV end-diastolic volume was 28% higher than control, and the heart mass-to-body mass ratio was increased (9.8 +/- 0.4 vs. 7.5 +/- 0.2 g/kg, P < 0.05). HF increased glucose oxidation (76.8 +/- 19.7 nmol.min(-1).g(-1)) and decreased FFA oxidation (20.7 +/- 6.4 nmol.min(-1).g(-1)), compared with normal dogs (24.5 +/- 6.3 and 51.7 +/- 9.6 nmol.min(-1).g(-1), respectively), and reversed to normal values at 10 days of recovery (25.4 +/- 6.0 and 46.6 +/- 6.7 nmol.min(-1).g(-1), respectively). However, similar to HF, the recovered dogs failed to increase glucose and fatty acid uptake in response to pacing stress. The activity of myocardial citrate synthase and aconitase was significantly decreased during recovery compared with that in control dogs (58 and 27% lower, respectively, P < 0.05), indicating a persistent reduction in mitochondrial oxidative capacity. In conclusion, cardiac energy substrate utilization is normalized in the early stage of post-HF recovery at baseline, but not under stress conditions.


Assuntos
Metabolismo Energético , Insuficiência Cardíaca/fisiopatologia , Hemodinâmica , Mitocôndrias Cardíacas/metabolismo , Miocárdio/metabolismo , Aconitato Hidratase/metabolismo , Acil-CoA Desidrogenase/metabolismo , Agonistas Adrenérgicos beta/farmacologia , Animais , Estimulação Cardíaca Artificial , Citrato (si)-Sintase/metabolismo , Modelos Animais de Doenças , Cães , Ácidos Graxos não Esterificados/metabolismo , Glucose/metabolismo , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/metabolismo , Hemodinâmica/efeitos dos fármacos , Masculino , Mitocôndrias Cardíacas/enzimologia , Contração Miocárdica , Miocárdio/enzimologia , Miocárdio/patologia , Oxirredução , Recuperação de Função Fisiológica , Fatores de Tempo , Ultrassonografia , Remodelação Ventricular
5.
Am J Physiol Heart Circ Physiol ; 295(5): H2149-55, 2008 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18820026

RESUMO

Acute intravenous infusion of ranolazine (Ran), an anti-ischemic/antiangina drug, was previously shown to improve left ventricular (LV) ejection fraction (EF) without a concomitant increase in myocardial oxygen consumption in dogs with chronic heart failure (HF). This study examined the effects of treatment with Ran alone and in combination with metoprolol (Met) or enalapril (Ena) on LV function and remodeling in dogs with HF. Dogs (n = 28) with microembolization-induced HF were randomized to 3 mo oral treatment with Ran alone [375 mg twice daily (bid); n = 7], Ran (375 mg bid) in combination with Met tartrate (25 mg bid; n = 7), Ran (375 mg bid) in combination with Ena (10 mg bid; n = 7), or placebo (PL; Ran vehicle bid; n = 7). Ventriculographic measurements of LV end-diastolic volume (EDV) and end-systolic volume (ESV) and LV EF were obtained before treatment and after 3 mo of treatment. In PL-treated dogs, EDV and ESV increased significantly. Ran alone prevented the increase in EDV and ESV seen in the PL group and significantly increased EF, albeit modestly, from 35 +/- 1% to 37 +/- 2%. When combined with either Ena or Met, Ran prevented the increase in EDV, significantly decreased ESV, and markedly increased EF compared with those of PL. EF increased from 35 +/- 1% to 40 +/- 1% with Ran + Ena and from 34 +/- 1% to 41 +/- 1% with Ran + Met. Ran alone or in combination with Ena or Met was also associated with beneficial effects at the cellular level on histomorphometric parameters such as hypertrophy, fibrosis, and capillary density as well as the expression for pathological hypertrophy and Ca2+ cycling genes. In conclusion, Ran prevented progressive LV dysfunction and global and cellular myocardial remodeling, and Ran in combination with Ena or Met improved LV function beyond that observed with Ran alone.


Assuntos
Acetanilidas/farmacologia , Antagonistas Adrenérgicos beta/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Cardiotônicos/farmacologia , Enalapril/farmacologia , Insuficiência Cardíaca/tratamento farmacológico , Metoprolol/farmacologia , Piperazinas/farmacologia , Disfunção Ventricular Esquerda/prevenção & controle , Remodelação Ventricular/efeitos dos fármacos , Animais , Modelos Animais de Doenças , Progressão da Doença , Cães , Quimioterapia Combinada , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Miocárdio/metabolismo , Miocárdio/patologia , Proteínas/metabolismo , Ranolazina , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
6.
J Hypertens ; 26(7): 1402-10, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18551017

RESUMO

OBJECTIVE: Sugar consumption affects insulin release and, in hypertension, may stimulate cardiac signaling mechanisms that accelerate left ventricular hypertrophy and the development of heart failure. We investigated the effects of high-fructose or sucrose diets on ventricular function and mortality in hypertensive Dahl salt-sensitive rats. METHODS: Rats were fed chows that were either high starch (70% starch, 10% fat by energy), high fat (20% carbohydrates, 60% fat), high fructose (61% fructose, 9% starch, 10% fat), or high sucrose (61% sucrose, 9% starch, 10% fat). Hypertension was induced by adding 6% salt to the chow (n = 8-11/group). RESULTS: After 8 weeks of treatment, systolic blood pressure and left ventricular mass were similarly increased in all rats that were fed high-salt diets. Hypertension caused a switch in mRNA myosin heavy chain isoform from alpha to beta, and this effect was greater in the high-salt sucrose and fructose groups than in starch and fat groups. The cardiac mRNA for atrial natriuretic factor was also increased in all high-salt groups compared to respective controls, with the increase being significantly greater in the hypertensive sucrose fed group. Mortality was greater in the sucrose group (44%) compared to all the other hypertensive groups (12-18%), as was cardiomyocyte apoptosis. Left ventricular ejection fraction was lower in the high-salt sucrose group, which was due to an increase in end-systolic volume, and not increased end-diastolic volume. CONCLUSION: Diets high in sugar accelerated cardiac systolic dysfunction and mortality in hypertension compared to either a low-carbohydrate/high-fat or high-starch diet.


Assuntos
Sacarose Alimentar/efeitos adversos , Hipertensão/fisiopatologia , Sódio na Dieta/efeitos adversos , Disfunção Ventricular Esquerda/etiologia , Animais , Carboidratos da Dieta/efeitos adversos , Gorduras na Dieta/efeitos adversos , Modelos Animais de Doenças , Frutose , Hipertensão/complicações , Hipertensão/etiologia , Hipertensão/mortalidade , Hipertrofia Ventricular Esquerda/etiologia , Masculino , Ratos , Ratos Endogâmicos Dahl , Sacarose , Sístole , Disfunção Ventricular Esquerda/mortalidade
7.
J Am Coll Cardiol ; 50(6): 551-7, 2007 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-17678740

RESUMO

OBJECTIVES: This study examined the effects of long-term monotherapy with rosuvastatin (RSV) on the progression of left ventricular (LV) dysfunction and remodeling in dogs with heart failure (HF). BACKGROUND: 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or "statins" possess other noncholesterol-lowering properties that include inhibiting proinflammatory cytokines, attenuating LV hypertrophy, and stimulating the release of bone marrow-derived stem cells (BMSCs). METHODS: Twenty-one dogs with microembolization-induced HF were randomized to 3 months oral monotherapy with low-dose (LD) RSV (0.5 mg/kg once daily, n = 7), high-dose (HD) RSV (3.0 mg/kg once daily, n = 7), or to no therapy (control group, n = 7). The change (Delta) from pre- to post-therapy (treatment effect) in LV end-diastolic volume (EDV) and end-systolic volume (ESV) and ejection fraction (EF) was measured. Protein level of tumor necrosis factor (TNF)-alpha in LV tissue and the number of circulating Sca-1-positive BMSCs was also determined. Blood and LV tissue from 6 normal dogs was obtained and used for comparison. RESULTS: There were no differences in DeltaEDV, DeltaESV, and DeltaEF between control group and LD RSV. In contrast, DeltaEDV and DeltaESV were significantly lower, and DeltaEF was significantly higher in HD RSV compared with control group. High-dose, but not LD, RSV also normalized protein levels of TNF-alpha and was associated with a significant increase in the number of circulating BMSCs. CONCLUSIONS: In dogs with HF, chronic therapy with HD RSV prevents progressive LV dysfunction and dilation. This benefit may be partly derived from normalization of TNF-alpha expression and partly from increased mobilization of BMSCs.


Assuntos
Fluorbenzenos/administração & dosagem , Insuficiência Cardíaca/tratamento farmacológico , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Disfunção Ventricular Esquerda/tratamento farmacológico , Remodelação Ventricular/efeitos dos fármacos , Animais , Angiografia Coronária , Cães , Insuficiência Cardíaca/diagnóstico por imagem , Insuficiência Cardíaca/patologia , Células-Tronco Hematopoéticas/metabolismo , Metaloproteinase 2 da Matriz/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Rosuvastatina Cálcica , Resultado do Tratamento , Fator de Necrose Tumoral alfa/metabolismo , Disfunção Ventricular Esquerda/diagnóstico por imagem , Disfunção Ventricular Esquerda/patologia
8.
J Am Coll Cardiol ; 49(21): 2120-8, 2007 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-17531662

RESUMO

OBJECTIVES: This study examined the effects of long-term delivery of cardiac contractility modulation (CCM) electric signals on left ventricular (LV) function and global, cellular, and molecular remodeling in dogs with chronic heart failure (HF). BACKGROUND: Acute studies in dogs with experimentally induced HF showed that CCM signals applied to the failing myocardium during the absolute refractory period improved LV function without increasing myocardial oxygen consumption. METHODS: In one study, dogs with intracoronary microembolization-induced HF were randomized to 3 months of active CCM monotherapy or to a sham-operated control group. In another study, 19 HF dogs were randomized to 3 months chronic monotherapy with extended release metoprolol succinate (MET-ER), MET-ER with CCM, or no therapy at all (control group). RESULTS: In CCM-only treated dogs, LV ejection fraction (EF) increased (27 +/- 1% vs. 33 +/- 1%, p < 0.0001) compared with a decrease in sham-operated control animals (27 +/- 1% vs. 23 +/- 1%, p < 0.001). The increase in EF seen with CCM-treated dogs was accompanied by reduced LV volumes, improved myocardial structure, reversal of the maladaptive fetal gene program, and an improvement in sarcoplasmic reticulum calcium cycling proteins. Dogs treated with a combination of MET-ER and CCM showed a greater increase in LV EF and a greater reversal of LV global, structural, and biochemical remodeling compared with dogs treated with MET-ER alone. CONCLUSIONS: In dogs with HF, long-term CCM therapy improves LV systolic function. The improvements are additive to those seen with beta-blockers. These findings are further strengthened by the concomitant benefits of CCM therapy on LV global, cellular, and biochemical remodeling.


Assuntos
Cardioversão Elétrica/métodos , Insuficiência Cardíaca/terapia , Contração Miocárdica , Disfunção Ventricular Esquerda/terapia , Remodelação Ventricular , Antagonistas Adrenérgicos beta/farmacologia , Animais , Desfibriladores Implantáveis , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/fisiopatologia , Metoprolol/análogos & derivados , Metoprolol/farmacologia , Distribuição Aleatória , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/patologia
9.
Cardiovasc Drugs Ther ; 21(1): 29-36, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17294127

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPARgamma) activators affect the myocardium through inhibition of inflammatory cytokines and metabolic modulation but their effect in the progression of heart failure is unclear. In the present study, we examined the effects of the PPARgamma activator, GW347845 (GW), on the progression of heart failure. METHODS AND RESULTS: Heart failure was produced in 21 dogs by intracoronary microembolizations to LV ejection fraction (EF) less than 30% and randomized to 3 months of therapy with high-dose GW (10 mg/Kg daily, n = 7), low-dose GW (3 mg/Kg daily, n = 7), or no therapy (control, n = 7). In control dogs, EF significantly decreased (28 +/- 1 vs. 22 +/- 1%, p < 0.001) and end-diastolic volume (EDV) and end-systolic volume (ESV) increased during the 3 months of the follow-up period (64 +/- 4 vs. 76 +/- 5; p = 0.003, 46 +/- 3 vs. 59 +/- 4 ml, p = 0.002, respectively). In dogs treated with low-dose GW, EDV increased significantly (69 +/- 4 vs.81 +/- 5 ml, p = 0.01), whereas ESV remained statistically unchanged (50 +/- 3 vs. 54 +/- 3 ml, p = 0.10) resulting in modestly increased ejection fraction (27 +/- 1 vs. 32 +/- 3%, p = 0.05). In dogs treated with high-dose GW, both EDV and ESV increased (72 +/- 4 vs. 79 +/- 5 ml, p = 0.04; 53 +/- 3 vs. 62 +/- 5 ml, p = 0.04) and EF decreased (26 +/- 1 vs. 23 +/- 1%, p = 0.04) as with control dogs. There was significantly increased myocardial hypertrophy as evidenced by increased LV weight to body weight ratio and myocyte cross-section area in the GW treated animals compared to controls. Compared to control, treatment with GW had no effect on mRNA expression of PPARgamma, inflammatory cytokines, stretch response proteins, or transcription factors that may induce hypertrophy. CONCLUSIONS: Long-term PPARgamma activation with GW did not prevent progressive LV remodeling in dogs with advanced heart failure.


Assuntos
Insuficiência Cardíaca/fisiopatologia , PPAR gama/agonistas , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Administração Oral , Animais , Fator Natriurético Atrial/genética , Peso Corporal/efeitos dos fármacos , Citocinas/genética , Modelos Animais de Doenças , Cães , Relação Dose-Resposta a Droga , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/tratamento farmacológico , Frequência Cardíaca/efeitos dos fármacos , Miocárdio/metabolismo , Miocárdio/patologia , Tamanho do Órgão/efeitos dos fármacos , PPAR gama/genética , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Proteínas Quinases/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Volume Sistólico/efeitos dos fármacos , Serina-Treonina Quinases TOR , Remodelação Ventricular/fisiologia , Proteínas Quinases p38 Ativadas por Mitógeno/genética
10.
J Mol Cell Cardiol ; 42(1): 150-8, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-17070837

RESUMO

We used isolated cardiomyocytes to investigate a possible role of mitochondrial permeability transition pore in mitochondrial abnormalities associated with heart failure. Cardiomyocytes were isolated from LV myocardium of normal control dogs and dogs with heart failure produced by intracoronary microembolizations. Mitochondrial permeability transition was measured in isolated cardiomyocytes with intact sarcolemma with and without 0.2 microM cyclosporin A using calcein AM and the fluorometer. State-3 mitochondrial respiration was also measured with the Clark electrode. Mitochondrial membrane potential was measured with JC-1 probe using the fluorometer. Propidium iodide was used to ensure sarcolemma integrity. 200 min after loading with calcein AM, mitochondria of failing cardiomyocytes showed only 50% of maximal level of calcein fluorescence while it remained unchanged in normal cells. The mitochondrial membrane potential in failing cardiomyocytes was significantly decreased by 38% compared to normal cardiomyocytes. Cyclosporine A significantly slowed the exit of calcein from mitochondria of failing cardiomyocytes and increased mitochondrial membrane potential by 29%. State-3 respiration was not affected with cyclosporine A in normal cardiomyocytes while it was significantly increased in failing cardiomyocytes by 20%. Exit of calcein (m.w. 1.0 kDa) from mitochondria of viable failing cardiomyocytes with intact sarcolemma suggests an existence of a reversible transitory permeability transition opening in high conductance mode. Attenuation of calcein exit, DeltaPsi(m) and improvement of state-3 respiration achieved with CsA (0.2 microM) show that permeability transition opening could be a cause of mitochondrial dysfunction described in the failing heart.


Assuntos
Ciclosporina/farmacologia , Insuficiência Cardíaca/metabolismo , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Animais , Respiração Celular/efeitos dos fármacos , Modelos Animais de Doenças , Cães , Técnicas In Vitro , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/efeitos dos fármacos , Proteínas de Transporte da Membrana Mitocondrial/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Sarcolema/metabolismo
11.
Cardiovasc Drugs Ther ; 21(1): 9-15, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17119875

RESUMO

BACKGROUND: Inhibition of myocardial fatty acid oxidation has been suggested as a therapeutic approach for improving cardiac function in chronic heart failure (HF). The novel piperazine derivative CVT-4325 was shown to inhibit fatty acid oxidation in cardiac mitochondria and in isolated perfused rat hearts. In the present study, we tested the hemodynamic and metabolic effects of acute intravenous CVT-4325 in dogs with HF. METHODS AND RESULTS: HF (LV ejection fraction

Assuntos
Ácidos Graxos/metabolismo , Insuficiência Cardíaca/fisiopatologia , Miocárdio/metabolismo , Oxidiazóis/farmacologia , Consumo de Oxigênio/efeitos dos fármacos , Função Ventricular Esquerda/efeitos dos fármacos , Animais , Doença Crônica , Modelos Animais de Doenças , Cães , Ácidos Graxos/farmacocinética , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/metabolismo , Injeções Intravenosas , Miocárdio/química , Oxidiazóis/administração & dosagem , Oxidiazóis/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Volume Sistólico/efeitos dos fármacos
12.
Hypertension ; 48(6): 1116-23, 2006 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-17060511

RESUMO

The effects of dietary fat intake on the development of left ventricular hypertrophy and accompanying structural and molecular remodeling in response to hypertension are not understood. The present study compared the effects of a high-fat versus a low-fat diet on development of left ventricular hypertrophy, remodeling, contractile dysfunction, and induction of molecular markers of hypertrophy (ie, expression of mRNA for atrial natriuretic factor and myosin heavy chain beta). Dahl salt-sensitive rats were fed either a low-fat (10% of total energy from fat) or a high-fat (60% of total energy from fat) diet on either low-salt or high-salt (6% NaCl) chow for 12 weeks. Hearts were analyzed for mRNA markers of ventricular remodeling and activities of the mitochondrial enzymes citrate synthase and medium chain acyl-coenzyme A dehydrogenase. Similar levels of hypertension were achieved with high-salt feeding in both diet groups (systolic pressure of approximately 190 mm Hg). In hypertensive rats fed low-fat chow, left ventricular mass, myocyte cross-sectional area, and end-diastolic volume were increased, and ejection fraction was decreased; however, these effects were not observed with the high-fat diet. Hypertensive animals on low-fat chow had increased atrial natriuretic factor mRNA, myosin heavy chain isoform switching (alpha to beta), and decreased activity of citrate synthase and medium chain acyl-coenzyme A dehydrogenase, which were all attenuated by high-fat feeding. In conclusion, increased dietary lipid intake can reduce cardiac growth, left ventricular remodeling, contractile dysfunction, and alterations in gene expression in response to hypertension.


Assuntos
Dieta com Restrição de Carboidratos , Dieta com Restrição de Gorduras , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Animais , Fator Natriurético Atrial/biossíntese , Pressão Sanguínea/fisiologia , Modelos Animais de Doenças , Expressão Gênica , Coração , Hipertensão/genética , Hipertrofia Ventricular Esquerda/genética , Contração Miocárdica/fisiologia , Cadeias Pesadas de Miosina/biossíntese , Ratos , Ratos Endogâmicos Dahl , Remodelação Ventricular/fisiologia
14.
Heart Fail Rev ; 10(2): 141-7, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16258721

RESUMO

Progressive left ventricular (LV) dilation in the setting of heart failure is associated with increased mortality and morbidity. The Acorn Cardiac Support Device (CSD, Acorn Cardiovascular, Inc., St. Paul, MN) is a preformed polyester device that is surgically placed over the cardiac ventricles, anchored to the AV-groove and tailored anteriorly to fit snugly over the epicardial surface of the heart. The CSD was shown to prevent progressive LV enlargement and, indeed, reduce LV size and attenuate global LV remodeling in both animal models of experimentally-induced heart failure as well as in patients with advanced heart failure. This review will examine the CSD from two histologic perspectives namely, (1) the interaction of the CSD with the epicardial surface of the heart and (2) the effects of long-term therapy with the CSD on cellular remodeling. The review will be based on available pre-clinical data generated in dogs with coronary microembolization-induced heart failure that underwent long-term (3 and 6 months) monotherapy with the CSD. The data will show that long-term implantation leads to encapsulation of the CSD by connective tissue that matures with time and that does not invade the underlying myocardium. Furthermore that implantation of the CSD has no adverse impact on epicardial coronary vessel. At the cellular level, existing data will show that long-term monotherapy with the CSD is associated with reduced cardiomyocyte hypertrophy, reduced volume fraction of replacement and interstitial fibrosis, normalization of capillary density and oxygen diffusion distance and attenuation of cardiomyocyte apoptosis. The outcomes strongly argue in favor of a structural modification of the failing myocardium by CSD therapy that is consistent with "reverse cellular remodeling".


Assuntos
Insuficiência Cardíaca/patologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/patologia , Coração Auxiliar , Animais , Modelos Animais de Doenças , Cães , Insuficiência Cardíaca/fisiopatologia , Remodelação Ventricular/fisiologia
15.
Heart Fail Rev ; 10(2): 149-55, 2005 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16258722

RESUMO

Abnormal Ca(2+)-homeostasis is a hall-marked characteristic of the failing heart. In the normal myocardium, the sarcoplasmic reticulum (SR) is a principal organelle that controls intracellular Ca(2+) concentration during the cardiac cycle. The SR consists of longitudinal and terminal cisternea regions. The former contains the Ca(2+)-ATPase pump or SERCA-2a whose function is to transport cytosolic Ca(2+) into the lumen of the SR during diastole and whose activity is regulated by reversible phosphorylation of the endogenously SR-bound phospholamban (PLB). The SR's terminal cisternea region contains ryanodine-sensitive Ca(2+)-release channels (RR), the activity of which is regulated by direct and indirect reversible phosphorylation. These channels release the SR-stored Ca(2+) during contraction. We have shown that in left ventricular (LV) myocardium from dogs with coronary microembolization-induced heart failure, ability of the SR to sequester and release Ca(2+) during the cardiac cycles is impaired. This abnormality was associated with reduced expression (protein and mRNA) levels of Ca(2+)-ATPase, PLB, and reduced PLB phosphorylation. Long-term therapy with the Acorn Cardiac Support Device (CSD) is associated with restoration of the ability of the SR to sequester Ca(2+). This improvement in SR function following chronic CSD therapy was due primarily to increased affinity of the SERCA-2a for calcium. The later was associated with (1) increased phosphorylation of PLB at serine 16 and threonine 17, (2) unchanged protein expression of PLB and (3) unchanged protein expression of SERCA-2a in LV myocardium of CSD-treated dogs compared to controls. This review summarizes our current understanding of the role of the CSD in modulating SR calcium cycling in an experimental canine model of chronic heart failure produced by multiple sequential intracoronary microembolizations.


Assuntos
Sinalização do Cálcio/fisiologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Coração Auxiliar , Retículo Sarcoplasmático/fisiologia , Animais , Modelos Animais de Doenças , Cães , Humanos , Mecanotransdução Celular/fisiologia , Remodelação Ventricular/fisiologia
16.
Heart Fail Rev ; 10(4): 297-303, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16583178

RESUMO

In the setting of chronic heart failure (HF), progressive left ventricular (LV) dysfunction and chamber remodeling may be due, in part, to altered expression and disorganization of cytoskeletal, linkage and extracellular proteins. This brief review describes changes in expression of cytoskeletal, linkage and extracellular protein using LV tissue obtained from dogs with progressive HF produced by multiple sequential intracoronary microembolizations. LV tissue samples from 6 untreated HF dogs (LV ejection fraction 20% to 25%) and 3 normal dogs were used. Sections from freshly frozen tissue were prepared, immunostained for specific proteins and studies by confocal microscopy. In failing hearts, confocal microscopy showed disorganization of key cytoskeletal proteins that, when combined with the loss of myofilaments and sarcomeric skeleton, suggest substantial cardiomyocyte remodeling. Cardiomyocytes in areas bordering old infarcts invariably exhibited disorganization of alpha-actinin. The cytoskeleton protein desmin showed increased expression in areas of extensive fibrosis. Staining for pancadherin showed interruptions of intercalated disks in areas of intensive interstitial fibrosis. Observation of increased fibronectin and increased interstitial cellularity based on vimentin labeling is suggestive of ongoing fibrosis. Based on these findings, we conclude that the structural changes observed in failing LV myocardium of dogs with intracoronary microembolizations-induced HF are extensive and typical of those seen and previously described in LV myocardium of explanted failed human hearts. The observed structural changes in this experimental model of HF also support the notion that these cytoskeletal, linkage and extracellular disorganization of structural proteins may be important maladaptations that contribute, albeit in part, to the progression of LV dysfunction and remodeling characteristic of the HF state.


Assuntos
Proteínas do Citoesqueleto/biossíntese , Proteínas da Matriz Extracelular/biossíntese , Insuficiência Cardíaca/metabolismo , Miocárdio/metabolismo , Miocárdio/patologia , Animais , Doença Crônica , Corantes , Proteínas Contráteis/biossíntese , Modelos Animais de Doenças , Cães , Amarelo de Eosina-(YS) , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Hematoxilina , Imuno-Histoquímica , Miocárdio/citologia , Miócitos Cardíacos/metabolismo , Coloração e Rotulagem , Volume Sistólico , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologia
17.
Heart Fail Rev ; 10(4): 305-10, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16583179

RESUMO

BACKGROUND: We previously showed that mitochondrial respiratory function is abnormal in dogs with chronic heart failure (HF). Mitochondrial permeability transition pores (MPTP) can affect mitochondrial inner membrane potential (DeltaPsim) and mitochondrial function in normal cardiomyocytes. The potential impact of MPTP on DeltaPsim and mitochondrial respiratory function in HF has not yet been determined. We tested the hypothesis that cyclosporine A, a potent blocker of the MPTP, can improve mitochondrial function in HF. METHODS: Cardiomyocytes were isolated from the left ventricular myocardium of 7 dogs with HF produced by intracoronary microembolizations and from 7 normal dogs. Cardiomyocytes were treated for 24 hours with cyclosporine A. DeltaPsim, cytochrome c oxidase protein expression, mitochondrial cytochrome c oxidase-dependent respiration (CDOR) and ATP synthesis were measured. RESULTS: DeltaPsim, protein expression of cytochrome c oxidase, CDOR and the rate of ATP synthesis were decreased in HF compared to normal controls. Inhibition of MPTP in failing cardiomyocytes with low dose of cyclosporine A (0.2 microM) increased DeltaPsim, preserved expression of cytochrome c oxidase, improved CDOR and the rate of ATP synthesis. CONCLUSION: MPTP opening contributes to the loss of mitochondrial function observed in the failing heart. Inhibition of MPTP opening represents a potential therapeutic target for the treatment of HF.


Assuntos
Trifosfato de Adenosina/biossíntese , Ciclosporina/farmacologia , Complexo IV da Cadeia de Transporte de Elétrons/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Insuficiência Cardíaca/metabolismo , Proteínas de Transporte da Membrana Mitocondrial/antagonistas & inibidores , Miócitos Cardíacos/efeitos dos fármacos , Animais , Respiração Celular/efeitos dos fármacos , Doença Crônica , Modelos Animais de Doenças , Cães , Complexo IV da Cadeia de Transporte de Elétrons/biossíntese , Insuficiência Cardíaca/fisiopatologia , Ventrículos do Coração/metabolismo , Ventrículos do Coração/patologia , Potenciais da Membrana/efeitos dos fármacos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/metabolismo , Poro de Transição de Permeabilidade Mitocondrial , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/metabolismo , Disfunção Ventricular Esquerda/metabolismo
18.
Circ Res ; 93(11): 1095-101, 2003 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-14563716

RESUMO

Passive mechanical containment of failing left ventricle (LV) with the Acorn Cardiac Support Device (CSD) was shown to prevent progressive LV dilation in dogs with heart failure (HF) and increase ejection fraction. To examine possible mechanisms for improved LV function with the CSD, we examined the effect of CSD therapy on the expression of cardiac stretch response proteins, myocyte hypertrophy, sarcoplasmic reticulum Ca2+-ATPase activity and uptake, and mRNA gene expression for myosin heavy chain (MHC) isoforms. HF was produced in 12 dogs by intracoronary microembolization. Six dogs were implanted with the CSD and 6 served as concurrent controls. LV tissue from 6 normal dogs was used for comparison. Compared with normal dogs, untreated HF dogs showed reduced cardiomyocyte contraction and relaxation, upregulation of stretch response proteins (p21ras, c-fos, and p38 alpha/beta mitogen-activated protein kinase), increased myocyte hypertrophy, reduced SERCA2a activity with unchanged affinity for calcium, reduced proportion of mRNA gene expression for alpha-MHC, and increased proportion of beta-MHC. Therapy with the CSD was associated with improved cardiomyocyte contraction and relaxation, downregulation of stretch response proteins, attenuation of cardiomyocyte hypertrophy, increased affinity of the pump for calcium, and restoration of alpha- and beta-MHC isoforms ratio. The results suggest that preventing LV dilation and stretch with the CSD promotes downregulation of stretch response proteins, attenuates myocyte hypertrophy and improves SR calcium cycling. These data offer possible mechanisms for improvement of LV function after CSD therapy.


Assuntos
Procedimentos Cirúrgicos Cardíacos , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/terapia , Ventrículos do Coração/fisiopatologia , Implantes Experimentais , Animais , Cálcio/metabolismo , Proteínas de Ligação ao Cálcio/metabolismo , ATPases Transportadoras de Cálcio/metabolismo , Cardiomegalia/metabolismo , Cardiomegalia/prevenção & controle , Tamanho Celular , Doença Crônica , Modelos Animais de Doenças , Cães , Estimulação Elétrica , Insuficiência Cardíaca/complicações , Ventrículos do Coração/cirurgia , Microesferas , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Contração Miocárdica , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , RNA Mensageiro/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático , Estresse Mecânico , Volume Sistólico , Resultado do Tratamento , Disfunção Ventricular Esquerda/etiologia , Miosinas Ventriculares/genética , Miosinas Ventriculares/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
19.
J Vasc Surg ; 38(4): 827-32, 2003 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-14560237

RESUMO

OBJECTIVE: Discrete morphologic, enzymatic and functional changes in skeletal muscle mitochondria have been demonstrated in patients with peripheral arterial disease (PAD). We examined mitochondrial respiration in the gastrocnemius muscle of nine patients (10 legs) with advanced PAD and in nine control patients (nine legs) without evidence of PAD. METHODS: Mitochondrial respiratory rates were determined with a Clark electrode in an oxygraph cell containing saponin-skinned muscle bundles. Muscle samples were obtained from the anteromedial aspect of the gastrocnemius muscle, at a level 10 cm distal to the tibial tuberosity. Mitochondria respiratory rate, calculated as nanoatoms of oxygen consumed per minute per milligram of noncollagen protein, were measured at baseline (V(0)), after addition of substrates (malate and glutamate; (V(SUB)), after addition of adenosine diphosphate (ADP) (V(ADP)), and finally, after adenine nucleotide translocase inhibition with atractyloside (V(AT)). The acceptor control ratio, a sensitive indicator of overall mitochondrial function, was calculated as the ratio of the respiratory rate after the addition of ADP to the respiratory rate after adenine nucleotide translocase inhibition with atractyloside (V(ADP)/ V(AT)). RESULTS: Respiratory rate in muscle mitochondria from patients with PAD were not significantly different from control values at baseline (0.31 +/- 0.06 vs 0.55 +/- 0.12; P =.09), but V(sub) was significantly lower in patients with PAD compared with control subjects (0.43 +/- 0.07 vs 0.89 +/- 0.20; P <.05), as was V(ADP) (0.69 +/- 0.13 vs 1.24 +/- 0.20; P <.05). Respiratory rates after atractyloside inhibition in patients with PAD were no different from those in control patients (0.47 +/- 0.07 vs 0.45 +/- P =.08). Compared with control values, mitochondria from patients with PAD had a significantly lower acceptor control ratio (1.41 +/- 0.10 vs 2.90 +/- 0.20; P <.001). CONCLUSION: Mitochondrial respiratory activity is abnormal in lower extremity skeletal muscle in patients with PAD. When considered in concert with the ultrastructural and enzymatic abnormalities previously documented in mitochondria of chronically ischemic muscle, these data support the concept of defective mitochondrial function as a pathophysiologic component of PAD.


Assuntos
Claudicação Intermitente/metabolismo , Isquemia/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Difosfato de Adenosina/farmacologia , Idoso , Atractilosídeo/farmacologia , Biópsia , Inibidores Enzimáticos/farmacologia , Feminino , Ácido Glutâmico/farmacologia , Humanos , Técnicas In Vitro , Malatos/farmacologia , Masculino , Pessoa de Meia-Idade , Translocases Mitocondriais de ADP e ATP/antagonistas & inibidores
20.
Eur J Heart Fail ; 5(2): 121-9, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12644001

RESUMO

BACKGROUND: Apoptosis may contribute to the myocardial dysfunction associated with heart failure (HF). Activation of the p38 MAPK cascade can induce apoptosis in non-cardiac cells through increased expression of Fas-L, or through decreased expression of cyclin D(1). AIMS: We tested the hypothesis that hypoxia (HX), angiotensin-II (A-II) and norepinephrine (NEPI) can mediate apoptosis by activating p38 MAPK, and thus initiating stimulus specific changes in Fas-L and cyclin D(1) expression in failing cardiomyocytes. METHODS AND RESULTS: Cardiomyocytes isolated from ten dogs with HF induced by coronary microembolizations were subjected to HX or A-II or NEPI with and without a p38 MAPK inhibitor (SB 203580). TUNEL staining for DNA fragmentation and Western blots for p38 MAPK, Fas-L and cyclin D(1) detection were performed. HX-induced apoptosis was associated with increased Fas-L expression, A-II-induced apoptosis was associated with increased Fas-L and decreased cyclin D(1) expression, and NEPI-induced apoptosis was associated with decreased cyclin D(1) expression. Inhibition of p38 MAPK activity attenuated stress-induced apoptosis in all experiments and reversed changes in Fas-L and cyclin D(1) expression. CONCLUSIONS: HX, A-II and NEPI mediate apoptosis in failing cardiomyocytes via different effects on Fas-L and cyclin D(1) expression. Inhibition of p38 MAPK reversed these effects, suggesting that apoptosis induced by HX, A-II and NEPI involves activation of p38 MAPK upstream from Fas-L and cyclin D(1).


Assuntos
Angiotensina II/farmacologia , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Hipóxia/fisiopatologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Norepinefrina/farmacologia , Animais , Ciclina D1/efeitos dos fármacos , Ciclina D1/fisiologia , Modelos Animais de Doenças , Cães , Proteína Ligante Fas , Seguimentos , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Hipóxia/metabolismo , Incidência , Glicoproteínas de Membrana/efeitos dos fármacos , Glicoproteínas de Membrana/fisiologia , Proteínas Quinases Ativadas por Mitógeno/efeitos dos fármacos , Proteínas Quinases Ativadas por Mitógeno/fisiologia , Modelos Cardiovasculares , Miócitos Cardíacos/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
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