RESUMO
It is well established that the vasculature plays a crucial role in maintaining oxygen and nutrients supply to the heart. Increasing evidence further suggests that the microcirculation has additional roles in supporting a healthy microenvironment. Heart failure is well known to be associated with changes and functional impairment of the microvasculature. The specific ablation of protective signals in endothelial cells in experimental models is sufficient to induce heart failure. Therefore, restoring a healthy endothelium and microcirculation may be a valuable therapeutic strategy to treat heart failure. This review article will summarize the current understanding of the vascular contribution to heart failure with reduced or preserved ejection fraction. Novel therapeutic approaches including next generation pro-angiogenic therapies and non-coding RNA therapeutics, as well as the targeting of metabolites or metabolic signalling, vascular inflammation and senescence will be discussed.
Assuntos
Indutores da Angiogênese/uso terapêutico , Vasos Coronários/efeitos dos fármacos , Terapia Genética , Insuficiência Cardíaca Diastólica/terapia , Insuficiência Cardíaca Sistólica/terapia , Microvasos/efeitos dos fármacos , Neovascularização Fisiológica/efeitos dos fármacos , Vacinas/uso terapêutico , Indutores da Angiogênese/efeitos adversos , Animais , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/metabolismo , Vasos Coronários/fisiopatologia , Terapia Genética/efeitos adversos , Insuficiência Cardíaca Diastólica/genética , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Insuficiência Cardíaca Sistólica/genética , Insuficiência Cardíaca Sistólica/metabolismo , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Microcirculação/efeitos dos fármacos , Microvasos/metabolismo , Microvasos/fisiopatologia , RNA não Traduzido/genética , RNA não Traduzido/metabolismo , Recuperação de Função Fisiológica , Vacinas/efeitos adversos , Função Ventricular Esquerda/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the potential association between neutrophil degranulation and patterns of myocardial dysfunction in a cohort of patients with type 2 diabetes mellitus (T2DM). BACKGROUND: Two distinct phenotypes of diabetic cardiomyopathy have been described: a restrictive phenotype with diastolic dysfunction (restrictive/DD) and a dilative phenotype with systolic dysfunction (dilative/SD). However, the underlying determinants of these two patterns are not yet recognized. METHODS: In this single-centre, observational, cross-sectional study, 492 patients were recruited. Ultrasonographic measurements were performed by two experienced sonographers, blinded to the clinical data of the participants. Serum biomarkers of neutrophil degranulation were measured by enzyme-linked immunosorbent sandwich assay (ELISA). RESULTS: After adjustment for confounders, resistin, myeloperoxidase, matrix metalloproteinase 8 and matrix metalloproteinase 9/tissue inhibitor of metalloproteinases 1 complex were positively associated with the restrictive/DD pattern compared with the normal pattern. Similarly, MPO was positively associated with the dilative/SD pattern compared with the normal pattern, and resistin was negatively associated with the dilative/SD pattern compared with the restrictive/DD pattern. CONCLUSIONS: Neutrophil degranulation is associated with the restrictive/DD echocardiographic pattern in patients with T2DM, but not with the normal pattern and dilative/SD patterns. Neutrophils could have a pivotal role in the pathogenesis of myocardial dysfunction, and particularly diastolic dysfunction, in patients with T2DM.
Assuntos
Cardiomiopatia Dilatada/metabolismo , Cardiomiopatia Restritiva/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Cardiomiopatias Diabéticas/metabolismo , Ativação de Neutrófilo , Idoso , Biomarcadores/metabolismo , Cardiomiopatia Dilatada/diagnóstico por imagem , Cardiomiopatia Dilatada/etiologia , Cardiomiopatia Dilatada/fisiopatologia , Cardiomiopatia Restritiva/diagnóstico por imagem , Cardiomiopatia Restritiva/etiologia , Cardiomiopatia Restritiva/fisiopatologia , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/fisiopatologia , Cardiomiopatias Diabéticas/diagnóstico por imagem , Cardiomiopatias Diabéticas/etiologia , Cardiomiopatias Diabéticas/fisiopatologia , Ecocardiografia , Feminino , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Insuficiência Cardíaca Sistólica/diagnóstico por imagem , Insuficiência Cardíaca Sistólica/etiologia , Insuficiência Cardíaca Sistólica/metabolismo , Insuficiência Cardíaca Sistólica/fisiopatologia , Humanos , Masculino , Metaloproteinase 8 da Matriz/metabolismo , Metaloproteinase 9 da Matriz/metabolismo , Pessoa de Meia-Idade , Peroxidase/metabolismo , Resistina/metabolismo , Inibidor Tecidual de Metaloproteinase-1/metabolismo , Inibidor Tecidual de Metaloproteinase-2/metabolismoRESUMO
AIMS: Heart failure with preserved left ventricular ejection fraction (HFpEF) is a serious health problem worldwide, as no effective therapy is yet available. We have previously demonstrated that our low-intensity pulsed ultrasound (LIPUS) therapy is effective and safe for angina and dementia. In this study, we aimed to examine whether the LIPUS therapy also ameliorates cardiac diastolic dysfunction in mice. METHODS AND RESULTS: Twelve-week-old obese diabetic mice (db/db) and their control littermates (db/+) were treated with either the LIPUS therapy [1.875 MHz, 32 cycles, Ispta (spatial peak temporal average intensity) 117-162 mW/cm2, 0.25 W/cm2] or placebo procedure two times a week for 4 weeks. At 20-week-old, transthoracic echocardiography and invasive haemodynamic analysis showed that cardiac diastolic function parameters, such as e', E/e', end-diastolic pressure-volume relationship, Tau, and dP/dt min, were all deteriorated in placebo-treated db/db mice compared with db/+ mice, while systolic function was preserved. Importantly, these cardiac diastolic function parameters were significantly ameliorated in the LIPUS-treated db/db mice. We also measured the force (F) and intracellular Ca2+ ([Ca2+]i) in trabeculae dissected from ventricles. We found that relaxation time and [Ca2+]i decay (Tau) were prolonged during electrically stimulated twitch contractions in db/db mice, both of which were significantly ameliorated in the LIPUS-treated db/db mice, indicating that the LIPUS therapy also improves relaxation properties at tissue level. Functionally, exercise capacity was also improved in the LIPUS-treated db/db mice. Histologically, db/db mice displayed progressed cardiomyocyte hypertrophy and myocardial interstitial fibrosis, while those changes were significantly suppressed in the LIPUS-treated db/db mice. Mechanistically, western blot showed that the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cGMP-protein kinase G (PKG) pathway and Ca2+-handling molecules were up-regulated in the LIPUS-treated heart. CONCLUSIONS: These results indicate that the LIPUS therapy ameliorates cardiac diastolic dysfunction in db/db mice through improvement of eNOS-NO-cGMP-PKG pathway and cardiomyocyte Ca2+-handling system, suggesting its potential usefulness for the treatment of HFpEF patients.
Assuntos
Insuficiência Cardíaca Diastólica/terapia , Volume Sistólico , Terapia por Ultrassom , Ondas Ultrassônicas , Disfunção Ventricular Esquerda/terapia , Função Ventricular Esquerda , Animais , Sinalização do Cálcio , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Modelos Animais de Doenças , Fibrose , Insuficiência Cardíaca Diastólica/genética , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Preparação de Coração Isolado , Camundongos Knockout , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/patologia , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Receptores para Leptina/genética , Receptores para Leptina/metabolismo , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/metabolismo , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Post-menopausal women exhibit an exponential increase in the incidence of heart failure with preserved ejection fraction compared with men of the same age, which indicates a potential role of hormonal changes in subclinical and clinical diastolic dysfunction. This paper reviews the preclinical evidence that demonstrates the involvement of estrogen in many regulatory molecular pathways of cardiac diastolic function and the clinical data that investigates the effect of estrogen on diastolic function in post-menopausal women. Published reports show that estrogen deficiency influences both early diastolic relaxation via calcium homeostasis and the late diastolic compliance associated with cardiac hypertrophy and fibrosis. Because of the high risk of diastolic dysfunction and heart failure with preserved ejection fraction in post-menopausal women and the positive effects of estrogen on preserving cardiac function, further clinical studies are needed to clarify the role of endogenous estrogen or hormone replacement in mitigating the onset and progression of heart failure with preserved ejection fraction in women.
Assuntos
Cálcio/metabolismo , Estrogênios/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Hipertrofia Ventricular Esquerda/metabolismo , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Pós-Menopausa/metabolismo , Volume Sistólico , Apoptose , Conectina/metabolismo , Diástole , Metabolismo Energético , Terapia de Reposição de Estrogênios , Feminino , Fibrose , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Humanos , Hipertrofia Ventricular Esquerda/fisiopatologia , Miocárdio/patologia , Estresse Oxidativo , Isoformas de ProteínasRESUMO
OBJECTIVE: To explore the effect of adeno-associated virus 9-mediated RNA interference targeting SOCS3 (AAV9-SOCS3 siRNA) on the treatment of diastolic heart failure (DHF). METHOD: A rat DHF model was established, and cardiac function and hemodynamic changes were measured. HE, Sirius red and TUNEL staining were applied to observe the pathological changes in the myocardium. Immunoblotting and immunohistochemical staining were utilized to detect SOCS3 expression. The expression levels of various factors, including fibrosis-related factors (collagen I, collagen II, α-SMA and TGF-ß), inflammatory-related factors (IL-1ß, IL-6, TNF-α, p-p65 and ICAM-1) and factors related to the JAK/STAT signal pathway were analyzed by immunoblotting and/or qPCR. The serum levels of IL-1ß, IL-6, and TNF-α were measured using ELISA. RESULTS: SOCS3 expression was significantly downregulated in the DHF rat model by SOCS3 siRNA delivery. In the successfully established DHF rat model, cardiac function was clearly decreased, and cardiomyocyte apoptosis and myocardial fibrosis were significantly increased. These changes were ameliorated by treatment with AAV9-SOCS3 siRNA. The expression levels of p-JAK2 and p-STAT3 were significantly upregulated in the AAV9-SOCS3 siRNA group compared with the sham and AAV9-siRNA control groups, indicating that SOCS3 is a negative regulator of this signaling pathway. The expression levels of collagen I/III, α-SMA and TGF-ß were also decreased at both the mRNA and protein levels. In addition, the serum and myocardial tissue expression levels of inflammatory-related factors, such as IL-6, IL-1ß, and TNF-α, were also reduced by the administration of AAV9-SOCS3 siRNA compared with the AAV9-siRNA control. CONCLUSIONS: SOCS3 gene silencing by AAV9-SOCS3 siRNA administration in a DHF rat model significantly reduced myocardial fibrosis and the inflammatory response and improved heart function. Therefore, this treatment is a potential therapeutic method for treating DHF.
Assuntos
Insuficiência Cardíaca Diastólica/genética , Proteína 3 Supressora da Sinalização de Citocinas/genética , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Actinas/metabolismo , Animais , Apoptose/fisiologia , Dependovirus/genética , Modelos Animais de Doenças , Inativação Gênica , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/patologia , Hemodinâmica , Interleucina-1beta/sangue , Interleucina-6/sangue , Janus Quinase 2/metabolismo , Masculino , Interferência de RNA , RNA Interferente Pequeno/genética , Ratos , Ratos Wistar , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Sex-related differences in cardiac function and iron metabolism exist in humans and experimental animals. Male patients and preclinical animal models are more susceptible to cardiomyopathies and heart failure. However, whether similar differences are seen in iron-overload cardiomyopathy is poorly understood. METHODS AND RESULTS: Male and female wild-type and hemojuvelin-null mice were injected and fed with a high-iron diet, respectively, to develop secondary iron overload and genetic hemochromatosis. Female mice were completely protected from iron-overload cardiomyopathy, whereas iron overload resulted in marked diastolic dysfunction in male iron-overloaded mice based on echocardiographic and invasive pressure-volume analyses. Female mice demonstrated a marked suppression of iron-mediated oxidative stress and a lack of myocardial fibrosis despite an equivalent degree of myocardial iron deposition. Ovariectomized female mice with iron overload exhibited essential pathophysiological features of iron-overload cardiomyopathy showing distinct diastolic and systolic dysfunction, severe myocardial fibrosis, increased myocardial oxidative stress, and increased expression of cardiac disease markers. Ovariectomy prevented iron-induced upregulation of ferritin, decreased myocardial SERCA2a levels, and increased NCX1 levels. 17ß-Estradiol therapy rescued the iron-overload cardiomyopathy in male wild-type mice. The responses in wild-type and hemojuvelin-null female mice were remarkably similar, highlighting a conserved mechanism of sex-dependent protection from iron-overload-mediated cardiac injury. CONCLUSIONS: Male and female mice respond differently to iron-overload-mediated effects on heart structure and function, and females are markedly protected from iron-overload cardiomyopathy. Ovariectomy in female mice exacerbated iron-induced myocardial injury and precipitated severe cardiac dysfunction during iron-overload conditions, whereas 17ß-estradiol therapy was protective in male iron-overloaded mice.
Assuntos
Cardiomiopatias/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Hemocromatose/metabolismo , Sobrecarga de Ferro/metabolismo , Estresse Oxidativo , Animais , Cardiomiopatias/diagnóstico por imagem , Cardiomiopatias/etiologia , Cardiomiopatias/patologia , Dieta , Ecocardiografia , Estradiol/farmacologia , Feminino , Ferritinas/metabolismo , Fibrose , Proteínas Ligadas por GPI , Coração/efeitos dos fármacos , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/patologia , Hemocromatose/complicações , Hemocromatose/patologia , Proteína da Hemocromatose , Sobrecarga de Ferro/complicações , Sobrecarga de Ferro/patologia , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Miocárdio/patologia , Ovariectomia , Estresse Oxidativo/efeitos dos fármacos , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Fatores Sexuais , Trocador de Sódio e Cálcio/metabolismoRESUMO
Type 2 diabetes mellitus (T2DM) is often complicated with diastolic heart failure, which decompensates under increased afterload. Focusing on cardiac metabolomes, we examined mechanisms by which T2DM augments ventricular diastolic stiffness in response to pressure overloading. Pressure-volume relationships (PVRs) and myocardial metabolomes were determined at baseline and during elevation of aortic pressure by phenylephrine infusion in a model of T2DM, OLETF, and its non-diabetic control, LETO. Pressure overloading augmented diastolic stiffness without change in systolic reserve in OLETF as indicated by a left-upward shift of end-diastolic PVR. In contrast, PVRs under cardioplegic arrest in buffer-perfused isolated hearts were similar in OLETF and LETO, indicating that extracellular matrix or titin remodeling does not contribute to the afterload-induced increase in stiffness of the beating ventricle of OLETF. Metabolome analyses revealed impaired glycolysis and facilitation of the pentose phosphate pathway in OLETF. Pressure overloading significantly reduced ATP and total adenine nucleotides by 34% and 40%, respectively, in OLETF but not in LETO, while NADH-to-NAD(+) ratios were similar in the two groups. The decline in ATP by pressure overloading in OLETF was associated with increased inosine 5-monophosphate and decreased adenosine levels, being consistent with the 2.5-times higher activity of cardiac AMP deaminase in OLETF. Tissue ATP level was negatively correlated with tau of LV pressure and LVEDP. These results suggest that ATP depletion due to excessive degradation of adenine nucleotides by up-regulated AMP deaminase underlies ventricular stiffening during acute pressure overloading in T2DM hearts.
Assuntos
AMP Desaminase/metabolismo , Nucleotídeos de Adenina/metabolismo , Diabetes Mellitus Tipo 2/complicações , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/metabolismo , AMP Desaminase/genética , Animais , Conectina/genética , Conectina/metabolismo , Modelos Animais de Doenças , Expressão Gênica , Insuficiência Cardíaca Diastólica/fisiopatologia , Testes de Função Cardíaca , Hemodinâmica , Metaboloma , Metabolômica , Contração Miocárdica , Miocárdio/metabolismo , Miocárdio/patologia , Fosforilação , Isoformas de Proteínas , Ratos , Função VentricularRESUMO
BACKGROUND: Although resveratrol has multiple beneficial cardiovascular effects, whether resveratrol can be used for the treatment and management of heart failure (HF) remains unclear. In the current study, we determined whether resveratrol treatment of mice with established HF could lessen the detrimental phenotype associated with pressure-overload-induced HF and identified physiological and molecular mechanisms contributing to this. METHODS AND RESULTS: C57Bl/6 mice were subjected to either sham or transverse aortic constriction surgery to induce HF. Three weeks post surgery, a cohort of mice with established HF (% ejection fraction <45) was administered resveratrol (≈320 mg/kg per day). Despite a lack of improvement in ejection fraction, resveratrol treatment significantly increased median survival of mice with HF, lessened cardiac fibrosis, reduced gene expression of several disease markers for hypertrophy and extracellular matrix remodeling that were upregulated in HF, promoted beneficial remodeling, and improved diastolic function. Resveratrol treatment of mice with established HF also restored the levels of mitochondrial oxidative phosphorylation complexes, restored cardiac AMP-activated protein kinase activation, and improved myocardial insulin sensitivity to promote glucose metabolism and significantly improved myocardial energetic status. Finally, noncardiac symptoms of HF, such as peripheral insulin sensitivity, vascular function, and physical activity, were improved with resveratrol treatment. CONCLUSIONS: Resveratrol treatment of mice with established HF lessens the severity of the HF phenotype by lessening cardiac fibrosis, improving molecular and structural remodeling of the heart, and enhancing diastolic function, vascular function, and energy metabolism.
Assuntos
Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Contração Miocárdica/efeitos dos fármacos , Miocárdio/metabolismo , Estilbenos/uso terapêutico , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/fisiologia , Animais , Modelos Animais de Doenças , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Resveratrol , Ribonucleotídeo Redutases/antagonistas & inibidores , Volume Sistólico/efeitos dos fármacos , Vasodilatadores/uso terapêutico , Remodelação Ventricular/efeitos dos fármacosRESUMO
Diastolic heart failure, or heart failure with preserved ejection fraction, is a leading cause of morbidity and mortality. There are no current therapies effective in improving outcomes for these patients. The aim of this article is to review the literature and examine the role of coenzyme Q10 in heart failure with preserved ejection fraction related to mitochondrial synthesis of adenosine triphosphate and reactive oxygen species production. The study results reflect that myocardial energetics alters in diastolic heart failure and that there is defective energy metabolism and increased oxidative stress. Studies are emerging to evaluate coenzyme Q10 , particularly ubiquinol, as a supplemental treatment for heart-failure patients. In diastolic heart-failure patients, clinicians are beginning to use supplemental therapies to improve patient outcomes, and one promising complementary treatment to improve left ventricular diastolic function is ubiquinol. Additional studies are needed using large-scale randomized models to confirm if ubiquinol would be beneficial. Since ubiquinol is an antioxidant and is required for adenosine triphosphate production, clinicians and health scientists should be aware of the potential role of this supplement in the treatment of diastolic heart failure.
Assuntos
Insuficiência Cardíaca Diastólica/tratamento farmacológico , Insuficiência Cardíaca Diastólica/metabolismo , Ubiquinona/análogos & derivados , Insuficiência Cardíaca Diastólica/fisiopatologia , Humanos , Hipertensão/fisiopatologia , Ubiquinona/uso terapêuticoRESUMO
The renin-angiotensin system (RAS) may alter cardiac energy metabolism in heart failure. Angiotensin II (ANG II), the main effector of the RAS in heart failure, has emerged as an important regulator of cardiac hypertrophy and energy metabolism. We studied the metabolic perturbations and insulin response in an ANG II-induced hypertrophy model. Ex vivo heart perfusion showed that hearts from ANG II-treated mice had a lower response to insulin with significantly reduced rates of glucose oxidation in association with increased pyruvate dehydrogenase kinase 4 (PDK4) levels. Palmitate oxidation rates were significantly reduced in response to insulin in vehicle-treated hearts but remained unaltered in ANG II-treated hearts. Furthermore, phosphorylation of Akt was also less response to insulin in ANG II-treated wild-type (WT) mice, suggestive of insulin resistance. We evaluated the role of PDK4 in the ANG II-induced pathology and showed that deletion of PDK4 prevented ANG II-induced diastolic dysfunction and normalized glucose oxidation to basal levels. ANG II-induced reduction in the levels of the deacetylase, SIRT3, was associated with increased acetylation of pyruvate dehydrogenase (PDH) and a reduced PDH activity. In conclusion, our findings show that a combination of insulin resistance and decrease in PDH activity are involved in ANG II-induced reduction in glucose oxidation, resulting in cardiac inefficiency. ANG II reduces PDH activity via acetylation of PDH complex, as well as increased phosphorylation in response to increased PDK4 levels.
Assuntos
Angiotensina II/farmacologia , Cardiomegalia/metabolismo , Metabolismo Energético/efeitos dos fármacos , Insuficiência Cardíaca Diastólica/metabolismo , Resistência à Insulina/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Animais , Cardiomegalia/induzido quimicamente , Cardiomegalia/diagnóstico por imagem , Modelos Animais de Doenças , Ecocardiografia , Metabolismo Energético/fisiologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Teste de Tolerância a Glucose , Coração/efeitos dos fármacos , Coração/fisiologia , Insuficiência Cardíaca Diastólica/induzido quimicamente , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Miocárdio/metabolismo , Oxirredução , Fosforilação/efeitos dos fármacos , Proteínas Serina-Treonina Quinases/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Complexo Piruvato Desidrogenase/efeitos dos fármacos , Complexo Piruvato Desidrogenase/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia , Sirtuína 3/metabolismoRESUMO
Diastolic heart failure (HF) accounts for up to 50% of all HF admissions, with hypertension being the major cause of diastolic HF. Hypertension is characterized by left ventricular (LV) hypertrophy (LVH). Proinflammatory cytokines are increased in LVH and hypertension, but it is unknown if they mediate the progression of hypertension-induced diastolic HF. We sought to determine if interferon-γ (IFNγ) plays a role in mediating the transition from hypertension-induced LVH to diastolic HF. Twelve-week old BALB/c (WT) and IFNγ-deficient (IFNγKO) mice underwent either saline (n = 12) or aldosterone (n = 16) infusion, uninephrectomy, and fed 1% salt water for 4 wk. Tail-cuff blood pressure, echocardiography, and gene/protein analyses were performed. Isolated adult rat ventricular myocytes were treated with IFNγ (250 U/ml) and/or aldosterone (1 µM). Hypertension was less marked in IFNγKO-aldosterone mice than in WT-aldosterone mice (127 ± 5 vs. 136 ± 4 mmHg; P < 0.01), despite more LVH (LV/body wt ratio: 4.9 ± 0.1 vs. 4.3 ± 0.1 mg/g) and worse diastolic dysfunction (peak early-to-late mitral inflow velocity ratio: 3.1 ± 0.1 vs. 2.8 ± 0.1). LV ejection fraction was no different between IFNγKO-aldosterone vs. WT-aldosterone mice. LV end systolic dimensions were decreased significantly in IFNγKO-aldosterone vs. WT-aldosterone hearts (1.12 ± 0.1 vs. 2.1 ± 0.3 mm). Myocardial fibrosis and collagen expression were increased in both IFNγKO-aldosterone and WT-aldosterone hearts. Myocardial autophagy was greater in IFNγKO-aldosterone than WT-aldosterone mice. Conversely, tumor necrosis factor-α and interleukin-10 expressions were increased only in WT-aldosterone hearts. Recombinant IFNγ attenuated cardiac hypertrophy in vivo and modulated aldosterone-induced hypertrophy and autophagy in cultured cardiomyocytes. Thus IFNγ is a regulator of cardiac hypertrophy in diastolic HF and modulates cardiomyocyte size possibly by regulating autophagy. These findings suggest that IFNγ may mediate adaptive downstream responses and challenge the concept that inflammatory cytokines mediate only adverse effects.
Assuntos
Insuficiência Cardíaca Diastólica/etiologia , Hipertensão/complicações , Hipertrofia Ventricular Esquerda/etiologia , Mediadores da Inflamação/metabolismo , Interferon gama/deficiência , Miocárdio/imunologia , Aldosterona , Animais , Autofagia , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Insuficiência Cardíaca Diastólica/genética , Insuficiência Cardíaca Diastólica/imunologia , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/patologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Hipertensão/etiologia , Hipertensão/metabolismo , Hipertensão/fisiopatologia , Hipertrofia Ventricular Esquerda/genética , Hipertrofia Ventricular Esquerda/imunologia , Hipertrofia Ventricular Esquerda/metabolismo , Hipertrofia Ventricular Esquerda/patologia , Hipertrofia Ventricular Esquerda/fisiopatologia , Hipertrofia Ventricular Esquerda/prevenção & controle , Interferon gama/administração & dosagem , Interferon gama/genética , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Knockout , Miocárdio/metabolismo , Miocárdio/patologia , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/imunologia , Miócitos Cardíacos/metabolismo , Nefrectomia , Ratos , Ratos Sprague-Dawley , Volume Sistólico , Fatores de Tempo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/genética , Disfunção Ventricular Esquerda/imunologia , Disfunção Ventricular Esquerda/fisiopatologia , Função Ventricular Esquerda , Remodelação VentricularRESUMO
Left ventricular (LV) diastolic dysfunction is an important contributor to many different cardiovascular diseases. LV diastolic dysfunction can manifest itself as slow LV relaxation, slow LV filling or high diastolic LV stiffness. Diastolic abnormalities have been described in the senescent heart, in heart failure with preserved ejection fraction (HFPEF), in diabetic cardiomyopathy, in aortic valve stenosis (AVS), in hypertrophic cardiomyopathy (HCM), as well as in Fabry disease (FD), however, exact cellular and molecular alterations behind the diastolic deterioration in these diseases are not yet completely characterized. Several studies thoroughly investigated altered cardiomyocyte function, changes of contractile myofilaments, extracellular collagen deposition and advanced glycation end products (AGEs) cross-linking in the background of diastolic dysfunction. These clinical and experimental data suggest that underlying mechanisms of LV diastolic dysfunction are divergent in different cardiac pathologies, therefore the present review aims to summarize mechanisms at the cellular level of diastolic abnormalities in various cardiovascular diseases.
Assuntos
Envelhecimento/patologia , Insuficiência Cardíaca Diastólica/patologia , Miocárdio/patologia , Disfunção Ventricular Esquerda/patologia , Envelhecimento/metabolismo , Estenose da Valva Aórtica/complicações , Estenose da Valva Aórtica/metabolismo , Estenose da Valva Aórtica/patologia , Cardiomiopatias Diabéticas/complicações , Cardiomiopatias Diabéticas/metabolismo , Cardiomiopatias Diabéticas/patologia , Diástole , Doença de Fabry/complicações , Doença de Fabry/metabolismo , Doença de Fabry/patologia , Fibrose , Glicoesfingolipídeos/metabolismo , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/metabolismo , Humanos , Miocárdio/metabolismo , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismoRESUMO
RATIONALE: Mechanisms underlying diastolic dysfunction need to be better understood. OBJECTIVE: To study the role of titin in diastolic dysfunction using a mouse model of experimental heart failure induced by transverse aortic constriction. METHODS AND RESULTS: Eight weeks after transverse aortic constriction surgery, mice were divided into heart failure (HF) and congestive heart failure (CHF) groups. Mechanical studies on skinned left ventricle myocardium measured total and titin-based and extracellular matrix-based passive stiffness. Total passive stiffness was increased in both HF and CHF mice, and this was attributable to increases in both extracellular matrix-based and titin-based passive stiffness, with titin being dominant. Protein expression and titin exon microarray analysis revealed increased expression of the more compliant N2BA isoform at the expense of the stiff N2B isoform in HF and CHF mice. These changes are predicted to lower titin-based stiffness. Because the stiffness of titin is also sensitive to titin phosphorylation by protein kinase A and protein kinase C, back phosphorylation and Western blot assays with novel phospho-specific antibodies were performed. HF and CHF mice showed hyperphosphorylation of protein kinase A sites and the proline glutamate valine lysine (PEVK) S26 protein kinase C sites, but hypophosphorylation of the PEVK S170 protein kinase C site. Protein phosphatase I abolished differences in phosphorylation levels and normalized titin-based passive stiffness levels between control and HF myocardium. CONCLUSION: Transverse aortic constriction-induced HF results in increased extracellular matrix-based and titin-based passive stiffness. Changes in titin splicing occur, which lower passive stiffness, but this effect is offset by hyperphosphorylation of residues in titin spring elements, particularly of PEVK S26. Thus, complex changes in titin occur that combined are a major factor in the increased passive myocardial stiffness in HF.
Assuntos
Doenças da Aorta/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Proteínas Musculares/metabolismo , Miocárdio/metabolismo , Proteínas Quinases/metabolismo , Animais , Doenças da Aorta/complicações , Conectina , Insuficiência Cardíaca Diastólica/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação/fisiologia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Esquerda/metabolismoRESUMO
Diastolic heart failure (DHF) and systolic heart failure (SHF) are two clinical subsets of chronic heart failure (CHF). Sarcoplasmic reticulum (SR) Ca²âº leak has been measured in SHF and might contribute to contractile dysfunction and arrhythmogenesis. However, no study has investigated a similar phenomenon in DHF. Thus, we established DHF and SHF rabbit models and compared the differences in Ca²âº leak between these models. New Zealand white rabbits were randomly divided into three groups (n = 8 in each group): sham operation (SO) group, DHF group and SHF group. Cardiac functions were determined by echocardiography and hemodynamic assays. The SR Ca²âº leak was measured with a calcium-imaging device and the expression and activities of related proteins were evaluated with Western blots and autophosphorylation. In the DHF group, there was significantly increased ventricular wall thickness and stiffness, reduced diastolic function, and total amount of FK506 binding protein 12.6 (FKBP12.6), increased expression and activity of protein kinase A (PKA) and phosphorylation site (P2809) in the ryanodine receptor (RyR2), but no prominent Ca²âº leak. In the SHF group, there was significantly increased ventricular cavity size, reduced systolic function, increased SR Ca²âº leak, reduced total amount of FKBP12.6 and FKBP12.6-RyR2 association, increased expression and activity of PKA and Ca²âº/calmodulin-dependent protein kinase II (CaMKII) and their RyR2 phosphorylation sites with unchanged P2030. Our results suggest that a prominent SR Ca²âº leak was not observed in the DHF model, which may provide a new idea for the reasons in preserved systolic function, and CaMKII possibly plays a more important role in SR Ca²âº leak.
Assuntos
Cálcio/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Sistólica/metabolismo , Retículo Sarcoplasmático/metabolismo , Animais , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Modelos Animais de Doenças , Ecocardiografia , Insuficiência Cardíaca Diastólica/diagnóstico por imagem , Insuficiência Cardíaca Diastólica/fisiopatologia , Insuficiência Cardíaca Sistólica/diagnóstico por imagem , Insuficiência Cardíaca Sistólica/fisiopatologia , Hemodinâmica/fisiologia , Coelhos , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismoAssuntos
Cálcio/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Biópsia , Ecocardiografia/métodos , Insuficiência Cardíaca Diastólica/diagnóstico , Insuficiência Cardíaca Diastólica/fisiopatologia , Frequência Cardíaca , Ventrículos do Coração/patologia , Humanos , Contração Miocárdica , Miocárdio/patologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Taquicardia/prevenção & controleRESUMO
BACKGROUND & AIMS: Significance of diastolic dysfunction in cirrhotic cardiomyopathy has been brought to the forefront with several reports of unexpected heart failure following liver transplantation and transjugular intrahepatic portosystemic stent-shunt, but the etiology remains unclear. The present study investigated the role of passive tension regulators - titin and collagen - in the pathogenesis of this condition. METHODS: Cirrhosis was induced by bile duct ligation (BDL) in rats, while controls underwent bile duct inspection with no ligation. Four weeks after operation, cardiac mRNA and protein levels of titin, collagen, and protein kinase A (PKA) were determined. Diastolic function was examined in isolated right ventricular cardiomyocytes, while passive tension was examined in right ventricular trabeculae muscles. RESULTS: In BDL animals, diastolic return velocity was significantly decreased, relaxation time increased and passive tension increased. However, no significant difference in mRNA and protein levels of titin was observed. PKA mRNA and protein levels were significantly decreased in BDL animals. Collagen levels were also significantly altered in the BDL group. CONCLUSIONS: Therefore, diastolic dysfunction exists in cirrhosis with alterations in titin modulation, PKA levels, and collagen configuration contributing to the pathogenesis of this condition.
Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Colágeno/metabolismo , Insuficiência Cardíaca Diastólica/etiologia , Insuficiência Cardíaca Diastólica/metabolismo , Cirrose Hepática Experimental/complicações , Cirrose Hepática Experimental/metabolismo , Proteínas Musculares/metabolismo , Animais , Sequência de Bases , Cardiomiopatias/genética , Colágeno/genética , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Colágeno Tipo III/genética , Colágeno Tipo III/metabolismo , Conectina , Proteínas Quinases Dependentes de AMP Cíclico/genética , Proteínas Quinases Dependentes de AMP Cíclico/metabolismo , Primers do DNA/genética , Insuficiência Cardíaca Diastólica/genética , Cirrose Hepática Experimental/genética , Masculino , Proteínas Musculares/genética , Miócitos Cardíacos/metabolismo , Miofibrilas/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos BN , Ratos Sprague-DawleyRESUMO
Advanced age, independent of concurrent cardiovascular disease, can be associated with increased extracellular matrix (ECM) fibrillar collagen content and abnormal diastolic function. However, the mechanisms causing this left ventricular (LV) remodeling remain incompletely defined. We hypothesized that one determinant of age-dependent remodeling is a change in the extent to which newly synthesized procollagen is processed into mature collagen fibrils. We further hypothesized that secreted protein acidic and rich in cysteine (SPARC) plays a key role in the changes in post-synthetic procollagen processing that occur in the aged myocardium. Young (3 mo old) and old (18-24 mo old) wild-type (WT) and SPARC-null mice were studied. LV collagen content was measured histologically by collagen volume fraction, collagen composition was measured by hydroxyproline assay as soluble collagen (1 M NaCl extractable) versus insoluble collagen (mature cross-linked), and collagen morphological structure was examined by scanning electron microscopy. SPARC expression was measured by immunoblot analysis. LV and myocardial structure and function were assessed using echocardiographic and papillary muscle experiments. In WT mice, advanced age increased SPARC expression, myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen. In SPARC-null mice, advanced age also increased myocardial diastolic stiffness, fibrillar collagen content, and insoluble collagen but significantly less than those seen in WT old mice. As a result, insoluble collagen and myocardial diastolic stiffness were lower in old SPARC-null mice (1.36 +/- 0.08 mg hydroxyproline/g dry wt and 0.04 +/- 0.005) than in old WT mice (1.70 +/- 0.10 mg hydroxyproline/g dry wt and 0.07 +/- 0.005, P < 0.05). In conclusion, the absence of SPARC reduced age-dependent alterations in ECM fibrillar collagen and diastolic function. These data support the hypothesis that SPARC plays a key role in post-synthetic procollagen processing and contributes to the increase in collagen content found in the aged myocardium.
Assuntos
Envelhecimento/metabolismo , Colágenos Fibrilares/metabolismo , Insuficiência Cardíaca Diastólica/metabolismo , Miocárdio/metabolismo , Osteonectina/metabolismo , Pró-Colágeno/metabolismo , Animais , Modelos Animais de Doenças , Elasticidade/fisiologia , Colágenos Fibrilares/ultraestrutura , Coração/fisiopatologia , Insuficiência Cardíaca Diastólica/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Remodelação Ventricular/fisiologiaRESUMO
Inhibition of the persistent or late Na current (INa) using ranolazine (Ranexa) represents a novel mechanism of action that was approved in the United States in 2006 and only recently in the European Union for use in patients with stable angina pectoris. In general, myocardial ischemia is associated with reduced adenosine triphosphate fluxes and decreased energy supply, resulting in severe disturbances of intracellular ion homeostasis in cardiac myocytes. In the recent years, increased late INa was suggested to contribute to this phenomenon by elevating intracellular Na concentration with subsequent rise in diastolic Ca levels by means of the sarcolemmal Na-Ca exchange system. Ranolazine, a specific inhibitor of late INa, reduces Na influx and hence ameliorates disturbed Na and Ca homeostasis. This is associated with a symptomatic improvement of angina in patients unlike other antianginal drugs without affecting heart rate or systemic blood pressure as shown in placebo-controlled studies. Therefore, ranolazine is a useful new option for patients with chronic stable angina not only as an add-on therapy. New clinical and experimental studies even point to potential antiarrhythmic effects, beneficial effects in diastolic heart failure, and under hyperglycemic conditions. In the present article, the relevant pathophysiological concepts for the role of late INa inhibition are reviewed and the most recent data from basic studies and clinical trials are summarized.
Assuntos
Acetanilidas/uso terapêutico , Angina Pectoris/tratamento farmacológico , Arritmias Cardíacas/tratamento farmacológico , Insuficiência Cardíaca Diastólica/tratamento farmacológico , Piperazinas/uso terapêutico , Bloqueadores dos Canais de Sódio/uso terapêutico , Sódio/metabolismo , Acetanilidas/administração & dosagem , Acetanilidas/farmacologia , Angina Pectoris/metabolismo , Animais , Arritmias Cardíacas/metabolismo , Ensaios Clínicos como Assunto , Insuficiência Cardíaca Diastólica/metabolismo , Humanos , Piperazinas/administração & dosagem , Piperazinas/farmacologia , Ranolazina , Bloqueadores dos Canais de Sódio/administração & dosagem , Bloqueadores dos Canais de Sódio/farmacologia , Canais de Sódio/metabolismo , Trocador de Sódio e Cálcio/metabolismoAssuntos
Processamento Alternativo , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de GMP Cíclico/fisiologia , Diástole/fisiologia , Proteínas Musculares/metabolismo , Proteínas Quinases/metabolismo , Processamento de Proteína Pós-Traducional , Animais , Conectina , Complicações do Diabetes/metabolismo , Complicações do Diabetes/patologia , Diacetil/análogos & derivados , Diacetil/farmacologia , Elasticidade , Matriz Extracelular/ultraestrutura , Gelsolina/farmacologia , Insuficiência Cardíaca Diastólica/metabolismo , Insuficiência Cardíaca Diastólica/fisiopatologia , Humanos , Camundongos , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/ultraestrutura , Fosforilação , Isoformas de Proteínas/metabolismo , Ratos , Sarcômeros/ultraestrutura , Tri-Iodotironina/fisiologia , Remodelação Ventricular/fisiologiaRESUMO
The sarcomeric titin springs influence myocardial distensibility and passive stiffness. Titin isoform composition and protein kinase (PK)A-dependent titin phosphorylation are variables contributing to diastolic heart function. However, diastolic tone, relaxation speed, and left ventricular extensibility are also altered by PKG activation. We used back-phosphorylation assays to determine whether PKG can phosphorylate titin and affect titin-based stiffness in skinned myofibers and isolated myofibrils. PKG in the presence of 8-pCPT-cGMP (cGMP) phosphorylated the 2 main cardiac titin isoforms, N2BA and N2B, in human and canine left ventricles. In human myofibers/myofibrils dephosphorylated before mechanical analysis, passive stiffness dropped 10% to 20% on application of cGMP-PKG. Autoradiography and anti-phosphoserine blotting of recombinant human I-band titin domains established that PKG phosphorylates the N2-B and N2-A domains of titin. Using site-directed mutagenesis, serine residue S469 near the COOH terminus of the cardiac N2-B-unique sequence (N2-Bus) was identified as a PKG and PKA phosphorylation site. To address the mechanism of the PKG effect on titin stiffness, single-molecule atomic force microscopy force-extension experiments were performed on engineered N2-Bus-containing constructs. The presence of cGMP-PKG increased the bending rigidity of the N2-Bus to a degree that explained the overall PKG-mediated decrease in cardiomyofibrillar stiffness. Thus, the mechanically relevant site of PKG-induced titin phosphorylation is most likely in the N2-Bus; phosphorylation of other titin sites could affect protein-protein interactions. The results suggest that reducing titin stiffness by PKG-dependent phosphorylation of the N2-Bus can benefit diastolic function. Failing human hearts revealed a deficit for basal titin phosphorylation compared to donor hearts, which may contribute to diastolic dysfunction in heart failure.