RESUMO
BACKGROUND: Kidney disease is associated with impaired work productivity. However, the collective effect of missed work days, reduced output at work, and early withdrawal from the workforce is rarely considered in health-economic evaluations. METHODS: To determine the effect on work productivity of preventing incident cases of kidney disease, using the novel measure "productivity-adjusted life year" (PALY), we constructed a dynamic life table model for the Australian working-age population (aged 15-69 years) over 10 years (2020-2029), stratified by kidney-disease status. Input data, including productivity estimates, were sourced from the literature. We ascribed a financial value to the PALY metric in terms of gross domestic product (GDP) per equivalent full-time worker and assessed the total number of years lived, total PALYs, and broader economic costs (GDP per PALY). We repeated the model simulation, assuming a reduced kidney-disease incidence; the differences reflected the effects of preventing new kidney-disease cases. Outcomes were discounted by 5% annually. RESULTS: Our projections indicate that, from 2020 to 2029, the estimated number of new kidney-disease cases will exceed 161,000. Preventing 10% of new cases of kidney disease during this period would result in >300 premature deaths averted and approximately 550 years of life and 7600 PALYs saved-equivalent to a savings of US$1.1 billion in GDP or US$67,000 per new case avoided. CONCLUSIONS: Pursuing a relatively modest target for preventing kidney disease in Australia may prolong years of life lived and increase productive life years, resulting in substantial economic benefit. Our findings highlight the need for investment in preventive measures to reduce future cases of kidney disease.
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To address the pathophysiological mechanisms underlying chronic kidney disease with comorbid cardiac dysfunction, we investigated renal and cardiac, functional and structural damage when myocardial infarction (MI) was applied in the setting of kidney injury (induced by 5/6 nephrectomy-STNx). STNx or Sham surgery was induced in male Sprague-Dawley rats with MI or Sham surgery performed 4 weeks later. Rats were maintained for a further 8 weeks. Rats (n = 36) were randomized into four groups: Sham+Sham, Sham+MI, STNx+Sham and STNx+MI. Increased renal tubulointerstitial fibrosis (P < 0.01) and kidney injury molecule-1 expression (P < 0.01) was observed in STNx+MI compared to STNx+Sham animals, while there were no further reductions in renal function. Heart weight was increased in STNx+MI compared to STNx+Sham or Sham+MI animals (P < 0.05), despite no difference in blood pressure. STNx+MI rats demonstrated greater cardiomyocyte cross-sectional area and increased cardiac interstitial fibrosis compared to either STNx+Sham (P < 0.01) or Sham+MI (P < 0.01) animals which was accompanied by an increase in diastolic dysfunction. These changes were associated with increases in ANP, cTGF and collagen I gene expression and phospho-p38 MAPK and phospho-p44/42 MAPK protein expression in the left ventricle. Addition of MI accelerated STNx-induced structural damage but failed to significantly exacerbate renal dysfunction. These findings highlight the bidirectional response in this model known to occur in cardiorenal syndrome (CRS) and provide a useful model for examining potential therapies for CRS.
Assuntos
Coração/fisiopatologia , Rim/patologia , Insuficiência Renal Crônica/fisiopatologia , Animais , Biomarcadores/metabolismo , Pressão Sanguínea , Cardiomegalia/complicações , Cardiomegalia/genética , Cardiomegalia/patologia , Cardiomegalia/fisiopatologia , Comorbidade , Eletrocardiografia , Fibrose , Regulação da Expressão Gênica , Coração/diagnóstico por imagem , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Hemodinâmica , Inflamação/complicações , Inflamação/patologia , Estimativa de Kaplan-Meier , Rim/fisiopatologia , Masculino , Infarto do Miocárdio/complicações , Infarto do Miocárdio/genética , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/patologia , Tamanho do Órgão , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/patologia , Transdução de SinaisRESUMO
Protein-bound uremic toxins (PBUTs) accumulate once renal excretory function declines and are not cleared by dialysis. There is increasing evidence that PBUTs exert toxic effects on many vital organs, including the kidney, blood vessels, and heart. It has been suggested that PBUTs are likely to be a potential missing link in cardiorenal syndrome, based on the high incidence of cardiovascular events and mortality in the dialysis population, which are dramatically reduced in successful kidney transplant recipients. These data have led the call for more effective dialysis or additional adjunctive therapy to eradicate these toxins and their adverse biological effects. Indoxyl sulfate and p-cresyl sulfate are the two most problematic PBUTs, conferring renal and cardiovascular toxicity, and are derived from dietary amino acid metabolites by colonic microbial organisms. Therefore, targeting the colon where these toxins are initially produced appears to be a potential therapeutic alternative for patients with chronic kidney disease. This strategy, if approved, is likely to be applicable to predialysis patients, thereby potentially preventing progression of chronic kidney disease to end-stage renal disease as well as preventing the development of cardiorenal syndrome.
Assuntos
Síndrome Cardiorrenal/metabolismo , Toxinas Biológicas/metabolismo , Uremia/metabolismo , Humanos , Ligação ProteicaRESUMO
Cardiorenal syndrome is a condition in which a complex interrelationship between cardiac dysfunction and renal dysfunction exists. Despite advances in treatment of both cardiovascular and kidney disease, cardiorenal syndrome remains a major global health problem. Characteristic of the pathophysiology of cardiorenal syndrome is bidirectional cross-talk; mediators/substances activated by the disease state of 1 organ can play a role in worsening dysfunction of the other by exerting their biologically harmful effects, leading to the progression of the syndrome. Accumulation of uremic toxins is a hallmark of renal excretory dysfunction. Removal of some toxins by conventional dialysis is particularly problematic because of their high protein binding. In this review, we demonstrate that protein-bound uremic toxins may play an important role in progression of cardiovascular disease in the setting of chronic kidney disease. The highly protein-bound uremic toxin indoxyl sulfate has emerged as a potent toxin adversely affecting both the kidney and heart. Direct cardiac effects of this toxin have been recently demonstrated both in vitro and in vivo. Specifically, potent fibrogenic and prohypertrophic effects, as well as oxidative stress-inducing effects, appear to play a central role in both renal and cardiac pathology. Many of these adverse effects can be suppressed by use of a gut adsorbent, AST-120. Potential mechanisms underlying indoxyl sulfate-induced cardiorenal fibrosis are discussed. Future research and clinical implications conclude this review.
Assuntos
Síndrome Cardiorrenal/metabolismo , Proteinúria/metabolismo , Toxinas Biológicas/metabolismo , Uremia/metabolismo , Carbono/uso terapêutico , Síndrome Cardiorrenal/prevenção & controle , Síndrome Cardiorrenal/urina , Humanos , Indicã/metabolismo , Indicã/urina , Estresse Oxidativo/efeitos dos fármacos , Óxidos/uso terapêutico , Ligação Proteica , Proteinúria/urina , Toxinas Biológicas/urina , Uremia/urinaRESUMO
BACKGROUND: Chronic kidney disease (CKD), and its associated cardiovascular events, is one of the major causes of morbidity and recurrent hospitalization in Asian Pacific region. The subtotal nephrectomy (STNx) model has remained the state-of-the-art prototype which closely mimics human CKD and cardiac-renal syndrome. AIM AND METHODS: In this article, we comprehensively outline the procedure and methodology required to develop the rat model 5/6 nephrectomy and the associated procedures involved in assessing cardiac and renal functional outcomes. RESULTS AND CONCLUSION: In addition, the expected functional outcomes from our own experience, and those of others, have been described. The STNx model in the rat is an established model of CKD and displays all the functional and structural hallmarks observed in the human condition. Lesser known are the cardiac effects of this model which make it ideal for studying cardiorenal syndrome.
Assuntos
Síndrome Cardiorrenal/diagnóstico , Testes de Função Cardíaca , Coração/fisiopatologia , Testes de Função Renal , Rim/fisiopatologia , Nefrectomia/métodos , Insuficiência Renal Crônica/diagnóstico , Animais , Cateterismo Cardíaco , Síndrome Cardiorrenal/etiologia , Síndrome Cardiorrenal/fisiopatologia , Modelos Animais de Doenças , Ecocardiografia Doppler , Eletrocardiografia , Taxa de Filtração Glomerular , Modelos Cardiovasculares , Valor Preditivo dos Testes , Proteinúria/etiologia , Proteinúria/fisiopatologia , Ratos , Insuficiência Renal Crônica/etiologia , Insuficiência Renal Crônica/fisiopatologia , Fatores de Tempo , Função Ventricular EsquerdaRESUMO
Cardiorenal syndrome (CRS) is a clinical disorder involving combined heart and kidney dysfunction, which leads to poor clinical outcomes. To understand the complex pathophysiology and mechanisms that lie behind this disease setting, and design/evaluate appropriate treatment strategies, suitable animal models are required. Described here are the protocols for establishing surgically induced animal models of CRS including important methods to determine clinically relevant measures of cardiac and renal function, commonly used to assess the degree of organ dysfunction in the model and treatment efficacy when evaluating novel therapeutic strategies.
Assuntos
Síndrome Cardiorrenal , Modelos Animais de Doenças , Síndrome Cardiorrenal/fisiopatologia , Síndrome Cardiorrenal/diagnóstico , Síndrome Cardiorrenal/etiologia , Animais , Ratos , Rim/fisiopatologia , Rim/patologia , Coração/fisiopatologia , Masculino , HumanosRESUMO
BACKGROUND: Tranilast has been shown to inhibit TGFß1-related fibrosis and organ failure in various disease models. We sought to examine the effects of tranilast on left ventricular (LV) remodelling post-MI. METHODS: Following coronary artery ligation, Sprague Dawley rats were randomised to receive tranilast (300mg/kg/d, p.o.) or vehicle control over one of two treatment periods: (1) from 24h until seven days post-MI, (2) from seven days to 28 days post-MI. Cardiac tissue was harvested for molecular, immunohistochemical and cell culture analyses. RESULTS: Tranilast treatment of MI rats from 24h until seven days post-MI reduced myocardial collagen content, α1 (I) procollagen, TGFß1 and CTGF mRNA transcripts, monocyte/macrophage infiltration and exacerbated infarct expansion compared with vehicle-treatment. Delaying the commencement of tranilast treatment to seven days post-MI attenuated myocardial fibrosis, gene expression of α1(I) procollagen, α1(III) procollagen, fibronectin, TGFß1 and CTGF mRNA transcripts, and monocyte/macrophage infiltration at 28d compared to vehicle-treatment, without detriment to infarct healing. Extended post-MI also preserved LV infarct size. In cultures of rat cardiac fibroblasts, tranilast attenuated TGFß1-stimulated fibrogenesis. CONCLUSION: Tranilast inhibits myocardial TGFß1 expression, fibrosis in rat post-MI and collagen production in cardiac fibroblasts. While tranilast intervention from 24h post-MI exacerbated infarct expansion, delaying the commencement of treatment to seven days post-MI impeded LV remodelling.
Assuntos
Anti-Inflamatórios não Esteroides/uso terapêutico , Expressão Gênica/efeitos dos fármacos , Infarto do Miocárdio/tratamento farmacológico , Miocárdio/patologia , Fator de Crescimento Transformador beta1/antagonistas & inibidores , Remodelação Ventricular/efeitos dos fármacos , ortoaminobenzoatos/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Contagem de Células , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Colágeno/análise , Colágeno/biossíntese , Colágeno Tipo I/genética , Cadeia alfa 1 do Colágeno Tipo I , Fator de Crescimento do Tecido Conjuntivo/genética , Vasos Coronários , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibrose/metabolismo , Fibrose/patologia , Fibrose/prevenção & controle , Ligadura , Macrófagos , Masculino , Monócitos , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Miocárdio/química , Tamanho do Órgão , Fosforilação , RNA Mensageiro , Ratos , Ratos Sprague-Dawley , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/farmacologia , ortoaminobenzoatos/farmacologiaRESUMO
Progressive decline in renal function coexists with myocardial infarction (MI); however, little is known about its pathophysiology. This study aimed to systematically identify post-MI renal changes (functional, histological, and molecular) over time in a rat MI model and examine potential mechanisms that may underlie these changes. Rats were randomized into three groups: nonoperated, sham, and MI. Cardiac and renal function was assessed before death at 1, 4, 8, 12, and 16 wk with tissues collected for histological, protein, and gene studies. Tail-cuff blood pressure was lower in MI than sham and nonoperated animals only at 1 wk (P < 0.05). Systolic function was reduced (P < 0.0001) while heart/body weight and left ventricle/body weight were significantly greater in MI animals at all time points. Glomerular filtration rate decreased following MI at 1 and 4 wk (P < 0.05) but not at 8 and 12 wk and then deteriorated further at 16 wk (P = 0.052). Increased IL-6 gene and transforming growth factor (TGF)-ß protein expression as well as macrophage infiltration in kidney cortex was detected at 1 wk (P < 0.05). Renal cortical interstitial fibrosis was significantly greater in MI animals from 4 wk, while TGF-ß bioactivity (phospho-Smad2) was upregulated at all time points. The degree of fibrosis increased and was maximal at 16 wk. In addition, kidney injury molecule-1-positive staining in the tubules was more prominent in MI animals, maximal at 1 wk. In conclusion, renal impairment occurs early post-MI and is associated with hemodynamic and structural changes in the kidney possibly via activation of the Smad2 signaling pathway.
Assuntos
Síndrome Cardiorrenal/etiologia , Síndrome Cardiorrenal/fisiopatologia , Moléculas de Adesão Celular/metabolismo , Rim/metabolismo , Rim/fisiopatologia , Infarto do Miocárdio/complicações , Animais , Biomarcadores/metabolismo , Síndrome Cardiorrenal/metabolismo , Modelos Animais de Doenças , Fibrose , Taxa de Filtração Glomerular/fisiologia , Hemodinâmica , Interleucina-6/metabolismo , Rim/irrigação sanguínea , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/fisiologia , Proteína Smad2/metabolismo , Fator de Crescimento Transformador beta/metabolismoRESUMO
Cardiorenal syndrome (CRS) describes the primary dysfunction in either the kidney or heart that initiates the combined impairment of both organs. The heart and kidney exert reciprocal control of the respective function to maintain constant blood volume and organ perfusion under continuously changing conditions. The pathophysiology of CRS is not fully understood, but appears to be caused by a complex combination of haemodynamic, neurohormonal, immunological and biochemical feedback pathways. Of these pathways, the contributory role of uraemic toxins that accumulate in CRS has been underexplored. One such toxin, namely indoxyl sulphate, has been found to have direct adverse effects on relevant cardiac cells. Early diagnosis by assessing cardiac and renal injury biomarkers may be critical for timely therapeutic intervention. Such therapies are directed at attenuation of neurohormonal activation, control of elevated blood pressure, correction of anaemia and relief of hypervolaemia. Reduction of non-dialysable uraemic toxins is a further potentially beneficial therapeutic strategy.
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Síndrome Cardiorrenal/patologia , Uremia/fisiopatologia , Animais , Biomarcadores , Síndrome Cardiorrenal/complicações , Síndrome Cardiorrenal/epidemiologia , Síndrome Cardiorrenal/etiologia , Síndrome Cardiorrenal/fisiopatologia , Modelos Animais de Doenças , Humanos , Infarto do Miocárdio/complicações , Infarto do Miocárdio/fisiopatologia , NefrectomiaRESUMO
The uremic toxin indoxyl sulfate (IS), elevated in chronic kidney disease (CKD), is known to contribute towards progressive cardiovascular disease. IS activates the aryl hydrocarbon receptor (AhR) mediating oxidative stress and endothelial dysfunction via activation of the CYP1A1 pathway. The present study examines AhR inhibition with the antagonist, CH223191, on IS-mediated impairment of vascular endothelial function and disruption of redox balance. The acute effects of IS on endothelium-dependent relaxation were assessed in aortic rings from Sprague Dawley rats exposed to the following conditions: (1) control; (2) IS (300 µM); (3) IS + CH223191 (1 µM); (4) IS + CH223191 (10 µM). Thereafter, tissues were assessed for changes in expression of redox markers. IS reduced the maximum level of endothelium-dependent relaxation (Rmax) by 42% (p < 0.001) compared to control, this was restored in the presence of increasing concentrations of CH223191 (p < 0.05). Rings exposed to IS increased expression of CYP1A1, nitro-tyrosine, NADPH oxidase 4 (NOX4), superoxide, and reduced eNOS expression (p < 0.05). CH223191 (10 µM) restored expression of these markers back to control levels (p < 0.05). These findings demonstrate the adverse impact of IS-mediated AhR activation on the vascular endothelium, where oxidative stress may play a critical role in inducing endothelial dysfunction in the vasculature of the heart and kidneys. AhR inhibition could provide an exciting novel therapy for CVD in the CKD setting.
Assuntos
Aorta Torácica/efeitos dos fármacos , Compostos Azo/farmacologia , Endotélio Vascular/efeitos dos fármacos , Indicã/farmacologia , Pirazóis/farmacologia , Receptores de Hidrocarboneto Arílico/antagonistas & inibidores , Animais , Aorta Torácica/metabolismo , Aorta Torácica/fisiologia , Citocromo P-450 CYP1A1/genética , Endotélio Vascular/fisiologia , Expressão Gênica/efeitos dos fármacos , Masculino , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Insuficiência Renal Crônica , Vasodilatação/efeitos dos fármacosRESUMO
AIMS: Myocardial injury is a major contributor to left ventricular (LV) remodelling activating neurohormonal and inflammatory processes that create an environment of enhanced oxidative stress. This results in geometric and structural alterations leading to reduced LV systolic function. In this study we evaluated the efficacy of NP202, a synthetic flavonol, on cardiac remodelling in a chronic model of myocardial infarction (MI). MAIN METHODS: A rat model of chronic MI was induced by permanent surgical ligation of the coronary artery. NP202 treatment was commenced 2 days post-MI for 6 weeks at different doses (1, 10 and 20 mg/kg/day) to determine efficacy. Cardiac function was assessed by echocardiography prior to treatment and at week 6, and pressure-volume measurements were performed prior to tissue collection. Tissues were analysed for changes in fibrotic and inflammatory markers using immunohistochemistry and gene expression analysis. KEY FINDINGS: Rats treated with NP202 demonstrated improved LV systolic function and LV geometry compared to vehicle treated animals. Furthermore, measures of hypertrophy and interstitial fibrosis were attenuated in the non-infarct region of the myocardium with NP202 at the higher dose of 20 mg/kg (P < 0.05). At the tissue level, NP202 reduced monocyte chemoattractant protein-1 expression (P < 0.05) and tended to attenuate active caspase-3 expression to similar levels observed in sham animals (P = 0.075). SIGNIFICANCE: Improved LV function and structural changes observed with NP202 may be mediated through inhibition of inflammatory and apoptotic processes in the MI setting. NP202 could therefore prove a useful addition to standard therapy in patients with post-MI LV dysfunction.
Assuntos
Flavonoides/farmacologia , Infarto do Miocárdio , Miocárdio/metabolismo , Função Ventricular Esquerda/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacos , Animais , Caspase 3/biossíntese , Quimiocina CCL2/biossíntese , Doença Crônica , Regulação da Expressão Gênica/efeitos dos fármacos , Masculino , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/fisiopatologia , Ratos , Ratos Sprague-DawleyRESUMO
AIMS: Indoxyl sulfate (IS) is a uraemic toxin found at high concentration in patients with chronic kidney disease (CKD) co-morbid with chronic heart failure (CHF). The aim of this study was to determine direct effects of IS on cardiac cells as well as the pro-inflammatory effect of IS. METHODS AND RESULTS: Indoxyl sulfate significantly increased neonatal rat cardiac fibroblast collagen synthesis (by 145.7% vs. control, P < 0.05) and myocyte hypertrophy (by 134.5% vs. control, P < 0.001) as determined by (3)H-proline or (3)H-leucine incorporation, respectively. Indoxyl sulfate stimulated tumour necrosis factor-alpha, interleukin-6 (IL-6), and IL-1beta mRNA expression in THP-1 cells as quantified by RT-PCR. Both p38 (RWJ-67657) and MEK1/2 (U0126) inhibitors suppressed all these effects by IS. Furthermore, western blot analysis showed that IS activated mitogen-activated protein kinase (MAPK) (p38, p42/44) and nuclear factor-kappa B (NFkappaB) pathways. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay showed that IS exerted its effects without affecting cell viability. CONCLUSION: This study has, for the first time, demonstrated that IS has pro-fibrotic, pro-hypertrophic, and pro-inflammatory effects, indicating that IS might play an important role in adverse cardiac remodelling mediated via activation of the p38 MAPK, p42/44 MAPK, and NFkappaB pathways. Targeting reduction of IS and/or the pathways it activates may represent a novel therapeutic approach to the management of CHF with concomitant CKD.
Assuntos
Fibroblastos/efeitos dos fármacos , Indicã/farmacologia , Miócitos Cardíacos/efeitos dos fármacos , Toxinas Biológicas/farmacologia , Animais , Western Blotting , Cardiomiopatia Hipertrófica/etiologia , Cardiomiopatia Hipertrófica/patologia , Sobrevivência Celular , Células Cultivadas , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Indicã/administração & dosagem , Falência Renal Crônica/etiologia , Falência Renal Crônica/patologia , RNA Mensageiro/metabolismo , Ratos , Ratos Sprague-Dawley , Toxinas Biológicas/administração & dosagemRESUMO
AIM: To assess the cost-effectiveness of dapagliflozin in addition to standard care versus standard care alone in patients with chronic heart failure and reduced ejection fraction. METHODS: A Markov model was constructed based on the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure trial to assess the clinical outcomes and costs of 1000 hypothetical subjects with established heart failure and reduced ejection fraction. The model consisted of three health states: 'alive and event-free', 'alive after non-fatal hospitalisation for heart failure' and 'dead'. Costs and utilities were estimated from published sources. The main outcome was the incremental cost-effectiveness ratio per quality-adjusted life-year gained. An Australian public healthcare perspective was employed. All outcomes and costs were discounted at a rate of 5% annually. RESULTS: Over a lifetime horizon, the addition of dapagliflozin to standard care in patients with heart failure and reduced ejection fraction prevented 88 acute heart failure hospitalisations (including readmissions) and yielded an additional 416 years of life and 288 quality-adjusted life-years (discounted) at an additional cost of A$3,692,440 (discounted). This equated to an incremental cost-effectiveness ratio of A$12,482 per quality-adjusted life-year gained, well below the Australian willingness-to-pay threshold of A$50,000 per quality-adjusted life-year gained. Subanalyses in subjects with and without diabetes resulted in similar incremental cost-effectiveness ratios of A$13,234 and A$12,386 per quality-adjusted life-year gained, respectively. CONCLUSION: Dapagliflozin is likely to be cost-effective when used as an adjunct therapy to standard care compared with standard care alone for the treatment of chronic heart failure and reduced ejection fraction.
Assuntos
Insuficiência Cardíaca , Austrália/epidemiologia , Compostos Benzidrílicos , Análise Custo-Benefício , Atenção à Saúde , Glucosídeos , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/tratamento farmacológico , HumanosRESUMO
AIMS: To determine the impact of preventing new (incident) cases of coronary heart disease (CHD) on years of life and productivity, using the novel measure 'productivity-adjusted life year' (PALY), over the next 10 years. METHODS AND RESULTS: A dynamic life table model was constructed for the total Australian working-age population (15-69 years) over 10 years (2020-2029), separated by CHD status. Productivity estimates were sourced from the literature. The PALY was ascribed a financial value in terms of gross domestic product (GDP) per equivalent full-time worker. The total number of years lived, PALYs, and economic burden (in terms of GDP per PALY) were estimated. The model simulation was repeated assuming incidence was reduced, and the differences represented the impact of CHD prevention. All outcomes were discounted by 5% per annum. Over 10 years, the total projected years lived and PALYs in the Australian working-age population (with and without CHD) were 133 million and 83 million, respectively, amounting to A$17.2 trillion in GDP. We predicted more than 290 000 new (incident) CHD cases over the next 10 years. If all new cases of CHD could be prevented during this period, a total of 4 000 deaths could be averted, resulting in more than 8 000 years of life saved and 104 000 PALYs gained, equivalent to a gain of nearly A$21.8 billion (US$14.8 billion) in GDP. CONCLUSION: Prevention of CHD will prolong years of life lived and productive life years, resulting in substantial economic benefit. Policy makers and employers are encouraged to engage in preventive measures addressing CHD.
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Doença das Coronárias , Efeitos Psicossociais da Doença , Adolescente , Adulto , Idoso , Austrália/epidemiologia , Doença das Coronárias/diagnóstico , Doença das Coronárias/epidemiologia , Doença das Coronárias/prevenção & controle , Eficiência , Humanos , Pessoa de Meia-Idade , Anos de Vida Ajustados por Qualidade de Vida , Adulto JovemRESUMO
Protein-bound uremic toxins (PBUTs) have adverse effects on vascular function, which is imperative in the progression of cardiovascular and renal diseases. The role of sphingolipids in PBUT-mediated vasculo-endothelial pathophysiology is unclear. This study assessed the therapeutic potential of dihydroceramide desaturase 1 (Des1) inhibition, the last enzyme involved in de novo ceramide synthesis, to mitigate the vascular effects of the PBUT indoxyl sulfate (IS). Rat aortic rings were isolated and vascular reactivity was assessed in organ bath experiments followed by immunohistochemical analyses. Furthermore, cultured human aortic endothelial cells were assessed for phenotypic and mechanistic changes. Inhibition of Des1 by a selective inhibitor CIN038 (0.1 to 0.3 µM) improved IS-induced impairment of vasorelaxation and modulated immunoreactivity of oxidative stress markers. Des1 inhibition also reversed IS-induced reduction in endothelial cell migration (1.0 µM) by promoting the expression of angiogenic cytokines and reducing inflammatory and oxidative stress markers. These effects were associated with a reduction of TIMP1 and the restoration of Akt phosphorylation. In conclusion, Des1 inhibition improved vascular relaxation and endothelial cell migration impaired by IS overload. Therefore, Des1 may be a suitable intracellular target to mitigate PBUT-induced adverse vascular effects.
Assuntos
Células Endoteliais , Indicã , Animais , Células Endoteliais/metabolismo , Indicã/toxicidade , Estresse Oxidativo , Oxirredutases/metabolismo , Oxirredutases/farmacologia , RatosRESUMO
AIMS: Indoxyl sulfate (IS), a protein-bound uremic toxin, is implicated in endothelial dysfunction, which contributes to adverse cardiovascular events in chronic kidney disease. Apoptosis signal regulating kinase 1 (ASK1) is a reactive oxygen species-driven kinase involved in IS-mediated adverse effects. This study assessed the therapeutic potential of ASK1 inhibition in alleviating endothelial effects induced by IS. MAIN METHODS: IS, in the presence and absence of a selective ASK1 inhibitor (GSK2261818A), was assessed for its effect on vascular reactivity in rat aortic rings, and cultured human aortic endothelial cells where we evaluated phenotypic and mechanistic changes. KEY FINDINGS: IS directly impairs endothelium-dependent vasorelaxation and endothelial cell migration. Mechanistic studies revealed increased production of reactive oxygen species-related markers, reduction of endothelial nitric oxide synthase and increased protein expression of tissue inhibitor of matrix metalloproteinase 1 (TIMP1). IS also increases angiopoietin-2 and tumour necrosis factor α gene expression and promotes transforming growth factor ß receptor abundance. Inhibition of ASK1 ameliorated the increase in oxidative stress markers, promoted autocrine interleukin 8 pro-angiogenic signalling and decreased anti-angiogenic responses at least in part via reducing TIMP1 protein expression. SIGNIFICANCE: ASK1 inhibition attenuated vasorelaxation and endothelial cell migration impaired by IS. Therefore, ASK1 is a viable intracellular target to alleviate uremic toxin-induced impairment in the vasculature.
Assuntos
Endotélio/metabolismo , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , MAP Quinase Quinase Quinase 5/metabolismo , Animais , Apoptose/efeitos dos fármacos , Células Cultivadas , Células Endoteliais/metabolismo , Endotélio/efeitos dos fármacos , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Indicã/efeitos adversos , Indicã/farmacologia , MAP Quinase Quinase Quinase 5/fisiologia , Masculino , NADPH Oxidases/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Vasodilatação/efeitos dos fármacosRESUMO
Non-dialysable protein-bound uremic toxins (PBUTs) contribute to the development of cardiovascular disease (CVD) in chronic kidney disease (CKD) and vice versa. PBUTs have been shown to alter sphingolipid imbalance. Dihydroceramide desaturase 1 (Des1) is an important gatekeeper enzyme which controls the non-reversible conversion of sphingolipids, dihydroceramide, into ceramide. The present study assessed the effect of Des1 inhibition on PBUT-induced cardiac and renal effects in vitro, using a selective Des1 inhibitor (CIN038). Des1 inhibition attenuated hypertrophy in neonatal rat cardiac myocytes and collagen synthesis in neonatal rat cardiac fibroblasts and renal mesangial cells induced by the PBUTs, indoxyl sulfate and p-cresol sulfate. This is at least attributable to modulation of NF-κB signalling and reductions in ß-MHC, Collagen I and TNF-α gene expression. Lipidomic analyses revealed Des1 inhibition restored C16-dihydroceramide levels reduced by indoxyl sulfate. In conclusion, PBUTs play a critical role in mediating sphingolipid imbalance and inflammatory responses in heart and kidney cells, and these effects were attenuated by Des1 inhibition. Therefore, sphingolipid modifying agents may have therapeutic potential for the treatment of CVD and CKD and warrant further investigation.
Assuntos
Doenças Cardiovasculares/induzido quimicamente , Oxirredutases/uso terapêutico , Esfingolipídeos/metabolismo , Toxinas Biológicas/efeitos adversos , Toxinas Biológicas/metabolismo , Uremia/sangue , Uremia/fisiopatologia , Animais , Inibidores Enzimáticos/uso terapêutico , Humanos , Modelos Animais , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/complicações , Esfingolipídeos/sangue , Toxinas Biológicas/sangueRESUMO
AIMS: To establish pre-clinical proof of concept that sustained subcutaneous delivery of the secretome of human cardiac stem cells (CSCs) can be achieved in vivo to produce significant cardioreparative outcomes in the setting of myocardial infarction. METHODS AND RESULTS: Rats were subjected to permanent ligation of left anterior descending coronary artery and randomized to receive subcutaneous implantation of TheraCyte devices containing either culture media as control or 1 × 106 human W8B2+ CSCs, immediately following myocardial ischaemia. At 4 weeks following myocardial infarction, rats treated with W8B2+ CSCs encapsulated within the TheraCyte device showed preserved left ventricular ejection fraction. The preservation of cardiac function was accompanied by reduced fibrotic scar tissue, interstitial fibrosis, cardiomyocyte hypertrophy, as well as increased myocardial vascular density. Histological analysis of the TheraCyte devices harvested at 4 weeks post-implantation demonstrated survival of human W8B2+ CSCs within the devices, and the outer membrane was highly vascularized by host blood vessels. Using CSCs expressing plasma membrane reporters, extracellular vesicles of W8B2+ CSCs were found to be transferred to the heart and other organs at 4 weeks post-implantation. Furthermore, mass spectrometry-based proteomic profiling of extracellular vesicles of W8B2+ CSCs identified proteins implicated in inflammation, immunoregulation, cell survival, angiogenesis, as well as tissue remodelling and fibrosis that could mediate the cardioreparative effects of secretome of human W8B2+ CSCs. CONCLUSIONS: Subcutaneous implantation of TheraCyte devices encapsulating human W8B2+ CSCs attenuated adverse cardiac remodelling and preserved cardiac function following myocardial infarction. The TheraCyte device can be employed to deliver stem cells in a minimally invasive manner for effective secretome-based cardiac therapy.
Assuntos
Infarto do Miocárdio/cirurgia , Miocárdio/patologia , Proteoma , Regeneração , Secretoma , Transplante de Células-Tronco , Células-Tronco/metabolismo , Animais , Antígenos de Superfície/metabolismo , Proliferação de Células , Sobrevivência Celular , Células Cultivadas , Meios de Cultivo Condicionados/metabolismo , Modelos Animais de Doenças , Fibrose , Humanos , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/fisiopatologia , Miocárdio/metabolismo , Neovascularização Fisiológica , Proteômica , Ratos Nus , Transplante de Células-Tronco/instrumentação , Fatores de TempoRESUMO
The vasoactive peptide urotensin-II (U-II) is likely to play a key causal role in cardiac remodeling that ultimately leads to heart failure. Its contribution, specifically to the development of diastolic dysfunction and the downstream intracellular signaling, however, remains unresolved. This study interrogates the effect of chronic U-II infusion in normal rats on cardiac structure and function. The contribution of Rho kinase (ROCK) signaling to these pathophysiological changes is evaluated in cell culture studies. Chronic high-dose U-II infusion over 4 wk significantly impaired diastolic function in rats on echocardiography-derived Doppler indexes, including E-wave deceleration time (vehicle 56.7 +/- 3.3 ms, U-II 118.0 +/- 21.5 ms; P < 0.01) and mitral valve annulus peak early/late diastolic tissue velocity (vehicle 2.01 +/- 0.19 ms, U-II 1.04 +/- 0.25 ms; P < 0.01). A lower dose of U-II infusion (1 nmol.kg(-1).h(-1)) yielded comparable changes. Diastolic dysfunction was accompanied by molecular [significant increases in procollagen-alpha(1)(I) gene expression on real-time PCR] and morphological (increases in total collagen, P < 0.05, and collagen type-I protein deposition, P < 0.001) evidence of left ventricular (LV) fibrosis following high-dose U-II infusion. The ROCK inhibitor GSK-576371 (10(-7) to 10(-5) M) elicited concentration-dependent inhibition of U-II (10(-7) M)-stimulated cardiac fibroblast collagen synthesis and cardiac myocyte protein synthesis. Chronic U-II infusion causes diastolic dysfunction, caused by fibrosis of the LV. The in vitro data suggest that this may be in part occurring via a ROCK-dependent pathway.