RESUMO
Activation of the CXCL12/CXCR4/ACKR3 axis is known to aid myocardial repair through ischemia-triggered hypoxia-inducible factor-1α (HIF-1α). To enhance the upregulation of HIF-1α, we administered roxadustat, a novel prolyl hydroxylase inhibitor (PHI) clinically approved by the European Medicines Agency 2021 for the treatment of renal anemia, with the purpose of improving LV function and attenuating ischemic cardiomyopathy. METHODS: We evaluated roxadustat's impact on HIF-1 stimulation, cardiac remodeling, and function after MI. Therefore, we analyzed nuclear HIF-1 expression, the mRNA and protein expression of key HIF-1 target genes (RT-PCR, Western blot), inflammatory cell infiltration (immunohistochemistry), and apoptosis (TUNEL staining) 7 days after MI. Additionally, we performed echocardiography in male and female C57BL/6 mice 28 days post-MI. RESULTS: We found a substantial increase in nuclear HIF-1, associated with an upregulation of HIF-1α target genes like CXCL12/CXCR4/ACKR3 at the mRNA and protein levels. Roxadustat increased the proportion of myocardial reparative M2 CD206+ cells, suggesting beneficial alterations in immune cell migration and a trend towards reduced apoptosis. Echocardiography showed that roxadustat treatment significantly preserved ejection fraction and attenuated subsequent ventricular dilatation, thereby reducing adverse remodeling. CONCLUSIONS: Our findings suggest that roxadustat is a promising clinically approved treatment option to preserve myocardial function by attenuating adverse remodeling.
Assuntos
Glicina , Subunidade alfa do Fator 1 Induzível por Hipóxia , Isoquinolinas , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Remodelação Ventricular , Animais , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Infarto do Miocárdio/metabolismo , Camundongos , Remodelação Ventricular/efeitos dos fármacos , Glicina/análogos & derivados , Glicina/farmacologia , Glicina/uso terapêutico , Masculino , Feminino , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Isoquinolinas/farmacologia , Isoquinolinas/uso terapêutico , Apoptose/efeitos dos fármacos , Quimiocina CXCL12/metabolismo , Quimiocina CXCL12/genética , Miocárdio/patologia , Miocárdio/metabolismoRESUMO
BACKGROUND: Iron deficiency (ID) is a frequent comorbidity in patients with acute (AHF) and chronic heart failure (CHF) associated with morbidity and death. We aimed to better characterize iron homeostasis in patients with heart failure applying different biomarkers and to evaluate the accuracy of current ID definition by the European Society of Cardiology/American College of Cardiology/American Heart Association to indicate tissue iron availability and demand. METHODS AND RESULTS: We performed a retrospective cohort study investigating 277 patients with AHF and 476 patients with CHF between February 2021 and May 2022. Patients with AHF had more advanced ID than patients with CHF, reflected by increased soluble transferrin receptor and soluble transferrin receptor-ferritin index, and lower ferritin, serum iron, transferrin saturation, hepcidin, and reticulocyte hemoglobin. Decreased iron availability or increased tissue iron demand, reflected by increased soluble transferrin receptor-ferritin index and decreased reticulocyte hemoglobin, was found in 84.1% (AHF) and 28.0% (CHF) with absolute ID and in 50.0% (AHF) and 10.5% (CHF) with combined ID according to the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition. Low hepcidin expression as an indicator of systemic ID was found in 91.1% (AHF) and 80.4% (CHF) of patients with absolute ID and in 32.3% (AHF) and 18.8% (CHF) of patients with combined ID. ID definitions with higher specificity reduce the need for iron supplementation by 25.5% in patients with AHF and by 65.6% in patients with CHF. CONCLUSIONS: Our results suggest that the current European Society of Cardiology/American College of Cardiology/American Heart Association-based ID definition might overestimate true ID, particularly in CHF. More stringent thresholds for ID could more accurately identify patients with heart failure with reduced tissue iron availability who benefit from intravenous iron supplementation.
Assuntos
Biomarcadores , Insuficiência Cardíaca , Ferro , Humanos , Insuficiência Cardíaca/epidemiologia , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/diagnóstico , Feminino , Masculino , Estudos Retrospectivos , Idoso , Ferro/metabolismo , Ferro/sangue , Biomarcadores/sangue , Ferritinas/sangue , Doença Crônica , Pessoa de Meia-Idade , Receptores da Transferrina/sangue , Anemia Ferropriva/sangue , Anemia Ferropriva/epidemiologia , Anemia Ferropriva/diagnóstico , Doença Aguda , Hepcidinas/sangue , Hepcidinas/metabolismo , Idoso de 80 Anos ou mais , Deficiências de FerroRESUMO
Most episodes of acute heart failure (AHF) are characterized by increasing signs and symptoms of congestion, manifested by edema, pleura effusion and/or ascites. Immediately and repeatedly administered intravenous (IV) loop diuretics currently represent the mainstay of initial therapy aiming to achieve adequate diuresis/natriuresis and euvolemia. Despite these efforts, a significant proportion of patients have residual congestion at discharge, which is associated with a poor prognosis. Therefore, a standardized approach is needed. The door to diuretic time should not exceed 60 min. As a general rule, the starting IV dose is 20-40 mg furosemide equivalents in loop diuretic naïve patients or double the preexisting oral home dose to be administered via IV. Monitoring responses within the following first hours are key issues. (1) After 2 h, spot urinary sodium should be ≥50-70 mmol/L. (2) After 6 h, the urine output should be ≥100-150 mL/hour. If these target measures are not reached, the guidelines currently recommend a doubling of the original dose to a maximum of 400-600 mg furosemide per day and in patients with severely impaired kidney function up to 1000 mg per day. Continuous infusion of loop diuretics offers no benefit over intermittent boluses (DOSE trial). Emerging evidence by recent randomized trials (ADVOR, CLOROTIC) supports the concept of an early combination diuretic therapy, by adding either acetazolamide (500 mg IV once daily) or hydrochlorothiazide. Acetazolamide is particularly useful in the presence of a baseline bicarbonate level of ≥27 mmol/L and remains effective in the presence of preexisting/worsening renal dysfunction but should be used only in the first three days to prevent severe metabolic disturbances. Patients should not leave the hospital when they are still congested and/or before optimized long-term guideline-directed medical therapy has been initiated. Special attention should be paid to AHF patients during the vulnerable post-discharge period, with an early follow-up visit focusing on up-titrate treatments of recommended doses within 2 weeks (STRONG-HF).