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Cardiac retinoic acid levels decline in heart failure.

ABSTRACT: Although low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we showed that proteomic analyses of human and guinea pig heart failure (HF) were consistent with a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry revealed 32% and 39% ATRA decreases in guinea pig HF and in patients with idiopathic dilated cardiomyopathy (IDCM), respectively, despite ample reserves of cardiac vitamin A. ATRA (2 mg/kg/d) was sufficient to mitigate cardiac remodeling and prevent functional decline in guinea pig HF. Although cardiac ATRA declined in guinea pig HF and human IDCM, levels of certain retinoid metabolic enzymes diverged. Specifically, high expression of the ATRA-catabolizing enzyme, CYP26A1, in human IDCM could dampen prospects for an ATRA-based therapy. Pertinently, a pan-CYP26 inhibitor, talarozole, blunted the impact of phenylephrine on ATRA decline and hypertrophy in neonatal rat ventricular myocytes. Taken together, we submit that low cardiac ATRA attenuates the expression of critical ATRA-dependent gene programs in HF and that strategies to normalize ATRA metabolism, like CYP26 inhibition, may have therapeutic potential.

SUBMITTER: Yang N

PROVIDER: S-EPMC8119182 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Cardiac retinoic acid levels decline in heart failure.

Yang Ni N Parker Lauren E LE Yu Jianshi J Jones Jace W JW Liu Ting T Papanicolaou Kyriakos N KN Talbot C Conover CC Margulies Kenneth B KB O'Rourke Brian B Kane Maureen A MA Foster D Brian DB

JCI insight 20210422 8

Although low circulating levels of the vitamin A metabolite, all-trans retinoic acid (ATRA), are associated with increased risk of cardiovascular events and all-cause mortality, few studies have addressed whether cardiac retinoid levels are altered in the failing heart. Here, we showed that proteomic analyses of human and guinea pig heart failure (HF) were consistent with a decline in resident cardiac ATRA. Quantitation of the retinoids in ventricular myocardium by mass spectrometry revealed 32% ...[more]

PMID: 33724958

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Project description:We previously demonstrated that the selective retinoic acid receptor (RAR) β 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. We hypothesized that by decreasing oxidative stress and consequent fibrogenesis, AC261066 could attenuate the development of contractile dysfunction in post-ischemic heart failure (HF). We tested this hypothesis in vivo using an established murine model of myocardial infarction (MI), obtained by permanent occlusion of the left anterior descending coronary artery. Treating mice with AC261066 in drinking water significantly attenuated the post-MI deterioration of echocardiographic indices of cardiac function, diminished remodeling, and reduced oxidative stress, as evidenced by a decrease in malondialdehyde level and p38 mitogen-activated protein kinase expression in cardiomyocytes. The effects of AC261066 were also associated with a decrease in interstitial fibrosis, as shown by a marked reduction in collagen deposition and α-smooth muscle actin expression. In cardiac murine fibroblasts subjected to hypoxia, AC261066 reversed hypoxia-induced decreases in superoxide dismutase 2 and angiopoietin-like 4 transcriptional levels as well as the increase in NADPH oxidase 2 mRNA, demonstrating that the post-MI cardioprotective effects of AC261066 are associated with an action at the fibroblast level. Thus, AC261066 alleviates post-MI cardiac dysfunction by modulating a set of genes involved in the oxidant/antioxidant balance. These AC261066 responsive genes diminish interstitial fibrogenesis and remodeling. Since MI is a recognized major cause of HF, our data identify RARβ 2 as a potential pharmacological target in the treatment of HF. SIGNIFICANCE STATEMENT: A previous report showed that the selective retinoic acid receptor (RAR) β 2 agonist AC261066 reduces oxidative stress in an ex vivo murine model of ischemia/reperfusion. This study shows that AC261066 attenuates the development of contractile dysfunction and maladaptive remodeling in post-ischemic heart failure (HF) by modulating a set of genes involved in oxidant/antioxidant balance. Since myocardial infarction is a recognized major cause of HF, these data identify RARβ 2 as a potential pharmacological target in the treatment of HF.

Project description:RATIONALE:Heart failure (HF) following heart damage leads to a decreased blood flow due to a reduced pump efficiency of the heart muscle. A consequence can be insufficient oxygen supply to the organism including the brain. While HF clearly shows neurological symptoms, such as fatigue, nausea, and dizziness, the implications for brain structure are not well understood. Few studies show regional gray matter decrease related to HF; however, the underlying mechanisms leading to the observed brain changes remain unclear. OBJECTIVE:To study the relationship between impaired heart function, hampered blood circulation, and structural brain change in a case-control study. METHODS AND RESULTS:Within a group of 80 patients of the Leipzig Heart Center, we investigated a potential correlation between HF biomarkers and the brain's gray matter density (GMD) obtained by magnetic resonance imaging. We observed a significant positive correlation between cardiac ejection fraction and GMD across the whole frontal and parietal medial cortex reflecting the consequence of HF onto the brain's gray matter. Moreover, we also obtained a relationship between GMD and the NT-proBNP (N-terminal prohormone of brain natriuretic peptide)-a biomarker that is used for screening, diagnosis, and prognosis of HF. Here, we found a significant negative correlation between NT-proBNP and GMD in the medial and posterior cingulate cortex but also in precuneus and hippocampus, which are key regions implicated in structural brain changes in dementia. CONCLUSIONS:We obtained significant correlations between brain structure and markers of heart failure including ejection fraction and NT-proBNP. A diminished GMD was found with decreased ejection fraction and increased NT-proBNP in wide brain regions including the whole frontomedian cortex as well as hippocampus and precuneus. Our observations might reflect structural brain damage in areas that are related to cognition; however, whether these structural changes facilitate the development of cognitive alterations has to be proven by further longitudinal studies.

Project description:AimsHeart failure (HF) patients have a high risk of mortality due to sudden cardiac death (SCD) and non-SCD, including pump failure death (PFD). Anaemia predicts more severe symptomatic burden and higher morbidity, as noted by markedly increased hospitalizations and readmission rates, and mortality, underscoring its importance in HF management. Herein, we aimed to determine whether haemoglobin (Hb) level at discharge affects the mode of death and influences SCD risk prediction.MethodsWe evaluated the data of 3020 consecutive acute HF patients from a Japanese prospective multicentre registry. Patients were divided into four groups based on discharge Hb levels. SCD was defined as an unexpected and otherwise unexplained death in a previously stable patient or death due to documented or presumed cardiac arrhythmia without a clear non-cardiovascular cause. The mode of death (SCD, PFD or other cause) was adjudicated by a central committee. Finally, we investigated whether adding Hb level to the Seattle Proportional Risk Model (SPRM; established risk score utilized to estimate 'proportion' of SCD among death events) would affect its performance.ResultsThe mean age of studied patients was 74.3 ± 12.9 years, and 59.8% were male. The mean Hb level was 12.0 ± 2.1 g/dL (61.3% of patients had anaemia defined by World Health Organization criteria). During the 2-year follow-up, 474 deaths (15.7%) occurred, including 93 SCDs (3.1%), 171 PFDs (5.7%) and 210 other deaths (7.0%; predominantly non-cardiac death). Absolute risk of PFD (P < 0.001) or other death (P < 0.001) increased along with the severity of anaemia, whereas the incidence of SCD was low but remained consistent across all four groups (P = 0.440). As a proportion of total deaths in each Hb level group, the contributions from non-SCD increased and from SCD decreased along with anaemia severity (P = 0.007). Adding Hb level to the SPRM improved the overall discrimination (c-index: 0.62 [95% confidence interval (CI) 0.56-0.69] to 0.65 [95% CI 0.59-0.71]), regardless of the baseline ejection fraction (EF) (c-index: 0.64 [95% CI 0.55-0.73] to 0.67 [95% CI 0.58-0.75] for reduced EF and 0.55 [95% CI 0.45-0.66] to 0.61 [95% CI 0.52-0.70] for preserved EF).ConclusionsThe discharge Hb level provides information about both absolute and proportional risks for each mode of death in acute HF patients, and the addition of Hb level improves the performance of SPRM by identifying more non-SCD cases. Future 'proportional' SCD risk models should incorporate Hb level as a covariate to meet this high performance.

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Cardiac retinoic acid levels decline in heart failure.

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Cardiac retinoic acid levels decline in heart failure.

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