Mitochondrion as a Target of Astaxanthin Therapy in Heart Failure

Mitochondria are considered to be important organelles in the cell and play a key role in the physiological function of the heart, as well as in the pathogenesis and development of various heart diseases. Under certain pathological conditions, such as cardiovascular diseases, stroke, traumatic brain injury, neurodegenerative diseases, muscular dystrophy, etc., mitochondrial permeability transition pore (mPTP) is formed and opened, which can lead to dysfunction of mitochondria and subsequently to cell death. This review summarizes the results of studies carried out by our group of the effect of astaxanthin (AST) on the functional state of rat heart mitochondria upon direct addition of AST to isolated mitochondria and upon chronic administration of AST under conditions of mPTP opening. It was shown that AST exerted a protective effect under all conditions. In addition, AST treatment was found to prevent isoproterenol-induced oxidative damage to mitochondria and increase mitochondrial efficiency. AST, a ketocarotenoid, may be a potential mitochondrial target in therapy for pathological conditions associated with oxidative damage and mitochondrial dysfunction, and may be a potential mitochondrial target in therapy for pathological conditions.     

Serum Selenium and Ceruloplasmin in Nigerians with Peripartum Cardiomyopathy

The study aimed to determine if selenium deficiency, serum ceruloplasmin and traditional birth practices are risk factors for peripartum cardiomyopathy (PPCM), in Kano, Nigeria. This is a case-control study carried out in three hospitals, and PPCM patients were followed up for six months. Critically low serum selenium concentration was defined as <70 µg/L. A total of 39 PPCM patients and 50 controls were consecutively recruited after satisfying the inclusion criteria. Mean serum selenium in patients (61.7 ± 14.9 µg/L) was significantly lower than in controls (118.4 ± 45.6 µg/L) (p < 0.001). The prevalence of serum selenium <70 µg/L was significantly higher among patients (76.9%) than controls (22.0%) (p < 0.001). The mean ceruloplasmin and prevalence of socio-economic indices, multiparity, pregnancy-induced hypertension, obesity and twin pregnancy were not different between the groups (p > 0.05). Logistic regression showed that rural residency significantly increased the odds for serum selenium <70 µg/L by 2.773-fold (p = 0.037). Baseline serum levels of selenium and ceruloplasmin were not associated with six-month mortality. This study has shown that selenium deficiency is a risk factor for PPCM in Kano, Nigeria, and is related to rural residency. However, serum ceruloplasmin, customary birth practices and some other characteristics were not associated with PPCM in the study area.     

C-Reactive Protein as a Risk Marker for Post-Infarct Heart Failure over a Multi-Year Period

Inflammatory activation during acute ST-elevation myocardial infarction (STEMI) can contribute to post-infarct heart failure (HF). This study aimed to determine prognostic value of high-sensitivity C-reactive protein concentration (CRP) for HF over a long-term follow-up in 204 patients with a first STEMI undergoing guideline-based therapies including percutaneous coronary intervention. CRP was measured at admission, 24 h (CRP₂₄), discharge (CRP_DC), and one month (CRP_1M) after index hospitalization for STEMI. Within a median period of 5.6 years post-index hospitalization for STEMI, hospitalization for HF (HFH) which is a primary endpoint, occurred in 24 patients (11.8%, HF+ group). During the study, 8.3% of HF+ patients died vs. 1.7% of patients without HFH (HF- group) (p = 0.047). CRP₂₄, CRP_DC, and CRP_1M were significantly higher in HF+ compared to HF- group. The median CRP_1M in HF+ group was 2.57 mg/L indicating low-grade systemic inflammation, in contrast to 1.54 mg/L in HF- group. CRP_1M ≥ 2 mg/L occurred in 58.3% of HF+ vs. 42.8% of HF- group (p = 0.01). Kaplan–Meier analysis showed decreased probability of survival free from HFH in patients with CRP₂₄ (p < 0.001), CRP_DC (p < 0.001), and CRP_1M (p = 0.03) in quartile IV compared to lower quartiles. In multivariable analysis, CRP_DC significantly improved prediction of HFH over a multi-year period post-STEMI. Persistent elevation in CRP post STEMI aids in risk stratification for long-term HF and suggests that ongoing cardiac and low-grade systemic inflammation promote HF development despite guideline-based therapies.     

Crosstalk between microRNA and Oxidative Stress in Heart Failure: A Systematic Review

Heart failure is defined as a clinical syndrome consisting of key symptoms and is due to a structural and/or functional alteration of the heart that results in increased intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. One of the key mechanisms determining myocardial dysfunction in heart failure is oxidative stress. MicroRNAs (miRNAs, miRs) are short, endogenous, conserved, single-stranded non-coding RNAs of around 21–25 nucleotides in length that act as regulators of multiple processes. A systematic review following the PRISMA guidelines was performed on the evidence on the interplay between microRNA and oxidative stress in heart failure. A search of Pubmed, Embase, Scopus, and Scopus direct databases using the following search terms: ‘heart failure’ AND ‘oxidative stress’ AND ‘microRNA’ or ‘heart failure’ AND ‘oxidative stress’ AND ‘miRNA’ was conducted and resulted in 464 articles. Out of them, 15 full text articles were eligible for inclusion in the qualitative analysis. Multiple microRNAs are involved in the processes associated with oxidative stress leading to heart failure development including mitochondrial integrity and function, antioxidant defense, iron overload, ferroptosis, and survival pathways.     

Multiplexed MRM-Based Proteomics Identified Multiple Biomarkers of Disease Severity in Human Heart Failure

Heart failure (HF) is a complex disease due to the intricate interplay of several mechanisms, which therefore implies the need for a multimarker strategy to better personalize the care of patients with HF. In this study, we developed a targeted mass spectrometry approach based on multiple reaction monitoring (MRM) to measure multiple circulating protein biomarkers, involved in cardiovascular disease, to address their relevance in the human HF, intending to assess the feasibility of the workflow in the disease monitoring and risk stratification. In this study, we analyzed a total of 60 plasma proteins in 30 plasma samples from eight control subjects and 22 age- and gender- matched HF patients. We identified a panel of four plasma proteins, namely Neuropilin-2, Beta 2 microglobulin, alpha-1-antichymotrypsin, and complement component C9, that were more abundant in HF patients in relation to disease severity and pulmonary dysfunction. Moreover, we showed the ability of the combination of these candidate proteins to discriminate, with sufficient accuracy, HF patients from healthy subjects. In conclusion, we demonstrated the feasibility and potential of a proteomic workflow based on MRM mass spectrometry for the evaluation of multiple proteins in human plasma and the identification of a panel of biomarkers of HF severity.     

Epigenetics and Heart Failure

Epigenetics refers to changes in phenotypes without changes in genotypes. These changes take place in a number of ways, including via genomic DNA methylation, DNA interacting proteins, and microRNAs. The epigenome is the second dimension of the genome and it contains key information that is specific to every type of cell. Epigenetics is essential for many fundamental processes in biology, but its importance in the development and progression of heart failure, which is one of the major causes of morbidity and mortality worldwide, remains unclear. Our understanding of the underlying molecular mechanisms is incomplete. While epigenetics is one of the most innovative research areas in modern biology and medicine, compounds that directly target the epigenome, such as epidrugs, have not been well translated into therapies. This paper focuses on epigenetics in terms of genomic DNA methylation, such as 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC) modifications. These appear to be more dynamic than previously anticipated and may underlie a wide variety of conditions, including heart failure. We also outline possible new strategies for the development of novel therapies.     

The Effectiveness of Glutathione Redox Status as a Possible Tumor Marker in Colorectal Cancer

The role of oxidative stress (OS) in cancer is a matter of great interest due to the implication of reactive oxygen species (ROS) and their oxidation products in the initiation of tumorigenesis, its progression, and metastatic dissemination. Great efforts have been made to identify the mechanisms of ROS-induced carcinogenesis; however, the validation of OS byproducts as potential tumor markers (TMs) remains to be established. This interventional study included a total of 80 colorectal cancer (CRC) patients and 60 controls. By measuring reduced glutathione (GSH), its oxidized form (GSSG), and the glutathione redox state in terms of the GSSG/GSH ratio in the serum of CRC patients, we identified significant changes as compared to healthy subjects. These findings are compatible with the effectiveness of glutathione as a TM. The thiol redox state showed a significant increase towards oxidation in the CRC group and correlated significantly with both the tumor state and the clinical evolution. The sensitivity and specificity of serum glutathione levels are far above those of the classical TMs CEA and CA19.9. We conclude that the GSSG/GSH ratio is a simple assay which could be validated as a novel clinical TM for the diagnosis and monitoring of CRC.     

Urine Aquaporin-2: A Promising Marker of Response to the Arginine Vasopressin Type-2 Antagonist,Tolvaptan in Patients with Congestive Heart Failure

Aquaporin-2, a member of the aquaporin family, is an arginine vasopressin-regulated water channel expressed in the renal collecting duct, and a promising marker of the concentrating and diluting ability of the kidney. The arginine vasopressin type-2 antagonist, tolvaptan, is a new-generation diuretic; it is especially indicated in patients with decompensated heart failure refractory to conventional diuretics. However, the ideal responders to tolvaptan have not yet been identified, and non-responders experience worse clinical courses despite treatment with tolvaptan. Urine aquaporin-2 has recently been demonstrated as a promising predictor of response to tolvaptan. We here validated aquaporin-2-guided tolvaptan therapy in patients with decompensated heart failure. Long-term efficacy of tolvaptan treatment in the responders defined by aquaporin-2 needs to be validated in the future prospective study.     

The Improvement of Functional State of Brain Mitochondria with Astaxanthin in Rats after Heart Failure

The relationship between neurological damage and cardiovascular disease is often observed. This type of damage is both a cause and an effect of cardiovascular disease. Mitochondria are the key organelles of the cell and are primarily subject to oxidative stress. Mitochondrial dysfunctions are involved in the etiology of various diseases. A decrease in the efficiency of the heart muscle can lead to impaired blood flow and decreased oxygen supply to the brain. Astaxanthin (AST), a marine-derived xanthophyll carotenoid, has multiple functions and its effects have been shown in both experimental and clinical studies. We investigated the effects of AST on the functional state of brain mitochondria in rats after heart failure. Isoproterenol (ISO) was used to cause heart failure. In the present study, we found that ISO impaired the functional state of rat brain mitochondria (RBM), while the administration of AST resulted in an improvement in mitochondrial efficiency. The respiratory control index (RCI) in RBM decreased with the use of ISO, while AST administration led to an increase in this parameter. Ca²⁺ retention capacity (CRC) decreased in RBM isolated from rat brain after ISO injection, and AST enhanced CRC in RBM after heart failure. The study of changes in the content of regulatory proteins such as adenine nucleotide translocase 1 and 2 (ANT1/2), voltage dependent anion channel (VDAC), and cyclophilin D (CyP-D) of mitochondrial permeability transition pore (mPTP) showed that ISO reduced their level, while AST restored the content of these proteins almost to the control value. In general, AST improves the functional state of mitochondria and can be considered as a prophylactic drug in various therapeutic approaches.     

Heart Failure and Drug Therapies: A Metabolic Review

Cardiovascular disease is the leading cause of mortality globally with at least 26 million people worldwide living with heart failure (HF). Metabolism has been an active area of investigation in the setting of HF since the heart demands a high rate of ATP turnover to maintain homeostasis. With the advent of -omic technologies, specifically metabolomics and lipidomics, HF pathologies have been better characterized with unbiased and holistic approaches. These techniques have identified novel pathways in our understanding of progression of HF and potential points of intervention. Furthermore, sodium-glucose transport protein 2 inhibitors, a drug that has changed the dogma of HF treatment, has one of the strongest types of evidence for a potential metabolic mechanism of action. This review will highlight cardiac metabolism in both the healthy and failing heart and then discuss the metabolic effects of heart failure drugs.     

Metabolomic Profiling of End-Stage Heart Failure Secondary to Chronic Chagas Cardiomyopathy

Chronic Chagas cardiomyopathy (CCC) is the most frequent and severe clinical form of chronic Chagas disease, representing one of the leading causes of morbidity and mortality in Latin America, and a growing global public health problem. There is currently no approved treatment for CCC; however, omics technologies have enabled significant progress to be made in the search for new therapeutic targets. The metabolic alterations associated with pathogenic mechanisms of CCC and their relationship to cellular and immunopathogenic processes in cardiac tissue remain largely unknown. This exploratory study aimed to evaluate the potential underlying pathogenic mechanisms in the failing myocardium of patients with end-stage heart failure (ESHF) secondary to CCC by applying an untargeted metabolomic profiling approach. Cardiac tissue samples from the left ventricle of patients with ESHF of CCC etiology (n = 7) and healthy donors (n = 7) were analyzed using liquid chromatography-mass spectrometry. Metabolite profiles showed altered branched-chain amino acid and acylcarnitine levels, decreased fatty acid uptake and oxidation, increased activity of the pentose phosphate pathway, dysregulation of the TCA cycle, and alterations in critical cellular antioxidant systems. These findings suggest processes of energy deficit, alterations in substrate availability, and enhanced production of reactive oxygen species in the affected myocardium. This profile potentially contributes to the development and maintenance of a chronic inflammatory state that leads to progression and severity of CCC. Further studies involving larger sample sizes and comparisons with heart failure patients without CCC are needed to validate these results, opening an avenue to investigate new therapeutic approaches for the treatment and prevention of progression of this unique and severe cardiomyopathy.     

Emerging Biomarkers in Heart Failure and Cardiac Cachexia

Biomarkers are objective tools with an important role for diagnosis, prognosis and therapy optimization in patients with heart failure (HF). To date, natriuretic peptides are closest to optimal biomarker standards for clinical implications in HF. Therefore, the efforts to identify and test new biomarkers in HF are reasonable and justified. Along the natural history of HF, cardiac cachexia may develop, and once at this stage, patient performance and prognosis is particularly poor. For these reasons, numerous biomarkers reflecting hormonal, inflammatory and oxidative stress pathways have been investigated, but only a few convey relevant information. The complex pathophysiology of HF appears far too complex to be embraced by a single biomarker; thus, a combined approach appears reasonable. With these considerations, we have reviewed the recent developments in the field to highlight key candidates with diagnostic, prognostic and therapy optimization properties, either alone or in combination.     

The Multi-Biomarker Approach for Heart Failure in Patients with Hypertension

We assessed the predictive ability of selected biomarkers using N-terminal pro-brain natriuretic peptide (NT-proBNP) as the benchmark and tried to establish a multi-biomarker approach to heart failure (HF) in hypertensive patients. In 120 hypertensive patients with or without overt heart failure, the incremental predictive value of the following biomarkers was investigated: Collagen III N-terminal propeptide (PIIINP), cystatin C (CysC), lipocalin-2/NGAL, syndecan-4, tumor necrosis factor-α (TNF-α), interleukin 1 receptor type I (IL1R1), galectin-3, cardiotrophin-1 (CT-1), transforming growth factor β (TGF-β) and N-terminal pro-brain natriuretic peptide (NT-proBNP). The highest discriminative value for HF was observed for NT-proBNP (area under the receiver operating characteristic curve (AUC) = 0.873) and TGF-β (AUC = 0.878). On the basis of ROC curve analysis we found that CT-1 > 152 pg/mL, TGF-β < 7.7 ng/mL, syndecan > 2.3 ng/mL, NT-proBNP > 332.5 pg/mL, CysC > 1 mg/L and NGAL > 39.9 ng/mL were significant predictors of overt HF. There was only a small improvement in predictive ability of the multi-biomarker panel including the four biomarkers with the best performance in the detection of HF—NT-proBNP, TGF-β, CT-1, CysC—compared to the panel with NT-proBNP, TGF-β and CT-1 only. Biomarkers with different pathophysiological backgrounds (NT-proBNP, TGF-β, CT-1, CysC) give additive prognostic value for incident HF in hypertensive patients compared to NT-proBNP alone.     

Deodorized Garlic Decreases Oxidative Stress Caused by Lipopolysaccharide in Rat Heart through Hydrogen Sulfide: Preliminary Findings

Deodorized garlic (DG) may favor the activity of the antioxidant enzymes and promote the synthesis of hydrogen sulfide (H₂S). The objective was to test if DG favors an increase in H₂S and if it decreases the oxidative stress caused by lipopolysaccharide (LPS) in rat hearts. A total of 24 rats were divided into 4 groups: Group 1 control (C), Group 2 LPS, Group 3 DG, and Group 4 LPS plus DG. The cardiac mechanical performance (CMP), coronary vascular resistance (CVR), and oxidative stress markers, such as total antioxidant capacity (TAC), glutathione (GSH), selenium (Se), lipid peroxidation (LPO), thiols, hydrogen sulfide (H₂S), and the activities and expressions of thioredoxin reductase (TrxR), glutathione peroxidase (GPx), and glutathione-S-transferase (GST), cystathionine synthetase (CBS), cystathionine γ-lyase (CTH), iNOS, and eNOS-p, were analyzed in the heart. Infarct zones in the cardiac tissue were present (p = 0.01). The CMP and CVR decreased and increased (p ≤ 0.05), TAC, GSH, H₂S, NO, thiols, and GST activity (p ≤ 0.01) decreased, and LPO and iNOS increased (p ≤ 0.05). The activities and expressions of TrxR, GPx, eNOS-p, CTH, and CBS (p ≤ 0.05) decreased with the LPS treatment; however, DG normalized this effect. DG treatment decreases heart damage caused by LPS through the cross-talk between the H₂S and NO systems.     

Minocycline Impact on Redox Homeostasis of Normal Human Melanocytes HEMn-LP Exposed to UVA Radiation and Hydrogen Peroxide

Minocycline is a semisynthetic tetracycline antibiotic. In addition to its antibacterial activity, minocycline shows many non-antibiotic, beneficial effects, including antioxidative action. The property is responsible, e.g., for anti-inflammatory, neuroprotective, and cardioprotective effects of the drug. However, long-term pharmacotherapy with minocycline may lead to hyperpigmentation of the skin. The reasons for the pigmentation disorders include the deposition of the drug and its metabolites in melanin-containing cells and the stimulation of melanogenesis. The adverse drug reaction raises a question about the influence of the drug on melanocyte homeostasis. The study aimed to assess the effect of minocycline on redox balance in human normal melanocytes HEMn-LP exposed to hydrogen peroxide and UVA radiation. The obtained results indicate that minocycline induced oxidative stress in epidermal human melanocytes. The drug inhibited cell proliferation, decreased the level of reduced thiols, and stimulated the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). The described changes were accompanied by an increase in the intracellular level of ROS. On the other hand, pretreatment with minocycline at the same concentrations increased cell viability and significantly attenuated the oxidative stress in melanocytes exposed to hydrogen peroxide and UVA radiation. Moreover, the molecular docking analysis revealed that the different influence of minocycline and other tetracyclines on CAT activity can be related to the location of the binding site.     

Heart Failure and Atrial Fibrillation: From Basic Science to Clinical Practice

Heart failure (HF) and atrial fibrillation (AF) are two growing epidemics associated with significant morbidity and mortality. They often coexist due to common risk factors and shared pathophysiological mechanisms. Patients presenting with both HF and AF have a worse prognosis and present a particular therapeutic challenge to clinicians. This review aims to appraise the common pathophysiological background, as well as the prognostic and therapeutic implications of coexistent HF and AF.     

Acute Severe Heart Failure Reduces Heart Rate Variability: An Experimental Study in a Porcine Model

There are substantial differences in autonomic nervous system activation among heart (cardiac) failure (CF) patients. The effect of acute CF on autonomic function has not been well explored. The aim of our study was to assess the effect of experimental acute CF on heart rate variability (HRV). Twenty-four female pigs with a mean body weight of 45 kg were used. Acute severe CF was induced by global myocardial hypoxia. In each subject, two 5-min electrocardiogram segments were analyzed and compared: before the induction of myocardial hypoxia and >60 min after the development of severe CF. HRV was assessed by time-domain, frequency-domain and nonlinear analytic methods. The induction of acute CF led to a significant decrease in cardiac output, left ventricular ejection fraction and an increase in heart rate. The development of acute CF was associated with a significant reduction in the standard deviation of intervals between normal beats (50.8 [20.5–88.1] ms versus 5.9 [2.4–11.7] ms, p < 0.001). Uniform HRV reduction was also observed in other time-domain and major nonlinear analytic methods. Similarly, frequency-domain HRV parameters were significantly changed. Acute severe CF induced by global myocardial hypoxia is associated with a significant reduction in HRV.     

Functional and Molecular Characterisation of Heart Failure Progression in Mice and the Role of Myosin Regulatory Light Chains in the Recovery of Cardiac Muscle Function

Heart failure (HF) as a result of myocardial infarction (MI) is a major cause of fatality worldwide. However, the cause of cardiac dysfunction succeeding MI has not been elucidated at a sarcomeric level. Thus, studying the alterations within the sarcomere is necessary to gain insights on the fundamental mechansims leading to HF and potentially uncover appropriate therapeutic targets. Since existing research portrays regulatory light chains (RLC) to be mediators of cardiac muscle contraction in both human and animal models, its role was further explored In this study, a detailed characterisation of the physiological changes (i.e., isometric force, calcium sensitivity and sarcomeric protein phosphorylation) was assessed in an MI mouse model, between 2D (2 days) and 28D post-MI, and the changes were related to the phosphorylation status of RLCs. MI mouse models were created via complete ligation of left anterior descending (LAD) coronary artery. Left ventricular (LV) papillary muscles were isolated and permeabilised for isometric force and Ca²⁺ sensitivity measurement, while the LV myocardium was used to assay sarcomeric proteins’ (RLC, troponin I (TnI) and myosin binding protein-C (MyBP-C)) phosphorylation levels and enzyme (myosin light chain kinase (MLCK), zipper interacting protein kinase (ZIPK) and myosin phosphatase target subunit 2 (MYPT2)) expression levels. Finally, the potential for improving the contractility of diseased cardiac papillary fibres via the enhancement of RLC phosphorylation levels was investigated by employing RLC exchange methods, in vitro. RLC phosphorylation and isometric force potentiation were enhanced in the compensatory phase and decreased in the decompensatory phase of HF failure progression, respectively. There was no significant time-lag between the changes in RLC phosphorylation and isometric force during HF progression, suggesting that changes in RLC phosphorylation immediately affect force generation. Additionally, the in vitro increase in RLC phosphorylation levels in 14D post-MI muscle segments (decompensatory stage) enhanced its force of isometric contraction, substantiating its potential in HF treatment. Longitudinal observation unveils potential mechanisms involving MyBP-C and key enzymes regulating RLC phosphorylation, such as MLCK and MYPT2 (subunit of MLCP), during HF progression. This study primarily demonstrates that RLC phosphorylation is a key sarcomeric protein modification modulating cardiac function. This substantiates the possibility of using RLCs and their associated enzymes to treat HF.     

安体舒通联合卡托普利治疗慢性心衰50例临床观察

目的探讨卡托普利与安体舒通联合治疗慢性心力衰竭的疗效观察。方法选择我院100例慢性心力衰竭患者,随机分为治疗组和对照组。2组均积极治疗原发病,对照组使用洋地黄及速尿。治疗组在对照组治疗方法的基础上加用卡托普利和安体舒通,3～4周为1个疗程,观察治疗后2组疗效。结果2组患者治疗前、后收缩压(SBP),舒张压(DBP)、心率、6min步行距离间差异均有显著性意义,2组患者治疗前、后左室射血分数(EF),每搏输出量(SV),每分输出量(CO)均有显著性意义,治疗组总有效率显著高于对照组。结论联合使用小剂量的安体舒通和卡托普利治疗CHF,能够有效的抑制RASS系统,拮抗醛固酮,从而改善左室血流动力学,长期使用安全有效。