The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is a matter of investigation and its diagnosis remains challenging. Although the mechanisms that are responsible for the ...development of HFpEF are not fully understood, it is well known that nearly 80% of patients with HFpEF have concomitant hypertension. We investigated whether early biochemical alterations were detectable during HFpEF progression in salt-induced hypertensive rats, using Fourier-transformed infrared (FTIR) and Raman spectroscopic techniques as a new diagnostic approach. Greater protein content and, specifically, greater collagen deposition were observed in the left atrium and right ventricle of hypertensive rats, together with altered metabolism of myocytes. Additionally, Raman spectra indicated a conformational change, or different degree of phosphorylation/methylation, in tyrosine-rich proteins. A correlation was found between tyrosine content and cardiac fibrosis of both right and left ventricles. Microcalcifications were detected in the left and right atria of control animals, with a progressive augmentation from six to 22 weeks. A further increase occurred in the left ventricle and right atrium of 22-week salt-fed animals, and a positive correlation was shown between the mineral deposits and the cardiac size of the left ventricle. Overall, FTIR and Raman techniques proved to be sensitive to early biochemical changes in HFpEF and preceded clinical humoral and imaging markers.
Abstract Coronary heart disease is the most common cause of death, and the number of individuals at risk is increasing. To better manage this pandemic, improved tool for risk prediction, including ...more accurate biomarkers are needed. The objective of this study was to assess the utility of circulating microRNAs (miRs) to predict future fatal acute myocardial infarction (AMI) in healthy participants. We performed a prospective nested case-control study with 10-year observation period and fatal AMI as endpoint. In total, 179 miRs were quantified by real-time polymerase chain reaction in serum of 112 healthy participants (40–70 years) that either (1) suffered from fatal AMI within 10 years n = 56, or (2) remained healthy n = 56, risk factor-matched controls. Candidate miRs were validated in a separate cohort of healthy individuals ( n = 100). Twelve miRs were differently expressed in cases and controls in the derivation cohort ( p < 0.05). Among these, 10 miRs differed significantly between cases and controls in the validation cohort ( p < 0.05). We identified gender dimorphisms, as miR-424-5p and miR-26a-5p were associated exclusively with risk in men and women, respectively. The best model for predicting future AMI consisted of miR-106a-5p, miR-424-5p, let-7 g-5p, miR-144-3p and miR-660-5p, providing 77.6% correct classification for both genders, and 74.1% and 81.8% for men and women, respectively. Adding these 5 miRs to the Framingham Risk Score, increased the AUC from 0.72 to 0.91 ( p < 0.001). In conclusion, we identified several miRs associated with future AMI, revealed gender-specific associations, and proposed a panel of 5 miRs to enhance AMI risk prediction in healthy individuals.
A significant body of evidence supports the protective role of exercise training (ET) in cardiovascular diseases, skeletal muscle dystrophies, several types of cancer, Alzheimer disease or even in ...the recovery of spinal cord injury. In spite of this, the molecular mechanisms underlying the beneficial effects of exercise training are not well understood and remain elusive. Several mechanisms have been proposed in the past, but more recently microRNAs (miRNAs), small non-coding RNA molecules involved in a variety of basic biological processes that negatively modulate gene expression, recognized as important regulatory molecules. In this review, we highlight recent advances on the miRNA involvement in the benefits of ET. Here, we assess the role of microRNAs expressed in the heart, in the skeletal muscle, detected in the circulation (serum and plasma), and in other conditions (e.g., spinal cord injury). Additionally, the long-term effects of diverse ET modalities (e.g., running, cycling, resistance training) in the cardiac miRNA profile are properly addressed.
Aim
Chronic heart failure (CHF) can be classified as heart failure with preserved ejection fraction (HFpEF) or with reduced ejection fraction (HFrEF). Currently, there is an unmet need for a ...minimally invasive diagnostic tool for different forms of CHF. We aimed to investigate the diagnostic potential of circulating microRNAs (miRNAs) for the detection of different CHF forms via a systematic review and meta‐analysis approach.
Methods and results
Comprehensive search on Medline, Web of Science, Scopus, and EMBASE identified 45 relevant studies which were used for qualitative assessment. Out of these, 29 studies were used for qualitative and quantitative assessment and allowed to identify a miRNA panel able to detect HFrEF and HFpEF with areas under the curve (AUC) of 0.86 and 0.79, respectively. A panel of eight miRNAs (hsa‐miR‐18b‐3p, hsa‐miR‐21‐5p, hsa‐miR‐22‐3p, hsa‐miR‐92b‐3p, hsa‐miR‐129‐5p, hsa‐miR‐320a‐5p, hsa‐miR‐423‐5p, and hsa‐miR‐675‐5p) detected HFrEF cases with a sensitivity of 0.85, specificity of 0.88 and AUC of 0.91. A panel of seven miRNAs (hsa‐miR‐19b‐3p, hsa‐miR‐30c‐5p, hsa‐miR‐206, hsa‐miR‐221‐3p, hsa‐miR‐328‐5p, hsa‐miR‐375‐3p, and hsa‐miR‐424‐5p) identified HFpEF cases with a sensitivity of 0.82 and a specificity of 0.61.
Conclusions
Although conventional biomarkers (N‐terminal pro‐B‐type natriuretic peptide and B‐type natriuretic peptide) presented a better performance in detecting CHF patients, the results presented here pointed towards specific miRNA panels with potential additive values to circulating natriuretic peptides in the diagnosis of different classes of CHF. Equally important, miRNAs alone showed a reasonable capacity for ‘ruling out’ patients with HFrEF or HFpEF. Additional studies with large populations are required to confirm the diagnostic potential of miRNAs for sub‐classes of CHF.
MicroRNA‐driven diagnostic biomarkers for heart failure with reduced or preserved ejection fraction. AUC, area under the receiver operating characteristic curve; BNP, B‐type natriuretic peptide; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; NT‐proBNP, N‐terminal prohormone B‐type natriuretic peptide; Sens, sensitivity; Spec, specificity.
MicroRNAs (miRNAs) are a class of non-coding RNAs of ∼22 nucleotides in length, and constitute a novel class of gene regulators by imperfect base-pairing to the 3'UTR of protein encoding messenger ...RNAs. Growing evidence indicates that miRNAs are implicated in several pathological processes in myocardial disease. The past years, we have witnessed several profiling attempts using high-density oligonucleotide array-based approaches to identify the complete miRNA content (miRNOME) in the healthy and diseased mammalian heart. These efforts have demonstrated that the failing heart displays differential expression of several dozens of miRNAs. While the total number of experimentally validated human miRNAs is roughly two thousand, the number of expressed miRNAs in the human myocardium remains elusive. Our objective was to perform an unbiased assay to identify the miRNOME of the human heart, both under physiological and pathophysiological conditions. We used deep sequencing and bioinformatics to annotate and quantify microRNA expression in healthy and diseased human heart (heart failure secondary to hypertrophic or dilated cardiomyopathy). Our results indicate that the human heart expresses >800 miRNAs, the majority of which not being annotated nor described so far and some of which being unique to primate species. Furthermore, >250 miRNAs show differential and etiology-dependent expression in human dilated cardiomyopathy (DCM) or hypertrophic cardiomyopathy (HCM). The human cardiac miRNOME still possesses a large number of miRNAs that remain virtually unexplored. The current study provides a starting point for a more comprehensive understanding of the role of miRNAs in regulating human heart disease.
Whereas heart failure with reduced ejection fraction (HFrEF) is associated with ventricular dilation and markedly reduced systolic function, heart failure with preserved ejection fraction (HFpEF) ...patients exhibit concentric hypertrophy and diastolic dysfunction. Impaired cardiomyocyte Ca2+ homeostasis in HFrEF has been linked to disruption of membrane invaginations called t-tubules, but it is unknown if such changes occur in HFpEF.
This study examined whether distinct cardiomyocyte phenotypes underlie the heart failure entities of HFrEF and HFpEF.
T-tubule structure was investigated in left ventricular biopsies obtained from HFrEF and HFpEF patients, whereas cardiomyocyte Ca2+ homeostasis was studied in rat models of these conditions.
HFpEF patients exhibited increased t-tubule density in comparison with control subjects. Super-resolution imaging revealed that higher t-tubule density resulted from both tubule dilation and proliferation. In contrast, t-tubule density was reduced in patients with HFrEF. Augmented collagen deposition within t-tubules was observed in HFrEF but not HFpEF hearts. A causative link between mechanical stress and t-tubule disruption was supported by markedly elevated ventricular wall stress in HFrEF patients. In HFrEF rats, t-tubule loss was linked to impaired systolic Ca2+ homeostasis, although diastolic Ca2+ removal was also reduced. In contrast, Ca2+ transient magnitude and release kinetics were largely maintained in HFpEF rats. However, diastolic Ca2+ impairments, including reduced sarco/endoplasmic reticulum Ca2+-ATPase activity, were specifically observed in diabetic HFpEF but not in ischemic or hypertensive models.
Although t-tubule disruption and impaired cardiomyocyte Ca2+ release are hallmarks of HFrEF, such changes are not prominent in HFpEF. Impaired diastolic Ca2+ homeostasis occurs in both conditions, but in HFpEF, this mechanism for diastolic dysfunction is etiology-dependent.
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Head and neck (HN) squamous cell carcinoma (SCC) is the eighth most common human cancer worldwide. Besides tobacco and alcohol consumption, genetic and epigenetic alterations play an important role ...in HNSCC occurrence and progression. microRNAs (miRNAs) are small noncoding RNAs that regulate cell cycle, proliferation, development, differentiation, and apoptosis by interfering in gene expression. Expression profiling of miRNAs showed that some miRNAs are upregulated or downregulated in tumor cells when compared with the normal cells. The present review focuses on the role of miRNAs deregulations in HNSCC, enrolled in risk, development, outcome, and therapy sensitivity. Moreover, the influence of single nucleotide variants in miRNAs target sites, miRNAs seed sites, and miRNAs‐processing genes in HNSCC was also revised. Due to its potential for cancer diagnosis, progression, and as a therapeutic target, miRNAs may bring new perspectives in HNSCC understanding and therapy, especially for those patients with no or insufficient treatment options.
Aims
Peripheral muscle dysfunction is a key mechanism contributing to exercise intolerance (i.e. breathlessness and fatigue) in heart failure patients with preserved ejection fraction (HFpEF); ...however, the underlying molecular and cellular mechanisms remain unknown. We therefore used an animal model to elucidate potential molecular, mitochondrial, histological, and functional alterations induced by HFpEF in the diaphragm and soleus, while also determining the possible benefits associated with exercise training.
Methods and results
Female Dahl salt‐sensitive rats were fed a low (CON; n = 10) or high salt (HFpEF; n = 11) diet of 0.3% or 8% NaCl, respectively, or a high salt diet in combination with treadmill exercise training (n = 11). Compared with low‐salt rats, high‐salt rats developed (P < 0.05) HFpEF. Compared with CON, the diaphragm of HFpEF rats demonstrated (P < 0.05): a fibre type shift from fast‐to‐slow twitch; fibre atrophy; a decreased pro‐oxidative but increased anti‐oxidant capacity; reduced proteasome activation; impaired in situ mitochondrial respiration; and in vitro muscle weakness and increased fatigability. The soleus also demonstrated numerous alterations (P < 0.05), including fibre atrophy, decreased anti‐oxidant capacity, reduced mitochondrial density, and increased fatigability. Exercise training, however, prevented mitochondrial and functional impairments in both the diaphragm and soleus (P < 0.05).
Conclusion
Our findings are the first to demonstrate that HFpEF induces significant molecular, mitochondrial, histological, and functional alterations in the diaphragm and soleus, which were attenuated by exercise training. These data therefore reveal novel mechanisms and potential therapeutic treatments of exercise intolerance in HFpEF.
Cardiac hypertrophy and renal damage associated with hypertension are independent predictors of morbidity and mortality. In a model of hypertensive heart disease and renal damage, we tested the ...actions of continuous administration of Vastiras, a novel compound derived from the linear fragment of ANP (atrial natriuretic peptide), namely pro-ANP
, on blood pressure and associated renal and cardiac function and remodeling. Of note, this peptide, unlike the ring structured forms, does not bind to the classic natriuretic peptide receptors. Dahl/Salt-Sensitive rats fed a 4% NaCl diet for 6 weeks developed hypertension, cardiac hypertrophy, and renal damage. Four weeks of treatment with 50 to 100 ng/kg per day of Vastiras exhibited positive effects on renal function, independent of blood pressure regulation. Treated rats had increased urine excretion, natriuresis, and enhanced glomerular filtration rate. Importantly, these favorable renal effects were accompanied by improved cardiac structure and function, including attenuated cardiac hypertrophy, as indicated by decreased heart weight to body weight ratio, relative wall thickness, and left atrial diameter, as well as reduced fibrosis and normalized ratio of the diastolic mitral inflow E wave to A wave. A renal subtherapeutic dose of Vastiras (25 ng/kg per day) induced similar protective effects on the heart. At the cellular level, cardiomyocyte size and t-tubule density were preserved in Vastiras-treated compared with untreated animals. In conclusion, these data demonstrate the cardiorenal protective actions of chronic supplementation of a first-in-class compound, Vastiras, in a preclinical model of maladaptive cardiac hypertrophy and renal damage induced by hypertension.
Cryptococcus gattii (Cg) is one of the agents of cryptococcosis, a severe systemic mycosis with a higher prevalence in men than women, but the influence of the female sex hormone, 17‐β‐estradiol ...(E2), on cryptococcosis remains unclear. Our study shows that female mice presented delayed mortality, increased neutrophil recruitment in bronchoalveolar lavage fluid, and reduced fungal load after 24 hr of infection compared to male and ovariectomised female mice (OVX). E2 replacement restored OVX female survival. Female macrophages have more efficient fungicidal activity, which was increased by E2 and reversed by the antagonist of G‐protein‐coupled oestrogen receptor (GPER), which negatively modulates PI3K activation. Furthermore, E2 induces a reduction in Cg cell diameter, cell charge, and antioxidant peroxidase activity. In conclusion, female mice present improved control of Cg infection, and GPER is important for E2 modulation of the female response.
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