Pathogenic Role In Heart Failure Research Articles

Serum aldosterone in right ventricular failure versus left ventricular failure before and after mineralocorticoid receptor antagonists: case-control clinical trial

Background Heart failure (HF) is a global growing health threat. This case-control clinical trial aimed to detect the predictive value and difference in aldosterone level between right side heart failure, heart failure with decreased ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF) and compare the efficacy and safety of adding mineralocorticoid receptor antagonist (MRA) for treatment. Patients and methods We recruited 151 participants, 135 HF patients divided equally into 45 patients in each group:(1) right side HF (2) HFrEF and (3) HFpEF and 16 healthy controls. Serum aldosterone, troponin and echocardiography were evaluated at the beginning of the study, three and six months after administration of MRA. Results Aldosterone level was significantly greater in HF patients relative to controls. Aldosterone level can detect HF with excellent accuracy. There were significantly lower levels of aldosterone in right side HF compared to left side HF. There was a significant decrease in right ventricle dimensions, pulmonary artery systolic pressure and pulmonary artery size and significant increase in tricuspid annular plane systolic excursion after treatment in patients with right side HF. In the HFrEF group, there was a significant decrease in left ventricular end diastolic dimension and a significant increase in left ventricular EF after treatment. In the HFpEF group, there was a significant decrease in E/A and E/e′ after treatment. Conclusions Aldosterone may have pathogenic role in HF. Measuring and follow-up of aldosterone levels should be considered in HF patients. MRA treatment gives a significant improvement in right side HF group.

Circular RNAs dysregulation in ischemic heart failure

Abstract Introduction Circular RNAs (circRNAs) are an emerging class of non-coding RNAs originating from the splicing and circularization of pre-mRNAs and long non-coding RNAs. CircRNAs can regulate transcription and splicing, sequester microRNAs acting as “sponge” and inducing the respective targets, and bind to RNA binding proteins. CircRNAs have been found deregulated in several cardiovascular diseases, including heart failure (HF). However, incomplete and sometimes contradictory results have been reported on their regulation and function in HF, possibly for the heterogeneity of patients analyzed, indicating that our understanding of the regulation and role of cardiac circRNAs is still very limited. Purpose We aim to identify novel circRNA candidates deregulated in ischemic HF and to functionally characterize them in HF. Methods To define the circRNA expression pattern in ischemic HF, a high-depth RNA-seq was performed on the remote zone of left ventricle (LV) samples of 20 non end-stage ischemic HF patients with reduced LV ejection fraction and 20 matched controls. Differentially expressed circRNAs identified using CIRIquant tool were validated by qRT-PCR. Samples from the border zone of non end-stage HF patients and LV biopsies from end-stage HF patients were also used to measure circRNAs expression. Results By RNA-seq, we identified 17 circRNAs as differentially expressed with FDR<0.1. qRT-PCR results confirmed the differential expression of 4 circRNAs, cSLC6A6, cNAA16, cMLIP and cHDCA9, which were upregulated in HF samples (t-test, p-value <0.001). To evaluate circRNAs deregulated independently of their linear counterparts, we also estimated the ratio between circular and linear isoforms. cSLC6A6, cMLIP and cHDCA9 showed also a statistically significant (t-test, p-value <0.002) increase of the circular-to-linear ratio between HF and control patients. To complement the unbiased strategy of RNA-seq, we evaluated the modulation of 18 candidate circRNAs identified by a literature analysis as dysregulated in ischemic or not-ischemic cardiomyopathies or in biological mechanisms relevant for ischemic HF. cPVT1, cANKRD17, cBPTF, displaying a concordant deregulation in different stages of the disease (non end-stage and end-stage HF) and in different regions of LV myocardium (remote and border zone), were chosen for further analysis. Using siRNAs targeting the backsplice junction, cPVT1 was specifically knockdown in a human cardiomyocyte cell line. RNA-seq analysis of cPVT1 knockdown samples identified 3577 significantly differentially expressed genes (FDR<0.01). Gene ontology and pathway analysis showed that these genes were mainly involved in the formation of extracellular matrix, fibrosis and in cellular senescence, suggesting the involvement of cPVT1 in these HF-related disease mechanisms. Conclusion We identified new deregulated circRNAs in ischemic HF patients that might play a pathogenic role in HF. Funding Acknowledgement Type of funding sources: Private hospital(s). Main funding source(s): Italian Ministry of Health, Ricerca Corrente 2021-2023 “CircularRNAs in heart failure: regulation, function and interaction with the transcriptome”

The Homeostatic Chemokine CCL21 Predicts Mortality and May Play a Pathogenic Role in Heart Failure

BackgroundCCL19 and CCL21, acting through CCR7, are termed homeostatic chemokines. Based on their role in concerting immunological responses and their proposed involvement in tissue remodeling, we hypothesized that these chemokines could play a pathogenic role in heart failure (HF).Methodology/Principal FindingsOur main findings were: (i) Serum levels of CCL19 and particularly CCL21 were markedly raised in patients with chronic HF (n = 150) as compared with healthy controls (n = 20). A CCL21 level above median was independently associated with all-cause mortality. (ii) In patients with HF following acute myocardial infarction (MI; n = 232), high versus low CCL21 levels 1 month post-MI were associated with cardiovascular mortality, even after adjustment for established risk factors. (iii). Explanted failing human LV tissue (n = 29) had markedly increased expression of CCL21 as compared with non-failing myocardium (n = 5). (iv) Our studies in CCR7−/− mice showed improved survival and attenuated increase in markers of myocardial dysfunction and wall stress in post-MI HF after 1 week, accompanied by increased myocardial expression of markers of regulatory T cells. (v) Six weeks post-MI, there was an increase in markers of myocardial dysfunction and wall stress in CCR7 deficient mice.Conclusions/SignificanceHigh serum levels of CCL21 are independently associated with mortality in chronic and acute post-MI HF. Our findings in CCR7 deficient mice may suggest that CCL21 is not only a marker, but also a mediator of myocardial failure. However, while short term inhibition of CCR7 may be beneficial following MI, a total lack of CCR7 during long-term follow-up could be harmful.

Myocardial Insulin-like Growth Factor-1 and Insulin-like Growth Factor Binding Protein-3 Gene Expression in Failing Hearts Harvested From Patients Undergoing Cardiac Transplantation

Insulin-like growth factor-1 (IGF-1) and insulin-like growth factor binding proteins (IGFBPs) might play a pathogenic role in heart failure. We showed significantly increased myocardial IGFBP-3 expression (investigated by real-time polymerase chain reaction) and apoptosis (detected by flow cytometry) in 23 failing hearts from patients undergoing cardiac transplantation for end-stage dilated or ischemic cardiomyopathy, when compared with 10 controls. Higher IGF-1 mRNA levels were shown only in end-stage dilated cardiomyopathy.

Soluble CD40 ligand in acute and chronic heart failure

Inflammatory cytokines may play a pathogenic role in heart failure (HF). CD40-CD40 ligand (CD40L) interactions are important in atherogenesis and based on its role in inflammation we sought to evaluate the role of CD40L in human HF. Serum levels of soluble (s) CD40L were measured in 236 patients with acute HF following myocardial infarction, treated with either angiotensin-converting enzyme (ACE)-inhibition or angiotensin II blockade and followed for 2 years, and in 116 patients with chronic HF. Our main findings were: (i) patients with acute HF had increased sCD40L levels, particularly those with severe HF, diabetes, or hypertension; (ii) when these patients were followed longitudinally, persistently raised sCD40L levels were found throughout the observation period with no effect of captopril or losartan; (iii) the increase in sCD40L during follow-up was not seen in patients receiving warfarin therapy; (iv) patients with chronic HF also had raised sCD40L, significantly correlated with clinical severity, neurohormonal dysregulation, and left ventricular dysfunction; (v) studies from different blood compartments suggest that the vasculature of lower extremities and the failing myocardium itself may produce and secrete sCD40L in chronic HF. Our findings may suggest a pathogenic role for enhanced CD40-CD40L interactions in human HF.

Cardiopulmonary alterations in mRNA expression for interleukin-1beta, the interleukin-6 superfamily and CXC-chemokines during development of postischaemic heart failure in the rat.

Cytokines and chemokines are believed to play a pathogenic role in heart failure (HF). Although some cytokines and chemokines have been examined in HF, information about others is still lacking. We aimed to examine the expression of cytokines belonging to the interleukin (IL)-6 superfamily [IL-6 and ciliary neurotrophic factor (CNTF)], as well as IL-1beta and the CXC-chemokines monocyte chemoattractant protein-1 (MCP-1) and IL-8. We examined their expression in the heart, lung and spleen during development of postischaemic HF 1 and 6 weeks following left coronary artery ligation. Rats, which after myocardial infarction had a left ventricular end-diastolic pressure above 15 mmHg, were considered to be in HF. Sham-operated rats served as controls. A substantial upregulation of cardiac IL-1beta was measured in HF at 1 week, whereas a downregulation was measured in the lungs. At 6 weeks no altered regulation was seen. CNTF was only upregulated in the viable left ventricle at 6 weeks and IL-6 was upregulated in the infarcted region at 1 week. Cardiac MCP-1 was upregulated in the viable and the infarcted region of the failing left ventricle at 1 week, with the highest expression in the latter. In the lung, another pattern of regulation was seen with a significant increase in pulmonary MCP-1 at 6 weeks. IL-8 was only detected in the infarcted region at 1 week. In the spleen, no regulation of cytokines was found. In conclusion, we report an organ-specific regulation of cytokines and chemokines in postischaemic HF. Our novel findings of increased cardiac CNTF and cardiopulmonary MCP-1 mRNA indicate a role for these factors in the pathogenesis of HF.