scholarly journals The Role of Serum Chloride in Acute and Chronic Heart Failure: A Narrative Review

2021 ◽  
Vol 11 (2) ◽  
pp. 87-98
Author(s):  
Frederick Berro Rivera ◽  
Pia Alfonso ◽  
Jem Marie Golbin ◽  
Kevin Lo ◽  
Edgar Lerma ◽  
...  
Keyword(s):  
Heart Failure ◽  
Chloride Channel ◽  
Chloride Channels ◽  
Prognostic Value ◽  
Diuretic Therapy ◽  
Juxtaglomerular Apparatus ◽  
Sodium Chloride Cotransporter ◽  
Serum Chloride ◽  
And Function

Clinical guidelines include diuretics for the treatment of heart failure (HF), not to decrease mortality but to decrease symptoms and hospitalizations. More attention has been paid to the worse outcomes, including mortality, associated with continual diuretic therapy due to hypochloremia. Studies have revealed a pivotal role for serum chloride in the pathophysiology of HF and is now a target of treatment to decrease mortality. The prognostic value of serum chloride in HF has been the subject of much attention. Mechanistically, the macula densa, a region in the renal juxtaglomerular apparatus, relies on chloride levels to sense salt and volume status. The recent discovery of with-no-lysine (K) (WNK) protein kinase as an intracellular chloride sensor sheds light on the possible reason of diuretic resistance in HF. The action of chloride on WNKs results in the upregulation of the sodium-potassium-chloride cotransporter and sodium-chloride cotransporter receptors, which could lead to increased electrolyte and fluid reabsorption. Genetic studies have revealed that a variant of a voltage-sensitive chloride channel (CLCNKA) gene leads to almost a 50% decrease in current amplitude and function of the renal chloride channel. This variant increases the risk of HF. Several trials exploring the prognostic value of chloride in both acute and chronic HF have shown mostly positive results, some even suggesting a stronger role than sodium. However, so far, interventional trials exploring serum chloride as a therapeutic target have been largely inconclusive. This study is a review of the pathophysiologic effects of hypochloremia in HF, the genetics of chloride channels, and clinical trials that are underway to investigate novel approaches to HF management.

scholarly journals New Insights into the Mechanism of NO3- Selectivity in the Human Kidney Chloride Channel ClC-Ka and the CLC Protein Family

2019 ◽  
Vol 30 (2) ◽  
pp. 293-302
Author(s):  
Laura Lagostena ◽  
Giovanni Zifarelli ◽  
Alessandra Picollo
Keyword(s):  
Chloride Channel ◽  
Chloride Channels ◽  
Human Kidney ◽  
Protein Family ◽  
Side Chain ◽  
Anion Selectivity ◽  
And Function ◽  
The Relationship ◽  
Insight Into

BackgroundThe mechanism of anion selectivity in the human kidney chloride channels ClC-Ka and ClC-Kb is unknown. However, it has been thought to be very similar to that of other channels and antiporters of the CLC protein family, and to rely on anions interacting with a conserved Ser residue (Sercen) at the center of three anion binding sites in the permeation pathway Scen. In both CLC channels and antiporters, mutations of Sercen alter the anion selectivity. Structurally, the side chain of Sercen of CLC channels and antiporters typically projects into the pore and coordinates the anion bound at Scen.MethodsTo investigate the role of several residues in anion selectivity of ClC-Ka, we created mutations that resulted in amino acid substitutions in these residues. We also used electrophysiologic techniques to assess the properties of the mutants.ResultsMutations in ClC-Ka that change Sercen to Gly, Pro, or Thr have only minor effects on anion selectivity, whereas the mutations in residues Y425A, F519A, and Y520A increase the NO3−/Cl− permeability ratio, with Y425A having a particularly strong effect.Conclusions ClC-Ka’s mechanism of anion selectivity is largely independent of Sercen, and it is therefore unique in the CLC protein family. We identified the residue Y425 in ClC-Ka—and the corresponding residue (A417) in the chloride channel ClC-0—as residues that contribute to NO3− discrimination in these channels. This work provides important and timely insight into the relationship between structure and function for the kidney chloride channels ClC-Ka and ClC-Kb, and for CLC proteins in general.

scholarly journals Getting to the heart of intracellular glucocorticoid regeneration: 11β-HSD1 in the myocardium

2017 ◽  
Vol 58 (1) ◽  
pp. R1-R13 ◽  
Author(s):  
Gillian A Gray ◽  
Christopher I White ◽  
Raphael F P Castellan ◽  
Sara J McSweeney ◽  
Karen E Chapman
Keyword(s):  
Myocardial Infarction ◽  
Heart Failure ◽  
Systemic Corticosteroid ◽  
Physiological Function ◽  
Pressure Overload ◽  
Hydroxysteroid Dehydrogenase ◽  
And Function ◽  
Glucocorticoid Metabolism

Corticosteroids influence the development and function of the heart and its response to injury and pressure overload via actions on glucocorticoid (GR) and mineralocorticoid (MR) receptors. Systemic corticosteroid concentration depends largely on the activity of the hypothalamic–pituitary–adrenal (HPA) axis, but glucocorticoid can also be regenerated from intrinsically inert metabolites by the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), selectively increasing glucocorticoid levels within cells and tissues. Extensive studies have revealed the roles for glucocorticoid regeneration by 11β-HSD1 in liver, adipose, brain and other tissues, but until recently, there has been little focus on the heart. This article reviews the evidence for glucocorticoid metabolism by 11β-HSD1 in the heart and for a role of 11β-HSD1 activity in determining the myocardial growth and physiological function. We also consider the potential of 11β-HSD1 as a therapeutic target to enhance repair after myocardial infarction and to prevent the development of cardiac remodelling and heart failure.

Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension

2008 ◽  
Vol 295 (2) ◽  
pp. F556-F567 ◽  
Author(s):  
Giovambattista Capasso ◽  
Maria Rizzo ◽  
Maria Lisa Garavaglia ◽  
Francesco Trepiccione ◽  
Miriam Zacchia ◽  
...  
Keyword(s):  
Chloride Channels ◽  
Renal Cortex ◽  
Outer Medulla ◽  
Western Blots ◽  
Sodium Chloride Cotransporter ◽  
Normotensive Strain ◽  
Active Channels ◽  
Salt Sensitive Hypertension ◽  
Convoluted Tubules

We investigated which of the NaCl transporters are involved in the maintenance of salt-sensitive hypertension. Milan hypertensive (MHS) rats were studied 3 mo after birth. In MHS, compared with normotensive strain (MNS), mRNA abundance, quantified by competitive PCR on isolated tubules, was unchanged, both for Na+/H+ isoform 3 (NHE3) and Na+-K+-2Cl− (NKCC2), but higher (119%, n = 5, P < 0.005) for Na+-Cl− (NCC) in distal convoluted tubules (DCT). These results were confirmed by Western blots, which revealed: 1) unchanged NHE3 in the cortex and NKCC2 in the outer medulla; 2) a significant increase (52%, n = 6, P < 0.001) of NCC in the cortex; 3) α- and β-sodium channels [epithelial Na+ channel (ENaC)] unaffected in renal cortex and slightly reduced in the outer medulla, while γ-ENaC remained unchanged. Pendrin protein expression was unaffected. The role of NCC was reinforced by immunocytochemical studies showing increased NCC on the apical membrane of DCT cells of MHS animals, and by clearance experiments demonstrating a larger sensitivity ( P < 0.001) to bendroflumethiazide in MHS rats. Kidney-specific chloride channels (ClC-K) were studied by Western blot experiments on renal cortex and by patch-clamp studies on primary culture of DCT dissected from MNS and MHS animals. Electrophysiological characteristics of ClC-K channels were unchanged in MHS rats, but the number of active channels in a patch was 0.60 ± 0.21 ( n = 35) in MNS rats and 2.17 ± 0.59 ( n = 23) in MHS rats ( P < 0.05). The data indicate that, in salt-sensitive hypertension, there is a strong upregulation, both of NCC and ClC-K along the DCT, which explains the persistence of hypertension.

scholarly journals Loss of Endothelial HIF-Prolyl hydroxylase 2 (PHD2) Induces Cardiac Hypertrophy and Fibrosis

2021 ◽  
Author(s):  
Zhiyu Dai ◽  
Jianding Cheng ◽  
Bin Liu ◽  
Dan Yi ◽  
Anlin Feng ◽  
...  
Keyword(s):  
Heart Failure ◽  
Cardiac Hypertrophy ◽  
Cardiac Fibrosis ◽  
Left Ventricular ◽  
Dependent Manner ◽  
Adaptive Responses ◽  
Genetic Ablation ◽  
Pathological Cardiac Hypertrophy ◽  
And Function

Cardiac hypertrophy and fibrosis are common adaptive responses to injury and stress, eventually leading to heart failure. Hypoxia signaling is important to the (patho)physiological process of cardiac remodeling. However, the role of endothelial Prolyl-4 hydroxylase 2 (PHD2)/hypoxia inducible factors (HIFs) signaling in the pathogenesis of heart failure remains elusive. We observed a marked decrease of PHD2 expression in heart tissues and cardiovascular endothelial cells from patients with cardiomyopathy. Mice with Tie2-Cre-mediated deletion of Egln1 (encoding PHD2) or tamoxifen-induced endothelial Egln1 deletion exhibited left ventricular hypertrophy and cardiac fibrosis. Genetic ablation and pharmacological inhibition of Hif2a but not Hif1a in endothelial Egln1 deficient mice normalized cardiac size and function. The present studies define for the first time an unexpected role of endothelial PHD2 deficiency in inducing cardiac hypertrophy and fibrosis in a HIF-2α dependent manner. Targeting PHD2/HIF-2α signaling may represent a novel therapeutic approach for the treatment of pathological cardiac hypertrophy and failure.

scholarly journals Valsartan Regulates PI3K/AKT Pathways through lncRNA GASL1 to Improve Isoproterenol-Induced Heart Failure

2022 ◽  
Vol 2022 ◽  
pp. 1-8
Author(s):  
Jian Zhou ◽  
Xiujuan Duan ◽  
Jibing Wang ◽  
Yunhong Feng ◽  
Jiangyong Yuan
Keyword(s):  
Heart Failure ◽  
Cardiac Function ◽  
Akt Pathway ◽  
Chain Reaction ◽  
Qrt Pcr ◽  
Polymerase Chain ◽  
And Function ◽  
Rat Tail

Objective. This study is aimed at determining the expression and function of the GASL1 and PI3K/AKT pathways in isoproterenol- (ISO-) induced heart failure (HF). To determine the moderating effect of valsartan (VAL) on the progression of ISO-induced HF and to elucidate the related mechanism. Materials and Methods. First, in in vivo experiment, we examined the effect of VAL on cardiac function in rats with ISO-induced HF. Similarly, quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to detect the effect of VAL on ISO-treated rat primary cardiomyocytes. Then, si-GASL1-transfected primary cardiomyocytes were constructed and Ad-si-GASL1 was injected through rat tail vein to achieve the effect of lowering GASL1 expression, so as to investigate the role of GASL1 in VAL’s treatment of ISO-induced HF. Results. In ISO-induced HF rat models, the GASL1 decreased while PI3K and p-AKT expressions were abnormally elevated and cardiac function deteriorated, and VAL was able to reverse these changes. In primary cardiomyocytes, ISO induces apoptosis of cardiomyocytes, and expression of GASL1 decreased while PI3K and p-AKT were abnormally elevated, which can be reversed by VAL. The transfection of primary cardiomyocytes with si-GASL1 confirmed that GASL1 affected the expression of PI3K, p-AKT, and the apoptosis of primary cardiomyocytes. Rat myocardium injected with Ad-si-GASL1 was found to aggravate the cardiac function improved by VAL. Conclusions. This study was the first to confirm that VAL improves ISO-induced HF by regulating the PI3K/AKT pathway through GASL1. And this study demonstrated a significant correlation between HF, VAL, GASL1, and the PI3K/AKT pathway.

Autophagy in health and disease: focus on the cardiovascular system

2017 ◽  
Vol 61 (6) ◽  
pp. 721-732 ◽  
Author(s):  
Jeanne Mialet-Perez ◽  
Cécile Vindis
Keyword(s):  
Heart Failure ◽  
Cardiovascular System ◽  
Crucial Role ◽  
Current Knowledge ◽  
Cardiovascular Disorders ◽  
Health And Disease ◽  
And Function ◽  
Autophagy Activity ◽  
Disease Focus

Autophagy is a highly conserved mechanism of lysosome-mediated protein and organelle degradation that plays a crucial role in maintaining cellular homeostasis. In the last few years, specific functions for autophagy have been identified in many tissues and organs. In the cardiovascular system, autophagy appears to be essential to heart and vessel homeostasis and function; however defective or excessive autophagy activity seems to contribute to major cardiovascular disorders including heart failure (HF) or atherosclerosis. Here, we review the current knowledge on the role of cardiovascular autophagy in physiological and pathophysiological conditions.

Protein kinase D in the hypertrophy pathway

2012 ◽  
Vol 40 (1) ◽  
pp. 287-289 ◽  
Author(s):  
Yuan Yan Sin ◽  
George S. Baillie
Keyword(s):  
Heart Failure ◽  
Protein Kinase ◽  
Potential Role ◽  
Protein Kinase D ◽  
Intact Cells ◽  
Hypertrophic Growth ◽  
Cardiac Gene ◽  
And Function ◽  
Regulatory Properties

Chronic neurohormonal stimulation can have direct adverse effects on the structure and function of the heart. Heart failure develops and progresses as a result of the deleterious changes. It is well established that phosphorylation of class II HDAC5 (histone deacetylase 5) is an important event in the transcriptional regulation of cardiac gene reprogramming that results in the hypertrophic growth response. To date, experimentation on phosphorylation-mediated translocation of HDAC5 has focused on the regulatory properties of PKD (protein kinase D) within intact cells. With regard to the potential role of PKD in myocardium, recent observations raise the possibility that PKD-mediated myocardial regulatory mechanisms may represent promising therapeutic avenues for the treatment of heart failure. The present review summarizes the most recent and important insights into the role of PKD in hypertrophic signalling pathways.

scholarly journals Multi-modality assessment and role of left atrial function as an imaging biomarker in cardiovascular disease

2021 ◽  
Author(s):  
Aseel Alfuhied ◽  
Prathap Kanagala ◽  
Gerry P. McCann ◽  
Anvesha Singh
Keyword(s):  
Cardiovascular Disease ◽  
Clinical Application ◽  
Prognostic Value ◽  
Imaging Techniques ◽  
Vital Role ◽  
Imaging Biomarker ◽  
Imaging Biomarkers ◽  
Number Of Publications ◽  
And Function

AbstractThe left atrium (LA) plays a vital role in maintaining normal cardiac function. LA volume and function have been utilised as important imaging biomarkers, with their prognostic value demonstrated in multiple cardiac conditions. More recently, there has been a sharp increase in the number of publications utilising LA strain by echocardiography and cardiac magnetic resonance (CMR) imaging. However, little is known about its prognostic value or reproducibility as a technique. In this review, we aim to highlight the conventional and novel imaging techniques available for LA assessment, using echocardiography and CMR, their role as an imaging biomarker in cardiovascular disease, the reproducibility of the techniques and the current limitations to their clinical application. We identify a need for further standardisation of techniques, with establishment of ‘normal’ cut-offs before routine clinical application can be made.

scholarly journals Prognostic role of right ventricular geometry and function in patients undergoing double valve surgery

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
Y K Tse ◽  
Y J Yu ◽  
H L Li ◽  
M Z Wu ◽  
Q W Ren ◽  
...  
Keyword(s):  
Heart Failure ◽  
Heart Disease ◽  
Mitral Valve ◽  
Adverse Events ◽  
Prognostic Value ◽  
Systolic Function ◽  
Systolic Dysfunction ◽  
Valve Surgery ◽  
Operative Outcomes ◽  
And Function

Abstract Introduction Multiple valvular heart disease, a combination of stenotic and regurgitant lesions occurring on two or more valves, is a highly prevalent condition. For these patients, surgical correction is the only definitive treatment to improve prognosis, yet concomitant aortic and mitral (double) valve surgery is associated with poor post-operative outcomes. While current guidelines outline left ventricular dimensions and function as surgical triggers, little is known regarding the importance of right ventricular (RV) remodelling in these patients. Purpose We sought to evaluate the prognostic value of RV remodelling in patients undergoing double valve surgery. Methods RV remodelling was characterised by transthoracic echocardiography in 152 patients undergoing concomitant aortic and mitral valve replacement (n=118) or aortic valve replacement and mitral valve repair (n=34). Four patterns of RV remodelling were defined according to the presence of RV dilation (tricuspid annulus diameter&gt;35mm) and RV systolic dysfunction (percentage RV fractional area change &lt;35%): normal RV size and systolic function (pattern 1); dilated RV with normal systolic function (pattern 2); RV systolic dysfunction with normal RV size (pattern 3); and dilated RV with systolic dysfunction (pattern 4). Adverse events were defined as the composite of all-cause mortality and hospitalisation for heart failure. Results Overall, 62 (41%), 31 (20%), 35 (23%), and 24 (16%) patients were classified as RV remodelling patterns 1, 2, 3, and 4, respectively. Patients with advanced RV remodelling patterns were more frequently male, had worse renal function, and a higher EuroSCORE II. During a median follow-up of 43 months, 41 adverse events (22 heart failure hospitalisation and 19 deaths) occurred. Patients with patterns 3 and 4 RV remodelling had an increased risk of adverse events compared to pattern 1 (log-rank χ2 27.42; p&lt;0.001; Figure 1). After adjustments for EuroSCORE II and significant tricuspid regurgitation, RV remodelling patterns 3 (Hazard Ratio [HR] 3.24, 95% Confidence Interval [CI] 1.27–8.24, p=0.014) and 4 (HR 6.18, 95% CI 2.49–15.32, p&lt;0.001) were independently associated with poor post-operative outcomes. Importantly, RV remodelling patterns provided incremental prognostic value to EuroSCORE II (χ2 increased from 18 to 38, p&lt;0.001). Conclusion In patients with concomitant aortic and mitral valve disease, RV remodelling is frequent and associated with poorer outcomes. Our study highlights the involvement of the RV in left-sided valvular heart disease and underlines the importance of preoperative assessment of RV geometry and function in patients undergoing double valve surgery. FUNDunding Acknowledgement Type of funding sources: None. Figure 1

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