scholarly journals Cardiac T-Tubule cBIN1-Microdomain, a Diagnostic Marker and Therapeutic Target of Heart Failure

2021 ◽  
Vol 22 (5) ◽  
pp. 2299
Author(s):  
Jing Li ◽  
Bradley Richmond ◽  
TingTing Hong
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Therapeutic Potential ◽  
Peripheral Circulation ◽  
Cardiac Contraction ◽  
Adeno Associated Virus ◽  
Cardiac Inotropy ◽  
Membrane Microdomain ◽  
Patients With Heart Failure ◽  
Contraction And Relaxation

Since its first identification as a cardiac transverse tubule (t-tubule) protein, followed by the cloning of the cardiac isoform responsible for t-tubule membrane microdomain formation, cardiac bridging integrator 1 (cBIN1) and its organized microdomains have emerged as a key mechanism in maintaining normal beat-to-beat heart contraction and relaxation. The abnormal remodeling of cBIN1-microdomains occurs in stressed and diseased cardiomyocytes, contributing to the pathophysiology of heart failure. Due to the homeostatic turnover of t-tubule cBIN1-microdomains via microvesicle release into the peripheral circulation, plasma cBIN1 can be assayed as a liquid biopsy of cardiomyocyte health. A new blood test cBIN1 score (CS) has been developed as a dimensionless inverse index derived from plasma cBIN1 concentration with a diagnostic and prognostic power for clinical outcomes in stable ambulatory patients with heart failure with reduced or preserved ejection fraction (HFrEF or HFpEF). Recent evidence further indicates that exogenous cBIN1 introduced by adeno-associated virus 9-based gene therapy can rescue cardiac contraction and relaxation in failing hearts. The therapeutic potential of cBIN1 gene therapy is enormous given its ability to rescue cardiac inotropy and provide lusitropic protection in the meantime. These unprecedented capabilities of cBIN1 gene therapy are shifting the current paradigm of therapy development for heart failure, particularly HFpEF.

Therapeutic potential of sildenafil in patients with heart failure and reactive pulmonary hypertension

2012 ◽  
Vol 154 (2) ◽  
pp. 205-206 ◽  
Author(s):  
Daniel Dumitrescu ◽  
Cathérine Seck ◽  
Luise Möhle ◽  
Erland Erdmann ◽  
Stephan Rosenkranz
Keyword(s):  
Heart Failure ◽  
Pulmonary Hypertension ◽  
Therapeutic Potential ◽  
Patients With Heart Failure

scholarly journals Diagnostic, prognostic and therapeutic potential of 6-minute walk test in patients with heart failure

2020 ◽  
Vol 19 (6) ◽  
pp. 2460
Author(s):  
A. V. Budnevsky ◽  
A. Ya. Kravchenko ◽  
R. E. Tokmachev ◽  
T. A. Chernik ◽  
E. V. Tokmachev ◽  
...  
Keyword(s):  
Heart Failure ◽  
Therapeutic Potential ◽  
Effective Control ◽  
Walk Test ◽  
Six Minute Walk Test ◽  
Patients With Heart Failure ◽  
Appropriate Therapy ◽  
Heart Disorders ◽  
6 Minute Walk Test ◽  
Minute Walk

The six-minute walk test (6MWT) is a well-known exercise test used in medical practice to assess the functional status of patients with various chronic cardiovascular and respiratory diseases. The results of modern research describe new potential of 6MWT, which allow a more accurate interpretation and predict the course of diseases. Heart failure (HF) is the outcome of many structural and functional heart disorders. To improve the prognosis of patients with HF, early diagnosis, appropriate therapy and effective control of the disease course are important components. This review describes the diagnostic, prognostic and therapeutic potential of 6MWT in patients with HF.

scholarly journals Pathophysiology of Calcium Mediated Ventricular Arrhythmias and Novel Therapeutic Options with Focus on Gene Therapy

2019 ◽  
Vol 20 (21) ◽  
pp. 5304 ◽  
Author(s):  
Paar ◽  
Jirak ◽  
Larbig ◽  
Zagidullin ◽  
Brandt ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Ventricular Arrhythmias ◽  
Molecular Mechanisms ◽  
Therapeutic Potential ◽  
Cardiac Contraction ◽  
Ongoing Research ◽  
Major Health Problem ◽  
Huge Impact ◽  
Arrhythmia Therapy ◽  
Care Costs

Cardiac arrhythmias constitute a major health problem with a huge impact on mortality rates and health care costs. Despite ongoing research efforts, the understanding of the molecular mechanisms and processes responsible for arrhythmogenesis remains incomplete. Given the crucial role of Ca2+-handling in action potential generation and cardiac contraction, Ca2+ channels and Ca2+ handling proteins represent promising targets for suppression of ventricular arrhythmias. Accordingly, we report the different roles of Ca2+-handling in the development of congenital as well as acquired ventricular arrhythmia syndromes. We highlight the therapeutic potential of gene therapy as a novel and innovative approach for future arrhythmia therapy. Furthermore, we discuss various promising cellular and mitochondrial targets for therapeutic gene transfer currently under investigation.

Incorporation of the factor IX Padua mutation into FIX-Triple improves clotting activity in vitro and in vivo

2013 ◽  
Vol 110 (08) ◽  
pp. 244-256 ◽  
Author(s):  
Chung-Yang Kao ◽  
Shu-Jhu Yang ◽  
Mi-Hua Tao ◽  
Yung-Ming Jeng ◽  
I-Shing Yu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Replacement Therapy ◽  
Therapeutic Potential ◽  
Factor Ix ◽  
Adeno Associated Virus ◽  
Viral Dose ◽  
Better Than

SummaryUsing gain-of-function factor IX (FIX) for replacement therapy for haemophilia B (HB) is an attractive strategy. We previously reported a high-activity FIX, FIX-Triple (FIX-V86A/E277A/R338A) as a good substitute for FIX-WT (wild-type) in protein replacement therapy, gene therapy, and cell therapy. Here we generated a new recombinant FIXTripleL (FIX-V86A/E277A/R338L) by replacing the alanine at residue 338 of FIX-Triple with leucine as in FIX-Padua (FIX-R338L). Purified FIX-TripleL exhibited 22-fold higher specific clotting activity and 15-fold increased binding affinity to activated FVIII compared to FIXWT. FIX-TripleL increased the therapeutic potential of FIX-Triple by nearly 100% as demonstrated with calibrated automated thrombogram and thromboelastography. FIX-TripleL demonstrated a normal clearance rate in HB mice. The clotting activity of FIX-TripleL was consistently 2- to 3-fold higher in these mice than that of FIX-Triple or FIXR338L. Gene delivery of adeno-associated virus (AAV) in HB mice showed that FIX-TripleL had 15-fold higher specific clotting activity than FIX-WT, and this activity was significantly better than FIX-Triple (10-fold) or FIX-R338L (6-fold). At a lower viral dose, FIX-TripleL improved FIX activity from sub-therapeutic to therapeutic levels. Under physiological conditions, no signs of adverse thrombotic events were observed in long-term AAV-FIX-treated C57Bl/6 mice. Hepatocellular adenomas were observed in the high- but not the medium- or the lowdose AAV-treated mice expressing FIX-WT or FIX-Triple, indicating the advantages of using hyperfunctional FIX variants to reduce viral doses while maintaining therapeutic clotting activity. Thus, incorporation of the FIX Padua mutation significantly improves the clotting function of FIX-Triple so as to optimise protein replacement therapy and gene therapy.

scholarly journals Adeno-associated viral (AAV) vector-mediated therapeutics for diabetic cardiomyopathy – current and future perspectives

2021 ◽  
Vol 135 (11) ◽  
pp. 1369-1387
Author(s):  
Darnel Prakoso ◽  
Mitchel Tate ◽  
Miles J. De Blasio ◽  
Rebecca H. Ritchie
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Diabetic Cardiomyopathy ◽  
Viral Vector ◽  
Therapeutic Potential ◽  
Future Perspectives ◽  
Cardiac Damage ◽  
Pharmacological Agents ◽  
Potential Alternative ◽  
Artery Disease

Abstract Diabetes increases the prevalence of heart failure by 6–8-fold, independent of other comorbidities such as hypertension and coronary artery disease, a phenomenon termed diabetic cardiomyopathy. Several key signalling pathways have been identified that drive the pathological changes associated with diabetes-induced heart failure. This has led to the development of multiple pharmacological agents that are currently available for clinical use. While fairly effective at delaying disease progression, these treatments do not reverse the cardiac damage associated with diabetes. One potential alternative avenue for targeting diabetes-induced heart failure is the use of adeno-associated viral vector (AAV) gene therapy, which has shown great versatility in a multitude of disease settings. AAV gene therapy has the potential to target specific cells or tissues, has a low host immune response and has the possibility to represent a lifelong cure, not possible with current conventional pharmacotherapies. In this review, we will assess the therapeutic potential of AAV gene therapy as a treatment for diabetic cardiomyopathy.

Abstract 85: Cardiac Pathology Is Worsened by Loss of the Cell Junction Protein Claudin-5 and Improved by Claudin-5 Gene Therapy

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Dawn A Delfín ◽  
Kevin E Schill ◽  
Ying Xu ◽  
Sarah Swager ◽  
Paul M L Janssen ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Preliminary Evidence ◽  
Cell Junction ◽  
Human Heart Failure ◽  
Adeno Associated Virus ◽  
Cardiac Pathology ◽  
Adhesion Protein ◽  
Junction Protein ◽  
A Cell

Claudin-5 is a cell-cell adhesion protein that plays established roles in the blood-brain barrier and cancer. We were the first to demonstrate that it plays a role in the heart with implications for heart failure and cardiomyopathy. Several animal models with cardiac pathology show reduced cardiac claudin-5 levels. Importantly, 60% of human heart failure patients show reduced levels of cardiac claudin-5, independent of changes in other cell junction proteins in the heart, supporting that the loss of cardiac claudin-5 has clinical relevance. To test our hypothesis that claudin-5 plays an important role in protecting the heart, we used mouse models to demonstrate whether circumventing reductions in cardiac claudin-5 is able to improve cardiac histology and physiology, and whether ablation of claudin-5 is able to induce cardiac pathology. We now show that maintaining cardiac claudin-5 levels using gene therapy (cldn5 transduction using an adeno-associated virus vector) significantly reduced cardiac pathology in mice which otherwise demonstrate heart failure and cardiomyopathy indicators. We also present preliminary evidence of the effects of knocking out the cldn5 gene specifically in cardiomyocytes using the inducible cre-loxP system.

Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure

2018 ◽  
Vol 27 (11) ◽  
pp. 1285-1300 ◽  
Author(s):  
Sebastian Bass-Stringer ◽  
Bianca C. Bernardo ◽  
Clive N. May ◽  
Colleen J. Thomas ◽  
Kate L. Weeks ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Future Prospects ◽  
Adeno Associated Virus ◽  
Virus Gene

scholarly journals 0464 : Selenoprotein T gene therapy with adeno-associated virus-9 improves cardiac function/remodeling in rats with heart failure

2016 ◽  
Vol 8 (3) ◽  
pp. 255
Author(s):  
Inès Boukhalfa ◽  
Orianne Henri ◽  
Jean-Paul Henry ◽  
Youssef Anouar ◽  
Vincent Richard ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Cardiac Function ◽  
Adeno Associated Virus ◽  
Selenoprotein T

1178Unsuspected role of the cardiac PKA type I in excitation-contraction coupling and in heart failure development

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Gandon-Renard ◽  
I Bedioune ◽  
S Karam ◽  
A Varin ◽  
P Lechene ◽  
...  
Keyword(s):  
Heart Failure ◽  
Ex Vivo ◽  
Cardiac Contractility ◽  
Cardiac Contraction ◽  
Type I ◽  
Excitation Contraction Coupling ◽  
Contraction Coupling ◽  
Contraction And Relaxation

Abstract The cAMP-dependent protein kinase (PKA) consists of two regulatory (R) and two catalytic (C) subunits and comprises two subtypes, PKAI and PKAII, defined by the nature of their regulatory subunits, RIα and RIIα respectively. Whereas PKAII is thought to play a key role in β-adrenergic (β-AR) regulation of cardiac contractility, the function of PKAI is unclear. To address this question, we generated mice with cardiomyocyte-specific and conditional invalidation of the RIα subunit of PKA. Tamoxifen injection in 8 weeks-old mice resulted in a >70% decrease in RIα protein without modification of other PKA subunits, which was associated with ∼2-fold increased basal PKA activity in RIα-KO mice (p<0.05, N=6/group). This translated into enhanced cardiac contraction and relaxation, as observed in vivo by increased fractional shortening and E-wave velocity (p<0.05, N=10/group) and ex vivo by increased LV pressure and maximal rate of contraction and relaxation (p<0.05, N=9/group). L-type Ca2+ current density was increased in ventricular myocytes from RIα-KO, and β-AR stimulation was decreased by ∼50% (p<0.05, n=38 cells for WT, and, n=40 for RIα-KO). Consistently, Ca2+ transients amplitude and relaxation kinetics were increased, along with increased occurrence of Ca2+ sparks and waves (p<0.05, n=44 cells for WT, and, n=50 for RIα KO). Phosphorylation of Ca2+ channels (CaV1.2), PLB, RyR2 and cMyBP-C at PKA sites was increased >2-fold (p<0.05, N=6/group) in RIα KO without modification of total protein expression. With age, these mice developed a congestive heart failure (HF) phenotype with massive hypertrophy and fibrosis which eventually led to death in 50% of RIα-KO mice at 50 weeks (versus 0% in WT, p<0.01). These results reveal a previously unsuspected role of PKA type I in cardiac excitation-contraction coupling and HF.

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