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Role of Amino Acids and Genetic Disorder in Pathogenesis of Heart Failure

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ClinicalTrials.gov Identifier: NCT03590522
Recruitment Status : Not yet recruiting
First Posted : July 18, 2018
Last Update Posted : January 9, 2019
Sponsor:
Information provided by (Responsible Party):
Reham I El-mahdy, Assiut University

Tracking Information
First Submitted Date July 7, 2018
First Posted Date July 18, 2018
Last Update Posted Date January 9, 2019
Estimated Study Start Date January 17, 2019
Estimated Primary Completion Date March 28, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures
 (submitted: July 7, 2018)
Decrease cardiac ryanodine Receptor 2 gene expression and change of amino acids levels in patients with heart failure. [ Time Frame: Baseline ]
better understanding of cardiac ryanodine Receptor 2 role as an essential player in excitation-contraction coupling in pathogenesis of heart failure and the role of amino acids in pathogenesis of heart failure
Original Primary Outcome Measures Same as current
Change History Complete list of historical versions of study NCT03590522 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures Not Provided
Original Secondary Outcome Measures Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title Role of Amino Acids and Genetic Disorder in Pathogenesis of Heart Failure
Official Title Role of Amino Acids and Genetic Disorder in Pathogenesis of Heart Failure
Brief Summary Heart failure (HF) is a continuously growing public health problem. The study aim to provide novel insights into the role of amino acids in pathogenesis of heart failure, to obtain a better understanding of cardiac ryanodine Receptor 2 role as an essential player in excitation-contraction coupling in pathogenesis of heart failure and clarify the potential value of these markers as targets for heart failure therapy
Detailed Description

Heart failure (HF) is a continuously growing public health problem. Presently, almost 40 million people are affected by heart failure worldwide. According to World Health Organization (WHO), cardiovascular diseases are number one cause of deaths globally . In developed countries, the prevalence of heart failure is approximately 1-2% of the adult population. In Egypt, the prevalence of HF with preserved ejection fraction represents about 34.2 % while heart failure with reduced ejection fraction represents 65.8 % of total heart failure cases .

A broad range of cardiac diseases, inherited disorders, and systematic diseases can result in heart failure. The situation is even more complex, as heart failure can have mixed etiologies. Heart failure itself represents a final common pathway in response to genetic and/or environmental influences. A clear genetic identification can positively influence patient treatment and, thereby, improve prognosis. Besides, understanding the pathogenesis of genetically induced heart failure at it molecular level may lead to the development of specific individual heart failure therapies in the future.

The human heart uses large amounts of amino acids (AAs) as regulators of both myocardium protein turnover and energy metabolism, but uses few AAs as substrates for direct energy production .The heart's reliance on AAs increases during heart failure because of high myocardium anabolic activity and cardiomyocyte energy shortage. Anabolic activity of the ventricle wall is induced by both high levels of ventricular pressure and a myocardial substrate shift from fatty acid oxidation (FAOX) to glucose oxidation (GLUOX).

Various mechanisms may potentially be operating during CHF to impair arterial AAs, including inadequate protein-energy intake, body AA overconsumption, particularly in hyper metabolic states, increased remodeling activity of the heart and lung and finally, the development of pathogenic gut flora. Understanding arterial AA levels could be useful to understand whether heart anabolic activity and remaining heart capacity of energy production are being threatened by low AA s and furthermore may allow us to correct altered AAs through diet and/or supplementation of specific free AAs.

A reduction in essential AAs in CHF subjects, shows the disease severity-related decline of arterial levels of those non-essential (and essential methionine) AAs with the greatest impact on myocardium energetics, anti-oxidative capacity and myocardial protein remodeling.

Calcium cycling protein and heart failure Ca2+-dependent signaling is highly regulated in cardiomyocytes and determines the force of cardiac muscle contraction. Ca2+ cycling refers to the release and reuptake of intracellular Ca2+ that drives muscle contraction and relaxation in failing hearts. Ca2+ cycling is profoundly altered, resulting in impaired contractility and fatal cardiac arrhythmias. The key defects in Ca2+ cycling occur at the level of the sarcoplasmic reticulum (SR), a Ca2+ storage organelle in muscle. Defects in the regulation of Ca2+ cycling proteins including the ryanodine receptor 2 (RyR2) a cardiac Ca2+ release channel macromolecular complexes and the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase2a (SERCA2a) contribute to heart failure.

Phosphorylation of the cardiac ryanodine receptor (RyR2) phospho-site S2808 has hallmark of heart failure (HF) and a critical mediator of the physiological fight or flight response of the heart. In support of this hypothesis, mice unable to undergo phosphorylation at RyR2-S2808 (S2808A) were significantly protected against HF and displayed a blunted response to adrenergic stimulation.

Study Type Observational
Study Design Observational Model: Case-Control
Time Perspective: Cross-Sectional
Target Follow-Up Duration Not Provided
Biospecimen Not Provided
Sampling Method Non-Probability Sample
Study Population Heart failure patients
Condition Heart Failure
Intervention Genetic: Ryanodine Receptor 2 gene expression
Ryanodine Receptor 2 gene expression will be measured by real time PCR. In addition, amino acids analysis will be measured in plasma by amino acid analyzer.
Study Groups/Cohorts
  • Group I:
    Thirty heart failure patients
    Intervention: Genetic: Ryanodine Receptor 2 gene expression
  • Group II:
    Twenty healthy controls
    Intervention: Genetic: Ryanodine Receptor 2 gene expression
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status Not yet recruiting
Estimated Enrollment
 (submitted: July 7, 2018)
50
Original Estimated Enrollment Same as current
Estimated Study Completion Date March 30, 2019
Estimated Primary Completion Date March 28, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria

Inclusion Criteria:

• According to American Heart Association, patients with manifestation of heart failure (dyspnea, edema in the feet, ankles, legs or abdomen, heart palpitations) as diagnosed by clinical examination, laboratory investigations and imaging techniques.

Exclusion Criteria:

  • Diabetic patients
  • Neurological disorders
  • Cancers.
  • Obese patient
  • Smokers
  • Patient with chest infection
Sex/Gender
Sexes Eligible for Study: All
Ages 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers Not Provided
Contacts
Contact: reham elmahdy +201002714637 rehamibrahimelmahdy@gmail.com
Listed Location Countries Not Provided
Removed Location Countries  
 
Administrative Information
NCT Number NCT03590522
Other Study ID Numbers Heart failure
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement Not Provided
Responsible Party Reham I El-mahdy, Assiut University
Study Sponsor Assiut University
Collaborators Not Provided
Investigators Not Provided
PRS Account Assiut University
Verification Date January 2019