Clinical Trial Details
— Status: Recruiting
Administrative data
| NCT number |
NCT05196594 |
| Other study ID # |
04456582 |
| Secondary ID |
|
| Status |
Recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
May 1, 2021 |
| Est. completion date |
May 31, 2023 |
Study information
| Verified date |
October 2021 |
| Source |
University of Sao Paulo General Hospital |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
Amyloidosis is a serious systemic disease. Cardiac involvement has a great impact on
prognosis and can occur in its three main forms: acquired monoclonal light chain, hereditary
transthyretinal and senile form. The physiopathogenesis basically results from the deposition
of an abnormal protein (amyloid) with toxic properties to the myocyte. The scope of this
study will be a hereditary transthyretinal amyloidosis (hATTR). It is known that amyloidotic
cardiomyopathy due to transthyretin deposit is an underdiagnosed cause of heart failure in
adults, being an important differential diagnosis of diseases that manifest with increased
myocardial thickness, such as hypertrophic cardiomyopathy or myocardial hypertrophy that
accompanies the different degrees of aortic valve stenosis.
The human gut microbiota is immensely diverse. It is estimated at around 100 trillion
microorganisms, including bacteria, fungi and viruses. The microbiota of each individual is
unique and determined by genetic factors such as age, type of delivery, use of antibiotics
and diet. Recent data point to the hypothesis that the resilience of the intestinal
microbiota plays a role in the process of disease development and health restoration.
Description:
The scope of this study will be hereditary transthyretinal amyloidosis (hATTR). It is known
that amyloidotic cardiomyopathy due to transthyretin deposition is an underdiagnosed cause of
heart failure in adults, being an important differential diagnosis of diseases that manifest
with increased myocardial thickness, such as hypertrophic cardiomyopathy or the myocardial
hypertrophy that accompanies the different degrees of aortic valve stenosis.
The transthyretin protein is synthesized and secreted into the bloodstream mainly by the
liver. Other organic sites also produce and secrete it in smaller amounts. The choroid plexus
produces and releases transthyretin in the cerebrospinal fluid, while the cells of the
pigmented retinal epithelium are also capable of producing and releasing it into the vitreous
body. Formerly called prealbumin, transthyretin is composed of four monomers that circulate
in tetrameric form. It has the main function of carrying retinol and thyroxine . The
degeneration of the protein tetramer and its deposition in the different fluids in which it
is present determine the clinical dysfunction and the specific phenotypes of ATTR.
The gene that decodes the transthyretin protein (TTR) is located on chromosome 18. In ATTRh,
alterations in the amino acid sequence destabilize the tetramer. It is conventional to
designate genetic variants by the initials of the normal amino acid followed by their
position in the gene and the amino acid that replaces it. Thus, the Val30Met variant
translates that methionine is in place of valine at position 30.
The cuminal event of the pathophysiology is the degeneration of the tetramer into monomers
that, once denatured, infiltrate several structures in the form of amyloid fibrils. In the
myocardium, this process causes rigidity and varying degrees of dysfunction secondary to the
intrinsic toxicity of these fibrils and to the occupation of the interstitium.
Clinically, ATTR can manifest itself as an autonomic polyneuropathy or as a cardiomyopathy.
Eventually, the phenotype can involve both manifestations . Changes in the cardiac conduction
system and arrhythmias usually precede heart failure by years.
Within the spectrum of alterations resulting from autonomic neuropathy, different degrees of
intestinal transit disorders may occur, manifested as diarrhea, constipation, nausea or even
asymptomatically.
Digestive symptoms are one of the most relevant and early clinical aspects of amyloidotic
polyneuropathy, due to their frequency and intensity and the negative influence they have on
the well-being of patients. Important changes in gastrointestinal motility are the main
justification for these manifestations, being an expression of neurovegetative dysautonomia.
Occurs: diarrhea, constipation, nausea, vomiting and feeling of gastric fullness.
Weight loss is a progressive and important feature, usually early and constant. It may be
linked to gastrointestinal manifestations, malabsorption or renal and digestive protein
losses. It is one of the worst prognosis manifestations of the disease.
The human gut microbiota is immensely diverse. It is estimated at around 100 trillion
microorganisms, including bacteria, fungi and viruses. The microbiota of each individual is
unique and determined both by genetic factors and by age, type of delivery, use of
antibiotics and diet. There is evidence that such microorganisms play a fundamental role in
food digestion, vitamin synthesis, production of short-chain fatty acids, modulation of the
immune system and protection against infections. In healthy individuals, bacteria of the
phyla Firmicutes and Bacterioidetes usually predominate, followed by Verrucromicrobia and
Actinobacteria. However, the relative proportions and species present can vary widely between
individuals and fluctuate over time, particularly during the early stages of life and during
the evolution of certain diseases. Recent data point to the hypothesis that the resilience of
the intestinal microbiota plays a role in the process of disease development and health
restoration.
