Mitochondrial Function in Transthyretin Amyloidosis

Study Overview
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Brief Summary
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Hereditary (familial) amyloidosis arising from the misfolding of a mutated or variant transthyretin, is the most frequent form of amyloid cardiomyopathy in the Caribbean basin. Affected organs invariably harbor extracellular amyloid deposits in the myocardium. Circulating or pre-fibrillar amyloidogenic proteins are implicated in the disruption of cell function. The investigators aim is to demonstrate that transthyretin mediated amyloid disease alter the mitochondrial function of cardiac cells.

Detailed Description
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Systemic amyloidosis are a family of diseases induced by misfolded and/or misassembled proteins. Extracellular deposits of these proteins disrupt vital organ function. Two types of amyloid commonly infiltrate the heart: immunoglobulin light-chain amyloid and transthyretin (TTR) amyloid. Among the TTR variants that predominantly target the heart, the valine to isoleucine substitution at position 122 (V122I or Ile122) is the most common. This TTR variant is responsible for the most frequent form of amyloid cardiomyopathy in the Caribbean basin. Increasingly study data supports a central role for circulating or pre-fibrillar amyloidogenic proteins in the disruption of cardiac function in TTR mediated amyloid disease. In vivo exposure of cultured cardiomyocytes to pre-fibrillar an amyloidogenic proteins stimulate the production of reactive oxygen species and disrupts calcium fluxes. (Recent studies indicate that pre-fibrillar amyloidogenic proteins may also induce apoptosis through the mitochondrial pathway, eventually leading to cardiac cell injury). Hence, growing evidence suggests that end-organ damage by pre-fibrillar TTR amyloid may be related to mitochondrial dysfunction. Diagnosis of cardiac amyloidosis can be based on invasive heart biopsies or a non-invasive approach including identification of amyloid tissue deposits from abdominal fat biopsies. The investigators aim is to demonstrate that transthyretin mediated amyloid disease alters the mitochondrial function of subcutaneous abdominal adipocytes. The investigators objective is to study mitochondrial respiration assessed by oxygraphy in fragments of subcutaneous abdominal fat biopsies performed for diagnosis of TTR amyloidosis. Mitochondrial respiration will be evaluated in the absence and in the presence of ADP. Follow the evaluation of mitochondrial respiration. So, no patient follow-up will be performed.

Official Title
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Mitochondrial Function in Transthyretin Amyloidosis : the MIT-AMYLOSE Study.

Conditions
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Cardiac Amyloidosis

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have a parietal thickness measuring more than 15 mm on the echocardiography or have structural and echogenicity abnormalities characteristic of cardiac amyloidosis, Live in Martinique, Accept the use of the residues coming from biopsies of the subcutaneous abdominal adipose tissue performed during the medical care. Exclusion Criteria: Be under 18 years old, Have a contraindication to subcutaneous biopsy, Be allergic to local anesthetics, Pregnant or nursing woman, Have a cardiovascular disease suggesting a secondary cardiac disease, such as documented severe hypertension, valvular stenosis, or a known familial cardiomyopathy, Be major under guardianship / curatorship or deprived of liberty, Not be able to answer to a simple administrative questionnaire or to give freely its non-opposition.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen consumption measure in subcutaneous abdominal fat biopsies | The mitochondrial respiration of the cells is measured by polarography with a Clark type oxygen electrode. The Clark electrode consists of a platinium cathode and a silver anode. When a potential difference of -0.6 volts is applied, the platinium electrode is negatively charged with respect to that of silver and each oxygen molecule dissolved in the medium diffuses through the gas-permeable Teflon membrane, and is reduced at the cathode according to the following reaction: O 2 + 4H + + 4e → 2H 2 O. The current thus generated is proportional to the concentration of dissolved oxygen. The oxygen saturation constant (406 nmol / ml) makes it possible to convert these results into oxygen consumption / minute. | Three months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rates of oxygen consumption | Rates of oxygen consumption (expressed as pmol O2.s-1.mg of fat tissue) will be recorded in-vivo in different conditions, which include routine respiration and after ADP addition. Carbonyl cyanide-4-(trifluoromethoxy) phenylhydrazone (FCCP), tetra methyl-p-phenylenediaminedihydrochloride (TMPD)-ascorbate and oligomycin will be tested in vitro to monitor uncoupled respiration, cytochrome c oxidase activity and leak state respiration by inhibition of ATP synthase, respectively. | Three months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Mitochondria, Oxidative phosphorylation (mitochondrial respiration), Subcutaneous abdominal adipose tissue, Heart.