AMYLOCARTESIAN: Prevalence and Post-surgical Outcomes of CARdiac Wild-type TransthyrEtin amyloidoSIs in Elderly Patients With Aortic steNosis Referred for Valvular Replacement.

Sponsor

French Cardiology Society (Other)

Overall Status

Recruiting

CT.gov ID

NCT02260466

Collaborator

Pfizer (Industry), Henri Mondor University Hospital (Other)

180

Enrollment

Locations

Arm

Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Background: The prevalence of both senile cardiac amyloidosis (CA) and aortic stenosis (AS) markedly increases with age. Aortic stenosis increases left ventricular pressure overload. Cardiac deposits have been observed in AS and the amount of these deposits has been correlated to post-surgical outcome. As they are strong echocardiographic and cardiac MRI imaging similarities between CA and AS, the investigators hypothesized that the deposit observed in AS is transthyretin amyloid deposit. The investigators objective is to demonstrate that amyloid deposit is associated with poor outcomes following aortic stenosis surgical valve replacement.

Materiel and methods: 180 patients with indication for surgical aortic valve replacement will be recruited prospectively and consecutively in 5 French centers. A replicative study will be performed in one Austrian center. Echocardiography, cardiac MRI and bone scintigraphy will be performed prior to surgery. During surgery, a basal LV septum biopsy will be collected for determination and quantification of interstitial deposits using specific staining which will be performed in a blind fashion. Clinical outcomes will be recorded during the hospitalization period following the surgery and at 1 year. Alive and re-hospitalization status will be determined. Patients will be classified according to the presence or not of amyloid deposits.

Expected results and impact: This study will emphasize how pressure overload stress accelerates and magnifies amyloid deposition usually known to be related to cardiac aging process. It will develop reliable imaging tools and markers to detect cardiac amyloid deposition. Correlation between anatomopathologic analyses and the three different imaging technics will identify accurate imaging markers of CA. A risk stratification model based on amyloid deposits level for the clinical management of these patients will be created combining imaging and biological markers.

Condition or Disease	Intervention/Treatment	Phase
Heart Disease Aging Amyloidosis Aortic Valve Stenosis	Other: a basal LV septum biopsy	N/A

Detailed Description

Cardiovascular diseases remain the major cause of mortality and morbidity in industrialised countries. Their prevalence increases steeply as consequence of the aging of the population in these countries. Curiously, cardiovascular and neurodegenerative diseases share common aging pathological pathways involving abnormal accumulation of insoluble amyloid proteins in the extracellular matrix disrupting normal organ function. Whereas neurological amyloid diseases has been considerably investigated, little attention has been paid to the aggregation of amyloid proteins in cardiovascular diseases. Post-mortem studies have identified cardiac wild-type transthyretin amyloidosis deposition in 25% of individuals over the age of 80 years leading to the concept of "senile cardiac amyloidosis" (CA) (Cornwell, Am j Med 1984; Pitkanen, Am J Pathol 1984). The cause of this deposition is not yet known but might be related primarily to aging process and enhanced by cardiac mechanical stress (overload), hypoxia, oxidative stress and inflammation. Since patients with transthyretin CA develop severe heart failure with poor prognosis, it is crucial to identify them especially among population at risk such those with aortic stenosis (AS). Indeed this common valvular heart disease affects mainly senescent subjects and combines so the adverse effects on myocardial function of both pressure overload and myocardial aging.

Interestingly, some elderly patients with severe AS exhibit similar echocardiographic and cardiac MRI patterns as those reported in CA including increased cardiac wall thickness and progressive left ventricular dysfunction starting with alteration of basal LV-2D strain. They also exhibit increased late gadolinium enhancement (LGE) at cardiac MRI. This has been interpreted as related to interstitial myocardial "fibrosis" and has been correlated with poor prognosis after aortic valve replacement i.e.; high mortality, persistence of heart failure symptoms and LV dysfunction (Weidemann Circ 2009; Dweck, JACC 2011; Hermann JACC 2011). However none of these patients have benefited from a detailed histology analysis with aiming at identifying amyloid deposits. The investigators have recently found similar clinical observations in the investigators AS cohort. Using specific staining, the investigators were able to unmask the association of severe AS and CA in these patients. These preliminary findings raise the question of a potential pathophysiological link between CA and AS and might explain why some patients with AS may not benefit from cardiac surgery.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

180 participants

Allocation:

N/A

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Screening

Official Title:

AMYLO-CARTESIAN Study :Prevalence and Post-surgical Outcomes of CARdiac Wild-type TransthyrEtin amyloidoSIs in Elderly Patients With Aortic steNosis Referred for Valvular Replacement.

Study Start Date :

Oct 1, 2014

Anticipated Primary Completion Date :

Mar 31, 2022

Anticipated Study Completion Date :

Mar 31, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: elderly patients with Aortic steNosis valvular replacement	Other: a basal LV septum biopsy During surgery, a basal LV septum biopsy will be collected for determination and quantification of interstitial deposits using specific staining which will be performed in a blind fashion

Arm

Intervention/Treatment

Other: elderly patients with Aortic steNosis valvular replacement

Other: a basal LV septum biopsy

During surgery, a basal LV septum biopsy will be collected for determination and quantification of interstitial deposits using specific staining which will be performed in a blind fashion

Outcome Measures

Primary Outcome Measures

Clinical composite criterion: All causes of death and cardiovascular hospitalization at 1 year after surgery [1 year]
All causes of death and cardiovascular hospitalization at 1 year after surgery

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Significant aortic stenosis. The aortic stenosis severity (aortic area : <1cm² or <0.6cm²/m² measured by echocardiography
Indication of surgical aortic valve replacement for AS: will be defined in each center in accordance with ESC guidelines.
Patient ≥ 70 years old and NYHA class ≥2 and LVEF <60% or global LV strain more than "-17%".
Written consent prior to surgery.

Exclusion Criteria:

Other severe disease with a life prognosis below than 1 year.
Already known other causes of amyloidosis than senile amyloidosis will be excluded.
Patients unsuitable for AS surgery as defined by ESC guidelines 2012.
Significant mitral valve disease needing a surgical treatment.
Significant aortic regurgitation (class >III).

NB: Patients with pacemaker will be included but will not perform the cardiac MRI.

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Hôpital Henri Mondor	Creteil	France	94010
2	CHU Limoges	Limoges	France	87000
3	CHU LYON	Lyon	France	69000
4	Chu Rennes	Rennes	France	35000
5	Centre Cardiologique du Nord	Saint-Denis	France	93200
6	CHU de Toulouse	Toulouse	France	31059