MYOCARDIAL SILENT INFARCTIONS AND FIBROSIS IN FAMILIAL HYPERCHOLESTEROLEMIA (CHOLCOEUR)

Familial Hypercholesterolemia - Heterozygous Clinical Trial

— CHOLCOEUR  

Official title:

MYOCARDIAL SILENT INFARCTIONS AND FIBROSIS IN FAMILIAL HYPERCHOLESTEROLEMIA

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT02517944
• Other study ID #: 14DRM_CHOLCOEUR
• Status: Recruiting
• Phase: N/A
• First received: January 14, 2015
• Last updated: August 4, 2015
• Start date: November 2014
• Est. completion date: November 2015

Study information

• Verified date: July 2015
• Source: Institute of Cardiometabolism and Nutrition, France
• Contact: Aurélie RABIER
• Email: a.rabier[@]ican-institute.org
• Is FDA regulated: No
• Health authority: France: Agence Nationale de Sécurité du Médicament et des produits de santéFrance: Commission nationale de l'informatique et des libertés
• Study type: Observational [Patient Registry]

Clinical Trial Summary

Patients with familial hypercholesterolemia (FH) at high cardiovascular risk may suffer from silent micro-infarctions (MI) before clinical coronary heart disease manifestations because of the lifetime exposure to elevated serum LDL-cholesterol levels.

The study aims to demonstrate the higher prevalence of silent myocardial infarction in a population of asymptomatic patients with familial hypercholesterolemia at high cardiovascular risk in comparison to control patients using Cardiac Magnetic Resonance sequences of delayed gadolinium enhancement.

Description:

To demonstrate the higher prevalence of silent myocardial infarction in a population of asymptomatic patients with familial hypercholesterolemia at high cardiovascular risk in comparison to control patients, the protocol is the following:

• to enroll 75 patients with familial hypercholesterolemia (FH)

• to enroll 35 subjects without FH (control group)

• for each subject, to collect data from his medical file (blood test results) and to perform a cardiac and aortic MRI in order to evaluate the micro-infarction proportion.

The study will be performed according to GCPs and with respect with french laws.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 110
• Est. completion date: November 2015
• Est. primary completion date: September 2015
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 40 Years to 60 Years

Eligibility

Inclusion criteria:

For patients with heterozygous form of familial hypercholesterolemia:

• Aged between 40 and 60 years

• With an identified genetic mutation (LDL-R, ApoB, PCSK9)

• Asymptomatic,

• With no EKG sign of ischemia

• No personal history of coronary heart disease.

• Treated or untreated by lipid lowering treatment

• High cardiovascular risk identified by 1 of the following criteria:

1. Current smoking (1 cigarette a day) 2 Family history of very premature onset CHD:

first- or second-degree male relative onset before age 45, first- or second-degree female relative onset before age 55 3.Two or more cardiovascular risk factors among this list: increasing age (men > 30, women > 40 years of age), LDL-C > 250 mg/dL, male sex, family history of premature onset CHD, first-degree male relative onset before age 55, first-degree female relative onset before age 65, metabolic syndrome, HDL-C < 40 mg/dL, hypertension (BP > 140/or > 90 mmHg or drug treatment), Lp (a) = 50 mg/dL, tendon xanthoma

For control subjects:

• Aged between 40 and 60 years

• With a normal lipid profile (LDL-C < 1.6g/L HDL-C > 0,45g/L and TG < 4g/L) and untreated by any lipid lowering therapies

• Asymptomatic,

• With EKG showing normal sinus rhythm , no sign of ischemia nor Left Bundle Branch Block

• No personal history of coronary heart disease.

• Control subjects will be matched for age/gender/smoking status and blood pressure

Exclusion criteria:

• Non-affiliation to a healthcare system

• Consent refusal

• Contra-indication to MRI or to gadolinium injection.

• Claustrophobia, metallic devices, pacemaker, mechanical valve implanted before 1985, pregnancy, nursing

• Renal failure

• Technical contra-indication: patient diameter > 70 cm weight > 250 kg

• Personal history of cardiovascular disease and myocardial infarction

• Diabetes mellitus

• Uncontrolled hypertension

• TG < 4 g/L

• Previous use of an Amgen product in the past 12 months

Study Design

Observational Model: Case Control, Time Perspective: Prospective

Related Conditions & MeSH terms

• Familial Hypercholesterolemia - Heterozygous
• Hypercholesterolemia
• Hyperlipoproteinemia Type II

Locations

Country	Name	City	State
France	Unité de prévention des maladies cardiovasculaires- Unité INSERM 939 Pôle Cardiologie/Métabolisme Groupe Hospitalier Pitié-Salpêtrière	Paris

Sponsors (2)

Lead Sponsor	Collaborator
Institute of Cardiometabolism and Nutrition, France	Amgen

Country where clinical trial is conducted

France, 

References & Publications (28)

Austin MA, Hutter CM, Zimmern RL, Humphries SE. Familial hypercholesterolemia and coronary heart disease: a HuGE association review. Am J Epidemiol. 2004 Sep 1;160(5):421-9. Review. — View Citation

Benn M, Watts GF, Tybjaerg-Hansen A, Nordestgaard BG. Familial hypercholesterolemia in the danish general population: prevalence, coronary artery disease, and cholesterol-lowering medication. J Clin Endocrinol Metab. 2012 Nov;97(11):3956-64. doi: 10.1210/jc.2012-1563. Epub 2012 Aug 14. Erratum in: J Clin Endocrinol Metab. 2014 Dec;99(12):4758-9. — View Citation

Cheng HM, Ye ZX, Chiou KR, Lin SJ, Charng MJ. Vascular stiffness in familial hypercholesterolaemia is associated with C-reactive protein and cholesterol burden. Eur J Clin Invest. 2007 Mar;37(3):197-206. — View Citation

Choi DS, Ha JW, Choi B, Yang WI, Choi EY, Rim SJ, Chung N. Extent of late gadolinium enhancement in cardiovascular magnetic resonance and its relation with left ventricular diastolic function in patients with hypertrophic cardiomyopathy. Circ J. 2008 Sep;72(9):1449-53. — View Citation

Dall'Armellina E, Ferreira VM, Kharbanda RK, Prendergast B, Piechnik SK, Robson MD, Jones M, Francis JM, Choudhury RP, Neubauer S. Diagnostic value of pre-contrast T1 mapping in acute and chronic myocardial infarction. JACC Cardiovasc Imaging. 2013 Jun;6(6):739-42. doi: 10.1016/j.jcmg.2012.11.020. — View Citation

Dayanikli F, Grambow D, Muzik O, Mosca L, Rubenfire M, Schwaiger M. Early detection of abnormal coronary flow reserve in asymptomatic men at high risk for coronary artery disease using positron emission tomography. Circulation. 1994 Aug;90(2):808-17. — View Citation

De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, Dallongeville J, Ebrahim S, Faergeman O, Graham I, Mancia G, Cats VM, Orth-Gomér K, Perk J, Pyörälä K, Rodicio JL, Sans S, Sansoy V, Sechtem U, Silber S, Thomsen T, Wood D; European Society of Cardiology. American Heart Association. American College of Cardiology. European guidelines on cardiovascular disease prevention in clinical practice. Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies and by invited experts). Atherosclerosis. 2004 Apr;173(2):381-91. — View Citation

Descamps OS, Gilbeau JP, Leysen X, Van Leuven F, Heller FR. Impact of genetic defects on atherosclerosis in patients suspected of familial hypercholesterolaemia. Eur J Clin Invest. 2001 Nov;31(11):958-65. — View Citation

Farnier M, Bruckert E. Severe familial hypercholesterolaemia: current and future management. Arch Cardiovasc Dis. 2012 Dec;105(12):656-65. doi: 10.1016/j.acvd.2012.05.011. Epub 2012 Oct 6. Review. — View Citation

Giulia Gagliardi M, Crea F, Polletta B, Bassano C, La Vigna G, Ballerini L, Ragonese P. Coronary microvascular endothelial dysfunction in transplanted children. Eur Heart J. 2001 Feb;22(3):254-60. — View Citation

Hovingh GK, Davidson MH, Kastelein JJ, O'Connor AM. Diagnosis and treatment of familial hypercholesterolaemia. Eur Heart J. 2013 Apr;34(13):962-71. doi: 10.1093/eurheartj/eht015. Epub 2013 Feb 14. Review. — View Citation

Kaufmann PA, Gnecchi-Ruscone T, Schäfers KP, Lüscher TF, Camici PG. Low density lipoprotein cholesterol and coronary microvascular dysfunction in hypercholesterolemia. J Am Coll Cardiol. 2000 Jul;36(1):103-9. — View Citation

Kolansky DM, Cuchel M, Clark BJ, Paridon S, McCrindle BW, Wiegers SE, Araujo L, Vohra Y, Defesche JC, Wilson JM, Rader DJ. Longitudinal evaluation and assessment of cardiovascular disease in patients with homozygous familial hypercholesterolemia. Am J Cardiol. 2008 Dec 1;102(11):1438-43. doi: 10.1016/j.amjcard.2008.07.035. Epub 2008 Sep 11. — View Citation

Kroon AA, Ajubi N, van Asten WN, Stalenhoef AF. The prevalence of peripheral vascular disease in familial hypercholesterolaemia. J Intern Med. 1995 Nov;238(5):451-9. — View Citation

Kuruvilla S, Adenaw N, Katwal AB, Lipinski MJ, Kramer CM, Salerno M. Late gadolinium enhancement on cardiac magnetic resonance predicts adverse cardiovascular outcomes in nonischemic cardiomyopathy: a systematic review and meta-analysis. Circ Cardiovasc Imaging. 2014 Mar;7(2):250-8. doi: 10.1161/CIRCIMAGING.113.001144. Epub 2013 Dec 20. Review. — View Citation

Kwong RY, Sattar H, Wu H, Vorobiof G, Gandla V, Steel K, Siu S, Brown KA. Incidence and prognostic implication of unrecognized myocardial scar characterized by cardiac magnetic resonance in diabetic patients without clinical evidence of myocardial infarction. Circulation. 2008 Sep 2;118(10):1011-20. doi: 10.1161/CIRCULATIONAHA.107.727826. Epub 2008 Aug 25. — View Citation

Lin Y, Yang SG, Chen H, Zhang HQ, Wang CS. [The predictive value of DE-CMR in patients with severe chronic aortic regurgitation and extremely dilated left ventricular chamber]. Zhonghua Wai Ke Za Zhi. 2012 Dec;50(12):1087-90. Chinese. — View Citation

Lipinski MJ, McVey CM, Berger JS, Kramer CM, Salerno M. Prognostic value of stress cardiac magnetic resonance imaging in patients with known or suspected coronary artery disease: a systematic review and meta-analysis. J Am Coll Cardiol. 2013 Aug 27;62(9):826-38. doi: 10.1016/j.jacc.2013.03.080. Epub 2013 May 30. — View Citation

Liu CY, Liu YC, Wu C, Armstrong A, Volpe GJ, van der Geest RJ, Liu Y, Hundley WG, Gomes AS, Liu S, Nacif M, Bluemke DA, Lima JA. Evaluation of age-related interstitial myocardial fibrosis with cardiac magnetic resonance contrast-enhanced T1 mapping: MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol. 2013 Oct 1;62(14):1280-7. doi: 10.1016/j.jacc.2013.05.078. Epub 2013 Jul 17. — View Citation

Mascherbauer J, Marzluf BA, Tufaro C, Pfaffenberger S, Graf A, Wexberg P, Panzenböck A, Jakowitsch J, Bangert C, Laimer D, Schreiber C, Karakus G, Hülsmann M, Pacher R, Lang IM, Maurer G, Bonderman D. Cardiac magnetic resonance postcontrast T1 time is associated with outcome in patients with heart failure and preserved ejection fraction. Circ Cardiovasc Imaging. 2013 Nov;6(6):1056-65. doi: 10.1161/CIRCIMAGING.113.000633. Epub 2013 Sep 13. — View Citation

Mewton N, Liu CY, Croisille P, Bluemke D, Lima JA. Assessment of myocardial fibrosis with cardiovascular magnetic resonance. J Am Coll Cardiol. 2011 Feb 22;57(8):891-903. doi: 10.1016/j.jacc.2010.11.013. Review. — View Citation

Nemati MH, Astaneh B. Optimal management of familial hypercholesterolemia: treatment and management strategies. Vasc Health Risk Manag. 2010 Dec 3;6:1079-88. doi: 10.2147/VHRM.S8283. Review. — View Citation

Nordestgaard BG, Chapman MJ, Humphries SE, Ginsberg HN, Masana L, Descamps OS, Wiklund O, Hegele RA, Raal FJ, Defesche JC, Wiegman A, Santos RD, Watts GF, Parhofer KG, Hovingh GK, Kovanen PT, Boileau C, Averna M, Borén J, Bruckert E, Catapano AL, Kuivenhoven JA, Pajukanta P, Ray K, Stalenhoef AF, Stroes E, Taskinen MR, Tybjærg-Hansen A; European Atherosclerosis Society Consensus Panel. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society. Eur Heart J. 2013 Dec;34(45):3478-90a. doi: 10.1093/eurheartj/eht273. Epub 2013 Aug 15. — View Citation

Risk of fatal coronary heart disease in familial hypercholesterolaemia. Scientific Steering Committee on behalf of the Simon Broome Register Group. BMJ. 1991 Oct 12;303(6807):893-6. — View Citation

Sacré K, Brihaye B, Hyafil F, Serfaty JM, Escoubet B, Zennaro MC, Lidove O, Laissy JP, Papo T. Asymptomatic myocardial ischemic disease in antiphospholipid syndrome: a controlled cardiac magnetic resonance imaging study. Arthritis Rheum. 2010 Jul;62(7):2093-100. doi: 10.1002/art.27488. — View Citation

Schmidt HH, Hill S, Makariou EV, Feuerstein IM, Dugi KA, Hoeg JM. Relation of cholesterol-year score to severity of calcific atherosclerosis and tissue deposition in homozygous familial hypercholesterolemia. Am J Cardiol. 1996 Mar 15;77(8):575-80. — View Citation

Vilahur G, Casani L, Juan-Babot O, Guerra JM, Badimon L. Infiltrated cardiac lipids impair myofibroblast-induced healing of the myocardial scar post-myocardial infarction. Atherosclerosis. 2012 Oct;224(2):368-76. doi: 10.1016/j.atherosclerosis.2012.07.003. Epub 2012 Jul 22. — View Citation

Watts GF, Sullivan DR, Poplawski N, van Bockxmeer F, Hamilton-Craig I, Clifton PM, O'Brien R, Bishop W, George P, Barter PJ, Bates T, Burnett JR, Coakley J, Davidson P, Emery J, Martin A, Farid W, Freeman L, Geelhoed E, Juniper A, Kidd A, Kostner K, Krass I, Livingston M, Maxwell S, O'Leary P, Owaimrin A, Redgrave TG, Reid N, Southwell L, Suthers G, Tonkin A, Towler S, Trent R; Familial Hypercholesterolaemia Australasia Network Consensus Group (Australian Atherosclerosis Society). Familial hypercholesterolaemia: a model of care for Australasia. Atheroscler Suppl. 2011 Oct;12(2):221-63. doi: 10.1016/j.atherosclerosissup.2011.06.001. Epub 2011 Sep 13. — View Citation

* Note: There are 28 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Percentage of patients presenting with at least one micro infarction at RMI	Cardiac and aortic RMI with gadolinium	Within 4 weeks after consent signature	No
Secondary	LDL-Cholesterol burden (compared to standard values)		The most recent value within the last 5 years.	No
Secondary	Anatomic and functional indexes of the aorta (maximal and minimal areas of aortic lumen, aortic flow)		Within 4 weeks after consent signature	No
Secondary	Correlations between LDL-Cholesterol burden & presence of micro infarction, between LDL-Cholesterol burden & myocardial fibrosis, and between LDL-Cholesterol burden & aortic stiffness indexes		1 year	No