Allograft Dysfunction in Heart Transplant

Official title

Defining Mechanisms for Cardiac Allograft Dysfunction to Improve Allograft Longevity and Survival in Heart-Transplant Patients

Overview

The investigators will evaluate for early evidence of cardiac allograft dysfunction by cardiac MRI and single cell sequencing to determine underlying molecular and macroscopic causes.

Detailed description

Adult heart-transplant patients, excluding those with a GFR less than 30 mL/min/1.73m2, contraindications to MRI and allergies to either regadenoson or gadolinium contrast, will be enrolled over 60 months. Patients will be recruited from UCSD. The investigators will specifically enroll all eligible heart-transplant patients.

Brief protocol:

Cardiac MRI is performed. Cine images in standard views are obtained. T1 and T2 mapping sequences are performed on short axis images pre- and post-gadolinium contrast. For stress imaging, intravenous regadenoson is given as a 0.4 mg bolus followed by a 5 mL saline flush. After 30 seconds, short-axis images are acquired for 30 consecutive heartbeats with administration of gadolinium. Rest imaging is performed 30 minutes after stress imaging. Lastly, late gadolinium enhancement images are obtained in standard views. Images are analyzed offline by a blinded independent reader. Patients will be followed for at least 1 year after enrollment for MACE.

Peripheral blood and endomyocardial biopsies will also be collected, timing as per usual clinical care as well as for-cause, for single cell RNAseq analyses.

Interventions

• Drug Regadenoson
  For use in stress myocardial perfusion imaging.

Primary outcome measures

• Myocardial Perfusion Reserve [Time frame: 60 months]

Secondary outcome measures (8)

• Rest and stress myocardial blood flow [Time frame: 60 months]
• LGE % [Time frame: 60 months]
• LVEF [Time frame: 60 months]
• LV end-diastolic volume index [Time frame: 60 months]
• LV mass index [Time frame: 60 months]
• native T1 and T2 myocardial values [Time frame: 60 months]
• extracellular volumes [Time frame: 60 months]
• myocardial strain rate [Time frame: 60 months]

Eligibility criteria

Inclusion criteria

• Age greater than or equal to 18 years old.
• At least three months status post heart transplantation.

Exclusion criteria

• Biopsy proven acute rejection episode in the past 3 months.
• Patients with symptoms or signs of acute myocardial ischemia or recent acute coronary syndrome in the past 3 months.
• Uncontrolled obstructive ventilatory disease including asthma and COPD.
• History of generalized tonic-clonic seizures.
• Second or third degree AV nodal block.
• Sinus node dysfunction.
• Contraindications to MRI including cardiovascular implantable electronic devices.
• Renal dysfunction with an estimated GFR less than 30 mL/min/1.73m2.
• Prior adverse reaction to either regadenoson or gadolinium contrast. Prior adverse reaction to adenosine or dipyridamole will be assessed on a case-by-case basis.
• Systolic blood pressure greater than 180 or less than 85 mmHg.
• Diastolic blood pressure greater than 120 or less than 40 mmHg.
• Resting heart rate greater than 120 or less than 45 beats per minute. - Severe claustrophobia.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Single blind

Primary purpose

Diagnostic

Study locations

United States · 1 center

• UC San Diego — La Jolla

Publications

• Stehlik J, Edwards LB, Kucheryavaya AY, Benden C, Christie JD, Dobbels F, Kirk R, Rahmel AO, Hertz MI. The Registry of the International Society for Heart and Lung Transplantation: Twenty-eighth Adult Heart Transplant Report--2011. J Heart Lung Transplant. 2011 Oct;30(10):1078-94. doi: 10.1016/j.healun.2011.08.003. No abstract available. PMID 21962016
• Berry GJ, Angelini A, Burke MM, Bruneval P, Fishbein MC, Hammond E, Miller D, Neil D, Revelo MP, Rodriguez ER, Stewart S, Tan CD, Winters GL, Kobashigawa J, Mehra MR. The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: evolution and current status (2005-2011). J Heart Lung Transplant. 2011 Jun;30(6):601-11. doi: 10.1016/j.healun.2011.02.0 PMID 21555100
• Costanzo MR, Dipchand A, Starling R, Anderson A, Chan M, Desai S, Fedson S, Fisher P, Gonzales-Stawinski G, Martinelli L, McGiffin D, Smith J, Taylor D, Meiser B, Webber S, Baran D, Carboni M, Dengler T, Feldman D, Frigerio M, Kfoury A, Kim D, Kobashigawa J, Shullo M, Stehlik J, Teuteberg J, Uber P, Zuckermann A, Hunt S, Burch M, Bhat G, Canter C, Chinnock R, Crespo-Leiro M, Delgado R, Dobbels F, PMID 20643330
• Uretsky BF, Murali S, Reddy PS, Rabin B, Lee A, Griffith BP, Hardesty RL, Trento A, Bahnson HT. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone. Circulation. 1987 Oct;76(4):827-34. doi: 10.1161/01.cir.76.4.827. PMID 3308166
• Fang JC, Kinlay S, Beltrame J, Hikiti H, Wainstein M, Behrendt D, Suh J, Frei B, Mudge GH, Selwyn AP, Ganz P. Effect of vitamins C and E on progression of transplant-associated arteriosclerosis: a randomised trial. Lancet. 2002 Mar 30;359(9312):1108-13. doi: 10.1016/S0140-6736(02)08154-0. PMID 11943259
• Pham MX, Teuteberg JJ, Kfoury AG, Starling RC, Deng MC, Cappola TP, Kao A, Anderson AS, Cotts WG, Ewald GA, Baran DA, Bogaev RC, Elashoff B, Baron H, Yee J, Valantine HA; IMAGE Study Group. Gene-expression profiling for rejection surveillance after cardiac transplantation. N Engl J Med. 2010 May 20;362(20):1890-900. doi: 10.1056/NEJMoa0912965. Epub 2010 Apr 22. PMID 20413602
• Bhalodolia R, Cortese C, Graham M, Hauptman PJ. Fulminant acute cellular rejection with negative findings on endomyocardial biopsy. J Heart Lung Transplant. 2006 Aug;25(8):989-92. doi: 10.1016/j.healun.2006.04.002. Epub 2006 Jun 30. PMID 16890123
• Miller CA, Sarma J, Naish JH, Yonan N, Williams SG, Shaw SM, Clark D, Pearce K, Stout M, Potluri R, Borg A, Coutts G, Chowdhary S, McCann GP, Parker GJ, Ray SG, Schmitt M. Multiparametric cardiovascular magnetic resonance assessment of cardiac allograft vasculopathy. J Am Coll Cardiol. 2014 Mar 4;63(8):799-808. doi: 10.1016/j.jacc.2013.07.119. Epub 2013 Dec 18. PMID 24355800

Identifiers

NCT: NCT03102125 · 190053

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗