Clinical trial NCT02798731: Physiologic Assessment of Microvascular Function in Heart Transplant Patients
Official title: Physiologic Assessment of Microvascular Function and Its Impact on Cardiac Allograft Vasculopathy in Heart Transplant Patients: Prospective Registry and Pilot Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: Cardiac Allograft Vasculopathy
Keywords: Heart transplant
Microvascular dysfunction
Cardiac allograft vasculopathy
Fractional flow reserve
Coronary flow reserve
Index of microvascular resistance
Lead sponsor: Samsung Medical Center
Sponsor class: OTHER
First posted: 2016-06-14
Enrollment: 200
Sex: ALL
Minimum age (years): 18
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Consecutive patients who received heart transplant undergoing coronary angiography for evaluation of coronary disease

Brief summary: The aim of the study is to evaluate the impact of early microvascular disease assessed by coronary physiologic indices such as fractional flow reserve (FFR), coronary flow reserve (CFR), index of microvascular resistance (IMR) on future occurrence of cardiac allograft vasculopathy (CAV) in heart transplant recipients.

Detailed description: Cardiac allograft vasculopathy (CAV) or acute cellular rejection (ACR) are a leading cause of mortality and morbidity in heart transplant recipients. Most of the cases occur within 5 years after transplant and later incidence was known to be infrequent.

Mechanisms of CAV or ACR are thought to be multi-factorial involving both immunologic and non-immunologic factors that leads to injury of coronary endothelium and intimal hyperplasia. This unique mechanism results in long, diffuse and concentric stenosis of coronary arteries, different from those with conventional coronary atherosclerosis.

Due to lack of typical ischemic symptoms by denervated heart, diagnosis of CAV depends on routine screening tests rather than symptom based investigation. International Society for Heart and Lung Transplantation (ISHLT) guideline recommends annual or biannual coronary angiography screening until 5 years after transplant, but sensitivity of coronary angiography is limited because of diffuse involvement of all segments of coronary arteries. Alternatively, Intravascular ultrasound (IVUS) is a current standard for diagnosis and prognostication of CAV. It is well studied that progressive intimal thickening during the first year after transplant predicts future incidence of CAV and poor prognosis. However, the use of IVUS in the diagnosis of CAV is not generalized due to technical issues, high cost, procedure complications and ISHLT guideline states it is an option to exclude donor coronary artery disease, to detect rapidly progressive CAV, and provide prognostic information.

Recent development of single guidewire thermodilution technique enabled simple way to measure microvascular indices such as FFR, CFR, IMR. Our previous study shows, in patients with ischemic heart disease, presence of microvascular disease defined by low CFR and high IMR, predicts poor prognosis even without apparent epicardial disease. Considering its mechanism to involve diffuse coronary vasculature, CAV is believed to affect microvascular circulation in the early phase and spread to epicardial disease in its course. For this reason, by evaluating coronary physiology early after transplant, it may be possible to predict future progression of CAV.

There were previous studies which evaluated microvascular dysfunction in heart transplant patients. These studies indicated microvascular dysfunction at time of transplantation is related to progression of epicardial disease during first year after transplant, but lack of follow up prohibited from drawing any conclusion on occurrence of CAV later on. Another study by the same group evaluated microvascular dysfunction at 1 year after transplant and revealed it was associated with allograft vasculopathy at 5 years after transplant. However, this study did not evaluate impact of earlier assessments of microvascular dysfunction at time of transplantation on occurrence of CAV.

Therefore the current study will perform early physiologic assessments including fractional flow reserve, coronary flow reserve, and index of microcirculatory resistance in patients who received heart transplant and evaluate the impact of initial microvascular dysfunction on future occurrence of CAV or ACR during 6 years of follow up. The investigators hope to develop strong predictors of CAV or ACR that can be evaluated early after heart transplant and to improve outcome by preemptive therapy before overt development of the disease.

This study will be a pilot study and target sample size will be 200 consecutive patients to receive heart transplant.

Eligibility criteria: Inclusion Criteria:

* Subject over age of 18
* Patients received heart transplant

Exclusion Criteria:

* Patients with cardiogenic shock
* Patients with unstable vital sign that precludes coronary angiography
* Patients with major bleeding in last 3 months
* Patients with active bleeding
* Patients with coagulopathy
* Patients with severe valvular heart disease
* Patients who refused to provide informed consent

Primary outcomes:
measure: Rates of cardiac death between patients with or without overt microvascular disease (CFR≤2 and IMR≥25) diagnosed with physiologic evaluation at 2-year follow-up after heart transplantation
timeFrame: 72 months
measure: Acute cellular rejection between patients with or without overt microvascular disease
timeFrame: 72 months
Secondary outcomes:
measure: Occurrence of anatomically significant cardiac allograft vasculopathy (% diameter stenosis > 50% on CCTA)
timeFrame: 72 months
measure: Comparison of total aggregated plaque volume and presence of adverse plaque characteristics on CCTA between transplant patients with or without overt microvascular disease (CFR≤2 and IMR≥25).
timeFrame: 72 months
measure: Comparison of all-cause mortality in transplant patients with or without overt microvascular disease (CFR≤2 and IMR≥25) diagnosed with physiologic evaluation at 2-year follow-up after heart transplantation.
timeFrame: 24 months
measure: Comparison of rates of cardiac death in transplant patients with or without overt microvascular disease (CFR≤2 and IMR≥25) diagnosed with physiologic evaluation at 1-year follow-up after heart transplantation.
timeFrame: 72 months
measure: Comparison of IVUS and physiologic indices in prediction of CAV progression.
timeFrame: 72 months
Other outcomes:
Locations:
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
Study officials:
affiliation: Samsung Medical Center
name: Joo Myung Lee, MD, MPH
role: PRINCIPAL_INVESTIGATOR
affiliation: Samsung Medical Center
name: Jin-Oh Choi, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Lee JM, Choi KH, Choi JO, Shin D, Park Y, Kim J, Lee SH, Kim D, Yang JH, Cho YH, Sung K, Choi JY, Park M, Kim JS, Park TK, Song YB, Hahn JY, Choi SH, Gwon HC, Oh JK, Jeon ES. Coronary Microcirculatory Dysfunction and Acute Cellular Rejection After Heart Transplantation. Circulation. 2021 Nov 2;144(18):1459-1472. doi: 10.1161/CIRCULATIONAHA.121.056158. Epub 2021 Sep 3.
citation: Lee SH, Choi KH, Lee JM, Hwang D, Rhee TM, Park J, Kim HK, Cho YK, Yoon HJ, Park J, Song YB, Hahn JY, Doh JH, Nam CW, Shin ES, Hur SH, Koo BK. Physiologic Characteristics and Clinical Outcomes of Patients With Discordance Between FFR and iFR. JACC Cardiovasc Interv. 2019 Oct 28;12(20):2018-2031. doi: 10.1016/j.jcin.2019.06.044. Epub 2019 Sep 25.