Invasive Coronary Physiology Assessment for Detecting Microcirculatory Dysfunction in Heart Transplant Recipients

Introduction

Cardiac allograft vasculopathy (CAV) is a common complication and one of the leading causes of long-term mortality in adults after heart transplantation (Htx). According to the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry data report, in adult cardiac transplant recipients, the prevalence of CAV at 1, 5, and 10 years after Htx was 8%, 29%, and 47%, respectively [1]. CAV is a specific form of coronary artery disease affecting heart transplant recipients. It is characterized by an early, widespread intimal proliferation that affects both the epicardial and microvascular vessels, which leads to stenosis of the epicardial coronary artery and occlusion of small vessels. According to the 2010 ISHLT guidelines, coronary angiography remains the criterion standard for diagnosing CAV and allows classification of disease severity based on defined angiographic changes [2]. Follow-up angiography is performed according to different protocols and at different times [3]. Thus, after Htx, macrocirculation is evaluated routinely; however, there is no validated tool to assess microcirculation in these patients. This issue is particularly important, as current studies show that elevated microvascular resistance can be an independent predictor of CAV [4,5]. Considering the significance of CAV following Htx, it can be beneficial to explore various techniques, invasive and noninvasive, for assessing microcirculation in these circumstances [6,7]. For the invasive assessment of coronary microcirculation, there are currently 2 different tools available: Doppler-based and thermodilution-derived tools (8]. In this study, we focused on a thermodilution-based technique involving fractional flow reserve (FFR) [9]. This tool was established among patients with native heart diseases for the functional assessment of the coronary artery; however, few data exist on the use of FFR in heart transplant recipients to assess coronary microcirculation [10]. To fill this gap, we aimed to evaluate the utility and safety of this method in this population. The FFR index, when measured concurrently with the index of microcirculatory resistance (IMR) and coronary flow reserve (CFR), provides a highly reproducible and comprehensive assessment of coronary physiology at both the epicardial and microvascular levels [11]. Research findings indicate that advancing age [12], hypercholesterolemia [13], smoking [14], obesity [15], hypertension [16], diabetes mellitus [17] and chronic kidney disease [18] are associated with microcirculatory dysfunction in humans. Thus, the primary objective of this study was to evaluate the safety of the invasive FFR method and its utility in assessing the occurrence of coronary microvascular dysfunction (CMD) in heart transplant recipients who underwent follow-up angiography. Recipient and donor factors that may influence the occurrence of this pathology were examined, treatment regimens were compared, laboratory parameters were analyzed, and transplantation details were reviewed.

Material and Methods

STATISTICAL ANALYSIS:

In the statistical analysis, for each quantitative variable, a histogram was created with the Shapiro-Wilk test. For quantitative variables with normal distribution, the Levene test was performed. For quantitative variables that met the homogeneity assumption of variance in this test, the independent-samples t test was performed. For the remaining quantitative variables that did not meet the homogeneity assumption of variance, the independent-samples t test with unequal variances was performed. For quantitative variables with non-normal distribution, a non-parametric test was performed: comparison of 2 independent samples (groups) using the Mann-Whitney U test. Qualitative variables were assessed using the Pearson chi-square test. A P value of <0.05 was considered statistically significant. Statistical analyses were performed in Statistica 13, Software Inc (Statsoft Poland). Visualizations were performed using Python 3.11.13 with matplotlib 3.10.0, pandas 2.2.2, numpy 2.0.2, scipy 1.15.3.

Results

The study included 33 heart transplant recipients. Twenty-one (64%) patients were men, and the mean age of patients was 49±14 years. The group under study was divided into patients with normal microcirculation and patients with abnormal microcirculation. The study variables are shown in Tables 1–3. Abnormal IMR or CFR values were found in 8 (24%) patients. The median [IQR] for IMR and CFR was 13 [10–20] and 3.6 [2.2–4.9]. CMD occurred more frequently in younger patients: 40±16 vs 51±13 years (P=0.045) and those with lower BMI: 22 kg/m2 vs 26 kg/m2 (P=0.016; Figure 2A). The median time since Htx was 2 [2–10] years, and it was higher in the group with CMD than in the group without, at 9.5 [6–16] vs 2 [1–8] years, respectively (P=0.042; Figure 2B). There were no significant differences in atherosclerotic changes in the epicardial arteries detected in coronary angiography: 5 (63%) vs 9 (36%) (P=0.186). The need for pacemaker implantation, thus chronotropic insufficiency of the graft, was noted in 4 (12%) patients, and occurred more frequently in those with CMD, 3 (38%), than in those with normal microcirculation, 1 (4%) (P=0.012; Figure 2C). In basic laboratory test results, triglyceride levels differed between groups, with 76 mg/dL [65–96] in those with CMD and 114 [77–158] mg/dL in patients with normal microcirculation (P=0.048; Figure 2D). No significant differences were observed in other basic laboratory test results or pharmacological treatment. In this study, there were no complications related to the applied FFR method, which was used in all patients qualified to participate.

Discussion

CAV remains one of the main causes of long-term mortality in heart transplant recipients [22]. Assessment of FFR, CMR, and IMR allows early detection of CAV by tracking changes in macro- and micro-coronary vessels [23]. In the present study, the invasive evaluation of these functional tests during routine follow-up angiography in patients who underwent Htx allowed us to effectively evaluate coronary microcirculation. In our study, 24% of patients examined had CMD, and none of the patients experienced complications, thereby supporting FFR as a reliable and safe tool. In the pathogenesis of CAV, macrocirculation and microcirculation are impaired. In our study, 3 of 8 patients with CMD did not show significant changes at last follow-up, according to the ISHLT classification of CAV. Therefore, in most cases examined, these changes coexisted, but microcirculatory dysfunction can also occur as an isolated pathology, possibly preceding changes in macrocirculation. According to a study by Tona et al, CMD evaluated beyond the first year after Htx can be used to independently predict the future occurrence of new-onset epicardial CAV [24]. In their 2025 study, Ha et al evaluated prognosis after Htx and reported that impaired microcirculatory function found early after transplantation was based on another new indicator, vascular resistance reserve, which was associated with a high risk of acute cellular rejection and death [25]. In our study, CMD occurrence was associated with a longer time since Htx. We believe this may be related to the increasing incidence of this pathology with length of time since Htx, as it occurred in approximately 30% of patients 5 years after Htx [1]. Patients with CMD also had a lower BMI than did those with normal microcirculation. It has been shown that in non-transplanted patients with obesity, greater BMI was correlated with declining coronary microvascular function [26,27], and in heart transplant recipients with normal functioning allografts, weight gain and BMI were independent predictors of the severity of CAV [28]. However, results similar to those of the present study have been found in other studies. Russo et al conducted a study using the United Network of Organ Sharing database and demonstrated that obesity I (BMI of 30–34.99) appeared to not be associated with significantly higher morbidity and mortality in heart transplant recipients. They reported that the groups with a BMI ranging from 22 to 28 kg/m2, classified as between normal and overweight, had the best risk-adjusted survival [29]. There is also a debated concept, called the “obesity paradox”, whereby patients with numerous chronic diseases who have overweight or moderate obesity appear to have better clinical outcomes than patients with a normal BMI [30]; however, this paradox has become less clinically relevant due to the many drawbacks of the concept [31]. In the present study, the same surprising association as with BMI was observed with triglyceride levels: significantly higher triglyceride levels were seen in the group of patients with normal microcirculation. The presence of CMD in patients with lower blood triglyceride levels may have resulted from these patients taking statins in greater amounts or for a longer time. Statin therapy should be considered in all heart transplant recipients, as it has been shown to reduce CAV and improve long-term outcomes, independent of lipid levels [3]. Unfortunately, we did not have data on the duration of treatment with statins and their dosage before the study, which prevented us from drawing conclusions.

In our study, pacemaker implantation was performed in 4 heart transplant recipients, accounting for 12% of patients. According to the 2024 analysis of pacemaker implantation frequency after Htx by Boluk et al, pacemaker implantation after Htx is a common phenomenon and was observed in 9% of the study population, which supports our findings. Another notable discovery in the study by Boluk et al includes factors influencing the risk of pacemaker implantation, namely higher donor age and BMI [32]. It appears that CMD can be related to damage to the cardiac conduction system. Moreover, in the present study, recipient age was younger in the group with CMD. We tried to explain this rather surprising result but concluded that the small number of patients included in the study was a significant limitation affecting the interpretation of this finding. CFR and IMR values differed significantly between groups with normal and abnormal microcirculation (Figure 3A, 3B). These anomalies were able to predict the development of CAV and further complications, such as acute cellular rejection or patient death [33]. In the study by Ahn et al, lower CFR was correlated with a higher risk of death and re-transplantation at 10 years, while elevated IMR at baseline (median 7.2 weeks) and after 1 year was correlated with an increased risk of major adverse cardiac events at 10 years [34]. Thus, early detection of CMD by modern invasive tests allows for the prediction of adverse events, modification of treatment, and personalizing of post-transplant management for the best possible outcome for the patient [35,36].

This study had limitations, including the small sample size of 33 patients, which was the main limitation to drawing definite conclusions. Other limitations were the lack of blinding and lack of predictive evaluation of the FFR method for adverse events in long-term follow-up. Further investigation of the prognostic and therapeutic role of intracoronary flow assessment in CAV surveillance after Htx and factors predisposing patients to microcirculatory dysfunction is needed. Investigating these factors in a larger number of patients could provide new useful information and even contribute to the reduction of CMD and CAV in this group of patients.

Conclusions

As well as being safe, FFR, CMR, and IMR are indicators that allow effective invasive evaluation of the coronary microcirculation of heart transplant recipients. Patients with CMD were younger, had a longer time since transplantation, exhibited a greater frequency of pacemaker implantation after Htx, and had a lower BMI and triglyceride values than did patients with normal coronary microcirculation. Further large-scale studies on factors that predispose heart transplant recipients to microvascular dysfunction are greatly needed.

Data Availability Statement

The datasets used and analyzed during the current study are available from the corresponding author on reasonable request.