Objectives: Posttransplant cardiac allograft vasculopathy affects long-term survival after heart transplant. Because cardiac transplant recipients do not feel angina pectoris as a result of denervation of the transplanted heart graft, early diagnosis is difficult. The Gensini score, a widely used and simple scoring system, can determine the severity of coronary artery disease by angiography. Although this system has been widely used to evaluate natural coronary atherosclerosis, its use in heart transplant recipients has not been studied. Here, we evaluated cardiac allograft vasculopathy using the Gensini score.
Materials and Methods: We retrospectively analyzed 105 heart transplant patients seen between February 2004 and April 2018, including their immunosuppressive therapies. The Gensini score was calculated to determine severity score for each coronary stenosis according to degree of luminal narrowing and location.
Results: Of 105 heart transplant patients, 21 were diagnosed with cardiac allograft vasculopathy. Most patients received tacrolimus, prednisolone, and mycophenolate mofetil as standard therapy. Of 63 included patients, 21 (33.3%) showed cardiac allograft vasculopathy on coronary angiography. In accordance with the International Society of Heart and Lung Transplantation rating system, 42 of 63 patients (66.6%) were rated as 0 (no detectable angiographic lesions). Mean Gensini score was 34.8 ± 26. In the 21 patients with cardiac allograft vasculopathy, Gensini score showed mild cardiac allograft vasculopathy (score ≤ 10) in 8 patients (38%), moderate (score >10 and ≤ 40) in 6 patients (28.5%), and severe (score > 40) in 7 patients (33.3%). Angiographic coronary artery disease burden using Gensini was strongly correlated with cardiac allograft vasculopathy severity.
Conclusions: The Gensini score could provide valid assessment of cardiac allograft vasculopathy burden for use in clinical practice. However, more research is needed to identify and treat cardiac allograft vasculopathy for successful long-term survival of heart transplant patients.
Key words : Angina pectoris, Cardiac allograft vasculopathy, Cardiac transplant, Coronary artery disease, Immunosuppression
Coronary artery disease (CAD) after cardiac transplant continues to represent a major limitation to long-term survival. Cardiac allograft vasculopathy (CAV) is different from typical atherosclerosis and is believed to be multifactorial and primarily immune related. Cardiac allograft vasculopathy is also a limiting factor in survival of recipients after orthotopic heart transplant, accounting for 5-year mortality rate of 33%. This disease is an accelerated and unique form of CAD that may present as sudden death, myocardial infarction, arrhythmia, or congestive heart failure.1
Cardiac allograft vasculopathy is characterized by diffuse concentric intimal hyperplasia, thickening of the epicardial arteries, fibrosis, and immune-mediated endothelial injury. Intimal thickening mostly occurs during the first year posttransplant and can be observed by coronary angiography. Pharmacologic therapies to prevent and reverse the development of CAV have so far been unsuccessful. The only effective treatment for this diffuse disease is retransplant.2
Cardiac allograft vasculopathy may involve not only large epicardial vessels but also smaller intramyocardial branches. The diagnosis of CAD in heart transplant recipients is difficult because graft denervation of the transplanted heart prevents the presence of angina pectoris as an expression of myocardial ischemia. Thus, early diagnosis is essential.3 Because current treatment of vasculopathy has been disappointing, early prevention and diagnosis are necessary. The diffuse vascular changes have limited revascularization procedures to a relatively small proportion of patients with appropriate coronary anatomy.
The angiographic definition of CAV has been somewhat unclear. In the literature, CAV has been defined as any luminal irregularity or stenosis of > 30%, 40%, 50%, or 70%.4 With regard to assessment of coronary atherosclerosis in heart transplant recipients, protocols are so far unclear and have had controversial results. For estimation of angiographic CAD burden, multiple scoring systems have been designed, including the Gensini score or Syntax score (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery), which analyzes the severity of CAD. These systems have allowed estimation of short-term and long-term cardiovascular risk. Both scoring systems use coronary artery anatomy and severity of stenosis in lesions in their calculations.5,6
The Gensini score is one of the most widely used scoring systems for determining the severity of coronary angiographic results. This system divides the 3 coronary arteries into several subsegments, and the percent diameter of stenosis is scored from zero to 32, depending on the severity of stenosis. According to the angiographic degree of stenosis, narrowing from 0% to 25%, 25% to 50%, 50% to 75%, 75% to 90%, 90% to 99%, and 100% is scored as 1, 2, 4, 8, 16, and 32 points, respectively.7
In this study, we evaluated CAV by using the Gensini scoring system. To the best of our knowledge, although it is thought to be a subform of CAD, a coronary scoring system has not been used to evaluate CAV. Our objective was to determine whether the Gensini score plays a role in CAV and whether it can be used to assess CAV severity with a goal to develop effective preventive measures against CAV in heart transplant recipients.
Materials and Methods
Between February 2003 and April 2018, 105 cardiac transplants were performed at our hospital. We retrospectively analyzed the clinical and angiographic data of all heart transplant patients undergoing routine coronary angiography posttransplant at the Department of Cardiology, University of Başkent (Ankara, Turkey), with clinical information obtained from our Nucleus Database. Our study was approved by the local ethics committee of our institution before study initiation, and protocols conformed to the ethical guidelines of the 1975 Helsinki Declaration.
The immunosuppression protocol followed the standard program for our hospital, which was developed when our center began heart transplant. Maintenance immunosuppressive therapy included calcineurin inhibitors, specifically sirolimus (8-10 ng/mL) or tacrolimus (9-14 ng/mL). All transplant recipients received standard therapy with mycophenolate mofetil and prednisone.
Coronary angiography was performed at year 1, with subsequent routine coronary angiograms performed annually. Early posttransplant angiograms (< 1 y) were not routinely performed. Coronary angioplasty was performed according to standard clinical practice by the femoral approach with a 6F or 7F catheter using the Judkins technique. All follow-up coronary angiographic studies posttransplant were classified retrospectively according to the Gensini score. Endomyocardial biopsy remains the criterion standard for identifying rejection. Right ventricular myocardial biopsies to evaluate humoral and cellular rejection were performed on all patients a minimum of every year. For standard clinical evaluations, we usually receive 4 or more samples of formalin-fixed tissue for light microscopy and 1 frozen sample for immunofluorescence. The International Society of Heart and Lung Transplantation (ISHLT) proposed a grading system based on a combination of angiographic findings and graft function defined by ultrasonography or invasive hemodynamic measurement to establish a uniform definition and staging allograft vasculopathy. Rating was as follows: CAV0 (no detectable angiographic lesions) = no vasculopathy; CAV1 (mild disease) = left main stenosis of < 50% or primary vessel stenosis of < 70% (including right coronary artery) or any branch stenosis of < 70% without graft dysfunction; CAV2 (moderate disease) = left main stenosis of < 50% or single primary vessel stenosis of > 70% or isolated branch stenosis of > 70% in 2 systems without graft dysfunction; and CAV3 (severe disease) = left main stenosis of ≥ 50% or stenosis of > 70% in 2 or more primary vessels or isolated branch stenosis of > 70% in 3 systems. A rating of CAV1 or CAV2 indicates severity of CAV and graft dysfunction.8 All biopsy specimens were graded for the presence of rejection in accordance with ISHLT standards by an experienced pathologist.
For patients with acute humoral rejection, our protocol was a 3-stage process. First, we administered therapeutic plasmapheresis to remove immunoglobulins and then administered intravenous immunoglobulin (0.4 g/kg/day). Finally, all patients received intravenous rituximab (375 mg/m2/day) followed by intravenous immunoglobulin treatment. Acute cellular rejection was classified by the ISHLT rating system at the onset of angiographically significant CAV in study patients posttransplant. An acute cellular rejection episode was defined as any event requiring treatment (ISHLT grade > 1R). Our standard protocol was pulse intravenous methylprednisolone at 500 mg administered daily for the first 3 days, followed by oral prednisolone by weight-appropriate dose.
Coronary artery disease scoring system
Cardiac allograft vasculopathy and the burden of plaque components were assessed by the Gensini score, which was calculated from the severity score of each coronary stenosis according to the degree of luminal narrowing and location (see illustration in Gensini5). To calculate the Gensini score, percent diameter of stenosis was scored from 0 to 32 depending on the severity of the stenosis: 1 point for ≤ 25% narrowing, 2 points for 26% to 50% narrowing, 4 points for 51% to 75% narrowing, 8 points for 76% to 90% narrowing, 16 points for 91% to 99% narrowing, and 32 points for total occlusion. Thereafter, each segment score was multiplied by a factor that considered the significance of the myocardial area supplied by that segment: 5 for the left main coronary artery; 2.5 for the proximal segment of the left anterior descending coronary artery; 2.5 for the proximal segment of the circumflex artery; 1.5 for the midsegment of the left anterior descending coronary artery; 1.0 for the right coronary artery, the distal segment of the left anterior descending coronary artery, the posterolateral artery, and the obtuse marginal artery; and 0.5 for other segments. The final Gensini score was calculated by summation of these scores.9 Mild CAV was classified as a Gensini score of ≤ 10, moderate CAV as score of > 10 and ≤ 40, and severe CAV as a score of > 40 in our study.10
Our single-center, retrospective, observational study included 105 heart transplant recipients. Our final analyses included 63 heart transplant recipients, with 19 patients excluded because of hyperacute rejection immediately after transplant, 16 patients excluded because they were less 18 years old, 3 patients excluded because they were under 18 years old and had hyperacute rejection, and 4 patients excluded because they died from malignancy. Clinical and demographic characteristics and angiographic Gensini scores of patients are listed in Table 1. Mean age was 40.4 ± 13 years, and 66% were males. Of 63 patients, 21 (33.3%) were diagnosed with CAV. Eight patients underwent percutaneous coronary intervention for CAV (all men). Biologic sex was an important factor for Gensini score; only 23.8% of patients with a high Gensini score were women. One patient, who used sirolimus, underwent coronary bypass grafting after coronary angiography procedure because of serious left main lesion. The prevalence of angiographic abnormalities increased posttransplant, but these abnormalities were mostly minor nonobstructive epicardial vessel edge irregularities. Of total study patients, 28.5% had diabetes mellitus and 30.1% had hypertension. Hyperlipidemia was commonly seen in cardiac transplant patients. Most patients received tacrolimus and prednisolone. A calcineurin inhibitor-based immunosuppressive therapy included mycophenolate mofetil as standard therapy. The second most commonly used immunosuppressive was sirolimus; because of the progressive deterioration in renal function, 8 patients switched to sirolimus. Other reasons for switching to sirolimus were progressive CAV, drug interactions, and side effects. Only 3 patients had received cyclosporine. Endomyocardial biopsies were performed for surveillance of acute cellular rejection; samples were graded per the 2005 ISHLT classification system.11 Acute cellular rejection was not detected in 24 patients. Of biopsy specimens showing rejection, 33% were mild (grade 1R). Grade 2R rejection was detected in 23.8% of patients, and 3 patients had grading of 3R. Furthermore, biopsy showed humoral rejection in 19 patients. Cardiac allograft vasculopathy was observed in 21 patients (33.3%) on coronary angiography; 42 patients (66.6%) were graded as CAV0 (no detectable angiographic lesions) according to ISHLT. Thirteen patients (20.6%) had echocardiographic allograft dysfunction (defined as left ventricular ejection fraction ≤ 45% with the presence of regional wall motion abnormalities). With regard to Gensini score, 42 patients (66.6%) had a score of 0. The highest score was calculated as 106.5, and mean score was 34.8 ± 26. Vasospasm (which regressed with nitroglycerine) was revealed in 5 patients. One had a coronary artery lesion in addition to vasospasm. Although 16% of patients had Gensini score of 0, 33.3% were using sirolimus; that is, CAV was found in more patients who used sirolimus. Among the 21 patients diagnosed with CAV, 8 (38%) were scored as having mild CAV (Gensini score ≤ 10), 6 (28.5%) were scored as having moderate CAV (Gensini score > 10 and ≤ 40), and 7 (33.3%) were scored as having severe CAV (Gensini score > 40).
Orthotopic heart transplant is an effective therapy for serious end-stage congestive heart failure. However, it is not a definitive cure and can cause various comorbidities like rejection, infection, solid-organ and hematologic malignancies, renal failure, and posttransplant CAD.3 Early posttransplant complications include acute rejection, acute allograft failure, and infections; late-stage complications are responsible for development of allograft CAD.12 It is still unclear whether the benefits seen in treatment of CAD are also available for CAV.13
Presently, the major problem of CAV is believed to be the manifestation of chronic rejection. Cardiac allograft vasculopathy, a unique and progressive pathologic process encountered in heart transplant patients, can limit long-term survival and is responsible for 32% of deaths after 5 years. According to the 2015 ISHLT report, CAV was detected in 8% of survivors within the first year, 30% by 5 years, and 50% by 10 years after heart transplant.14
The pathophysiology of CAV, although not completely understood, includes both immune- and nonimmune-mediated endothelial damage. It is characterized by concentric fibrous intimal hyperplasia along the length of coronary vessels. Autoimmunity has been accepted to play a major role in CAV. Previous studies have shown that immunologic factors such as histoincompatibility mismatch, acute rejection episodes, and chronic inflammation play significant roles in the development of CAV.15 Before heart transplant, patients receive a screening panel reactive antibody test to determine the potential presence of anti-HLA antibodies and to minimize the risk of antibody-mediated rejection. High panel reactive antibody titers greater than 10% are associated with increased graft rejection frequency and decreased survival.16
Denervation of the transplanted heart limits the usefulness of typical symptoms of coronary disease, such as angina; this can lead to more serious late clinical presentations, heart failure, and sudden death. Despite advances in immunosuppressive care regimens and strategies for the detection and treatment of cellular and antibody-mediated rejection, CAV remains a serious complication. In addition, its treatment and early diagnosis remain challenging. Percutaneous coronary intervention and coronary artery bypass grafting are associated with lower mortality in patients with treatable vessels; however, for selected patients with severe CAV, retransplant is still the best option.14
Despite many noninvasive modalities, coronary angiography is still the most commonly used diagnostic tool for CAV. Coronary angiography is recommended for CAV screening, and annual surveillance angiography is performed routinely in most centers like ours.17 However, angiography may have poor sensitivity as a screening test for the diagnosis of CAV. Therefore, the use of a coronary scoring system, detailed imaging of the vessel wall, plaque characterization, and evaluation of coronary vascularity seem to be a logical approach.
Current research remains focused on identifying the cause of CAV and developing treatment strategies to prevent or limit its extent. A quantitative assessment of atherosclerosis in heart transplant recipients is essential to better understand the pathophysiology of CAV and to develop optimal prevention strategies. Although the pathologic features of CAV are considered different from CAD, we used the Gensini score, which has been useful in evaluation of CAD, to determine the severity of CAV. To the best of our knowledge, no study so far has assessed CAV with any scoring system.
Evaluation of the severity of CAV, similar to CAD evaluation, using the Gensini score could be a useful auxiliary parameter. When we evaluated the severity of CAV in heart transplant recipients with angiographic Gensini score, we observed differences in CAD stages. Patients were divided into groups according to Gensini score severity, with those having 0 Gensini score not showing luminal stenosis in the coronary artery (therefore, non-CAD and non-CAV). The remaining patients were evaluated as mild, moderate, and severe. Only edge irregularities were detected in some patients. We suggest that this situation is an initial stage of CAV and that these patients require ongoing follow-up.
We found no relationship between the high Gensini score and rejection process (P < .001). Our study demonstrated that the angiographic CAD burden scoring system (Gensini) was strongly correlated with CAV severity and therefore may be used to provide a valid assessment of CAV burden in the clinic. Invasive coronary angiography is already the clinical criterion standard for diagnosis of CAD. It measures luminal diameter and compares the narrowing segments to normal reference diameters and previous angiograms.15
The Gensini score and coronary angiography can be easily used to evaluate CAV severity according to the degree and pattern of lumen stenosis. Interest in the use of coronary scoring systems such as the Gensini score continues to increase. Although overall outcomes of heart transplant have improved, CAV remains the primary cause of graft failure after the first year posttransplant. Retransplant is the only definitive treatment for CAV but is associated with lower survival and higher CAV recurrence. Because prevention of rejection and the best options for immunosuppression therapies after heart transplant are not yet clear, other supporting and therapeutic methods to reduce problems such as graft dysfunction and CAV are needed.
Volume : 18
Issue : 1
Pages : 99 - 104
DOI : 10.6002/ect.TOND-TDTD2019.P37
From the 1Department of Cardiology, Ankara Hospital, and the 2Department of
General Surgery, Ankara Hospital, Başkent University Faculty of Medicine,
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare.
Corresponding author: Emir Karaçağlar, Başkent University Hospital, Ankara, Turkey
Phone: +90 535 3441523 E-mail: firstname.lastname@example.org
Table 1. Clinical and Demographic Characteristics and Angiographic Gensini Score of Heart Transplant Recipients