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Eur J Cardiothorac Surg 2007;31:457-461. doi:10.1016/j.ejcts.2006.12.014
Copyright © 2007, European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved
a Department of Cardiothoracic Surgery, University of Tokyo, Tokyo, Japan
b Division of Cardiothoracic Surgery, University of Washington, Seattle, WA 98115, United States
c Department of Surgery, University of Washington, Seattle, WA 98115, United States
d Division of Cardiology, University of Washington, Seattle, WA 98115, United States
Received 16 August 2006; received in revised form 5 December 2006; accepted 7 December 2006.
* Corresponding author. Address: Division of Cardiothoracic Surgery, University of Washington, 1959 NE Pacific, Seattle, WA 98195, United States. (Email: csalerno{at}u.washingon.edu).
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Abstract |
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 Top Abstract 1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Key Words: Heart transplantation • Vascular disease • Mortality • CVA • Allograft coronary artery disease
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1. Introduction |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Updated review of selection criteria was recently published by Cimato and Jessup [3] in 2002. This summary described the most common recipient-dependent risk factors for mortality after HTx as PVR >3 Wood units, mechanical circulatory support (either with LVAD or intra-aortic balloon pump), advanced age, female gender, increased serum creatinine concentration, ischemic cardiomyopathy, previous sternotomy, and liver failure. The impact of vascular disease on transplant outcome was not mentioned in this review article. However, severe peripheral vascular disease is recognized as a major comorbidity that might preclude eligibility. The basis for this practice stems from the belief that vascular disease impacts negatively on both survival and quality of life, and that the risk factors of vascular disease increase the risk for the development of the allograft coronary artery disease [4]. Given these practices, we set out to further explore the relationship between vascular disease and outcome following HTx.
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2. Materials and methods |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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2.2 Data abstraction
The medical records of subjects undergoing transplantation at the University of Washington over the interval November 1985 to August 2004 were reviewed. We abstracted data pertaining to risk factors for adverse outcomes including age, gender, hypertension, hyperlipidemia, diabetes mellitus, and tobacco use, all of which are commonly cited as predisposing risks for the development of atherosclerosis. In addition, the presence of chronic obstructive pulmonary disease (COPD), renal dysfunction, alcohol abuse, cerebrovascular accident (CVA), and previous cardiac surgery were recorded.
2.3 Pre-transplant surveillance of vascular disease
Routine pre-transplant vascular evaluation included duplex ultrasound of carotid, lower extremity, renal artery, and abdominal aorta. CT angiogram of the aorta was added when clinically indicated. The severity of pre-transplant vasculopathy was scaled into three categories: severe and nontreatable, less severe (severe but treatable, moderate, and mild), and no vascular lesions. Patients were classified into these three categories on the basis of the clinical picture and the results of these surveillance studies. Severe and nontreatable vascular lesions were defined as morbidly symptomatic and anatomically significant lesions, which were not amenable for any endovascular or surgical revascularization therapy. Patients with these vascular lesions were considered to have a contraindication to HTx. Thus, this analysis focuses on a comparison of patients with less severe (severe but treatable, moderate, and mild) vascular disease (Group 1) and those with no vascular lesions (Group 2).
2.4 Follow-up
The subjects in this study were followed up until September 30, 2004. The majority of recipients have received follow-up at the University of Washington, with a relatively small number followed up at institutions with whom a close relationship existed such that both post-transplant care and follow-up are similar.
2.5 Outcomes of interest
The outcome measurements of the current study included death, development of CVA, and/or allograft coronary artery disease after HTx. The diagnosis of post-transplant CVA was established when recipients were found to have neurological deficit and/or radiological evidence of CVA either with ischemic and/or hemorrhagic stroke. No routine surveillance imaging study was performed.
Surveillance of allograft coronary artery disease was performed with dobutamine stress echocardiogram, stress cardiac nuclear perfusion scan, and/or coronary angiogram. A definitive diagnosis was made by coronary angiogram.
Development of new vascular disease after the transplantation was also compared between the groups.
2.6 Statistical methods and multivariate analyses
Means and standard deviations were calculated for continuous variables, and absolute and relative frequencies were measured for discrete variables. Differences between groups were examined for statistical significance by the t-test in the case of continuous variables (age) and by 
2 analysis in the case of discrete variables. Poisson regression was used to evaluate differences in outcomes (mortality, development of CVA, and/or allograft coronary artery disease) after adjusting for the confounders. Confounding variables were chosen for inclusion in the model by using a change in estimates approach. Briefly, if the addition of a variable to the model changed the estimate of the main effect by greater than 10%, then the variable was considered an important confounder and was kept in the model [5]. To explore the relationship between risk factors and time to death while accounting for follow-up time, we used a Cox proportional hazards model with a similar approach to the management of potential confounders. The effect of vascular disease on outcomes is presented as either relative rates or relative increases in the risk (or hazard in the case of survival analysis), along with its 95% confidence intervals.
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3. Results |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Group 1 included a total of 24 patients (6.0% of all recipients) with 25 pre-transplant vascular lesions. Fifteen of 25 lesions were treated with interventions prior to HTx. Three patients had aortic disease. One patient with an ascending aortic dissection and another with an abdominal aortic aneurysm (AAA) underwent repair prior to the HTx. Another patient with a 4.9 cm AAA that did not undergo repair ruptured 3 months after HTx. Carotid artery stenosis of more than 50% was detected in five patients, two of whom underwent carotid endarterectomy prior to HTx. One patient had a renal artery stent placed for renal artery hypertension. Peripheral vascular disease (PVD), defined as arterial disease in extremities, was detected in 16 patients. Twelve of PVD's were atherosclerotic peripheral vascular lesions. Seven patients with atherosclerotic PVD underwent bypass surgery and one patient underwent peripheral angioplasty with a stent placement prior to the HTx. One patient had thromboembolism at the femoral artery, which was treated with thrombectomy and fasciotomy. One patient had Berger's disease and underwent femorofemoral bypass surgery. Two patients suffered from traumatic peripheral vascular complications: one had common femoral artery stenosis from the placement of an intra-aortic balloon pump requiring a patch repair at the time of the HTx, and the other had a blunt trauma compromising vascular system resulting in below knee amputation.
Group 2 consisted of 384 recipients who were found to have no vascular disease in the pre-transplant screening.
3.2 Patient demographics
Table 1
shows the pre-transplant demographics of the two groups. Patients with vascular disease were significantly older, had a higher prevalence of tobacco and alcohol use, and were more likely to have hypertension, COPD, or prior cardiac surgery. Although hyperlipidemia was over-represented in Group 1, the difference in proportions did not achieve statistical significance.
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The diagnosis of allograft coronary artery disease was made in 6 patients in Group 1 and in 74 patients in Group 2 (25% vs 19%, p = 0.49). Using a similar approach, the adjusted odds ratio for allograft cad was 1.5 times greater (95% CI: 0.53–4.08) in Group 1 versus Group 2.
3.5 Development of new vascular disease after heart transplantation
Prevalence of development of a new vascular lesion was compared between the groups. Patients in Group 1 developed a total of 8 new lesions (33% of patients: 2 of thoracic aortic disease, 4 of AAA, 1 of renal artery stenosis, and 1 of PVD) as compared to a total of 27 patients in Group 2 (7.0% of patients: 2 of carotid artery stenosis, 2 of thoracic aortic disease, 8 of AAA, 2 of renal artery stenosis, and 13 of PVD). These numbers did not include the two patients in Group 1, who underwent vascular intervention due to progression of pre-transplant vascular disease.
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4. Discussion |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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Julia et al. [9] reviewed patients who underwent HTx in their unit between1984 and 1991, and found 17 patients (8.5%), who were diagnosed prior to HTx, to have systemic vascular disease. Their pre-transplant vascular workup consisted of duplex scanning of the cervical vessels, the aorta, and the lower limb arteries. This was one of the earliest studies addressing pre-transplant vascular disease and HTx, but it was only to advocate elevated cholesterol level as a risk factor for presence of vascular lesions in HTx recipients without assessing the effect of vascular disease on HTx outcomes. Ganesh et al. [10] recently reported risk factors for post-transplant mortality from the United Kingdom Cardiothoracic Transplant Audit database. The database included 1254 adult recipients, and Cox analysis identified recipient's PVD (definition not provided), along with donor age, organ ischemia time, recipient creatinine clearance, recipient diagnosis, ventilation, diabetes, and donor–recipient size mismatch, as a risk factor for early, late, or overall mortality (p < 0.10). Hazard ratios of PVD for early, late, and overall mortality were 3.30 (95% CI: 1.50–7.27, p = 0.03), 0.53 (95% CI: 0.07–3.81, p = 0.5), and 1.93 (95% CI: 0.94–3.95, p = NA), respectively. The focus of this study was, however, to address the effect of donor cause of death on post-transplant survival, and therefore, the detailed information on PVD was not reported.
The present study was one of the first studies that addressed the direct impact of recipient vascular disease on HTx outcomes. In our series, 6% of our recipients had vascular disease diagnosed prior to the HTx, and 60% of the vascular lesions were treated with intervention before the HTx. The demographics of the recipients who had systemic vascular disease were significantly different from those without. They were older, had ischemic cardiomyopathy as a cause of heart failure more commonly, and had more frequent history of smoking, hypertension, COPD, and prior heart operations. These findings support the existing concern that vasculopathic recipients are more likely to fail post-HTx. More importantly, we found that the recipient systemic vascular disease was a significant risk factor for post-transplant CVA. This was still significant after adjusting the confounding variables suggesting that vascular disease itself was an independent risk factor for CVA. Its presence was also associated with somewhat higher risk of mortality and allograft coronary artery disease, although this was not statistically significant.
The strong relationship between development of AAA and HTx has been well described in the literature [11,12]. It is also well known that patients with PVD have a higher incidence of AAA [13,14]. In our series, six recipients in the cohort group developed AAA including two cases diagnosed before HTx (25% of the cohort patients). The incidence of AAA in nonvasculopathic recipients was 2.1% (eight cases in Group 2). The combination of HTx and pre-transplant vascular disease might have exacerbated the predisposing risk of development of post-transplant AAA.
Our study has several limitations. First, the number of the cohort was small. Our series included a total of only 23 recipients with vascular disease among 402 recipients. The actual number of outcomes of interest in the cohort group was small. This might explain the reason why the detrimental effect of pre-transplant vascular disease on HTx did not reach statistical significance in our study.
Second, our current practice does not have objective algorism to classify the severity of the vascular disease of the transplant candidates. We determined the severity based on the results of the vascular studies as well as on patient's clinical picture. The severe vascular lesions not amenable to interventional treatment were considered contraindication to the HTx, and transplant candidates with these lesions were excluded from the transplant waiting list. The lack of precise definition of the severity makes the interpretation of the current study more difficult and confusing.
In conclusion, this study was a first attempt to evaluate the effect of vascular disease on HTx. It showed that recipient vascular disease was associated with higher incidence of risk factors, and appeared to result in worse outcomes. These results provide clinical information, and support the current practice of recipient selection based on the severity of the vascular disease. It is, however, too premature to retrieve a solid conclusion from the study due to small number of patients as well as lack of objective definition of the severity of vascular disease. A larger scale study using multicenter or nationwide database is necessary to further evaluate this important subject.
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Footnotes |
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References |
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TopAbstract1. Introduction2. Materials and methods3. Results4. DiscussionReferences |
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