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(Chest. 1999;116:874-879.)
© 1999 American College of Chest Physicians

Coronary Artery Disease in Potential Lung Transplant Recipients > 50 Years Old*

The Role of Coronary Intervention

Gregory I. Snell, FRACP; Meroula Richardson, FRACP; Anne P. Griffiths, RN; Trevor J. Williams, FRACP and Donald S. Esmore, FRACS

* From the Lung and Heart Transplant Service, Alfred Hospital, Prahran, 3181, Victoria, Australia.

Correspondence to: Gregory I. Snell, MBBS, Lung and Heart Transplant Service, Alfred Hospital, Prahran, 3181, Victoria, Australia


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objectives: To review the experience of the Alfred Hospital in the systematic assessment of coronary artery disease (CAD) using coronary angiography (CA), and the subsequent management of CAD, in potential lung transplant recipients.

Design: Retrospective study.

Setting: The Alfred Hospital Lung and Heart Transplant Service.

Patients: CAD risk factors were sought in potential recipients of lung transplantation (LTx) who were > 50 years old, including a history of smoking, male gender, hypertension, diabetes, hypercholesterolemia, angina, and a family history of CAD. When feasible, and in the presence of more than one cardiac risk factor, CA was performed.

Results: From 243 referral patients who were > 50 years old, 97 were listed for LTx, and 77 underwent LTx. Four patients were refused LTx on the basis of CAD. Of 101 patients undergoing a detailed cardiac assessment for LTx, 83 had smoked, 56 were male, 48 had hypercholesterolemia, 22 had hypertension, 4 had diabetes, and 3 had a history consistent with angina. Eighty-five patients underwent CA. In 32 cases, CA revealed CAD, and half of these cases were significant stenoses. Eight patients who were assessed required intervention. Five patients of this group have been transplanted; of these, three patients underwent coronary artery grafting at the time of LTx, and two patients underwent preoperative angioplasty or stenting. Only one of these five patients died < 90 days postoperatively.

Conclusion: Significant CAD is a common finding in older patients who are presenting for LTx. Coronary revascularization for severe large vessel stenoses can allow safe LTx. CAD risk factors may predict who should undergo CA, but further studies of clinical and noninvasive assessments of CAD are needed if CA is to be safely avoided in patients at low risk of CAD.

Key Words: coronary artery disease • coronary angiography • lung transplantation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Many patients with end-stage lung disease who are referred for lung transplantation (LTx) have a history of smoking. In association with the other common cardiac risk factors (male gender, hypercholesterolemia, diabetes, hypertension, family history of cardiac disease, and age), a significant incidence of coronary artery disease (CAD) is not a surprising finding in this population.1 2

Traditionally, the presence of significant CAD would exclude a patient from LTx, or it would mandate the consideration of combined heart-lung transplantation. Most transplant centers limit LTx to patients who have advanced pulmonary disease but do not have significant comorbidities that may complicate or limit survival after transplantation.3 4 Despite this, the International Lung Transplant Registry describes a 5% mortality in lung transplant recipients due to CAD, and a 3% risk of unexplained sudden death, to which CAD may well be a significant contributor.5 Consequently, investigations to determine the presence of significant CAD must be considered part of the routine workup of a potential transplant candidate.

Coronary angiography (CA) is the definitive investigation to exclude significant CAD, but the procedure is invasive and relatively costly, both in terms of dollars and patient morbidity. As a result, the routine use of CA as a screening tool in the pretransplant setting has recently been challenged.1 However, the detection of CAD using noninvasive means may be inadequate to exclude significant disease in this patient group. Exercise testing is of little value in patients whose exertion tolerance is limited by pulmonary disease.2 Dipyridamole scanning cannot be used in the presence of theophylline therapy, and dobutamine thallium scanning has limited specificity and unknown sensitivity in this patient population.6

There is limited data regarding preoperative interventions for significant CAD in potential LTx recipients.1 2 7 There are no published reports of LTx and coronary artery bypass surgery being performed simultaneously, although a combined procedure may be technically feasible with acceptable morbidity and mortality.

This study reviews our experience with the systematic assessment of CAD with CA in potential LTx recipients, and its subsequent management.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
An assessment protocol for CAD was followed for all potential lung transplant candidates > 50 years old who referred to the Alfred Hospital Lung and Heart Transplant Service between December 1989 and August 1997. This protocol included an evaluation for known CAD risk factors, such as smoking, male gender, hypertension, diabetes, hypercholesterolemia (defined as a fasting level > 6 mmol/L), angina, or a history of ischemic heart disease in a first-degree relative.

All patients underwent CA unless specific circumstances rendered the procedure unfeasible or unnecessary. CA (being the most invasive procedure) was usually the last investigation prior to the final consideration of listing a patient for transplant . Left heart catheterization was performed via the standard percutaneous femoral approach, and selective angiography was undertaken with multiple cineangiographic views. A significant coronary lesion was defined as a stenosis of >= 50% in any major epicardial vessel. Significant coronary lesions of uncertain clinical relevance were further assessed using dobutamine thallium imaging to ascertain the extent of myocardium at risk of ischemia. In a small number of cases, the risk of significant CAD was considered to be low, and dobutamine thallium scanning was performed as the initial investigation.

When the presence of a significant coronary lesion had the potential to compromise a patient's perioperative clinical outcome (in an otherwise-appropriate LTx candidate), revascularization was planned. Elective coronary angioplasty, with or without coronary artery stenting, was performed pretransplant. If coronary stenoses were not amenable to angioplasty, coronary artery grafting was planned simultaneously with allograft implantation. The continued patency of arteries that were subjected to angioplasty or stenting was aided by antiplatelet therapy (aspirin, plus ticlopidine for stented arteries). The patency of the angioplastied vessel was reassessed using repeat CA 4 months after the initial procedure.

When a single lung transplant was required, the procedure was performed through a midline sternotomy, the standard incision for coronary artery bypass surgery. Through this incision, right single LTx can be performed in the majority of patients without having to utilize a cardiopulmonary bypass (CPB) procedure. Left single LTx through a midline incision was avoided in the CAD patients, as it would mandate the use of CPB in conjunction with a significant manipulation of the heart.

In general, coronary revascularization was performed initially and was followed by right pulmonary allograft implantation.8 9 10 The primary aim was to stabilize the cardiac anatomy prior to subsequent lung implantation. The secondary aim was to avoid exposing the newly implanted lung to CPB, because of concerns of exacerbating or precipitating early graft dysfunction or reperfusion injury. As per standard practice, a left internal mammary artery graft was applied to a stenosed left anterior descending coronary artery, and saphenous vein grafts (SVGs) were applied to other arteries requiring revascularization.10

A myocardial ischemic event was defined as the presence of ischemic ECG abnormalities coexistent with anginal chest pain or the elevation of myocardial creatine kinase > 100 IU/L. Significant ECG changes include localized ST-segment changes and/or the development of Q waves.

The results are presented as mean values ± SD for continuous data. The comparison of continuous data between patient groups was performed with an unpaired t test, and in the case of categorical data, by the use of {chi}2 analysis and Fisher's Exact Test where applicable.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Two hundred forty-three patients >= 50 years old were referred to the Alfred Hospital Lung and Heart Transplant Service for possible LTx (Fig 1 ). Ninety-seven patients were listed for LTx, and 77 patients were subsequently transplanted.



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  		Figure 1. A breakdown of the outcomes of 243 LTx referral patients aged > 50 years old.

 
One hundred forty-six patients were not listed for LTx. The reasons for nonacceptance were many and varied, and four patients were rejected primarily for cardiac-related reasons. One of these four patients had CAD with attendant poor left ventricular function (nuclear gated blood pool scan ejection fraction < 40%), and three patients had significant diffuse CAD that was not amenable to revascularization.

The demographics of the 101 patients > 50 years old who underwent cardiac assessment with the intention to proceed with LTx are shown in Table 1 . Sixty-four patients (65%) were subsequently listed for single lung transplantation for emphysema. The risk factors for CAD, apart from advanced age, were present in 94 patients: 83 had smoked, 56 were males, 48 had hypercholesterolemia, 22 had hypertension, 4 had diabetes, and 3 had a history of chest pain consistent with angina. One third of the patients had >= 3 risk factors.


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  		Table 1. Demographics of Patients Accepted for LTx*

 
Eighty-five of 101 patients (85%) > 50 years old who were otherwise acceptable for LTx underwent CA. Sixteen patients had significant CAD. In 12 of these patients, significant findings in CA required intervention, and these cases are detailed in Table 2 . Of the 16 patients who did not undergo CA, all but one had negative results on a dobutamine thallium study.


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  		Table 2. Coronary Angiographic Findings and Cardiac Interventions Planned for Significant CAD Found on CA*

 
The latter patient, a 50-year-old male ex-smoker with scleroderma-related pulmonary hypertension (PHT), had originally been assessed at age 48 for heart-lung transplantation (and therefore did not undergo CA). However, with an acute deterioration in the patient's condition, with the newly described technique of bilateral single LTx, and with the availability of a double lung allograft, LTx was performed without further CAD screening. Unfortunately, despite an unremarkable intraoperative course, the patient suffered an acute anterior myocardial infarct and died 1 h after LTx. Extensive large vessel CAD was confirmed at postmortem.

Thirty-two patients (32%) had CA-proven CAD, although in 16 cases the disease was not considered clinically or angiographically significant and no intervention was planned.

Of the 16 patients with preoperatively demonstrated significant CAD, 8 patients were considered appropriate for intervention (Table 2) . All 8 had normal left ventricular function. As shown, two patients had preoperative procedures without complications, and repeat CA 16 weeks later demonstrated patent vessels in both patients. For six patients, simultaneous revascularization and LTx were planned. This combination has been performed in three patients. One patient with significant CAD died while on the waiting list, and two patients continue to await LTx. Eight patients had angiographically significant stenoses, but were not operated on because the area at risk was perceived to be noncritical. These lesions tended to be single vessel, distal, with < 70% occlusive lesions, and they had negative results on dobutamine thallium test.

The technique used for coronary artery bypass grafting varied a little, depending on the surgeon and on time considerations. Patient 8 had coronary grafts performed prior to pneumonectomy. Technical difficulties led to the reinstitution of CPB to perform the LTx, for a total CPB time of 154 min. Patient 9 had a single vein graft performed (CPB time of 28 min) after the LTx. Patient 10 had a single vein graft performed first, with a CPB time of 51 min. After the subsequent bilateral LTx, inferior ECG changes and a decrease in cardiac output resulted in the temporary insertion of an intra-aortic balloon pump. Early pulmonary allograft function was satisfactory in all cases.

The relation of risk factor assessment and the presence of CA evidence of CAD is shown in Figure 2 . The subgroup with significant CAD has been identified separately. Three patients were included with a history consistent with angina. One of the latter group had normal results on CA, one had diffuse inoperable disease (patient 4), and one was accepted for LTx and simultaneous coronary grafting (patient 6). Of those patients undergoing dobutamine thallium testing, eight potential recipients had one cardiac risk factor, and three potential recipients had two risk factors (male and ex-smoker).



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  		Figure 2. The relation of risk-factor assessment and the presence of CA evidence of CAD. Significant CAD was defined as a stenosis of >= 50% in any major epicardial vessel.

 
A comparison of patients with and without CAD is shown in Table 3 . The average waiting time for transplant in the CAD subgroup compares favorably with our total transplant experience. Male gender and interstitial lung disease (as the indication for LTx) are overrepresented in the group requiring intervention (p < 0.05). There was a trend to longer ICU stays for patients with coronary grafts (n = 3; 2, 43, and 75 days, respectively; mean, 30.8 days; median, 43 days) or with any coronary intervention (n = 5; 2, 5, 8, 43, and 75 days, respectively; mean, 23.0 days; median, 6.5 days), when compared to patients having no coronary intervention (n = 72; mean, 7.5 days; median, 3.0 days). The relative importance of associated risk factors for CAD is shown in Table 4 .


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  		Table 3. Comparison of Patients With and Without CAD, Including Subgroups Requiring Intervention*

 

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  		Table 4. Sensitivity, Specificity and Predictive Value for CAD of Different Risk Factors*

 
Five patients died on the waiting list (four patients with diffuse interstitial lung disease [DILD], and one patient with PHT), including patient 7 (Table 2) , who would have required coronary artery bypass grafts. No deaths in this group were directly cardiac related. Fifteen patients remain on the waiting list for LTx. No cardiac ischemic events were noted following LTx in any patient, other than in the previously cited case.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This series documents a clinically relevant incidence of CAD of 17% in those patients > 50 years old who are being considered for LTx. With appropriate interventions, which may include coronary artery grafting in some cases, LTx can be safely and practicably performed in a group of patients who might otherwise be excluded from lung transplantation or face an unacceptably high risk of cardiac-related morbidity and mortality.

Our protocol mandates CA as the definitive investigation for the vast majority of those individuals who have been accepted for LTx. Some of our low-risk patients underwent dobutamine thallium scanning alone, and this may slightly underestimate the presence of CAD in our population.6 11 Leibowitz et al1 describe an incidence of significant CAD of 12% in a similar patient population, although the incidence of other known cardiac risk factors is higher in our study cohort. Thaik et al2 looked at a younger (mean age, 49 years old) and female-gender biased population, and recorded a 4% incidence of significant CAD in patients who were asymptomatic, and a 66% incidence of significant CAD in patients with symptomatic CAD.

If careful and objective assessment is not undertaken, serious cardiovascular complications can follow, as described above, where one patient died postoperatively of myocardial infarction. Late cardiac morbidity and mortality after LTx may be less clear cut.5 Leibowitz et al1 used CA evidence of CAD as the main reason not to list 6.5% of assessed patients, although no interventions were undertaken. Thaik et al2 used CA to guide angioplasty in two patients; in one of these patients, a restenosis occurred preoperatively, and another patient with known abnormal cardiac anatomy died of a noncardiac cause while on a waiting list for LTx. Despite these events, this group2 believed that CA findings did not preclude LTx in any of their patients. Both groups1 2 have not described perioperative follow-up on more than a small number of evaluated LTx recipients.

The risks of performing CA and any subsequent intervention need to also be considered. Although the risk of serious complications is low, angioplasty or stenting can lead to acute myocardial infarction in a patient who may not tolerate emergency coronary artery bypass surgery. Elective coronary grafting, separate from the LTx procedure, is also a high-risk strategy.7 Coronary grafting at the time of LTx may delay the transplant, either because of the need for extra technical expertise, or because the procedure itself would be prolonged. The pulmonary allograft is prone to early graft dysfunction, and CPB may exacerbate this.12 It is clear that any intervention involving the coronary arteries should be objectively directed by the extent and severity of disease, the available surgical expertise, and the general condition of the potential LTx recipient.

There is no data on long-term patency of grafts, stents, or angioplastied vessels after LTx. Steroids and cyclosporine may contribute to hyperlipidemia and accelerated atherosclerotic vascular disease after solid organ transplantation, variables that may be additive to any underlying cardiac risk factors.13 Following an intervention, restenosis may theoretically occur at a higher rate than in a nontransplant cohort, suggesting that internal mammary grafts may be preferable to SVGs. Despite this, hyperlipidemia seems a relatively benign condition in terms of adverse clinical sequelae in the general LTx population.14

The risk factors for CAD from our analysis (male gender, smoking history, hypertension, diabetes, and prior ischemic pain) are relatively easily assessed from the patient's history. The weighting of the different risk factors varies a little, as evidenced in Table 4 . Diabetes and ischemic chest pain have the highest positive predictive values (PPVs), and smoking history and hypercholesterolemia have the lowest PPVs. With four or more risk factors, CAD becomes very common and is always significant (Fig 2) . However, our data suggests that the presence of less than three risk factors still correlates with an 11% risk of significant CAD. A risk-factor analysis is therefore useful in describing the features of a population, but it does not allow a noninvasive means of accurately predicting CAD for any single individual. These findings are similar to those of Thaik et al,2 who constructed a point score of up to 7 points and found a relationship with CA-demonstrated CAD. The weighting of their point scale is questionable. The scale included single points for ECG or echocardiographic abnormalities (however, these correlated poorly with the incidence of CA disease), and yet the presence of both diabetes and hyperlipidemia represented only 1 point.

Although it is important to define flow-limiting coronary stenoses prior to LTx, the absence of a stenosis > 50% may not guarantee an uncomplicated cardiac course after LTx. Lesser levels of CAD can still lead to myocardial infarction via superimposed thrombus on relatively minor coronary atheromatous plaque.

In conclusion, significant CAD is not an uncommon finding in patients presenting for LTx assessment. Coronary revascularization for severe large vessel stenoses can allow individuals with CAD to safely undergo LTx (or at least to avoid combined heart-lung transplantation) when it would traditionally be contraindicated. However, cardiac intervention does complicate perioperative LTx management (thereby potentially lengthening intensive care stay), and long-term patency is unknown. Coronary risk factors have clinically useful predictive powers to indicate which patients should undergo CA. However, further studies are required to delineate the accuracy of clinical assessment and noninvasive investigations if CA is to be safely avoided in patients at low risk of CAD.


   Footnotes
 
Abbreviations: CA = coronary angiography; CAD = coronary artery disease; CPB = cardiopulmonary bypass; DILD = diffuse interstitial lung disease; LTx = lung transplantation; PHT = pulmonary hypertension; PPV = positive predictive value; SVG = saphenous vein graft

Received for publication October 1, 1998. Accepted for publication April 1, 1998.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Leibowitz, DW, Caputo, AL, Shapiro, GC, et al (1994) Coronary angiography in smokers undergoing evaluation for lung transplantation: is routine use justified? J Heart Lung Transplant 13,701-703[ISI][Medline]
  2. Thaik, CM, Semigran, MJ, Ginns, L, et al (1995) Evaluation of ischemic heart disease in potential lung transplant recipients. J Heart Lung Transplant 14,257-266[ISI][Medline]
  3. Marshall, SG, Cramer, MR, Lewiston, NJ (1990) Selection and evaluation of recipients for heart-lung and lung transplantation. Chest 98,1988-1994
  4. Smith, C (1997) Patient selection, evaluation, and preoperative management for lung transplant candidates. Clin Chest Med 18,183-197[CrossRef][ISI][Medline]
  5. St. Louis International Lung Transplant Registry Report. St. Louis, MO: Washington University School of Medicine, April 1997
  6. Henzlova, MJ, Padilla, ML, Freilich, A, et al (1995) Dobutamine thallium 201 perfusion imaging in candidates for lung transplantation. J Heart Lung Transplant 14,251-256[ISI][Medline]
  7. La Francesca, S, Shennib, H (1995) Coronary artery revascularisation followed by single-lung transplantation in a patient with combined idiopathic pulmonary fibrosis and left main coronary artery stenosis. Texas Heart Inst J 22,189-191[Medline]
  8. Esmore, DS, Brown, R, Buckland, M, et al (1994) Techniques and results in bilateral sequential single lung transplantation. J Card Surg 9,1-14[ISI][Medline]
  9. Cooper, JD, Pearson, FG, Patterson, GA (1987) Technique of successful lung transplantation in humans. J Thorac Cardiovasc Surg 93,173-181[Abstract]
  10. Kirklin, JW, Barratt-Boyes, BG (1993) Stenotic arteriosclerotic coronary artery disease. Cardiac surgery 2nd ed. ,285 Churchill Livingstone New York, NY.
  11. Pennell, DJ, Underwood, RS, Swanton, RH, et al (1991) Dobutamine thallium myocardial perfusion tomography. J Am Coll Cardiol 118,1471-1479
  12. De Hoyos, A, De Majo, W, Winton, T, et al (1993) Preparative predictors for cardiopulmonary bypass in lung transplantation. J Thorac Cardiovasc Surg 106,787-796[Abstract]
  13. Kuster, GM, Drexel, H, Bleisch, JA, et al (1994) Relation of cyclosporine blood levels to adverse effects on lipoproteins. Transplantation 57,1479-1483[ISI][Medline]
  14. Kesten, S, Mayne, L, Scavuzzo, M, et al (1997) Lack of left ventricular dysfunction associated with sustained exposure to hyperlipidemia following lung transplantation. Chest 112,931-936[Abstract/Free Full Text]



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