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In patients who have undergone a heart transplant, the major cause of death is coronary artery disease (CAD). The etiology of cardiac-allograft vasculopathy is thought to be multifactorial, but due in large part to immune mechanisms that cause elevations in serum cholesterol levels. The dextran sulfate cellulose low-density lipoprotein (LDL) adsorption (DSA) apheresis procedure has been shown to reduce lipoprotein levels and markers of blood rheology to improve coronary perfusion to the transplanted heart. We report the first described case of the stabilization and reversal of progressive transplant CAD with DSA. We followed a 50-year-old male orthotopic heart transplant recipient with familial hyperlipidemia refractory to lipid lowering therapy with bi-weekly LDL-apheresis (DSA system) for 12 months. Quarterly pre- and post-apheresis blood investigations were obtained, as well as annual adenosine thallium (AT) studies. Creatinine kinase (CPK), creatinine, LDL, fibrinogen, and lipoprotein (a) were reduced by 70%, 26%, 23%, 47%, and 47%, respectively. AT before the initiation of apheresis revealed a small to medium sized, partially reversible perfusion defect in the anterolateral and inferoapical walls, with an ejection fraction (EF) of 49%, elevated left ventricular volume (171 mL), and an elevated pulmonary-to-myocardial (PMR) count ratio of 0.67 (normal <0.52). After 12 months of LDL apheresis with DSA, a repeat AT demonstrated no fixed or reversible perfusion abnormality, an EF of 51%, and the PMR had normalized (0.46). This is the first reported case demonstrating that in a heart transplant survivor with hyperlipidemia and progression of coronary artery disease, LDL apheresis with DSA therapy can lead to regression and is an effective treatment of post-transplant coronary disease.
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- CASE REPORT
Our patient is a 50-year-old male with familial hyperlipidemia (FH) refractory to lipid lowering therapy, hypertension, and sleep apnea. He underwent an orthotopic heart transplant in 1989 for idiopathic dilated cardiomyopathy that had deteriorated to class IV functional status causing him recurrent hospitalizations. Subsequently, he developed carotid sinus hypersensitivity with a cardioinhibitory response in the transplanted heart and was treated with a dual chamber permanent pacemaker. He could not tolerate lipid lowering therapy secondary to myalgias and elevated creatinine kinase (CPK) levels.
Heart catheterization in January 2003 revealed normal coronary arteries and normal left ventricular systolic function. He was followed subsequently over many years with adenosine thallium studies (ADAC/Philips dual head nuclear camera; Philips, MA, USA) to assess for progression of transplant coronary artery disease. A study from January 2, 2007, demonstrated a small-to-medium sized partially reversible perfusion defect in the anterolateral and inferoapical walls with preserved viability. During this time he was also found to have a mildly reduced ejection fraction (EF) of 49% with an elevated left ventricular volume (LVV) (171 mL) and an elevated pulmonary-to-myocardial (PMR) count ratio of 0.67 (normal <0.52) (Fig. 1A). At this time the patient's risk factors for the development of coronary artery disease included diabetes mellitus (HbA1c = 5.9%) controlled with oral medical therapy, hyperlipidemia, and hypertension. His cardiovascular medications included aspirin, atenolol, hydrochlorothiazide, rosuvastatin at a very low dose due to the patient's intolerance (5 mg po weekly), and ezetimibe. His immunosuppressants included cyclosporine, cellcept, and low-dose prednisolone.
Figure 1. (A) Adenosine thallium from January 2007 demonstrating a small to medium sized partially reversible perfusion defect in the anterolateral and inferoapical walls with preserved viability. (The thin arrow indicates the anterolateral defect and the thick arrow indicates the inferoapical defect); (B) Adenosine Thallium six months after treatment initiation with DSA apheresis. It demonstrates a mild to moderate intensity reversible perfusion defect involving the inferior segments from apex to base with a mild reversible perfusion defect extending into the basal inferolateral segments, suggesting ischemia in the right coronary artery territory with retained viability. (This is indicated by the thick arrow). (The prior anterolateral perfusion abnormality was not seen); (C) Adenosine Thallium one year after the initiation of LDL-apheresis treatment with DSA. It demonstrates resolution of perfusion abnormalities.
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After qualifying for treatment the patient initiated bi-monthly low-density lipoprotein (LDL)-apheresis on February 1, 2007. Six months later (7/12/07) he had a follow-up adenosine thallium test which demonstrated a mild-to-moderate intensity reversible perfusion defect involving the inferior segments from the apex to the base with a mild reversible perfusion defect extending into the basal inferolateral segments, suggesting ischemia in the right coronary artery territory with retained viability. There was subtle basal-to-mid inferior wall motion abnormality. The EF was noted to be 50% with increased lung uptake. The prior anterolateral perfusion abnormality was not seen (Fig. 1B). His risk factors for coronary disease had not changed, and his only medication change was the cessation of rosuvastatin.
After an additional six months of apheresis treatment with the dextran sulfate cellulose LDL adsorption (DSA) system, a repeat thallium study was obtained (1/11/08). The test demonstrated no fixed or reversible perfusion abnormality, a left ventricular systolic function of 51%, and no regional wall motion abnormalities. The pulmonary-to-myocardial count ratio (0.46) and left ventricular volume (161 mL) had normalized (Fig. 1C). The patient's risk factors again had not changed and his only medication change was the cessation of ezetimibe.
Measurements of the following markers obtained pre- and post-treatment also demonstrated significant improvement with LDL apheresis DSA treatment. Creatinine kinase decreased by 70% (907 ng/mL to 275 ng/mL). Creatinine was reduced by 26% (1.9 mg/dL to 1.4 mg/dL). LDL had a 23% reduction (231 mg/dL to 177 mg/dL). Fibrinogen decreased by 47% (359 mg/dL to 190 mg/dL). Lipoprotein (a) (Lp (a)) reduced by 47% (17 mg/dL to 9 mg/dL). These results were obtained on a DXC800machine (Beckman Coulter, CA, USA) (Table 1).
Table 1. Comparison of labs immediately pre and post-apheresis
| ||Pre- apheresis||Post- apheresis||% Change|
|Creatinine kinase (ng/mL)||907||275||70|
|Low-density lipoprotein (mg/dL)||231||177||23|
|Lipoprotein (a) (mg/dL)||17||9||47|
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- CASE REPORT
This is the first case report describing the stabilization and reversal of progressive transplant coronary artery disease (CAD) demonstrated by adenosine thallium with the DSA apheresis procedure. An extensive literature review failed to identify any similar cases with the DSA.
The DSA apheresis procedure has been shown in long-term studies to reduce lipoprotein levels and markers of blood rheology to improve coronary perfusion to the transplanted heart. The DSA system separates heparinized plasma with a polysulfone plasmafilter. The plasma is exposed to a dextran sulfate cellulose filter which absorbs the LDL cholesterol. The machine contains two filters: after 500 mL of plasma has passed through the first filter, it is regenerated using a rinsing solution of 4.1% sodium chloride; during the rinsing process the plasma flow is redirected to the second filter. Due to the double filtration and rinsing process there is potentially no limit to the amount of LDL cholesterol adsorbed from the plasma.
The DSA system lowers fibrinogen levels by 15–20% (1). The DSA system also lowers several pro-inflammatory markers, such as monocyte chemotactic protein-1 (MCP-1) and matrix metallopeptidase 9 (MMP-9), by 20%, tissue inhibitor of metalloproteinase 1 (TIMP-1) by 30%, endothelin-1 (ET-1) by 75%, vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) by 10%, and oxidized LDL and C-reactive protein (CRP) by 65%(1).
The etiology of cardiac-allograft vasculopathy is thought to be multifactorial, but due in large part to immune mechanisms that cause elevations in serum cholesterol levels. Complications such as hyperlipidemia, rejection crisis, and hypertension accelerate atherosclerosis in comparison to the general population (2). An elevated serum concentration of Lp (a), irrespective of other factors, is an independent risk factor for the development of accelerated CAD among patients with a cardiac transplant (CTX) (3).
Graft atherosclerosis is a proliferative disease of the arterial intima with fast progression. The pathogenesis of the disease is thought to be due to three main factors: (i) multiple rejection episodes of the graft associated with infiltration of T lymphocytes into the intima; (ii) elevated plasma fibrinogen, which is chemotactic for smooth muscle cells and increases smooth muscle cell proliferation, also increases blood and plasma viscosity as well as erythrocyte aggregation—this may have an impact on hemorheology and microcirculation in the graft tissue (4); and (iii) elevated plasma LDL-cholesterol, which induces the development of atheromas with the accumulation of monoctye-derived macrophages (4).
LDL apheresis could improve coronary perfusion and therefore reduce the chronic ischemia of the myocardium of the transplanted heart (5). A study by Park et al. of CTX patients with cardiac allograft vasculopathy (CAV) found significant increases in the mean luminal diameter following LDL apheresis (6). Another study identified that CTX patients with CAV receiving LDL apheresis increased their intramuscular (anterior tibial) partial pressure (pO2) by >150%, values similar to those found in healthy subjects (7). Jaeger et al. studied CTX patients with graft vessel disease and demonstrated that in patients on lipid lowering therapy, the addition of weekly heparin extracorporeal LDL/fibrinogen precipitation (HELP) apheresis significantly reduced vessel disease when compared to medication alone (8). In another study by Jaeger et al. the combination of lipid lowering therapy and HELP apheresis allowed simultaneous and drastic reductions of LDL, Lp (a), and fibrinogen blood levels, and significantly prevented graft vessel disease (9). Our study does not underestimate the described benefits of HELP apheresis in the prevention of graft vessel disease. We hope to provide an alternative therapy to this patient population.