Cardiology

Screening and Treating Transplant Coronary Artery Disease

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I. Coronary Allograft Vasculopathy: what every physician needs to know

Cardiac allograft vasculopathy (CAV), also known as transplant coronary artery disease and cardiac transplant vasculopathy, is characterized by diffuse intimal thickening and luminal narrowing in the arteries of the allograft. It may affect the epicardial coronary arteries as well as the microcirculation. It is the second most prevalent cause of death after malignancy in heart transplant patients after the first year post-transplant.

Approximately 32% of patients have angiographic CAV at 5 years, and 53% by 10 years post-transplant, with the incidence increasing over time. The disease is believed to be predominantly immune-mediated and represents a form of chronic allograft rejection, but several nonimmunologic factors may contribute to its progression, including hypertension, diabetes, hyperlipidemia, and smoking.

The diagnosis of CAV is challenging due to cardiac denervation and the diffuse nature of the disease. CAV is diagnosed by coronary angiography when the diameter of the stenosis is greater than 50% of a reference vessel diameter. Intravascular ultrasound during invasive angiography is the most sensitive method for detection of CAV, and progressive intimal thickening in the first post-transplant year identifies patients at high risk for future cardiovascular events. The management of CAV includes use of improved immunosuppressive drugs, statins, and, in select patients, coronary revascularization. The only definitive long-term treatment for advanced CAV is re-transplantation.

II. Diagnostic confirmation: are you sure your patient has CAV?

Early CAV is clinically silent, and ischemia is usually not evident until the disease is far advanced. In general, non-invasive methods cannot detect early disease due to its diffuse nature of CAV and the absence of flow-limiting coronary lesions. Invasive coronary angiography is required to definitively diagnose CAV. Intravascular ultrasound is a useful adjunct to confirm the presence of CAV during invasive coronary angiography.

A. History part I: pattern recognition

CAV is difficult to diagnose based upon clinical evaluation, as symptoms of CAV usually appear when the disease is far advanced. Due to the lack of early clinical symptoms, patients with CAV typically present late with silent myocardial infarction, loss of allograft function, or sudden death.

As cardiac transplant recipients have both afferent and efferent denervation, patients with CAV seldom experience classic angina pectoris. However, rarely a patient develops reinnervation and experiences angina as the presenting symptom. Other symptoms of CAV may be like those of heart failure and include excessive fatigue, peripheral edema, and shortness of breath. Palpitations associated with arrhythmias may also occur as a manifestation of advanced CAV. Premonitory symptoms are often missing or atypical, and hence it is important to identify asymptomatic patients early by screening studies.

B. History part 2: prevalence

Some angiographic evidence of transplant vasculopathy is seen in 30%-50% of heart transplant recipients by 5 years. In the 2013 International Society of Heart and Lung Transplantation (ISHLT) registry report, the prevalence of CAV in heart transplant recipients was 20% at 3 years, 30% at 5 years, and 45% at 8 years post-transplant. The proportion of deaths confirmed to be caused by CAV in the report was 10% between 1 and 3 years post-transplant, with further increases in subsequent years. IVUS has been shown to detect abnormal coronary intimal thickness in 50% of patients as early as 1 year after cardiac transplantation.

Risk factors associated with the development of CAV

Although the exact pathophysiological mechanisms leading to CAV are incompletely understood, several immune and non-immune risk factors have been associated with its development. Immune risk factors include HLA donor/recipient mismatches (especially HLA DR mismatches), recurrent cellular rejection, and antibody mediated rejection.

The incidence of CAV is higher when the donor allograft has coronary artery disease. Advanced age, male sex, and hypertension are risk factors if they occur in either donor or recipient. Recipient risk factors associated with increased development of CAV include a younger recipient age, presence of diabetes mellitus, hyperlipidemia, smoking, obesity, and hyperhomocysteinemia. Recent studies have shown that cytomegalovirus infection, whether symptomatic or not, is associated with an increased incidence of CAV.

C. History part 3: competing diagnoses that can mimic CAV

CAV is characterized by diffuse intimal hyperplasia, which may affect the epicardial vessels as well as the microcirculation in a longitudinal and concentric manner. This is in contrast to ordinary atherosclerotic coronary artery disease, which is usually more focal and eccentric in nature and involves only the epicardial coronary vessels. Plaque rupture is uncommon in CAV due to its diffuse and non-focal morphology. Spasm of the coronary arteries may also be mistaken for CAV and must be ruled out by intracoronary injection of nitroglycerin during angiography.

D. Physical examination findings

Patients with advanced CAV may develop allograft dysfunction and demonstrate typical signs of heart failure, such as elevated jugular venous pressure, pulmonary rales, and lower extremity edema. They may also present with signs of hemodynamic instability if they develop an acute myocardial infarction. Most patients have normal exams, however.

E. What diagnostic tests should be performed?

As the diagnosis of CAV is difficult to clinically establish due to the paucity of specific signs or symptoms, screening for CAV is more important than waiting for symptoms of allograft dysfunction.

CAV may be diagnosed and monitored by invasive and non-invasive imaging studies. Invasive coronary angiography is the gold standard for diagnosing CAV. In general, most non-invasive methods cannot identify early disease due to the diffuse nature of the disease and the absence of flow-limiting coronary lesions.

1. What laboratory studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Cardiac troponins and CK-MB may be evaluated during acute ischemia or myocardial infarction secondary to CAV to help diagnose and indicate the damage to the myocardium. Persistently elevated levels of troponin I early postoperatively are associated with a significantly increased risk for subsequent development of CAV.

Recent studies have focused on different markers related to the extracellular matrix, renin angiotensin system, fibrinolytic system, adhesion receptors, and markers of inflammation. Markers such as N-terminal pro-brain natriuretic peptide (NT-proBNP), C-reactive protein (CRP), and von Willebrand factor (vWF) have all been shown to be predictive of all-cause mortality. Although elevated levels of these biomarkers predict a higher risk of developing CAV, further studies are needed to evaluate their role in the identification of CAV.

2. What imaging studies (if any) should be ordered to help establish the diagnosis? How should the results be interpreted?

Invasive diagnostic studies

Coronary angiography

The most definitive way to diagnose CAV is by coronary angiography. At many centers, 'baseline' angiography is performed early after the heart transplant (4-6 weeks post-transplant) to exclude donor coronary artery disease, particularly when donors over the age of 35 have not undergone angiography prior to the organ procurement. Subsequently, unless the patient has signs or symptoms suggestive of ischemia or unexplained graft dysfunction, most CAV is diagnosed by routinely scheduled annual surveillance angiography.

Coronary angiography helps identify areas of luminal narrowing and the rate of contrast filling of the coronary arteries. Gao et al. (Figure 1) codified varied lesion types for communicating angiography results in heart transplant recipients. The rate of contrast filling helps detect small vessel and distal disease, but is difficult to quantify.

In the ISHLT guidelines from July 2010, a grading system for CAV was established based on angiographic findings and allograft function, the latter determined by echocardiography and invasive hemodynamic data. Based on this grading system, CAV is classified as follows:

Figure 1.

CAV lesion types.

  • ISHLT CAV0 (Not significant): No detectable angiographic lesion

  • ISHLT CAV1 (Mild): Angiographic left main (LM) <50%, or primary vessel with maximum lesion of <70%, or any branch stenosis <70% (including diffuse narrowing) without allograft dysfunction

  • ISHLT CAV2 (Moderate): Angiographic LM >= 50%, a single primary vessel >= 70%, or isolated branch stenosis >= 70% in branches of 2 systems, without allograft dysfunction

  • ISHLT CAV3 (Severe): Angiographic LM >= 50%, or two or more primary vessels >= 70% stenosis, or isolated branch stenosis >= 70% in all 3 systems, or ISHLT CAV1 or CAV2 with allograft dysfunction (defined as left ventricular ejection fraction by less than or equal to 45%) or evidence of significant restrictive physiology

Angiography can miss or underdiagnose CAV due to its diffuse, concentric, and longitudinal pattern, as there is no normal reference segment for comparison (Figure 2). Therefore serial angiograms should be interpreted by experienced reviewers as new and concentric lesions may be missed on a one-time angiogram. Several adjuncts to coronary angiography, including intravascular ultrasound and coronary flow reserve, add value to the diagnosis of CAV on routine angiography.

Figure 2.

Coronary angiography showing moderate-severe allograft vasculopathy with diffuse concentric narrowing of the allograft coronaries.

Intravascular ultrasound (IVUS)

IVUS at the time of angiography provides a high resolution image of the cross-section of the vessel, providing an accurate assessment of lumen size and intimal thickening. IVUS is useful to identify donor-related CAD in the early post-operative period and the development of CAV in serial evaluations.

Any intimal lesion more than or equal to 0.5 mm at the baseline study usually performed at 4-6 weeks post-transplantation suggests donor disease. Rapid progression of minimal intimal thickness by more than 0.5 mm during the first year is a powerful predictor of all-cause mortality, myocardial infarction, and later angiographic abnormalities. Thus, IVUS has become useful in the diagnosis and prognosis of CAV in cardiac transplant patients. By IVUS criteria, the presence of allograft vasculopathy is diagnosed when the minimal intimal thickness (MIT) of the epicardial coronary vessel is >0.3 mm, and significant allograft vasculopathy is diagnosed when the MIT is >0.5 mm.

The Stanford classification system (Table I) classifies lesion morphologies visualized during angiography.

Table I.

Stanford Classification of CAV Severity on IVUS

Approximately 80% of patients demonstrate IVUS-evidence of intimal thickening within a year of transplantation. The most rapid rate of intimal thickening occurs in the first year post-transplantation. In proximal segments of the coronary arteries, the intimal thickening is focal and eccentric, similar to native coronary artery disease. However, in the mid and distal segments, the intimal thickening is diffuse and circumferential. Thus, proximal de novo CAV needs to be differentiated from native donor coronary artery disease which may be evaluated by serial angiograms and IVUS.

After 5 years post-transplantation, many feel that the frequency of angiography and IVUS may be decreased in patients free of CAV, especially if they develop renal insufficiency. If percutaneous coronary intervention is done for CAV, repeat angiography should be performed after 6 months to follow-up the lesions due to a high restenosis rate in transplant recipients.

Abnormal coronary flow reserve (CFR)

In addition to IVUS, coronary flow reserve is another measure which can be performed at the time of angiography to detect endothelial dysfunction and microvascular abnormalities occurring with CAV. CFR is the ratio of coronary flow during maximal hyperemia to basal coronary flow. It interrogates the entire coronary circulation and does not distinguish between an epicardial artery stenosis and microcirculatory dysfunction. Thus, conditions such as diabetes or left ventricular hypertrophy, which may impair microvascular function, can cause an abnormal CFR.

Intracoronary flow velocities are determined using a Doppler transducer mounted on a guide wire placed in the coronary artery. Changes in coronary blood flow in response to endothelium dependent and independent vasodilators may be assessed.

In heart transplant patients with angiographically normal coronaries, impaired CFR correlates with IVUS-derived plaque measurements and predicts deterioration of left ventricular function 2 years later.

Endomyocardial biopsy

Endomyocardial biopsies are not routinely performed to diagnose CAV.

Non-invasive diagnostic studies

Non-invasive studies serve as a useful adjunct in the screening for and detection of CAV. Some transplant programs perform non-invasive imaging studies every other year alternating with coronary angiography in low risk patients who have normal angiograms and/or IVUS after 5 years post-transplant. Non-invasive screening is generally performed in patients more than 5 years post-transplantation. Non-invasive testing is also useful in patients who develop renal dysfunction to minimize the risk of contrast nephropathy.

Electrocardiogram (ECG)

ECG is not very useful in the diagnosis of CAV as there are frequently baseline abnormalities present. It may be useful to detect new arrhythmias, ischemia, or infarction on comparison with prior ECGs if changes are present.

Dobutamine stress echocardiography (DSE)

DSE has been successfully used for CAV screening with a high correlation between an abnormal DSE and angiographically detectable CAV. This is the best validated technique and correlates with prognosis in cardiac transplant patients. Improved sensitivity and specificity may be obtained by using quantitative enhancements with myocardial echocontrast and tissue Doppler imaging. The sensitivity of resting left ventricular ejection fraction and regional wall motion for detecting CAV is low.

Dobutamine-stress appears to be more sensitive than exercise stress, most likely because allograft denervation results in a blunted heart-rate response to exercise. A large study including 109 patients found DSE to have a sensitivity and specificity of 72% and 88%, respectively, for the diagnosis of CAV. Most importantly, DSE has a negative predictive value for adverse cardiac events. In a large prognostic study, only 1 of 159 normal DSEs (0.6%) was followed by an adverse cardiac event during a mean 2.5-year follow up.

DSEs should be performed with caution if at all in patients with severe CAV. These patients should be followed clinically by coronary angiography instead of DSE. Also, coronary angiography should be performed instead of DSE in patients with symptoms suggestive of CAV, even if the DSE is negative for ischemia.

Nuclear imaging

Although other noninvasive techniques have been evaluated in an attempt to decrease the need for invasive testing, DSE appears to have the best predictive accuracy when compared to nuclear perfusion techniques. There is considerable variation in methodology and results of studies assessing the accuracy of SPECT for detecting CAV. SPECT has only been assessed in relation to angiography, most commonly using luminal narrowing of >=50%.

In the largest study, dipyridamole-stress sestamibi SPECT had a sensitivity and specificity of 92% and 86%, respectively, when compared with luminal narrowing of >=50%, but a sensitivity of only 56% when compared to any angiographic abnormalities, including minor luminal irregularities.

Like DSE, dobutamine-stress SPECT provides important prognostic information. In two studies of 77 and 166 patients followed up for 22 and 30 months, respectively, the 12-month negative predictive values for major cardiac events were 98% and 95%. The prognostic value of dipyridamole-stress SPECT may be lower, with a negative predictive value of 86% in a study of 78 patients, albeit with a substantially longer follow-up.

Positron emission tomography

The ability of Positron Emission Tomography to readily quantify myocardial blood flow (MBF) suggests that this may allow PET to be more sensitive for detecting CAV than other noninvasive techniques. In two studies using 13N-ammonia, PET and IVUS were performed in 17 patients at 18 months post-transplant, when MPR predicted the changes in total vessel area and luminal diameter seen on repeated IVUS 15 months later. Further studies are under way to evaluate its role in the identification of CAV.

A limitation of nuclear imaging as a screening tool is the associated radiation dose, particularly with serial studies. PET is also quite expensive and has limited availability. Additionally, cardiac transplant patients have an enhanced sensitivity to adenosine due to denervated sinus and atrioventricular notes and, therefore, a high degree of vigilance is required for any functional imaging technique using adenosine as the stressor agent.

Multislice computerized tomography (CT)

CT angiography has high specificity and negative predictive value (NPV) for detection of CAV. 16-slice multidetector computed tomography (MDCT) with adaptive multisegment reconstruction has a sensitivity and specificity of 86% and 99%, respectively, for stenoses greater than 50% in segments >1.5 mm on quantitative coronary angiography.

Of note, coronary calcium scoring is of limited value in CAV because clarification is often absent, even in severe disease.

A limitation of MDCT is its inability to provide detailed information about the vessel wall and lumen and a lower sensitivity for distal and small vessel disease. The major drawbacks with the routine use of MDCT after heart transplantation include the high resting heart rate of the denervated heart, which can compromise image quality. Contrast-induced nephropathy and radiation exposure are also concerns.

Magnetic Resonance Imaging (MRI) is being evaluated as a noninvasive tool to screen for CAV, but evidence is limited at present.

According to the 2010 ISHLT guidelines for the care of heart transplant recipients:

  • Annual or biannual invasive coronary angiography is a class I recommendation, Level of Evidence C

  • DSE and SPECT are a class IIa recommendation, Level of Evidence B

  • CTA is a class IIb recommendation, Level of Evidence C

  • PET and CMR are not in the guidelines

III. Management

Prevention

Given the relatively poor prognosis of CAV, prevention remains the most important strategy. Management of allograft vasculopathy, which focuses on the aggressive management of risk factors, must be initiated early. Important preventive measures include aggressive therapy for CAV risk factors, reduction of acute rejection episodes with therapeutic immunosuppression, and CMV prophylaxis. Statins, mammalian Target of Rapamycin (mTOR) inhibitors sirolimus and everolimus, and diltiazem have also been beneficial in the prevention of CAV. Although antiplatelet agents like aspirin are commonly used, their efficacy has not been clearly established in patients with CAV.

HMG-CoA reductase inhibitors (Statins)

In heart transplant patients, statins have improved patient survival and reduced the incidence and severity of CAV as well as allograft rejection. The benefits of statins may be linked to their anti-inflammatory activity and anti-endothelial dysfunction properties, in addition to their lipid-lowering properties. Pravastatin had a beneficial effect on the lipid profile and a significant reduction in 1-year mortality (6% vs. 20%), a lower maximal intimal thickness, and a significant increase in patient survival, 94% vs. 78%.

Similar improvements in outcome were observed with simvastatin in a prospective trial of 72 patients. At 4 years, patients treated with simvastatin had 17% vs. 42% lower incidence in CAV, and 89% vs. 70% improvement in survival. It is noteworthy that regular doses of statins may lead to myositis and rhabdomyolysis if used concomitantly with calcineurin inhibitors due to drug interactions. Thus, when used in combination with cyclosporine or tacrolimus, the lowest dose possible of lipid-lowering agent should be prescribed. Fluvastatin or pravastatin may be the safest of the statins in transplant recipients.

There have not been any randomized trials of other lipid lowering drugs, such as fibric acid derivatives (gemfibrozil), bile acid sequestrants, nicotinic acid, or ezetimibe, in heart transplant recipients.

Proliferation signal inhibitors (mTOR inhibitors)

Everolimus and sirolimus have been evaluated for the prevention and treatment of CAV due to their antiproliferative effects. They are in the class of drugs termed mTOR (or mammalian Target of Rapamycin) inhibitors. Sirolimus and everolimus have a similar mechanism of action, exerting potent inhibition of growth factor-induced proliferation of lymphocytes, as well as other hematopoietic and nonhematopoietic cells of mesenchymal origin.

Similar to the calcineurin inhibitors, sirolimus and everolimus are biotransformed by the cytochrome P450, 3A4 isozyme. Everolimus is a derivative of sirolimus and is more hydrophilic, exhibits a shorter elimination half-life (approximately 30 hours), and demonstrates greater relative bioavailability compared to sirolimus. In a study by Keogh et al, the use of sirolimus in 136 de novo heart transplant recipients was associated with deceased development of CAV at 2 years compared with patients receiving azathioprine.

In a subsequent multicenter study by Eisen et al, 634 heart transplant patients were randomized to everolimus or azathioprine (in addition to cyclosporine and steroids in both arms) within 72 hours post-transplantation. Intravascular ultrasonography (IVUS) showed that the average increase in maximal intimal thickness at 12 months was significantly smaller with everolimus as compared with azathioprine. This was an important finding, as a significant increase in maximal intimal thickness at 1 year is associated with a much higher 5-year post-transplant mortality. Thus, in patients who have documented vasculopathy, sirolimus or everolimus should be considered to prevent the progression of CAV. However, these drugs impair wound healing, and should not generally be used in early post-transplantation until the wound has adequately healed.

Mycophenolate mofetil

In a randomized trial, heart transplant patients on mycophenolate mofetil had lower maximal intimal thickness on IVUS compared with azathioprine at 3 years post-transplant and it is now the most commonly used drug (combined with a calcineurin inhibitor) in long-term immunosuppression regimens.

Diltiazem

Diltiazem may also attenuate the development of CAV and lower death rates at 5 years post-transplant. It was evaluated in a randomized trial with 106 heart transplant recipients. In patients on diltiazem, the average coronary diameter was unchanged, whereas in the patients not on diltiazem, the average coronary diameter decreased on annual quantitative coronary angiograms at 1 and 2 years from 2.4 mm at baseline to 2.19 mm and 2.22 mm. However, the study is limited in that it predated routine use and there has not been IVUS confirmation of these findings. Furthermore, in a later multicenter retrospective study of 719 patients, only the use of statins, and not diltiazem, was associated with a reduction in CAV by coronary angiography.

Thus, although clear benefit from diltiazem has not been shown, it may be considered to treat concomitant hypertension in post-transplant patients.

Antioxidant vitamins

Antioxidant vitamins, such as 500 mg of Vitamin C and 400 IU of Vitamin E twice daily, performed better than placebo at decreasing the progression of CAV at 1 year in 40 heart transplant patients. Their ability to decrease oxidative stress may be beneficial in heart transplant patients. Further studies are needed to establish their benefit.

A. Immediate management

Acute management

Alteration in immunosuppression with the use of mTOR inhibitors

The use of sirolimus or everolimus may prevent or slow the progression of CAV by inhibiting smooth muscle cell proliferation, a key component in the development of CAV. Mancini et al. randomized 46 patients with severe CAV, based on a semiquantitative catheterization score at a mean 4.3 years post-transplantation, to sirolimus or a continuation of prior therapy with azathioprine or mycophenolate. The rest of the immunosuppressive regimen, including a calcineurin inhibitor, was continued. At the 2 year follow up, patients treated with sirolimus demonstrated slowed angiographic disease progression and a significantly reduced combined end point of death, percutaneous coronary intervention (PCI) and coronary artery bypass surgery ( 5 vs. 25 cases, odds ratio 0.11).

Raichlin et al. replaced the calcineurin inhibitor (cyclosporine or tacrolimus) with sirolimus in a nonrandomized study in 29 patients with impaired renal function. The secondary immunosuppressant like azathioprine or mycophenolate was continued. The results were compared with 40 patients who were maintained on calcineurin inhibitors. At 3.8+/-3.4 years post -transplant, the mean coronary plaque volume and plaque index (plaque volume/vessel volume percentage) increased in the calcineurin group but not in the sirolimus group. These findings suggest that sirolimus (and everolimus) should be considered in patients with CAV to prevent or decrease disease progression.

Arora et al. randomized 111 patients who were over 5 years post-transplant and who had IVUS evidence of CAV to four subgroups: 1) everolimus + low dose calcineurin inhibitor (CNI) and AZA (n=16); 2) standard dose CNI+ASA (n=23); 3) everolimus + low dose CNI and mycophenolate mofetil (MMF) (n=31); and 4) standard CNI+MMF (n=39). In this study, the addition of everolimus and reduced CNI did not influence the progression of CAV by IVUS at 12 months follow up.

However, in the sub-group of patients receiving everolimus, reduced-dose CNI, and azathioprine therapy, CAV progression and a number of inflammatory markers implicated in CAV were attenuated compared with the control CNI group. In comparison, the subgroup of patients receiving everolimus, reduced-dose CNI, and MMF was associated with accelerated CAV and a parallel increase in inflammatory markers.

These results are thought provoking and suggest that the addition of everolimus to a regimen with MMF may not help prevent CAV when used late after heart transplantation. However, the applicability of these findings to the contemporary management of heart transplant patients is questionable, as most clinicians now switch antiproliferative medications as opposed to adding them. Further studies are needed to elucidate the effect of mTOR inhibitors on established CAV later after heart transplantation.

Percutaneous coronary intervention

Percutaneous revascularization of allograft vasculopathy is often considered for focal lesions, but the long-term benefits of the procedure are usually limited by the diffuse nature of the disease. Balloon angioplasty in these patients has a high restenosis rate and the need for repeat interventions is high due to the development of new lesions. Rates of in-stent restenosis are higher as compared with stenting of native coronary arteries, although the advent of drug-eluting stents has decreased CAV restenosis rates (15% vs. 31%). PCI is safe and has been associated with an immediate success rate of 92%-94%, but a restenosis rate of 20%-55% at 6 to 15 months post PCI.

No survival benefit has been demonstrated for drug-eluting stents over bare-metal stents, with a 1 year mortality after PCI of 32%. Thus, PCI with stenting should be considered in a select group of patients amenable to these approaches who have an abnormal stress test or evidence of myocardial ischemia.

Coronary artery bypass grafting

Coronary artery bypass grafting (CABG) has been performed rarely due to the diffuse nature of CAV. It is associated with a high periprocedural mortality of up to 40% and with limited midterm success. In one report, 4 out of 12 patients died perioperatively and 7 were alive at a mean of 9 months post-surgery without retransplantation. The performance of bypass surgery in these patients should be evaluated very carefully.

B. Long-term management

In addition to risk factor modification, change to mTOR inhibitors and PCI, the only definitive long term treatment for established CAV appears to be retransplantation. Retransplantation for CAV may result in outcomes comparable to those after primary transplantation if performed specifically for CAV, with survival rates of more than 85% 1 year after transplantation. The optimal retransplantation patient is young and has an intertransplant interval of >2 years. In practice, retransplantation is considered to be a real solution for only highly selected patients with CAV.

C. Common pitfalls and side-effects of management

Heart transplant patients treated with statins must be monitored for myopathies and rhabdomyolysis due to the inhibition of CYP3A4 by concurrently administered calcineurin inhibitors, which results in increased levels of the statin. Pravastatin and fluvastatin are not metabolized by CYP3A4, hence the risk is lower with these statins. Most other statins should be used with caution, with frequent monitoring in patients on tacrolimus or cyclosporine due to the potential for drug interactions and rhabdomyolysis.

mTOR inhibitors, like sirolimus and everolimus, are associated with significant side effects and may be poorly tolerated. Some of the side effects of mTOR inhibitors include hypertension, headaches, acne, impaired wound healing, oral ulceration, anemia, thrombocytopenia, thrombotic microangiopathy, venous thromboses, lymphedema, pulmonary toxicity, alveolar hemorrhage, hypertriglyceridemia and hypercholesterolemia, and rarely progressive multifocal encephalopathy and optic neuropathy.

Due to impaired wound healing, the use of mTOR inhibitors early post-transplant is not recommended. They are usually started at least 3 months post-transplant, their use should be discontinued 3 months prior to any large elective surgical procedure, and they may be restarted 1 month post-procedure if the wound has healed adequately.

There is an increased risk of acute rejection during the replacement of calcineurin inhibitor with sirolimus, and so caution should be used and the patient should be monitored closely for symptoms and signs of rejection. This risk of precipitating acute rejection may decrease with time post-transplantation.

After PCI, the need for repeat interventions is high due to the development of new lesions. Hence, their use is usually limited to select patients with focal proximal lesions.

Dobutamine stress echocardiography should be avoided in patients with severe allograft vasculopathy. These patients should be followed clinically by coronary angiography. Also, symptomatic patients should be directly evaluated by angiography instead of by noninvasive studies.

IV. Management with co-morbidities

Diabetes, hypertension, obesity, and dyslipidemia may all contribute to the development and progression of CAV and should be aggressively managed. Glycosylated hemoglobin (HgbA1c) has been correlated with severity of CAV, hence strict glycemic control is important in CAV prevention and progression.

Although obesity has been correlated with poor graft and patient survival, a direct association with CAV has not been shown. It is common in heart transplant patients, however, due to their medications, and obesity likely contributes to the CAV risk factors.

Hypertension may correlate with an increased risk for CAV. The use of calcium channel blockers like diltiazem may attenuate CAV. Smoking is associated with CAV, and its cessation must be emphasized. CMV infection is also associated with the development of CAV. However, the role of prophylaxis with CMV immunoglobulin, ganciclovir, and valganciclovir on CAV are not clear.

Prognosis

Once mild disease is identified angiographically, the likelihood of progression to severe CAV within 5 years is increased from 9% to 19%.

The presence of significant angiographic stenosis conveys a poor prognosis. In patients with at least 1 focal stenosis of more than or equal to 40%, survival was found to be 67% at 1 year, 44% at 2 years, and 17% at 5 years. With 3 vessels involved, survival was 13% at 2 years.

Patients with a moderate coronary lesion (>30% and <60%) who showed angiographic progression 1 year later experienced higher rates of revascularization and sudden death. The lack of progression at 1 year identifies those who are likely to remain free of clinical events through 6 years of follow-up.

A. What's the evidence for specific management and treatment recommendations?

Costanzo, MR, Dipchand, A, Starling, R. "The International Society of Heart and Lung Transplantation Guidelines for the care of heart transplant recipients". J Heart Lung Transplant. vol. 29. 2010. pp. 914-56.

(The authors, all authorities in the field of cardiac transplantation, provide the most recent guidelines for the general care of heart transplant patients. The consensus of the ISHLT working group was to base the definition and diagnosis of transplant vasculopathy on conventional invasive coronary angiography. A grading system based on angiographic findings and graft function was recommended.)

Lund, LH, Edwards, LB, Kucheryavaya, AY. "The Registry of the International Society of Heart and Lung Transplantation: Thirtieth Adult Heart Transplant Report –2013; Focus There: Age". J Heart Lung Transplant. vol. 32. 2013. pp. 951-964.

(This is the most recent report of the International Society of Heart and Lung Transplantation Transplant Registry, which is based on data submitted by 388 heart transplant centers worldwide since 1982. It reviews important statistics for the entire cohort of patients registered in the database, including important donor, recipient, and medical center demographics. It also provides an overview of immunosuppressive therapies and survival and mortality data post adult heart transplantation.)

Miller, CA, Chowdhary, S, Ray, SG. "Role of noninvasive imaging in the diagnosis of cardiac allograft vasculopathy". Circ Cardiovasc Imaging. vol. 4. 2011. pp. 583-93.

(The article provides an up-to-date review of the current noninvasive imaging modalities used in the diagnosis of CAV.)

Gao, SZ, Alderman, EL, Schroeder, JS, Silveman, JF, Hunt, SA. "Accelerated coronary vascular disease in the heart transplant patient: coronary arteriographic findings". J Am Coll Cardiol. vol. 12. 1988. pp. 334-40.

(In this publication, the authors compared and contrasted angiographic CAV lesions in 81 transplanted patients with lesions in nontransplant patients with CAV. It also provides the classification of CAV lesions by angiography.)

Schmauss, D, Weis, M. "Cardiac allograft vasculopathy: recent developments". Circulation. vol. 117. 2008. pp. 2131-41.

(This paper summarizes the diagnosis and management of CAV. It also provides insights into the pathophysiology of CAV, and provides a foundation for understanding its treatment.)

Lee, MS, Finch, W, Kirtane, AS. "Cardiac allograft vasculopathy". Rev Cardiovasc Med. vol. 12. 2011. pp. 143-52.

(This is an article with a detailed review of the management of CAV.)
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