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Heart Transplantation Allograft Vasculopathy
Introduction
There are 5.1 million patients with chronic heart failure in the United States, and heart failure is the leading cause of hospitalization among adults greater than 65 years of age.[1] With more than 1 million patients being hospitalized for the primary diagnosis of heart failure, Medicare spending exceeds $17 billion per annum on this diagnosis.[2] Despite advances in mechanical circulatory support, cardiac transplant remains the definitive treatment intervention for patients with advanced heart failure and refractory symptoms who cannot be managed with optimal medical therapy.
Since the first human heart transplant by Dr. Christiaan Barnard in 1967, a slew of disruptive innovations and multidisciplinary efforts have sophisticated the field.[3] At present, over 5,000 heart transplants are carried out worldwide every year.[4] Despite the encouraging numbers, obstacles still exist.
Cardiac allograft vasculopathy (CAV) is a recognized long-term complication seen post-cardiac transplant. Considered a chronic fibroproliferative rejection to the transplanted heart, it is amongst the top three causes of death after the first year of transplantation. The prevalence of CAV in patients post-cardiac transplant at 1, 5, and 10 years was 8%, 29%, and 47%, respectively as described by the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry data report.[5]
Etiology
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Etiology
Cardiac allograft vasculopathy is a pan-arterial disease limited to the allograft. Its etiology is multifactorial in origin, with the primary cause being inflammation driven by both cellular and antibody-mediated rejection processes and anti-HLA antibodies against donor tissue. In accordance with the inflammatory burden in this disease process, elevation in serum C-reactive protein is a marker for CAV and allograft failure.[6][7][8] Other contributing factors include hypercholesterolemia, diabetes, hypertension, and Cytomegalovirus infection.[9][10]
Epidemiology
Cardiac allograft vasculopathy is one of the top three causes of death 1-year post-cardiac transplant, accounting for an estimated 1 in 8 deaths in transplant survivors who live beyond one year.[11] The prevalence of CAV in patients post-cardiac transplant at 1, 5, and 10 years was 8%, 29%, and 47%, respectively, as described by the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry data report.[5] Male donors and older age donors were linked to an increased risk of CAV.[12] Younger aged recipients were found to be at a higher risk for CAV.[13][14]
Pathophysiology
The pathophysiology of CAV is complex, with an interplay of immunological and non-immunological factors. Inflammation may be triggered by donor arrest, organ procurement, and allograft ischemia and reperfusion. CAV is a pan-arterial process characterized by diffuse concentric hyperplasia of the intima seen in epicardial coronary arteries. It also extends to the microvasculature, causing concentric medial disease.[15][16][17] This is in contrast to atherosclerosis, which is non-circumferential, focal, and common in the proximal epicardial vessels. Thrombotic occlusion of the vessel lumen, which is seen in atherosclerosis is an uncommon finding in CAV. However, the two frequently coexist. There is a strong association between platelet activation and CAV.[18] This has been hypothesized as the reason for intramural thrombi formation associated with the disease.[19]
Intravascular ultrasound-guided studies have shown that most of the intimal thickening occurs during the first year post-transplant.[20] An increase in maximal intimal thickness less than 0.5 mm within the first-year post-transplant is associated with an unfavorable prognosis.[21][22]
Histopathology
Cardiac allograft vasculopathy encompasses a constellation of vascular changes characterized by intimal fibromuscular hyperplasia (arteriosclerosis), vasculitis, and atherosclerosis. Veins, in addition to arteries, are affected. Immunohistochemistry demonstrates the infiltration of macrophages and T lymphocytes into the intima, media, and/or adventitia of affected vessels. In contrast to atherosclerosis, calcium deposition is not a prominent finding, even in severely stenotic arteries.[23]
History and Physical
Since the transplanted heart is denervated, the recipient typically does not perceive angina or ischemic pain. Thus, patients with CAV may be asymptomatic or complain of non-specific symptoms such as fatigue, dyspnea, palpitations, abdominal discomfort, and nausea.[24] If the diagnosis is made late, after the onset of heart failure and reduced left ventricular ejection fraction, the prognosis is usually poor. In rare cases, sudden cardiac death may be the initial presentation of CAV. Consequently, surveillance testing is imperative to monitor recipients closely for early evidence of CAV as clinical manifestations are an unreliable metric.[3]
Evaluation
All post-cardiac transplant patients should undergo routine screening for cardiac allograft vasculopathy, as early detection may improve prognosis.
During the first 5 years post-transplant, coronary angiography should be performed every 1 or 2 years if renal function is preserved (estimated glomerular filtration rate ≥30 to 40 mL/min/1.73 m). In cases of significant renal impairment (<30 to 40 mL/min/1.73 m), annual dobutamine stress echocardiography should be performed to assess for inducible coronary ischemia.[25][26] Dobutamine stress echo has been extensively validated as a non-invasive assessment correlating with prognosis in post-cardiac transplant patients.[27][28][29]
Five years post-transplant, low-risk patients can continue surveillance with annual dobutamine stress echocardiography. If patients have evidence of evolving CAV, they should undergo annual coronary angiograms so long as renal function permits. For those patients with poor quality echocardiography images, a dobutamine or dipyridamole stress radionuclide myocardial perfusion study can be performed.[30]
Coronary angiography should be performed on post-transplant patients who present with a change in clinical status and graft dysfunction with a drop in left ventricular ejection fraction, which cannot be explained by acute rejection.
It should be noted that CAV narrows the coronary arteries in a diffuse, concentric pattern, unlike atherosclerosis, which is eccentric and focal and easier to detect on coronary angiography. Thus, angiography has its limitations, especially in early CAV, and may underestimate the severity and burden of the disease. Intravascular ultrasound (IVUS), in conjunction with coronary flow reserve measurements, overcome this limitation.[31][32][33][34][35] In the future, optical coherence tomography (OCT) may replace or supplement intravascular ultrasound (IVUS) as it allows for high-resolution assessment of the coronary artery wall architecture and composition.[36] Conversely, the absence of coronary angiographic disease was a predictor of survival without adverse cardiac events at two years.[37]
Once the diagnosis of CAV has been established, echocardiograms should be performed to follow left ventricular ejection fraction and allograft dysfunction serially. In addition, annual coronary angiograms aid in the diagnosis of lesions amenable to percutaneous coronary interventions or, in advanced cases, if re-transplantation should be considered.
Treatment / Management
Prevention of Cardiac Allograft Vasculopathy
mTOR inhibitors such as everolimus and sirolimus have been shown to prevent or slow the progression of cardiac allograft vasculopathy given their anti-proliferative properties. However, adverse effects, such as renal impairment and impaired wound healing, may limit their use.[38][39][40](A1)
Statin therapy has been shown to reduce the incidence of CAV post-transplant. In addition, these patients have a high incidence of hyperlipidemia, which is also benefitted by statin therapy.[41] Thus, all post-transplant patients should be on statin therapy. Within the statin group, pravastatin and simvastatin have proven to improve survival in these patients.[42][43](A1)
Treatment of CAV
Short-term augmentation of immunosuppressive therapy with mTOR inhibitors may halt progression or cause regression of CAV; however, more data are required to substantiate this.[44] In addition, the risks of increased immunosuppression, including infection and malignancy, may negate these supposed benefits. In a cohort of 163 post-cardiac transplant patients, the anti-CD-20 antibody rituximab was studied as a treatment for CAV. However, IVUS guided imaging showed an increased progression of CAV in patients on Rituximab as compared to placebo.[45]
If the extent of CAV is limited, percutaneous transluminal angioplasty may be used as a palliative option to treat discrete lesions; however, restenosis is a complication. In such cases, there may be a role for directional coronary atherectomy.[46] Coronary artery bypass grafting has been performed in a selected group of cases with good medium-term outcomes. However, there remained a risk of disease progression and future need for percutaneous or surgical intervention. At this time, re-transplantation is the only definitive treatment option for patients with a significant burden of CAV.[47] (B3)
Differential Diagnosis
Graft dysfunction may present as acute or chronic heart failure or arrhythmias. In such cases, it is important to distinguish cardiac allograft vasculopathy from rejection reaction (cellular or humoral) and non-specific graft dysfunction. Rejection reactions are diagnosed on endomyocardial biopsy. If CAV is suspected, coronary angiography should be performed if renal function permits. The diffuse luminal narrowing is suggestive of CAV. In contrast, focal eccentric lesions, more commonly in the proximal epicardial vessels is more suggestive of atherosclerosis, though the two may exist in tandem.
- Atherosclerosis
- Non-specific graft dysfunction
- Posttransplantation lymphoproliferative disorder
- Transplant rejection
Prognosis
The presence of cardiac allograft vasculopathy portends a worse prognosis for patients post-cardiac transplant. A reliable surrogate marker for subsequent mortality, non-fatal major adverse cardiac events, and development of angiographically significant CAV through five years post-transplant is the progression of intimal thickening ≥0.5 mm in the first year post-transplant.[21] The prevalence of CAV in patients post-cardiac transplant at 1, 5, and 10 years was 8%, 29%, and 47% respectively, as described by the 2019 International Society for Heart and Lung Transplantation (ISHLT) registry data report.[5][48]
Complications
Cardiac allograft vasculopathy may manifest as graft dysfunction in the form of arrhythmias, acute or chronic heart failure and in the worst cases as sudden cardiac death.
Deterrence and Patient Education
Proper diagnosis and management of cardiac allograft vasculopathy can majorly impact a heart transplant patient's lifespan and can have long-term quality of life effects. Healthcare practitioners should thoroughly counsel patients post-cardiac transplant about the implications of cardiac allograft vasculopathy so that they can make informed decisions about their treatment.
Enhancing Healthcare Team Outcomes
The management of cardiac allograft vasculopathy in post-cardiac transplant patients requires an interprofessional team of healthcare professionals that includes a nurse, physician assistant, laboratory technologists, pharmacists, pathologists, social workers, and a number of physicians in different specialties. Before the transplant, a social worker must assess the patient's socioeconomic factors to see if compliance with medication and support through the process of transplant is adequate. Nurses, especially advanced practice nurses, and PAs play an essential link between patients and cardiologists. Given the high number of medications prescribed post-transplant, with various interactions and side effects, pharmacists become an integral part of the management team, and emphasis should be placed on patient education. CAV may be confused for graft rejection, in which case endomyocardial biopsies aid in the diagnosis, and for this, a pathologist trained in immunology is vital. Lastly, not only cardiologists and cardiac surgeons but primary care physicians, nephrologists, hemato-oncologists, and pulmonologists may have a role to play in the management of these patients, and interprofessional rounds during inpatient hospitalizations are imperative to improving the quality of care delivered.
Media
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Heart Transplantation Allograft Vasculopathy, heart transplantation, vasculopathy, coronary artery disease, intimal thickening, vessels, atherosclerosis, plaque Illustration by Emma Gregory
References
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