Cardiac allograft vasculopathy

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Cardiac allograft vasculopathy (CAV) is a fibro-proliferative disorder of graft coronary arteries in heart transplant recipients. It is characterized by longitudinal concentric intraluminal narrowing secondary to intimal proliferation in epicardial coronary arteries. There is also concentric medial hyperplasia in the myocardial microvasculature. In contrast, native atherosclerotic process is non-circumferential, focal and localized to epicardial coronary vessels.

The pathogenesis of CAV is believed to be an interplay between immunological and non-immunological factors. Histologically, immunological and non-immunological factors cause sub-endothelial inflammation resulting in migration of lymphocytes (T cells especially), proliferation of smooth muscle cells, formation of lipid laden foam cells and fibrosis. This further accelerates the process of endothelial dysfunction. The end result is progressive luminal compromise, reduced coronary blood flow and vasodilatory capacity leading to ischemia and chronic ventricular dysfunction ^[1].

Early-CAV is associated with thickening of the intima with or without expansion of external elastic lamina (positive remodeling) and is not accompanied by decrease in the intraluminal diameter. This is followed by concentric remodeling and luminal compromise (negative remodeling). There may also be associated mural thrombi which may lead to acute myocardial infarction. Early clots are platelet rich which may later be replaced by organized thrombus rich in fibrin. Increased platelet activation with expression of surface membrane glycoproteins has been linked to accelerated progression of CAV. Serial intravascular ultrasound imaging has demonstrated that majority of the intraluminal narrowing occurs in the first year after transplant.

In the early post-transplant period, lesions tend to be non-circumferential, focal, composed of fibrous and fibro-fatty material. This fibro-fatty tissue may represent either CAV or traditional atherosclerosis, and represents the most common lesions found on IVUS studies. However, presence of necrotic core may be in this period may be associated with graft atherosclerotic coronary artery disease, donor age, male gender, and other traditional risk factors ^{[1] [2]}. Calcified lesions and necrotic core begin to appear within 2 years of transplantation.

The pathogenesis of CAV appears to multifactorial with immunological and non-immunological factors both contributing to the process. Predominant factors include donor specific HLA antibodies, cellular mediated injury, cytomegalovirus infection and hypercholesterolemia. Immunological insult is the most accepted theory owing to the fact that CAV develops in donor arteries only.

Acute phase reactants may be elevated and is thought to be a marker of progression of CAV.

• HLA mismatch and antibody production:

Studies have reported a higher incidence of CAV in recipients with HLA mismatch. HLA-DR and HLA-A mismatches have been more strongly associated with occurrence of CAV ^[3]. Moreover presence of HLA class I and class II antibodies by solid phase, flow cytometry, panel reactive antibody (PRA) assay post heart transplant co-relate with worse graft outcomes. Tambur et al. showed that class II HLA specific antibodies were associated with IVUS evidence of severe vasculopathy.

• Interplay between T-cell lymphocytes and endothelium:

Proposed mechanism is outlined in the following algorithm ^[4].

A recent study by Labarrere et al. ^[5] found elevated levels of soluble intercellular adhesion molecule – 1 in the graft arterial endothelial surface during the first three months post transplant, further increasing the risk of CAV development and graft failure. ICAM-1 has been recently proven to have prognostic importance for those at risk for developing CAV, acute myocardial infarction and subsequent allograft failure ^[6].

• Cytokines:

Numerous cytokines such as IL-1, IL-6, TNF alpha, fibroblastic growth factor, vascular endothelial growth factor, insulin-like growth factor-1, transforming growth factor, and platelet-derived growth factor have proliferative effects on the vascular smooth muscle cells. Interferon-gamma is also thought to play a role by enhancing the expression of adhesion molecules and recruitment of cells, thereby accelerating the process of vascular damage ^{[7] [8]}.

• Donor age:

Gao et al. ^[9] demonstrated that older donors and donors with pre-existing angiographic evidence of coronary artery disease were more likely to develop CAV in 3 years following transplant, however no significant difference in long term survival was noted in patients who received heart transplants from donors belonging to an older age group. This finding was further validated in retrospective studies by Patavov et al. ^[10] and Blanche et al ^[11].

• Donor- recipient sex mismatch:

Multiple single centered studies showed significant associations between donor- recipient gender mismatch but the results are conflicting. A study by Al-Khaldi et al. ^[12] and Erinc K et al. ^[13] showed worse graft related outcomes in those with female allografts, especially in males above 45 years of age.

Recently, a prospective analysis of the data from United Network for Organ Sharing was studied to look for donor- recipient sex mismatch. It demonstrated significantly improved short and long- term mortality in men receiving organ from same sex donor. However, no survival advantage was noted in females with same sex donors ^[14].

• Insulin resistance syndrome:

Studies performed in animal models have demonstrated that insulin resistance (hyperinsulinemia) can accelerate the process of development of CAV in post-transplant subjects ^[15]. Further research by the same group demonstrated some degree of insulin resistance, hyperinsulinemia, LDL, triglycerides, total cholesterol and higher plasma glucose in non-diabetic post-transplant patients. In addition to insulin resistance, typical pattern of dyslipidemia observed in patients with CAV was hypertriglyceridemia and reduced HDL levels. The mechanisms underlying the development of insulin resistance and dyslipidemia post-transplant is unclear, but is thought to be an interplay between genetic predisposition and adverse effects from immunosuppressants.

• • Hyperlipidemia:

Recent studies using intravascular ultrasound have shown continuing increase in intimal hyperplasia, especially within first year post transplant and is strongly associated with LDL levels ^[16]. The elevations in LDL, triglycerides and total cholesterol occur within the first year post-transplant and is probably secondary to immunosuppressive drugs as mentioned above. In another prospective study by Kapadia SR et al. ^[17] using intravascular ultrasound, severe CAV was related to greater changes in serum LDL cholesterol levels rather than absolute levels during the first year status post cardiac transplant.

LDL and oxidized LDL enhance vascular inflammation by causing endothelial dysfunction, activating coagulation pathways and recruitment of inflammatory cells. They are also known to upregulate the HLA-DR and CD86 in immature dendritic cells in the allograft coronary arteries, thereby activating them and accelerate the process of vasculopathy ^[18]. Use of statins have been proven to have long term survival benefits in heart transplant recipients ^[19]. A study that compared impact on 1 year survival with use of simvastatin versus pravastatin found similar beneficial effects with a higher drop in LDL levels with simvastatin compared to pravastatin ^[20].

• • Hypertension:

Analysis of the data from The Registry of the International Society of Heart and Lung Transplant ^[21], reported incidence of hypertension one year after heart transplant is 76% compared to 94% at the end of 5 years. Development of hypertension post transplant leads to indothelial injury and has been significantly associated with CAV. In a study by Mehra MR et al. using IVUS ^[22], intimal thickness at the end of 1 year was significantly greater in those left untreated compared to patients treated with ACE inhibitors and/or calcium channel blockers or both. There is evidence to suggest that both immunosuppressive therapy (especially calcineurin antigonists) and de-nervation of cardiac volume and chemo-receptors ^[23].

• • Hyperglycemia:

In a prospective study^[24], 66 patients without overt diabetes underwent IVUS 2 to 3 years after transplant surgery. Intimal thickness was significant higher in patients with higher glucose and serum insulin levels (P < 0.05 and P < 0.01). Also, use of immunosuppressants like cyclosporine and corticosteroids may cause increase in baseline glucose and insulin levels which further increases the risk of CAV.

• Cytomegalovirus infection:

CMV infection is particularly known to predict progression and accelerate the development of CAV resulting in discrete stenosis in major epicardial vessels ^[25]. In a study by Koshiken et al. ^[26], the number of vessels affected was significantly higher in CMV patients compared to CMV-free patients particularly after 2nd postoperative year. Moreover, the arteriolar endothelial proliferation and intimal thickening in endomyocardial biopsy specimens preceded the angiographically detected vascular changes. The author also quoted that the endothelial injury was more pronounced during the first two years post-transplant and remained stable thereafter. Studies using combination prophylaxis consisting of CMV hyperimmune globulin (CMV IVIG) and ganciclovir have shown decreased intimal thickening, reduced incidence of coronary artery disease and thereby improved survival ^[27].

• History of coronary artery disease:

Presence of atherosclerotic coronary artery disease in the either recipient or donor is a well established risk factor in predicting poor long-term graft survival. In a prospective analysis^[28], CAV was more frequent in patients with angiographically significant donor coronary artery disease.

Other factors that affect the pathogenesis and development of CAV include:

• Smoking ^[28]
• Obesity ^[18]
• Endothelial dysfunction ^{[29] [30]}
• Etiology of brain death in donor, accidental or cerebrovascular cause ^{[31] [32]}
• Pre-transplant diagnosis of ischemic cardiomyopathy vs. non-ischemic cardiomyopathy
• Long graft ischemia time ^[33]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

As per the data from the Registry of the International Society of Heart and Lung transplantation^[1], the number of reported heart transplants has increased slowly in the recent years, especially in North America. The overall prevalence of CAV in post-cardiac transplant patients at 1, 5 and 10 years is 8, 30 and 50% respectively.

As per the ISHLT, the prevalence of CAV in post- cardiac transplant patients at 1, 5 and 10 years is 8, 30 and 50% respectively. The actual incidence of CAV has decreased slightly over time. Moreover, CAV as a cause of death in patients post- transplantation has decreased over the last decade. However, the Kaplan-Meier curves demonstrates a steady increase in the incidence of CAV post-transplant, such that only 46% of patients are free from angiographic evidence of CAV at the end of 10 years. Moreover, the survival after development of CAV appears to have minimal improvement in recent years in comparison to immediately preceding years. Donor age, donor history of hypertension, hyperlipidemia, number of HLA mismatches and recipient diagnosis of ischemic heart disease were important predictors for development of CAV. Similar results were derived from the review of the United Network of Organ Sharing (UNOS) heart transplant database was performed by Nagji and colleagues in 2010 ^[2].

The Cardiac Transplant Research Database revealed a higher incidence of CAV in post-transplant patients of 42% at the end of 5 years, whereas only 7% of patients were found to have severe CAV on coronary angiogram over the same period of time. The presence of severe CAV was highly predictive of subsequent events or re-transplantation. Similar to the ISHLT and UNOS, older donor age, male donor or recipient, donor hypertension, diabetes were predictive of development of CAV ^[3].

Another prospective cross sectional study done by Torres and colleagues showed almost doubled prevalence of CAV when measured by intravascular ultrasound (IVUS) in contrast to conventional coronary angiography, which suggests that the incidence of CAV may in reality be more than predicted.

Gao et al. demonstrated that older donor age has a strong co-relation with development of CAV within 3 years following transplant. However, no significant difference was noted in long term mortality in patients receiving heart transplants from older age group donors. Similar results were obtained from the ISHTL registry and UNOS database.

The UNOS database found significant improvement in short and long term mortality in males who received transplants from same sex donors. However, no survivial advantage was found in females receiving transplants from female donors. A study done by Al-Khaldi et al. showed worse graft outcomes especially in men above 45 years of age who received female allografts.

Template:WH Template:WS CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Cardiac allograft vasculopathy (CAV) is characterized by concentric intimal proliferation leading to diffuse narrowing of the entire length of the epicardial vessel. Immune mediated processes are thought to be the biggest risk factors driving the process of graft vessel narrowing. However, traditional risk factors for coronary artery disease such as hyperlipidemia, diabetes mellitus, hypertension and smoking have been shown to play a considerable role in the pathogenesis of CAV.

Few immune mediated risk factors reported include:

• Increased levels of B cell antibodies
• Increased levels of HLA-antibodies
• Acute cellular and humoral mediated rejection
• Sensitization to monoclonal antibody OKT3
• Cytomegalovirus infection
• Elevated soluble interleukin-2 receptor levels

Non-immune risk factors include:

• Hyperlipidemia
• Diabetes mellitus
• Hypertension
• Smoking
• Older donor age
• Male donor
• Recepient age
• Recepient gender
• Obesity
• Pretranplant diagnosis
• Donor ischemic time

LDL and triglycerides as risk factors for CAV have been studied more in depth. LDL oxidation leads to recruitment of macrophages and lymphocytes along with increased expression of HLA antigens and interleukin receptors on T cells. This further accelerates the process of vasculopathy.

Template:WH Template:WS CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

Cardiac allograft vasculopathy (CAV) is the leading cause of morbidity and mortality beyond the first year after heart transplantation. In most cardiac transplant centers coronary angiography currently remains the screening tool of choice for CAV. Early diagnosis is important as it may allow for alterations in medical therapy before the disease progresses to the stage where revascularization is required.

The 2010 International Society of Heart and Lung Transplant Guidelines for the care of heart transplant recipients recommend annual invasive coronary angiography as the screening tool of choice for CAV.^[1] In most centers screening of graft coronary arteries for signs of CAV is usually performed six weeks after cardiac transplantation and then annually thereafter. In a retrospective study by Haddad et al it was reported that angiographic evidence of CAV increases by approximately 10% with every 2-year period after cardiac transplantation.^[2] The principal advantages of coronary angiography are its wide acceptability, low cost compared with other novel imaging techniques, and ease of performance.^[3] Studies have shown that coronary angiography is 80% sensitive and 96% specific in detecting CAV.^[4][5]

Although coronary angiography is the preferred screening modality in many centers it lacks sensitivity in detecting early-CAV associated arterial wall changes. In early CAV due to positive arterial remodeling coronary vascular lumen is relatively preserved until negative remodeling occurs resulting in narrowing of the arterial lumen.^[6] This positive remodeling is not detected by coronary angiography leading to an under-estimation of the extent of CAV.^[6] Novel intracoronary imaging techniques such as intravascular ultrasound and optical coherence tomography have shown promising results in detecting these early-CAV associated coronary arterial wall changes.^{[7][8][9][10]} Therefore supplementing these techniques to annual coronary angiography, especially in the initial years of heart transplantation may aid in identifying high-risk subjects and appropriately risk stratifying them. However, currently studies do not exist to support this strategy.

Template:WH Template:WS CME Category::Cardiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aarti Narayan, M.B.B.S [2]; Raviteja Guddeti, M.B.B.S. [3]

CAV is responsible for approximately 40% of deaths in heart transplant recipients. Survival in these patients has improved significantly over the decades, owing primarily to improved diagnostic techniques, and optimal immunosuppression and risk factor modification. The 2013 adult heart transplant registry noted that 5-year survival in both pediatric and adult heart transplant recipients is 69%.

• CAV is a slowly progressive disease of the graft vessels. However it may progress rapidly in some post-transplant patients. For example, about 7% of patients from the Cardiac Transplant Research Database had severe disease that progressed rapidly by the end of 5 years.
• In a few years post-transplant, the disease progresses from clean coronary vasculature to diffusely diseased, obstructive pattern.
• A 5 year prospective study by Tsutsui and colleagues using intravascular ultrasound (IVUS) revealed that most of the intimal thickening in CAV develops during the first year after heart transplantation ^[1].
• Late onset of CAV is infrequent. The process of development of CAV is rather slow in those who develop CAV 10 years post-transplant.

Most of the complications of CAV are related to myocardial hypoperfusion. These include:

• Graft failure
• Myocardial infarction
• Sudden death
• Congestive heart failure (sometimes in the form of rapidly developing systolic failure)
• Arrhythmias

• All-cause mortality data from 1982 up to June 2011 shows 1 year survival of 81% and 5 year survival of 69%, with median survival of 10 years for all and 13 years for those surviving until the end of first year. The most recent cohort of patients show unadjusted 1 year survival of 84%.
• The survival curve demonstrates a steep fall in survival in the first 6 months post-transplant. Thereafter, it steadily decreases by 3.5% per year and continues to do so well beyond 15 years. Presence of CAV is the strongest predictor of mortality in patients who survive beyond 1 year post-transplant.
• The ISHLT Registry showed that CAV together with late graft failure was responsible for about 33% of deaths 5 years post-transplant.
• Also the survival of patients with CAV has in fact improved over the last decade.

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