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Cardiac Transplant

- Clinical:

Survival from heart transplant in the modern era is over 90% at 1 year and the 5 year survival is over 80% [4]. The median survival exceeds 10 years [4]. Newly transplanted hearts have chronotropic incompetence due to cardiac denervation [7]. Transplant recipients demonstrate higher resting heart rates due to loss of parasympathetic innervation, yet decreased peak exercise heart rates due to loss of sympathetic tone (and ultimately attenuated exercise induced coronary flow reserve) [7].

Transplant related complications may be categorized into early (0-30 days), intermediate (1-12 months), and late complications (>12 months) [9].

Complications:

Infection:

Infection is the most common post-transplant complication and can occur the early, intermediate, or late phase [9]. Bacteria account for almost 44% of cases, and in more than half of the infections are due to the gram negative bacteria E. coli and P. aeruginosa, while Staph species are isolated in about a third of cases [9].

CMV infection affects nearly half of transplant recipients in the first year (despite prophylaxis), but the majority of cases are asymptomatic (active infection is seen in only 7.5% of patients) [9]. In patients with active infection, CMV pneumonitis affects 9-11% of patients and has a mortality rate of 14% [9]. CT findings include consolidation, patchy or diffuse ground glass opacities, and centrilobular, tree-in-bud or random micronodules [9].

Graft failure:

Primary graft failure occurs in 2-25% of patients and is the most common cause of death in the first 30 days following transplant (responsible for up to about 40%) [9].

Cardiac allograft rejection:

Rejection represents the leading cause of mortality in the first year post transplant [6].

The risk for allograft rejection is greatest during the first year following transplant, with a peak between weeks 2-12 [9]. Risk factors for rejection include young age, African American, and female [9].

Hyperacute rejection typically occurs in the immediate post transplant period and results from preformed recipient antibodies directed against antigens expressed on the donor vascular endothelium (typically human leukocyte antigens) [9]. The condition is almost invariably fatal, but extremely rare due to antigen screening [9].

Acute cellular rejection is the most common form of rejection- 20-40% of patients during the first year post transplant [9]. The condition is a T cell-mediated process with leukocytes in the myocardium. Acute antibody mediated rejection is less common- occurring in 10-20% of patients in the first year [9]. Acute antibody mediated rejection develops when recipient antibodies (de novo donor specific antibodies may develop over time) are directed against donor antigens, resulting in complement activation and subsequent allograft dysfunction [9].

Endomyocardial biopsy (EMB) is the procedure of choice for surveillance and diagnosis of rejection [9]. Histologic analysis of the RV wall via endovascular biopsy is the gold standard for diagnosis, but is invasive and carries a 0.5-1.5% complication rate [6]. Delayed contrast enhanced MR is a non-invasive imaging modality that can be used to assess for acute rejection [6]. Other authors suggest that increased T2 signal in the myocardium correlates with moderate acute rejection with a sensitivity of 89% and a specificity of 70% [9].

Coronary artery/allograft vasculopathy (CAV):

CAV is an inflammatory vasculopathy distinct from traditional atherosclerotic coronary artery disease [7] and represents a late complication of transplant (> 1 year) [9]. CAV is characterized by the presence of an intact elastic lamina and a diffuse concentric disease affecting the entire coronary tree with intimal hyperplasia composed of vascular smooth muscle cells (it is defined as an accelerated fibrous intimal hyperplasia within donor coronary arteries that manifests with smooth muscle proliferation, lipid deposition, and inflammatory cell accumulation in the walls of the coronary arteries) [8,9]. CAV develops in 8-10% of cardiac transplant patients at one year  post transplant, 30-50% by 5 years, and in over 50% of patients at 10 years [1,4]. Anginal symptoms are usually lacking due to cardiac denervation and the first clinical signs are frequently severe with heart failure, infarction, ventricular arrhythmia, or sudden death [2,4,7]. CAV progresses rapidly [4]. The diffuse nature of the process renders conventional coronary revascularization less useful and re-transplantation is the only definitive therapy [1].

CAV is a leading cause of long term graft failure, need for re-transplantation, and death  [7]. The mortality is between 10-20% within 1 year of diagnosis [4,7] and CAV is the most common cause for late-stage mortality in heart transplant recipients [5]. Risk factors for CAV include the number of HLA mismatches with the allograft and the number of rejection episodes [4]. Alloantigenic-indpendent risk factors include traditional cardiac risk factors such as HTN, dyslipidemia, DM, and obesity) and CMV infection [4,8]. Statin therapy decreases CAV and improves survival [4]. Proliferation signal inhibitors (sirolimus, everolimus) also decrease the progression of CAV [4]. Interestingly, regular exercise has also been shown to reduce the progression of CAV [7].

Currently, CAV is felt to be related to an inflammatory process in the spectrum of chronic rejection and the result of immunological differences between the graft and host, leading to immunologically mediated arterial hyperplasia [1,6]. Early diagnosis is important because this may allow modified immunosuppression therapy and judicious percutaneous intervention of areas of focal stenosis [6]. The disease is most commonly characterized by concentric and diffuse intimal thickening of the middle and distal segments of the epicardial vessels (as well as distal branch coronary arteries) and thus may be underestimated by coronary angiography [1,4,5,7]. CT angiography allows for visualization of the coronary vessel walls [9]. Studies have shown that 30-50% of coronary segments classified as normal with conventional angiography show wall thickening at CT angiography [9]. Intravascular US is the most sensitive imaging modality for the diagnosis of CAV [9]. The condition is diagnosed when intimal thickness is greater than 0.3mm [9]. An intimal thickness greater than 0.3mm at 1 year after transplant is associated with a 23% decreased survival rate (96% vs 73%) [9].

Valvular complications:

Tricuspid regurge is the most common valvular complication after OHT, with a prevalence of 19-84% [9]. Many surgical centers perform tricuspid annuloplasty at the time of transplant, which decreases the incidence of regurge [9].

Malignancy:

Malignancy is a leading cause of morbidity and mortality in the late post transplant period- developing in 16% of survivors at 5 years, and 28% of survivors at 10 years [9].

Skin cancer is the most common malignancy affecting OHT patients- and it develops in nearly 10% of patients within the first 5 years, most commonly basal cell and squamous cell [9]. After skin cancer, lung cancer is the most common malignancy in OHT patients, most commonly non-small cell [9]. The incidence of post transplant lung cancer is 1.86 times higher than the general population [9]. Risk factors include male sex and prior smoking [9].

PTLD and/or lymphoma is the second most common malignancy in OHT patients [9]. Pediatric and young adult patients have a markedly increased risk for PTLD and lymphoma (patients age 18-35 years have a 27 x increased risk compared to non-transplant control patients), possibly due to a lack of protection against oncogenic viruses such as Ebstein-Barr [9]. An EBV positive donor in an EBV negative pediatric recipient constitutes a strong risk factor for PTLD [9].

-X-ray:

Coronary angiography has served as the primary imaging modality for CAV diagnosis [7]. The major limitation of angiography is its limited sensitivity in identifying eraly, small-vessel, or even advanced diffuse CAV [7]. The diffuse luminal narrowing of advanced CAV leads to difficulties in identifying reference segments and branch vessel obliteration may go unrecognized [7].

Intravascular US is the most sensitive imaging modality for the detection of CAV (CAV is defined as [maximial intimal thickness] - [intima and media thickess] of greater than 0.5 mm) [4]. The presence of severe intimal thickening  ≥ 0.5 mm in the first year after transplant by IVUS predicts cardiac events, graft loss, and death [7]. Coronary angiography is known to underestimate CAV when compared to IVUS [6].

The presence of coronary calcium indicates the presence of CAV and is a strong predictor of future cardiac events, however, CAC is an insensitive marker for CAV and can be absent in 6% of patients with substantial CAV at angiography [5,6]. Multidetector coronary CT has an advantage over conventional angiography for the detection of CAV (the diffuse nature of the process may hinder it's identification by angiography) [1,4]. Difficulties with CTA imaging may occur with elevated HR's and lack of response to beta-blockers in post-cardiac transplant patients [4]. Retrospective gating can be used, but this will increase patient radiation exposure [5]. The reported sensitivity of CTA for CAV on a per segment (and per patient) basis is 83% (86%), specificity 99% (89%), PPV 76% (67%) and NPV 99% (96%) [4].

SPECT myocardial perfusion imaging can detect perfusion abnormalities secondary to CAV [2]. The reported sensitivity is 84%, specificity 70%, and NPV at 12 months is 95-98% [6]. Because of the diffuse nature of CAV, SPECT MPI may underestimate the severity due to image normalization errors [6]. Dobutamine stress can utilized instead of exercise because of the blunted heart rate response to exercise common in post cardiac transplant patients [6]. Adenosine is not commonly used in heart transplant patients given concerns for AV block and sinus pauses or arrest that can occur due to adenosine supersensitivity in denervated hearts (although the effects are typically transient) [7,8]. Compared to adenosine, regadenoson has been shown to cause less conduction abnormalities in patients that are several years post-transplant (its safety in the early post-transplant period has not been fully evaluated) [6].

However, using dynamic PET to accurately determine myocardial blood flow, impaired coronary flow reserve can be detected in up to 20% of patients with normal semiquantitative imaging [3]. Note that resting MBF is higher in heart transplant patients compared to controls likely due to increasing resting heart rate and rate-pressure product in the denervated heart [8].

For the diagnosis of CAV (>50% stenosis), coronary CTA has a mean weighted sensitivity of 94%, specificity of 92%, NPV of 99%, PPV of 67%, and a diagnostic accuracy of 94% [7]. CCTA is limited for the evaluation of small coronary vessels and motion artifacts can degrade the exam, particularly in association with the high heart rates that are commonly encountered with denervated hearts [7].

REFERENCES:

(1) J Nucl Cardiol 2010; Soman P, et al. Surveillance for post-transplant coronary artery vasculopathy: shifting gears from diagnosis to prognosis. 17: 172-174

(2) J Nucl Cardiol 2010; Manrique A, et al. Diagnostic and prognostic value of myocardial perfusion gated SPECT in orthotopic heart transplant recipients. 17: 197-206

(3) J Nucl med 2010; Wu YW, et al. PET assessment of myocardial perfusion reserve inversely correlates with intravascular ultrasound findings in angiographically normal cardiac transplant recipients. 51: 906-912

(4) J Cardiovasc Comput Tomogr 2012; Ferencik M, et al. Computed tomography imaging of cardiac vasculopathy. 6: 223-231

(5) Radiology 2013; Mittal TK, et al. Cardiac allograft vasculopathy after heart transplantation: electrocardiographically gated cardiac CT angiography for assessement. 268: 374-381

(6) J Nucl Cardiol 2015; Gupta B, et al. Imaging in patients after cardiac transplantation and in patients with ventricular assist devices. 22: 617-638

(7) J Nucl Cardiol 2016; Payne GA, et al. Transplant allograft vasculopathy: role of multimodality imaging in surveillance and diagnosis. 23: 713-727

(8) J Nucl Cardiol 2017; Sevag RR, Maddahi J. Regadenoson-induced hyperemia for absolute myocardial blood flow quantitation by 13N-ammonia PET and detections of allograft vasculopathy. 24: 1145-1148

(9) Radiographics 2019; Smith JD, et al. Evaluation after orthotopic heart transplant: what the radiologist should know. 39: 321-343

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