1. (D) Irritability and tremulousness are common side effects of tacrolimus which tend to happen when serum levels are high. At high enough levels, tacrolimus toxicity can cause seizures to occur. The most common complication of azathioprine and mycophenolate is leukopenia, though many patients may have gastrointestinal side effects as well (constipation, diarrhea, nausea). The most common side effects of sirolimus are diarrhea and the development of mouth sores. The side effects of prednisone are well documented, including mood changes, increased appetite, increased blood glucose, weight gain, and a Cushingoid appearance. Long-term use is associated with the development of osteoporosis.

2. (B) Patient presents mild pulmonary hypertension (mean PAP = 30 mm Hg) with moderately elevated pulmonary resistance (PVR = 6.7 WU) at baseline, with decreased PVR to 4.8 and 3.8 with 100% oxygen and NO, respectively. According Answers to the latest Pediatric Pulmonary Hypertension guidelines (Abman et al., 2015), for patients with idiopathic pulmonary arterial hypertension (IPAH) (and no CHD), a positive response to acute vasoreactivity testing (AVT) (to either oxygen and/or nitric oxide) is defined as (1) a decrease in mPAP of at least 10 mm Hg to <40 mm Hg with a normal or increased cardiac output; and/or (2) a decrease in mPAP of ≥20%, an increase or no change in CI, and a decrease or no change in PVR/SVR ratio. For IPAH patients, responsive PVR carries increased likelihood to long-term response to calcium channel blockers and better prognosis.

3. (D) Of all examination findings listed above, the presence of a new gallop rhythm is the most sensitive for rejection, though there typically are a constellation of findings. There may also be tachycardia, new murmurs of mitral regurgitation or tricuspid regurgitation, or evidence of congestion (hepatomegaly, jugular venous distension, abnormal chest x-ray, etc.). Early after transplant, the patient may be anemic resulting in the soft flow murmur as in answer (E).

4. (E) There is no single echocardiographic finding that, by itself, has been shown to have perfect sensitivity or specificity for rejection in transplant patients. This being said, the most common findings seen in patients with active rejection include new effusions, increased wall thickness and ventricular mass, and increased mitral or tricuspid valve regurgitation. Recent studies have shown that decreases in mitral valve tissue Doppler velocities may be very sensitive at detecting potential rejection episodes. The remainder of the findings listed are unlikely to be associated with rejection.

5. (C) The patient has evidence of diastolic continuation of forward flow in the abdominal aorta, consistent with upstream obstruction, most likely recoarctation. Patients with a history of hypoplastic left heart syndrome are at a particular risk for this complication after heart transplant.

6. (D) Reversed Potts shunt is a surgical or interventional alternative in the management of severe PH with intractable right heart failure. It involves the anastomosis of the left pulmonary artery and the descending aorta, with systolic right-to-left shunt, leading to decreased right afterload and improved function. As opposed to atrial septostomy, it does not decrease central venous pressure or increase left ventricular preload, although it does increase left ventricular afterload. As right-to-left shunt occurs at the descending aorta, there is lower risk of stroke, and central saturation is maintained (at the expense of peripheral cyanosis).

7. (D) Antifungal medications are a consistent cause of increased calcineurin inhibitor levels in transplant patients. As such, any time any of these medications are considered being started, close monitoring of tacrolimus or cyclosporine is required. Other medications that may increase their levels include amiodarone, macrolide antibiotics, calcium channel blockers, and metoclopramide. Medications that may decrease calcineurin inhibitor levels include: octreotide, some anticonvulsants (phenytoin, phenobarbital, carbamazepine), and some antibiotics (nafcillin, IV Bactrim). Beta blockers have little effect on tacrolimus or cyclosporine levels. Patients who have tacrolimus toxicity have irritability and tremulousness and may have seizures if levels are high enough.

8. (A) For patients over the age of 1 year, especially in teenagers, the most common underlying diagnosis in patients undergoing orthotopic heart transplantation is cardiomyopathy (including dilated, restrictive, hypertrophic, and noncompaction cardiomyopathies). For infants, congenital heart disease is the most common indication, though this has been decreasing in the last several years. In the 1990s, almost 75% of infants having transplants had congenital heart disease; this has decreased to 53% in the most recent 5 years. The reasons behind this are multifactorial but are at least in part indicative of improved Norwood outcomes for patients with hypoplastic left heart syndrome.

9. (A) In patients with restrictive cardiomyopathy, the presence of significant cardiomegaly and pulmonary venous congestion on chest x-ray are poor prognostic indicators. Cath-measured left ventricular end-diastolic pressure and the degree of left atrial dilatation are also predictive of poor survival. Patients with restrictive cardiomyopathy have low tissue Doppler parameters, including the medial mitral valve annular E′ velocity. Right atrial enlargement on echo and a murmur consistent with tricuspid regurgitation have not been shown to predict poor outcomes, though they may be indicative of the degree of right ventricular dysfunction.

10. (E) Despite advances in other imaging technologies in recent years, the gold standard test to “rule out” rejection in a patient remains a myocardial biopsy obtained in the cardiac catheterization laboratory. Cardiac MRI may be useful in certain situations; however, the lack of tissue diagnosis, the relative lack of availability in the acute setting, and lack of data in pediatric patients do not yet support its use. Electrocardiographic changes may be seen in patients with rejection, including low-voltage QRS signals, though this is rarely diagnostic in isolation. Plasma BNP has been shown in several studies to be indicative of potential rejection when compared to baseline, though this is more an adjunctive test than a diagnostic one. Echocardiography is used at many centers on an intermittent basis to rule out rejection and can be very useful at limiting the number of biopsies performed. However, biopsy remains the gold standard.

11. (B) New-onset arrhythmia in a cardiac transplant recipient should raise concern for either rejection or coronary artery vasculopathy. In this patient 14 years out from transplant, the most likely diagnosis is coronary artery vasculopathy. Early after transplant, arrhythmias or ectopy may be a sign of rejection, though this is relatively nonspecific.

12. (B) An elevated pulmonary vascular resistance is a contraindication for heart transplantation, primarily due to the inability of the donor right ventricle to tolerate pumping against the elevated pressure and resistance. If the pulmonary hypertension is somewhat reversible with pulmonary vasodilators, transplantation might be considered, recognizing that significant right ventricular support may be needed postoperatively. A history of Fontan operation, protein-losing enteropathy, or plastic bronchitis are not contraindications to transplant; however, they do increase the risk of transplant due to multiple factors (extracardiac organ dysfunction, poor nutrition and wound healing, increased infection risk, increased risk of antibody-mediated rejection, and difficulty assessing prior sensitization). Drug or alcohol addiction is a contraindication, unless the patient is able to fulfill a predetermined period of time of sobriety—the exact length of time is institution dependent. A history of resolved pulmonary embolism is not a contraindication, though an active pulmonary embolism is.

13. (B) Risk factors for SCD in pediatric DCM patients have been reported to include LV end-diastolic dimension Z score ≥2.6, age at diagnosis of cardiomyopathy <14 years, ratio of LV posterior wall thickness to LV end-diastolic dimension ratio <0.14, and presence of congestive heart failure at presentation of DCM. Sex, ethnicity, cause of DCM, and family history were not associated with SCD (impact of LVEF was not evaluated).

14. (A) Hemodynamic data are consistent with ventricular diastolic dysfunction. In the context of a previously healthy child, the likelihood of constrictive pericarditis is extremely low, so the most likely diagnosis is restrictive cardiomyopathy (RCM). The most sensitive finding in the pediatric population is a dilated left atrium. Other findings include clinical or subclinical (abnormal S’ wave on tissue Doppler) left ventricular systolic dysfunction (LVEF <55%), left ventricular hypertrophy, abnormal mitral inflow Doppler with inversed E:A ratio, and increased pulmonary vein atrial reversal on pulsed-wave Doppler (remember that with mitral inflow Doppler, normal E:A ratio is between 1.0 and 3.0). Left ventricular dilation is not a feature of RCM. Septal bowing with inspiration is suggestive of constrictive pericarditis.

15. (E) In patients with restrictive cardiomyopathy, the presence of significant cardiomegaly and pulmonary venous congestion on chest x-ray are poor prognostic indicators. Current medical therapy options are ineffective, and thus cardiac transplantation is considered the definitive therapy. Without transplantation, some authors have reported up to 50% mortality within 2 to 3 years of diagnosis of restrictive cardiomyopathy. Outside of transplant, the only medical therapy that has been reported to be useful is limited diuresis to help improve symptoms. However, caution must be used in this situation, as these patients are very sensitive to preload, and over-diuresis can be problematic. ACE-inhibition has not been shown to be of benefit in pediatric patients with restrictive cardiomyopathy. Ultrasound of the liver will likely be performed as part of a transplant evaluation, as there is a risk of long-term hepatic congestion; however, this is very unlikely to change the ultimate course in a pediatric patient. Pulmonary vein stenosis should be ruled out in a patient with elevated right ventricular systolic pressure; however, the massive left atrial enlargement points to the ventricles being the problem rather than the pulmonary veins.

16. (D) Treprostinil is a prostacyclin analog, which causes pulmonary vasodilation through increased cyclic adenylate monophosphate and enhanced adenylate cyclase action in vascular smooth muscle cells. If administered intravenously, it is not associated with acute PH crisis given its half-life of 4 hours, unlike Epoprostenol which will cause an acute PH crisis if infusion is stopped. Treprostinil can also be administered via subcutaneous infusion, avoiding the need of a central catheter, and it is currently in trial phases for oral administration. Treprostinil is not associated with hepatotoxicity (endothelin receptor antagonists are).