Heart Failure, Pulmonary Hypertension, and Cardiac Transplantation
Charlotte Van Dorn
Jonathan N. Johnson
Robert E. Shaddy
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1. A 13-year-old male sees you in clinic for routine followup. He is 2 years post orthotopic heart transplantation for dilated cardiomyopathy. He reports that he has felt “jittery” lately. When he lifts his hand, he is unable to keep it still. Which of the following medications most likely is causing this degree of tremulousness in this patient?
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. A 3-year-old male with normal intracardiac anatomy is undergoing a cardiac catheterization procedure with the following measurements:
Nitric oxide 80 ppm
LVSP 68 mm Hg
LVSP 72 mm Hg
LVSP 74 mm Hg
LVEDP = 6 mm Hg
LVEDP = 5 mm Hg
LVEDP = 4 mm Hg
CI = 3.0 L/min/m2
CI = 3.1 L/min/m2
CI = 2.9 L/min/m2
RPA = 41/17 mean 30 mm Hg
RPCW = mean 10 mm Hg
RPA = 32/13 mean 22 mm Hg
RPCW = mean 7 mm Hg
RPA = 29/12 mean 20 mm Hg
RPCW = mean 9 mm Hg
LVSP: Left ventricular systolic pressure
LVEDP: Left ventricular end-diastolic pressure
RPA: Right pulmonary artery
RPCW: Right pulmonary capillary wedge
CI: Cardiac index
Which of the following is the best treatment for this patient?
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
ratio. For IPAH
patients, responsive PVR
carries increased likelihood to long-term response to calcium channel blockers and better prognosis.
3. A 15-month-old male infant is 4 weeks post orthotopic heart transplantation. His parents bring him in with new-onset fussiness over the past day. He has been refusing to eat or drink for the last 4 hours. Of the following new physical examination findings, which one is most concerning for allograft rejection?
A. Petechiae on his right foot
B. Splitting of the first heart sound
E. Soft 1/6 systolic murmur at the left upper sternal border
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. A 14-year-old patient, 2 years post orthotopic heart transplantation for dilated cardiomyopathy, presents with new-onset shortness of breath. An echocardiogram is performed as part of the workup. Which of the following echo findings is most concerning for rejection?
A. Increase in the descending aorta flow velocity from 1.2 to 1.4 m/s
B. Decrease in the left ventricular ejection fraction from 68% to 62%
C. Increase in the lateral mitral valve e′ velocity from 0.08 to 0.12 m/s
Decrease in the IVC
diameter from 2.3 to 1.8 cm.
E. Increase in the degree of mitral regurgitation from trivial to moderate
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.
A 14-year-old female presents for routine follow-up. She had an orthotopic heart transplantation at age 7 months for hypoplastic left heart syndrome and ventricular dysfunction. On examination, she has a blood pressure in her right arm of 150/85 mm Hg. Echocardiography reveals the following abdominal aortic Doppler signal (see Figure 11.1
). Which of the following is the next best step?
for administration of a steroid bolus (10 mg/kg/dose q24 hours × 3)
B. Operating room for tricuspid valve repair
C. Cardiac cath lab for balloon angioplasty or stenting
Operating room for revision of IVC
Cardiac cath lab for coronary angiography with intravascular ultrasound (IVUS
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.
You are evaluating a 16-year-old male for a second opinion. He has a history of d-transposition of the great arteries and uneventful arterial switch operation at 3 days of life. He now complains of severe pulmonary hypertension, complicated by syncope and ascites. He underwent a cardiac catheterization procedure elsewhere. Which of the following is a theoretical advantage of the procedure pointed to by the arrow in Figure 11.2
over atrial septostomy?
A. Decreases central venous pressure
B. Increases left ventricular preload
C. Decreases left ventricular afterload
E. Higher peripheral arterial saturations
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. A 7-year-old female with a history of orthotopic heart transplantation 2 years ago presents with new-onset seizures. The seizures are controlled successfully with benzodiazepine administration. Laboratory evaluation reveals that the patient’s tacrolimus level is 31.2 (goal range 6 to 8). Two weeks ago, the child’s tacrolimus level was 7.9. The family reports that the child was started on a new medication 1 week ago by their primary care pediatrician. Which of the following is the most likely medication that was started?
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 14-year-old female is referred for evaluation for orthotopic cardiac transplantation. In the teenage years, which of the following is the most common indication for orthotopic heart transplantation?
B. Congenital heart disease
E. Intractable arrhythmias
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. An 8-year-old male with restrictive cardiomyopathy is admitted to the hospital with shortness of breath. Which of the following examination or test findings portends a poor prognosis for this child?
A. Pulmonary venous congestion on chest radiography
B. Increased medial mitral valve annular E′ velocity on echo
C. 2/6 low-pitched systolic murmur heard at the left lower sternal border
D. Right atrial enlargement on echo
E. Isolated PACs on 24-hour Holter monitoring
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. You are seeing a 2-year-old patient in clinic who is now 4 months post orthotopic heart transplantation. His mother recently has gone back to work, and the patient is cared for by maternal grandmother. For the past 2 weeks, the child’s mother reports that he has been more irritable and has a poor appetite. The child’s pediatrician saw him the day prior and noted no significant examination findings other than a potential gallop rhythm. There have been several recent ill contacts for the patient, all of whom have been diagnosed with upper respiratory viral illnesses.
In this patient, which of the following tests is the best to rule out rejection?
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. A 14-year-old female is admitted to the intensive care unit for monitoring after elective surgery. She has a history of hypoplastic left heart syndrome and underwent orthotopic heart transplantation as a neonate. She has had a relatively uncomplicated course, with no arrhythmias or other complications. During monitoring overnight, her nurse noted intermittent premature ventricular contractions, with brief runs of ventricular tachycardia. Which of the following is the most likely cause of her new-onset arrhythmia?
B. Coronary artery vasculopathy
Posttransplant lymphoproliferative disorder (PTLD
Posterior reversible encephalopathy syndrome (PRES
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. Which of the following is a contraindication to orthotopic heart transplantation to a pediatric patient?
A. History of Fontan operation
B. Pulmonary vascular resistance ≥ 12 Woods units after nitric oxide administration
C. History of protein-losing enteropathy
D. Prior alcohol addiction, has been sober for 1 year
E. History of pulmonary embolism, resolved
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.
A 5-year-old female comes to the emergency department after one episode of loss of consciousness and “heart fluttering” for the last 12 hours. She has a history of dilated cardiomyopathy (DCM
) secondary to an episode of myocarditis 6 months ago; she is currently on enalapril and propranolol, and echocardiogram shows LV
end-diastolic dimension Z score of 1.6 with LV
ejection fraction of 15%. Which of the following is her strongest predictor of sudden cardiac death (SCD
A. History of myocarditis
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).
A previously healthy 4-year-old female is referred due to fatigue. Echocardiogram shows normal LV
systolic function (LV
ejection fraction 60%). Physical examination is unremarkable, and cardiac catheterization reveals the following:
75/6 mm Hg
Left ventricular end-diastolic pressure
15 mm Hg
72/46 mm Hg
28/2 mm Hg
Right ventricular end-diastolic pressure
9 mm Hg
Main pulmonary artery
25/10 mm Hg
Which of the following is most likely to be present on echocardiography?
A. Mitral inflow E:A ratio = 0.6
end-diastolic diameter Z score = 2.5
C. Septal bowing to the left with inspiration
E. Normal indexed left atrial size
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. An 8-year-old male with restrictive cardiomyopathy is admitted to the hospital with shortness of breath. He has pulmonary venous congestion on his chest radiogram. His echocardiogram shows normal ventricular systolic function, massively dilated atria, and an estimated right ventricular systolic pressure of 65 mm Hg (systemic systolic blood pressure 120 mm Hg). Which of the following is the next best step in management of this patient?
to rule out pulmonary vein stenosis
D. Begin ACE-inhibitor medication
E. Begin evaluation for orthotopic heart transplantation
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. A 13-year-old male is admitted for initiation of treprostinil. Which of the following is true regarding this medication?
A. Liver function should be monitored before and during treatment
Discontinuation of IV
infusion can lead to pulmonary hypertension crisis in minutes
C. It exerts its effect through potentiation of nitric oxide
D. It causes vasodilation through increased cyclic AMP signaling
E. Head imaging is recommended within 24 hours of initiation of the medication
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).
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