Authors: Lyana Labrada, Tripti Gupta, Christiane Haeffele, Adam D. DeVore, Jonathan Menachem
Categories: Congenital Heart Disease, cardiac transplant, congenital heart defect, pulmonary hypertension
Source: JACC Case Reports
Authors: Lyana Labrada, Tripti Gupta, Christiane Haeffele, Adam D. DeVore, Jonathan Menachem
“Shone's syndrome” was identified in 1963 as a constellation of 4 coexisting lesions leading to left ventricular inflow and outflow obstruction. This congenital heart disease syndrome has hemodynamic consequences throughout the lifetime of patients with this syndrome, and these patients often progress to requiring advanced therapies. This case series reviews the complex decision-making involved in advanced therapy evaluation for this specific patient population. We present 8 cases of patients with Shone's syndrome who were referred for advanced therapies. Of these patients, 6 patients went on to heart transplant alone and 2 patients underwent dual organ transplant. Two patients died after transplant. These cases each highlight important considerations for transplant in this patient population, including the development of pulmonary hypertension, potential need for single vs dual organ transplant, and complex pre- and postoperative courses. We emphasize the importance of early referral for advanced therapies, multidisciplinary evaluation, and individualized care for these complex patients.
As the population of adults with congenital heart disease (CHD) has aged and required advanced therapies such as heart transplant, increasing emphasis has been placed on understanding the mechanism of failure for complex CHD. Patients with CHD with biventricular physiology have been shown to have better outcomes with transplant than patients with univentricular physiology, and their long-term risk for poor outcomes has been considered similar to patients without CHD.^1^^,^^2^ Although patients with “Shone's syndrome” have biventricular physiology, there remains a unique set of challenges when pursuing advanced therapies.
Shone's syndrome was described by Dr John Shone in 1963 as a complex of 4 coexisting lesions leading to left ventricular (LV) inflow and outflow obstruction, including parachute mitral valve (MV), supravalvular ring, subaortic stenosis, and aortic coarctation.^3^ In reality, there exists a wide spectrum of both the presence and severity of lesions, and it is not uncommon for patients to undergo multiple staged surgeries.^4^
Although still rare, more of these patients have been referred for advanced therapies. Despite these patients having biventricular physiology, they frequently present late in their course, leading to challenging transplant courses. In some cases, by the time of referral, the patients are too ill to be considered candidates. We present a series of 8 patients (Table 1) from 3 institutions with Shone's syndrome who were referred for advanced therapy evaluation and proceeded to transplant.Table 1Case CharacteristicsCase 1Case 2Case 3Case 4Case 5Case 6Case 7Case 8Age, y4324203732374129No. of sternotomies64644276cPRA >50%NoYesNoNoNoNoYesYesWaitlist time (d)993281052202110588Pretransplant hemodynamics RA mean (mm Hg)10131010155174 PA s/d/m (mm Hg)60/22/37142/71/10159/16/3760/26/41136/68/8632/14/2180/43/5713/7/10 PCWP a/v/m (mm Hg)23/28/2428/36/3114/28/1618/26/201814169 RA/PCWP0.410.40.630.50.80.3610.4 PVR (Wood unit)3.914.42.73.820.41.612.60.4 PVR/SVR0.190.60.340.3410.10.60.02 CO/CI3/24.7/2.66.4/3.25.5/2.93.3/2.34.3/2.63.3/2.22.8/1.4 Reversible nitroprusside challengeYesN/aN/aYesN/aN/aNoN/a Preoperative pulmonary vasodilatorsYesYesYesYesYesNoYesNoEcho parameters LVEF41%655550%55204045 RVSP (mm Hg)48105504156314535 RV functionMildNLNLMildModerateMildNLModerate RV sizeMildMildNLMildNLNLNLMildPostoperative course OrganOHTOHTOHTOHT/LiverOHT/LungOHTOHTOHT Pulmonary vasodilatorsYesYesYesYesNoYesYesYes ICU stay (d)5724121214664 (died)32 Intubation (days)11421534 (died)11 MCSNoYesNoNoYesYesYesYes PGDNoNoNoNoYesYesYesYes Death at 30 d/1 yNo/NoNo/NoNo/NoNo/NoNo/YesNo/NoYes/YesNo/NoPreoperative data, hemodynamic data, echocardiographic data and post-operative details for each Shone's patient referred for advanced therapies are outlined.CI = cardiac index; CO = cardiac output; cPRA = calculated panel reactive antibody; ICU = intensive care unit; LVEF = left ventricular ejection fraction; MCS = mechanical circulatory support; N/a = not applicable; NL = normal; OHT = orthotopic heart transplant; PA = pulmonary artery; PCWP = pulmonary capillary wedge pressure; PGD = primary graft dysfunction; PVR = pulmonary vascular resistance; RA = right atrium; RV = right ventricle; RVSP = right ventricular systolic pressure; SVR = systemic vascular resistance.
Patient 1 was a 43-year-old woman with a history of a bicuspid aortic valve (AV), subaortic membrane, aortic coarctation, and parachute MV, who required 6 sternotomies. She was referred for advanced therapy evaluation at age 41 for worsening LV systolic function. The echocardiogram demonstrated a mildly dilated right ventricle (RV), and right heart catheterization demonstrated mild pulmonary hypertension (PH) reversible with nitroprusside, and no evidence of elevated pulmonary vascular resistance (PVR). Given that PH was reversible, a decision was made to proceed with heart transplant alone. She underwent heart transplant at age 41. Her postoperative course was complicated by a bradycardic arrest; acute kidney injury, which progressed to end-stage renal disease; hypoxic respiratory failure, which led to tracheostomy; and RV dysfunction, which required pulmonary vasodilators.
Patient 2 was a 24-year-old woman with a history of congenital mitral stenosis, which required multiple MV interventions during childhood. She underwent a third MV intervention at age 23, with a mechanical MV positioned superior to the annulus in the left atrium to avoid subaortic obstruction and resection of LV outflow tract endocardial fibrosis. Postoperatively, she had elevated right-sided filling pressures and an elevated PVR value, but with preserved RV size and function. A decline in her functional capacity prompted advanced therapy evaluation. The etiology of her PH was deemed to be secondary to mechanical obstruction of her pulmonary veins, in addition to pulmonary venous hypertension (PVH) secondary to LV outflow obstruction and long-standing MV disease. Given these circumstances along with preserved RV size and function, her PH was determined not to be a barrier to transplant. In multidisciplinary discussions, it was deemed that without transplant, she would likely require multiple future valve interventions and therefore multiple subsequent sternotomies, which made a future transplant even riskier. Therefore, a decision was made to proceed with transplant at that time, and she underwent isolated heart transplant. Her postoperative course was complicated by graft dysfunction requiring extracorporeal membrane oxygenation (ECMO), high PVR requiring pulmonary vasodilators, and renal dysfunction requiring dialysis. With progressive improvement, she was decannulated and was eventually discharged but did require long-term dialysis.
Patient 3 was a 20-year-old man with a history of severe mitral stenosis and regurgitation, aortic stenosis, and a subaortic membrane. His surgical history included 6 sternotomies for various MV and AV interventions, subaortic membrane resection, and septal myectomy. At age 19, he was noted to have severe diastolic dysfunction. He also had frequent hospitalizations for hemoptysis secondary to aortopulmonary collaterals requiring coiling. Given the increased frequency of heart failure hospitalizations, he was evaluated for advanced therapies. He was noted to have mixed precapillary and postcapillary PH, with normal RV function, and was optimized with treprostinil pretransplant. Given a predominantly postcapillary PH phenotype and normal RV function, he was evaluated for heart transplant alone, rather than heart-lung transplant. As symptoms progressed, he was placed on milrinone and underwent heart transplantation at age 20. His postoperative course was complicated by PH and RV dysfunction, for which he was treated with inhaled and intravenous pulmonary vasodilators. This regimen was eventually transitioned to tadalafil and weaned off within 4 months of transplant.
It is well known that patients with Shone's syndrome are prone to developing PH, with a lifetime of LV inflow and outflow obstruction.^5^^,^^6^ Chronically elevated left atrial and LV end-diastolic pressures can lead to development of postcapillary PH. In most patients with postcapillary PH or PVH, correction of left-sided lesions may reverse PH. However, long-standing left-sided disease may cause irreversible remodeling of the pulmonary vasculature and arterial walls, leading to precapillary PH. Indeed, it has been shown that despite their relatively young age, these patients have a high prevalence of LV diastolic dysfunction and develop a mixed picture of PH, with both pre- and postcapillary components.^6^
This complicates consideration for heart transplant, given that PH, but more specifically pulmonary vascular disease, with a PVR value of >3 WU is a well-known contraindication for transplant.^7^^,^^8^ These guidelines stem from the risk of early RV failure secondary to an inability to adapt to an acute increase in afterload from the pulmonary vascular disease of the recipient. It is primarily progressively elevated PVR, rather than PVH, that may ultimately lead to RV failure after cardiac transplantation. Therefore, in this patient population being referred for advanced therapies with varying degrees of elevated PVR and PVH, it is important to clarify the forefront phenotype of PH, as this will affect the decision for transplant candidacy. PVH is usually not a barrier for heart transplant alone, while true precapillary PH may necessitate combined heart-lung transplant. This differentiation between elevated PVR and PVH can be made by careful clinical examination of both echocardiographic and hemodynamic characteristics, as was important in the cases above.^9^
In patients with Shone's syndrome who develop PH, careful treatment with pulmonary vasodilators may be indicated. In these patients, the goal of treatment with pulmonary vasodilators remains to reduce PVR enough to maintain near-normal RV function.
Patient 4 was a 38-year-old man with a history of mitral stenosis, subaortic stenosis, bicuspid AV, and aortic coarctation, in addition to cardiac cirrhosis and PH. He had 4 sternotomies by the time he was referred for advanced therapy evaluation at age 36 because of progressive right and left heart failure. He was initially deferred for advanced therapies because PH was not completely reversible with a nitroprusside challenge, but then he was started on pulmonary vasodilators with interval improvement in PVR. Given biopsy proven cirrhosis, he was evaluated for and approved for dual heart-liver transplant. As he had improvement in his PH with pulmonary vasodilators, he was deemed not to need lung transplant. Pretransplant, he was hospitalized for 2 months with volume overload and renal dysfunction, which required high doses of diuretic agents. He underwent dual heart-liver transplant. His postoperative course was complicated by ongoing PH, renal dysfunction, and sepsis. He received inhaled epoprostenol immediately postoperatively, which was transitioned to sildenafil and weaned off.
Patient 5 was a 32-year-old woman with a history of mitral stenosis, subaortic stenosis, bicuspid AV, and coarctation of aorta. She had aortic coarctation repair and closure of a patent ductus arteriosus as a neonate and resection of a supravalvular MV ring and MV replacement as a child. She subsequently required 2 more mechanical MV replacements and an AV replacement. She eventually presented to a quaternary care center with an elevated MV gradient and severe PH. She was treated with pulmonary vasodilators without improvement in her pressures and underwent heart-lung transplant. Her postoperative course was complicated by primary graft dysfunction requiring mechanical support and renal dysfunction requiring dialysis. She subsequently developed multiple infectious complications and was transitioned to comfort care.
The potential for development of PH or cardiac cirrhosis in the setting of long-standing left-sided heart disease in patients with Shone's syndrome may prompt the need for dual organ transplant. In the setting of progressive pulmonary vascular disease, there remains the risk of RV failure with heart transplant alone, and therefore, dual heart-lung transplant may be indicated in these settings, as in patient 5. Furthermore, the development of irreversible cardiac cirrhosis may prompt heart-liver transplant, as was done for patient 4 in our series. As the risks of dual organ transplant are significantly higher than single organ transplant, early referral for evaluation before the development of irreversible PH or cardiac cirrhosis is favorable.
Patient 6 was a 37-year-old woman with a parachute MV, bicuspid AV, coarctation of aorta, and a ventricular septal defect, who underwent surgical repair of the coarctation of aorta and pulmonary artery band placement as a neonate and subsequent repair of the ventricular septal defect as a child. As an adult, she developed LV dysfunction and severe MV regurgitation requiring MV replacement. She did well for several years, but her LV dysfunction progressed and she developed advanced heart failure requiring inotropic support. She underwent isolated heart transplant. Her postoperative course was complicated by primary graft dysfunction, which required ECMO. Graft function recovered, and she was discharged home on postoperative day 14.
Patient 7 was a 41-year-old woman with congenital MV stenosis, subaortic stenosis, AV stenosis, and coarctation of aorta. Her surgical history included 7 sternotomies for MV and AV repairs, subsequent replacement, and multiple subaortic stenosis resections. She developed recurrent atrial and ventricular arrhythmias as well as progressive LV dysfunction requiring inotropic support and PH requiring pulmonary vasodilators. Although multiple prior sternotomies increased surgical risk, a decision was made to proceed with transplant rather than continuing to address each valvular issue separately. Her young age and high likelihood of needing multiple future valvular interventions otherwise tipped the favor toward transplant. She underwent isolated heart transplant, and her postoperative course was complicated by primary graft dysfunction requiring ECMO. She had significant coagulopathy and died of multiorgan dysfunction on postoperative day 4.
Patient 8 was a 29-year-old man with a history of congenital MV stenosis, subaortic stenosis, and AV stenosis. He underwent aortic valvotomy, followed by surgical enlargement of the LV outflow tract, AV replacement, and redo AV replacement, complicated by coronary injury requiring placement of coronary bypass grafts. He developed a perivalvular leak and was treated with vascular plugs on separate occasions. He eventually developed advanced heart failure requiring inotropes and underwent heart transplantation. His postoperative course was complicated by primary graft dysfunction, which required mechanical support, and renal dysfunction, which required dialysis, but both his heart and kidneys recovered, and he was discharged to home on postoperative day 49.
This series demonstrates that patients with Shone's syndrome who ultimately undergo heart transplant not only have a complex road to transplant but also often have complicated postoperative courses. At the time of referral, most of these patients had multiple sternotomies, which greatly increases surgical risk during transplant. Multidisciplinary discussion and individualized assessment are key in these cases, and the surgical approach must require a thorough review of imaging preoperatively and meticulous entry during redo sternotomy, recognizing and being prepared for the increased risk of bleeding. Postoperatively, our case series demonstrates a high rate of mechanical circulatory support (62.5%), prolonged intensive care unit courses (mean = 36.6 days), and a high rate of primary graft dysfunction (50%). Two of the 8 patients transplanted died at 1 year. This highlights the complexity of these patients despite their young age.
All 8 patients were referred for transplant evaluation after multiple prior sternotomies. Complicating decision-making, it is often not progressive systolic dysfunction that prompts evaluation. Four of our 8 patients had normal LV systolic function at the time of referral. In the setting of progressive left-sided lesions, clinicians must use an individualized approach to weigh the risk and benefits of proceeding with further medical therapy and/or surgical lesion repair vs proceeding with transplant. Other important considerations included the degree of PH and RV dysfunction, the number of prior sternotomies, the predicted number of future sternotomies with surgical lesion repair, the potential need for dual organ transplant, and the degree of sensitization given multiple prior surgeries. In our cohort, 7 of the 8 patients required pulmonary vasodilators either pre- or postoperatively to maintain normal RV function, and 3 of the 8 patients had a calculated panel reactive antibody level >50%. These considerations prompt the Shall we do one fewer surgical repair in these patients before transplant? (Figure 1). In each case, clinicians must use an individualized approach to weigh the risk and benefits of proceeding with further medical therapy and/or surgical repair vs proceeding with transplant.Figure 1Important Considerations Regarding Optimal Timeline of ReferralThe optimal timeline of referral for advanced therapies in patients with Shone's Syndrome ideally should be prior to a significant decline in functional capacity, worsening liver disease, pulmonary hypertension, and allosensitization. The number of sternotomies and predicted future sternotomies are also taken into consideration. cPRA = calculated panel reactive antibody; PH = pulmonary hypertension; PVR = pulmonary vascular resistance.
We present a series of 8 patients with Shone's syndrome referred for transplant. In summary, 6 patients went on to heart transplant alone and 2 patients underwent dual organ transplant. Despite biventricular physiology, the physiological derangements in the setting of long-standing left heart disease complicate decision-making regarding advanced therapy evaluation and post-transplant management. Although Shone's syndrome is defined by the presence of left-sided lesions, it is interesting that it is the assessment of the right heart that may inform appropriate timing of referral, need for pulmonary vasodilators, and need for dual organ transplant. Despite the lack of evidence in this field, it remains clear that early referral for advanced therapy evaluation and an individualized approach are key.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose.Take-Home Messages•There are multiple considerations for transplant evaluation in patients with Shone's syndrome, including medical complexity, multiple prior sternotomies, and allosensitization.•Pulmonary hypertension and cirrhosis can develop over time, complicating evaluation and potentially necessitating dual organ transplant.•Early referral and an individualized approach are key in considering advanced therapies for this patient population.