Author: Melissa Colizza, MD - Stollery Children’s Hospital - Edmonton, Alberta
A 6-day-old neonate with hypoplastic left heart syndrome (HLHS) requires venoarterial extracorporeal membrane oxygenation for low cardiac output and inability to wean from cardiopulmonary bypass after a Norwood/Sano procedure. The patient expires due to multi-system organ failure without recovery of myocardial function. Autopsy demonstrates diffuse biventricular fibroelastosis and evidence of ventriculo-coronary connections. Which of the following anatomical subtypes of HLHS is MOST likely associated with these autopsy findings?
The 2021 International Paediatric and Congenital Cardiac Code (IPCCC) and the eleventh revision of the International Classification of Diseases (ICD-11) defines hypoplastic left heart syndrome (HLHS) as a “spectrum of congenital cardiovascular malformations with normally related great arteries, without a common atrioventricular junction, characterized by underdevelopment of the left heart and significant hypoplasia of the left ventricle, including atresia, stenosis, or hypoplasia of the aortic or mitral valve, or both valves, and hypoplasia of the ascending aorta and aortic arch”. While the etiology remains unknown, pathological studies suggest it is a disease acquired during fetal life after closure of the interventricular septum. Four anatomical subtypes have been recognized, according to the degree of obstruction of mitral inflow and aortic outflow which include mitral atresia/aortic atresia (MA/AA), mitral stenosis/aortic atresia (MS/AA), mitral stenosis / aortic stenosis (MS/AS) and mitral atresia / aortic stenosis (MA/AS). MA/AA is the most common subtype, comprising approximately 35-45% of patients with HLHS. MS/AA and MS/AS occur at a similar incidence of 20-25%, and MA/AS is the rarest subtype.
These subtypes also differ with regards to the shape of the left ventricle (LV), endocardial lining and myocardial perfusion. Stephens et al performed pathological examinations on 119 HLHS specimens, most of them being archived prior to the development of palliative surgical/interventional procedures. They found that the majority of MA/AA hearts had slit-like ventricles, the smallest aortas, and that endocardial fibroelastosis (EFE) was rare. Conversely, most MS/AA hearts have a globular shape, and approximately 75% of them had EFE. Hearts with MS/AS had the most variable anatomy with very few having a slit-like LV, approximately half with a globular LV shape, and some with LVs that could qualify as HLHS “complex”, meaning the LV size is proportional to the valvar opening and could be considered for a biventricular repair. Interestingly, almost 75% of MS/AS hearts had EFE. An additional study from Stephens et al reported described the coronary anatomy of the same patient cohort, and noted that MS/AS hearts had more frequent anomalies of coronary artery position with greater potential for coronary obstruction, but that fistulous connections were significantly more frequent in MS/AA hearts.
From a clinical standpoint, interstage mortality after the Norwood operation is estimated at 10-15%. Studies from 2000 to 2010 have reported a significantly higher mortality rate in patients with MS/AA when compared to the other subtypes. The hypothesis behind that is HLHS patients with mitral stenosis have larger LV cavities, thus higher left ventricular end diatolic pressure (LVEDP), and a higher incidence of ventriculo-coronary connections, increasing the risk of myocardial ischemia, especially during cardiopulmonary bypass when the ventricle is decompressed.
A retrospective study by Siehr et al comparing perioperative mortality of MS/AA to all other subtypes of HLHS reported a perioperative mortality rate of 29% versus 7%, respectively, after the Stage I procedure. Eight of fourteen MS/AA patients had coronary angiography, and six were found to have ventriculo-coronary connections. Four of the six with fistulous connections died. Rickers et al performed cardiac magnetic resonance imaging (cMRI) studies to quantify coronary blood flow and determine factors affecting the coronary microcirculation in all four types of HLHLS patients after the Fontan procedure. Myocardial blood flow was quantified at rest and during adenosine-induced hyperemia. They demonstrated that systemic right ventricular (RV) hyperemic myocardial blood flow, which depends on ventricular capillarization and coronary vasoreactivity, was decreased in patients with MS/AA, RV diastolic dysfunction, and those who had their Fontan at a later age. Moon et al analyzed long-term outcomes in HLHS patients, and found that patients with MS/AA had decreased transplant-free survival at 15 years (68%) versus those with MS/AS (84%) or MA/AA (79%). MS/AA patients were also more likely to have ventricular failure. Aortic atresia (AA) is also a known risk factor for mortality after the Norwood procedure, especially in patients with aortic diameters less than 1.5mm, which may reflect the technical challenges of the surgery as well as retrograde coronary blood flow.
Thus, HLHS prognosis varies according to subtype. With globular-shaped and EFE-lined LVs, patients with MS/AA have worsened outcomes versus patients with MS/AS. Patients with MA/AA do not share those pathologic characteristics, nor the same mortality as MS/AA after the Stage I procedure. In patients with MS/AA, the combination higher LVEDP, ventricular sinusoids, and ventriculo-coronary connections increases the risk of myocardial ischemia and could be a likely explanation for these findings. The presence of a rudimentary LV could also lead to unfavorable RV-LV interactions, impaired diastolic function of the RV leading to compromised coronary blood flow, and contribute to the long-term systemic RV failure. The MA/AS subtype remains rare and is often grouped with MS/AS patients in studies.
Stephens EH, Gupta D, Bleiweis M, Backer CL, Anderson RH, Spicer DE. Pathologic Characteristics of 119 Archived Specimens Showing the Phenotypic Features of Hypoplastic Left Heart Syndrome. Semin Thorac Cardiovasc Surg. 2020;32(4):895-903. doi: 10.1053/j.semtcvs.2020.02.019
Stephens EH, Gupta D, Bleiweis M, Backer CL, Anderson RH, Spicer DE. Coronary Arterial Abnormalities in Hypoplastic Left Heart Syndrome: Pathologic Characteristics of Archived Specimens. Semin Thorac Cardiovasc Surg. 2020;32(3):531-538. doi: 10.1053/j.semtcvs.2020.02.007
Siehr SL, Maeda K, Connolly AA, et al. Mitral Stenosis and Aortic Atresia--A Risk Factor for Mortality After the Modified Norwood Operation in Hypoplastic Left Heart Syndrome. Ann Thorac Surg. 2016;101(1):162-167. doi: 10.1016/j.athoracsur.2015.09.056
Rickers C, Wegner P, Silberbach M, et al. Myocardial Perfusion in Hypoplastic Left Heart Syndrome. Circ Cardiovasc Imaging. 2021;14(10):e012468. DOI: 10.1161/CIRCIMAGING.121.012468
Moon J, Lancaster T, Sood V, Si MS, Ohye RG, Romano JC. Long-term impact of anatomic subtype in hypoplastic left heart syndrome after Fontan completion. J Thorac Cardiovasc Surg. Published online November 10, 2023. doi: 10.1016/j.jtcvs.2023.11.008