Flow disturbances and progression of endocardial fibroelastosis — a case report (2023)


Thickening of the left ventricular (LV) endocardium termed endocardial fibroelastosis (EFE) is associated with hypoplastic left heart syndrome (HLHS) and is thought to be linked to the inability of the LV to grow and develop normally. We have previously established that endocardial endothelial cells are the origin of EFE which is derived through a mechanism called endothelial-to-mesenchymal transition (EndMT) [1]. It is still unclear what stimulates EndMT, but hemodynamic changes may play a role in this pathological process.

We present the case of a 4-year-old female patient who was prenatally diagnosed with HLHS and was transferred to Boston Children's Hospital (BCH) shortly after birth for staged palliation. The first postnatal echocardiogram and magnetic resonance imaging (MRI) confirmed mitral (MV) and aortic valve (AV) stenosis with restrictive, thickened leaflets, moderately sized atrial septal defect with left to right shunt. A bright thick layer of EFE covering the endocardial surface of the LV was described.

Two days after birth, stage-I palliation was performed with a 5-mm Sano-shunt and atrial septectomy. The 5-month-old patient was evaluated for the second staged operation, and echocardiographic and MRI confirmed EFE. LV end-diastolic volume (EDV) was measured as 8.4 ml/m2.

The Sano-shunt was replaced by a Glenn anastomosis, accompanied by resection of EFE from the LV cavity.

At 17 months old, symptoms reoccurred and also EFE on echocardiography and MRI. By MRI, LV-EDV was 24.5 ml/m2, and at catheterization, the LV-EDP measured 11 mmHg and mean LA pressure was 22 mmHg.

The MV and AV were repaired and EFE was resected from the LV. Intraoperatively, it was noted that motion of the MV leaflets was restricted by an introleaflet membrane, most probably EFE.

At 2 years and 3 months of age, despite successful repair, valvar disease progressed, and MRI follow-up showed gadolinium enhancement in the LV involving the MV. However, the LV-EDV had increased to 32 ml/m2 with an ejection fraction of 75%. The LA pressure at catheterization was 18 mmHg with an LV-EDP of 12 mmHg.

EFE was resected from the LV and the posterior leaflet of the MV, which was attached to the LV free wall. MV and AV both necessitated valvuloplasty due to restricted motion and thickened leaflets. A Blalock–Taussig shunt was added to augment pulmonary venous return and, hence, flow across the MV and into the LV.

One year after surgery at 3 years, 5 months old, echocardiography and MRI showed moderate MV stenosis and regurgitation, but extensive gadolinium-enhancement was present with improvement of LV-EDV to 45 ml/m2 and an LV-EDP of 9 mmHg on catheterization.

Due to sufficient catch-up growth of the LV, conversion to biventricular circulation was performed with take-down of the Damus–Kaye–Stansel and Blalock–Taussig shunts and attachment of the RV directly to the pulmonary arteries. EFE was resected from the LV, and the MV was replaced with a 16-mm Melody valve.

At 4 years of age, the patient developed symptoms of tachypnea, cough, and cyanosis. On echocardiography, the mean gradient across the Melody valve was 7 mmHg, and the LVOT peak gradient was 36 mmHg. At catheterization, the LV-EDP was 26 mmHg, and MRI showed an EDV of 37.7 ml/m2 with gadolinium enhancement at the apical and basal septum (Fig. 1A–C).

After 3 months at 4 years and 2 months old, without symptomatic improvement and with unchanged structural and hemodynamic findings on imaging studies, the Melody valve was replaced with a 19-mm Epic porcine valve and the AV was repaired. EFE was resected from the septal surface and posteriorly.

At last follow-up at 4 years and 10 months of age, the patient's symptoms had significantly improved. Echocardiography showed normal prosthetic valve function, and normal LV size and systolic function. At catheterization, LV-EDP was 12 mmHg with a cardiac index of 3.3 L/min/m2. LA pressure was 14–16 mmHg with half systemic pulmonary artery pressure.

EFE is described as fibroelastic thickening of the endocardium mainly localized in the LV, diagnosed in 1.6% of newborns' pathological specimens with heart disease [2]. It is linked to different underlying structural diseases and most commonly to HLHS [3]. Following analysis of EFE from 27 HLHS patients, we identified a potential root cause of EFE in aberrant EndMT affecting the endocardium of the LV [1]. EndMT is a physiologic process during the development of heart valves, but the stimulus for pathologic EndMT in HLHS is unknown. In association with HLHS, many potential triggers have been hypothesized, but clinical observations and animal models point toward flow disturbances exposing endocardial cells to alterations in shear stress [4].

BCH advocates an approach toward LV recruitment in HLHS to support the systemic circulation which entails resection of EFE tissue. Resection of EFE is technically feasible and results in catch-up growth of the LV indicated by an increase in LV-EDV, but many patients experience regrowth of EFE [5], [6]. Furthermore, as indicated by this case, as the patient grows older, EFE switches to an infiltrative growth pattern affecting the myocardium. Until now, no underlying reason for reoccurrence and infiltrative growth patterns has been described [5]. With multiple EFE tissue samples from consecutive surgical resections available in this patient, we could show that EFE growth was directly associated with flow disturbances across the mitral valve. Flow disturbances due to mitral valve stenosis followed by a malpositioned Melody valve were associated with alterations of endocardial tissue in this area. Furthermore, despite repeated EFE resections but without resolution of the pathological flow pattern, EFE regrew and changed from a subendocardial growth pattern to more infiltrative growth into the myocardium as the patient grew older and flow disturbances across the MV persisted (Fig. 2A–D). Infiltrative growth is associated with elevated LV-EDP, but growth of the once diminutive LV is maintained indicated by increasing LV-EDV.

Plasticity of endothelial cells allows for adaptation to physiologic and pathologic processes whereof the latter is represented by EndMT. It is well known that flow disturbances in the vasculature generate a microenvironment supportive of EndMT [7], [8]. Our case study now supports the idea that flow disturbances play a role in endocardial EndMT as well (Fig. 3A–C). Through the course of disease progression, EFE formation was directly associated with flow disturbances across the MV. With definitive repair of the valve, thickening of the endocardium indicative of EFE has not reoccurred 7 months following the last surgery.

  • Factors associated with morbidity, mortality, and hemodynamic failure after biventricular conversion in borderline hypoplastic left hearts

    2023, Journal of Thoracic and Cardiovascular Surgery

    A subset of patients with borderline hypoplastic left heart may be candidates for single to biventricular conversion, but long-term morbidity and mortality persist. Prior studies have shown conflicting results regarding the association of preoperative diastolic dysfunction and outcome, and patient selection remains challenging.

    Patients with borderline hypoplastic left heart undergoing biventricular conversion from 2005 to 2017 were included. Cox regression identified preoperative factors associated with a composite outcome of time to mortality, heart transplant, takedown to single ventricle circulation, or hemodynamic failure (defined as left ventricular end-diastolic pressure >20mm Hg, mean pulmonary artery pressure >35mm Hg, or pulmonary vascular resistance >6 international Woods units).

    Among 43 patients, 20 (46%) met the outcome, with a median time to outcome of 5.2years. On univariate analysis, endocardial fibroelastosis, lower left ventricular end-diastolic volume/body surface area (when <50mL/m2), lower left ventricular stroke volume/body surface area (when <32mL/m2), and lower left:right ventricular stroke volume ratio (when <0.7) were associated with outcome; higher preoperative left ventricular end-diastolic pressure was not. Multivariable analysis demonstrated that endocardial fibroelastosis (hazard ratio, 5.1, 95% confidence interval, 1.5-22.7, P=.033) and left ventricular stroke volume/body surface area 28mL/m2 or less (hazard ratio, 4.3, 95% confidence interval, 1.5-12.3, P=.006) were independently associated with a higher hazard of the outcome. Approximately all patients (86%) with endocardial fibroelastosis and left ventricular stroke volume/body surface area 28mL/m2 or less met the outcome compared with 10% of those without endocardial fibroelastosis and with higher stroke volume/body surface area.

    History of endocardial fibroelastosis and smaller left ventricular stroke volume/body surface area are independent factors associated with adverse outcomes among patients with borderline hypoplastic left heart undergoing biventricular conversion. Normal preoperative left ventricular end-diastolic pressure is insufficient to reassure against diastolic dysfunction after biventricular conversion.

  • Intraventricular Septation in the Context of Dilated Cardiomyopathy Associated With TTN Mutation

    2021, JACC: Case Reports

    Citation Excerpt :

    Congenital LV diverticula and aneurysms involve dilations of the left ventricle wall that contain all three layers of the ventricular wall contracting synchronously within the heart, which was not observed in this case (2). The pathologic specimen contained features of EFE, which is generally limited to the endocardial layer but was observed here as a separate intracavity sheet or septation (3). The case presentation, echocardiographic imaging, and gross pathologic changes fail to meet the diagnostic criteria for any known condition.

    A 6-month-old infant boy presented with symptomatic heart failure. Dilated cardiomyopathy was found in associationwith a mutation in TTN. Structural heart disease included novel septation of the left ventricle with a fenestrated membrane resulting from aberrant congenital mitral valve apparatus formation. (Level of Difficulty: Advanced.)

  • Flow disturbances and the development of endocardial fibroelastosis

    2020, Journal of Thoracic and Cardiovascular Surgery

    Endothelial-to-mesenchymal transition (EndMT) has been identified as the underlying mechanism of endocardial fibroelastosis (EFE) formation. The purpose of this study was to determine whether hemodynamic alterations due to valvar defects promote EndMT and whether age-specific structural changes affect ventricular diastolic compliance despite extensive surgical resection of EFE tissue.

    We analyzed EFE tissue from 24 patients with hypoplastic left heart syndrome (HLHS) who underwent left ventricular (LV) rehabilitation surgery at Boston Children's Hospital between December 2011 and March 2018. Six patients with flow disturbances across the aortic valve and/or mitral valve but no HLHS diagnosis and macroscopic appearance of “EFE-like tissue” in the LV were included for comparison. All samples were examined for amount of collagen/elastin production and degradation, and presence of active EndMT by histologic analysis.

    EFE tissue from patients with and without HLHS consisted predominantly of elastin and collagen fibers. There was no alteration in degradation activity for collagen or elastin as shown by in situ zymography. Active EndMT was found in all patients with and without HLHS with flow disturbances (“EFE-like”). In patients with HLHS, EFE infiltrated into the underlying myocardium with increasing age.

    Patients with and without HLHS with flow disturbances due to stenotic or incompetent valves develop EndMT-derived fibrotic tissue covering the LV. When EFE recurs, it is directly associated with flow disturbances and switches to an infiltrative growth pattern with increasing age, leading to increased diastolic stiffness of the LV.

  • Pathologic Characteristics of 119 Archived Specimens Showing the Phenotypic Features of Hypoplastic Left Heart Syndrome

    2020, Seminars in Thoracic and Cardiovascular Surgery

    Citation Excerpt :

    In this regard, it is notable that left ventricular endocardial fibroelastosis was frequent in the hearts fulfilling the criteria for description as belonging to the “hypoplastic left heart complex.” This is consistent with a recent study implicating the key role of flow in producing the fibroelastotic lining found in the setting of mitral valvar stenosis rather than atresia.16 Hypotheses have abounded regarding the role of flow in the development, or at least the perpetuation, of the insults underscoring hypoplastic left heart syndrome.7

    To assess the phenotypic variations found among hearts diagnosed at autopsy with hypoplastic left heart syndrome, with attention to implications related to this syndrome as an acquired disease of fetal life, rather than being the consequence of abnormal embryogenesis. We assessed 119 specimens, from 2 archives, diagnosed initially as representing hypoplastic left heart syndrome. Among the 119 specimens, the majority of which had been entered into the archives prior to the availability of surgical treatment for the syndrome, 36 (30%) had the combination of mitral and aortic atresia, 26 (22%) had mitral and aortic stenosis, and 57 (48%) had mitral stenosis combined with aortic atresia. Of the hearts with combined atresia, 92% (33 specimens) had slit-like left ventricles, compared to 12% (3 specimens) of hearts with stenosis of both aortic and mitral valves, and 2 hearts (4%) with mitral stenosis and aortic atresia (P < 0.001). Hypoplasia of the left atrial appendage was present in half (18 specimens, 51%) of those with combined atresia, as opposed to just 18% (10 specimens) of mitral stenosis combined with aortic atresia (P = 0.001). Small left ventricles with valves deemed proportional in size were found in 11 (42%) of those with combined mitral and aortic stenosis. Fibroelastosis was significantly more common in the hearts with mitral stenosis compared to those with mitral atresia (76% vs 11%, P < 0.001). The ascending aorta was significantly smaller in the hearts with aortic atresia. The variability in the morphologic findings support the notion that the lesions seen represent acquired disease occurring subsequent to closure of the embryonic interventricular communication, rather than representing abnormal embryogenesis.

  • Endothelial-to-Mesenchymal Transition as Underlying Mechanism for the Formation of Double-Chambered Right Ventricle

    2022, Pediatric Cardiology

  • Research article

    Brainstem stroke caused by left atrial cardiac papillary fibroelastoma: an increasingly recognized rare cause of stroke

    Cardiovascular Pathology, Volume 40, 2019, pp. 65-67

    Cardiac papillary fibroelastoma is a rare but increasingly recognized cause of embolic stroke that is prevalent in the older population and requires prompt surgical management. We report an unusual case of left atrial appendage cardiac fibroelastoma in a 76-year-old gentleman who presented with left internuclear ophthalmoplegia and ataxia, with corresponding diffusion-weighted imaging on magnetic resonance imaging of the brain. This case illustrates the importance of echocardiographic imaging in the workup of cardioembolic stroke in the older adult population in the acute setting.

  • Research article

    Cerebral amyloid-β-related angiitis without cerebral microbleeds in a patient with subarachnoid hemorrhage

    Cardiovascular Pathology, Volume 42, 2019, pp. 36-40

    Amyloid-β-related angiitis (ABRA), a subtype of cerebral amyloid angiopathy (CAA), is vasculitis occurring in relation to amyloid-β (Aβ) deposition in the walls of intracranial blood vessels. ABRA is presumed to be caused by some immune response to the deposited Aβ. An 81-year-old man on oral anticoagulant therapy complained of headache, nausea, and difficulty with standing after a head injury. Head computed tomography revealed subcortical bleeding in the right temporoparietal lobe, and 3 days after admission, magnetic resonance imaging (MRI) showed subarachnoid hemorrhage (SAH) around the hematoma. Cerebral microbleeds, a characteristic of CAA, were not detected on MRI. On worsening of his symptoms, intracranial brain biopsy and hematoma removal were performed. Intraoperative rapid diagnosis with a frozen section suspected vasculitis, which enabled the prompt initiation of steroid therapy. He was pathologically diagnosed with ABRA (granulomatous angiitis) using a formalin-fixed paraffin-embedded section. Vasculitis was prominent around blood vessels in the pia matter covering the cerebrum. In this case, the inflammatory cells seemed to appear via the subarachnoid space following cerebral hemorrhage and SAH. ABRA seemed to be developed by intracranial hemorrhage in this case.

  • Research article

    Polymer-free drug-eluting stent in unselected patient population: A single center experience

    Cardiovascular Revascularization Medicine, Volume 15, Issues 6–7, 2014, pp. 350-353

    To evaluate the clinical performance of the Cre8™ polymer-free drug-eluting-stent in unselected real-life population.

    Inflammation plays a key role in the multi-factorial process eventually leading to target vessel failure (TVF) after drug-eluting-stent (DES) implantation. The local chronic inflammatory reaction in the vessel wall at the site of stent implantation is, at least in part, attributed to interaction between the polymer coating of DES and vessel wall components. The belief that elimination of the polymer will reduce the occurrence of short and long-term TVF has led to the field of polymer-free DES development.

    In this prospective, open-labeled, single-center, uncontrolled trial we enrolled consecutive patients undergoing PCI to receive the Cre8™ stent. The only exclusion criteria were instent restenosis and target vessel diameter <2.5mm. Primary end points were cardiac death and target vessel failure (TVF) at 1-year.

    Overall, 215 patients were enrolled, in which 318 Cre8 stents were implanted. Study population was characterized by a high prevalence of comorbidities including 38% of diabetics. More than 50% presented with acute coronary syndromes. During 1-year of follow-up there were 1 case of sudden death and 1 case of non-cardiac death, as well as 2 cases of TVF.

    In this small single-center trial of unselected real-life population, the polymer-free Cre8™ DES appears to be effective, as it was associated with very low rates of target-vessel-failure up to 1-year follow-up.

  • Research article

    Iatrogenic Tracheal Stenosis After Yasui Operation in a Neonate With Aortic Atresia and Type B Aortic Interruption

    Journal of Cardiothoracic and Vascular Anesthesia, Volume 33, Issue 5, 2019, pp. 1370-1374

    <dm:abstracts xmlns:dm="http://www.elsevier.com/xml/dm/dtd"><ce:abstract xmlns:ce="http://www.elsevier.com/xml/common/dtd" id="abs0001" view="all" class="author"><ce:section-title id="cesectitle0001">Abstract</ce:section-title><ce:abstract-sec id="abss0001" view="all"><ce:simple-para id="spara0004" view="all">Extrinsic airway compression resulting in respiratory insufficiency commonly occurs in patients with anomalies of the aortic arch system and vascular rings. Respiratory problems ranging from abnormal findings on chest radiography to severe respiratory difficulty can occur both preoperatively as well as after cardiac surgery in these patient subgroups. It is important that following surgeries for interrupted aortic arch, one should be aware of complications arising due to mechanical extrathoracic or intrathoracic airway obstructions and their manifestations.</ce:simple-para><ce:simple-para id="spara0005" view="all">Tracheal obstructions usually manifest as both inspiratory and expiratory stridor. A case of iatrogenic tracheal stenosis caused by a clip that was applied during the act of separation of a dorsal aortic arch vessel in the course of a Yasui operation is reported. The diagnosis and surgical management of the complication is highlighted.</ce:simple-para></ce:abstract-sec></ce:abstract></dm:abstracts>

  • Research article

    Alternatives to Standard Fractionation Radiation Therapy After Lumpectomy: Hypofractionated Whole-Breast Irradiation and Accelerated Partial-Breast Irradiation

    Surgical Oncology Clinics of North America, Volume 27, Issue 1, 2018, pp. 181-194

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    Tomosynthesis in Breast Cancer Imaging: How Does It Fit into Preoperative Evaluation and Surveillance?

    Surgical Oncology Clinics of North America, Volume 27, Issue 1, 2018, pp. 33-49

© 2019 Elsevier Inc. All rights reserved.

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