Contribution of VEGF-B-Induced Endocardial Endothelial Cell Lineage in Physiological Versus Pathological Cardiac Hypertrophy.

BACKGROUND: Preclinical studies have shown the therapeutic potential of VEGF-B (vascular endothelial growth factor B) in revascularization of the ischemic myocardium, but the associated cardiac hypertrophy and adverse side effects remain a concern. To understand the importance of endothelial proliferation and migration for the beneficial versus adverse effects of VEGF-B in the heart, we explored the cardiac effects of autocrine versus paracrine VEGF-B expression in transgenic and gene-transduced mice. METHODS: We used single-cell RNA sequencing to compare cardiac endothelial gene expression in VEGF-B transgenic mouse models. Lineage tracing was used to identify the origin of a VEGF-B-induced novel endothelial cell population and adeno-associated virus-mediated gene delivery to compare the effects of VEGF-B isoforms. Cardiac function was investigated using echocardiography, magnetic resonance imaging, and micro-computed tomography. RESULTS: Unlike in physiological cardiac hypertrophy driven by a cardiomyocyte-specific VEGF-B transgene (myosin heavy chain alpha-VEGF-B), autocrine VEGF-B expression in cardiac endothelium (aP2 [adipocyte protein 2]-VEGF-B) was associated with septal defects and failure to increase perfused subendocardial capillaries postnatally. Paracrine VEGF-B led to robust proliferation and myocardial migration of a novel cardiac endothelial cell lineage (VEGF-B-induced endothelial cells) of endocardial origin, whereas autocrine VEGF-B increased proliferation of VEGF-B-induced endothelial cells but failed to promote their migration and efficient contribution to myocardial capillaries. The surviving aP2-VEGF-B offspring showed an altered ratio of secreted VEGF-B isoforms and developed massive pathological cardiac hypertrophy with a distinct cardiac vessel pattern. In the normal heart, we found a small VEGF-B-induced endothelial cell population that was only minimally expanded during myocardial infarction but not during physiological cardiac hypertrophy associated with mouse pregnancy. CONCLUSIONS: Paracrine and autocrine secretions of VEGF-B induce expansion of a specific endocardium-derived endothelial cell population with distinct angiogenic markers. However, autocrine VEGF-B signaling fails to promote VEGF-B-induced endothelial cell migration and contribution to myocardial capillaries, predisposing to septal defects and inducing a mismatch between angiogenesis and myocardial growth, which results in pathological cardiac hypertrophy.

Endocardial fibroelastosis causing sudden death in an infant: Autopsy case report of an unusual lesion.

ABSTRACT: Endocardial fibroelastosis is characterized by proliferation of both elastic and collagenous fibers within the endocardium, causing diffuse or localized thickening. A four-and-a-half-month-old baby was admitted to a local hospital, with a history of seizures for one day. Baby developed features of heart failure and died within one week after admission. At the post-mortem examination, heart was found to be enlarged with dilated ventricles. The endocardium of left ventricle was markedly thickened with a whitish appearance. Histopathology showed a thick layer of collagenous fibrous tissue in the endocardium, which was confirmed by Masson trichrome stain. The cause of death was offered as dilated cardiomyopathy due to endocardial fibroelastosis. The underlying mechanisms of myocardial fibrosis remain unclear. It is hypothesized that genetic, infectious, inflammatory, and nutritional processes are involved in this condition. This case highlights the importance of gross specimen examination and special staining methods to support histopathology after postmortem examination, for ascertaining the cause of death.

Pathological features of primary cardiac myxoid tumour in dogs: a review of 11 cases (2002-2022).

This report documents the pathological features of primary cardiac myxoid tumour (MT) in 11 dogs. Macroscopically, all the tumours were located in the tricuspid valve (TV), its septal leaflet being predominantly affected. Therefore, it appears that the TV is the most common site of occurrence for cardiac MT in dogs. Two gross anatomical types of canine valvular MT were evident. Seven of the 11 tumours were round or oval with a smooth or gently lobulated and glistening surface, while the other four were gelatinous, multilobulated and polypoid, with an irregular surface. Microscopically, in nine cases the tumours had an abundant myxoid matrix within which elongated spindle-shaped cells with no remarkable cytological atypia were sparsely embedded, suggesting a benign character (ie, myxoma). In the other two cases the tumours consisted of variably dense, haphazardly arranged, interlacing streams of anaplastic spindle-shaped or polygonal cells containing many mitotic figures, indicative of a malignant form of myxoma (ie, myxosarcoma). Isolated or clustered collections of myxoma cells (eg, cords, rings, syncytia) characteristic of human atrial myxoma were only rarely evident or lacking in all 11 cases, indicating that rarity or absence of such structural features may be specific to valvular MTs. Immunohistochemical findings were indicative of smooth muscle differentiation of the neoplastic cells. Tumour embolization to the intrapulmonary arteries and/or tumour implantation on the endocardium of the right heart chambers was evident only in the four cases of irregular-surfaced MT.

Case Report: COVID-19 Infection of a Transplanted Heart Simulating Cellular Rejection.

Contemporary reports showed that solid organ transplantation patients who contract SARS-CoV-2 infection have a high mortality rate. There are sparse data about recurrent cellular rejections and the immune response to the SARS-CoV-2 virus in patients after heart transplantation. Herein, we report a case of a 61-year-old male post-heart transplant patient who tested positive for COVID-19 and developed mild symptoms 4 months after transplantation. Thereafter, a series of endomyocardial biopsies showed histologic features of acute cellular rejection despite optimal immunosuppression, good cardiac functions, and hemodynamic stability. Demonstration of SARS-CoV-2 viral particles by electron microscopy in the endomyocardial biopsy confirmed the presence of the virus in the foci of the cellular rejection, pointing to a possible immunologic reaction to the virus. To our knowledge, there is limited information regarding the pathology of COVID-19 infection in immunocompromised heart transplant patients, and there are no well-established guidelines for treating such patients. Based on the demonstration of SARS-CoV-2 viral particles within the myocardium, we concluded that myocardial inflammation visible on endomyocardial biopsy might be attributed to the host's immune response to the virus, which mimics acute cellular rejection in newly heart transplanted patients. We report this case to increase awareness of such events post-transplantation and to add to knowledge regarding the management of patients with ongoing SARS-CoV-2 infection that proved to be challenging.

Elective and non-elective endomyocardial biopsy in heart transplant patients and procedural outcomes: An IMPACT registry analysis.

BACKGROUND: Endomyocardial biopsies are standard of care for transplant surveillance, however the procedural risks are not well established, especially in children. The purpose of the study was therefore to assess procedural risks and outcomes associated with elective (surveillance) biopsies and non-elective (clinically indicated) biopsies. METHODS: We used the NCDR IMPACT registry database for this retrospective analysis. Patients undergoing an endomyocardial biopsy were identified using the procedural code, with a diagnosis of heart transplantation required. Data regarding indication, hemodynamics, adverse events and outcomes was gathered and analyzed. RESULTS: A total of 32 547 endomyocardial biopsies were performed between 2012-2020; 31 298 (96.5%) elective and 1133 (3.5%) were non-elective biopsies. Non-elective biopsy was more commonly performed in infants and in those above 18 years of age, in female and in Black race patients and in those with non-private insurance (all p < .05) and showed hemodynamic derangements. Overall rate of complications was low. Combined major adverse events were more common in non-elective patients, with sicker patient profile, use of general anesthesia and femoral access with overall decline in these events over time. CONCLUSIONS: This large-scale analysis shows safety of surveillance biopsies and that non-elective biopsies carry a small but significant risk of major adverse event. Patient profile impacts the safety of the procedure. These data may serve as important comparison point for newer non-invasive tests and for bench marking, especially in children.

The anatomical basis of third-degree atrioventricular block in dogs with atrioventricular valve endocardiosis.

The cardiac conduction system was examined histologically in 13 canine cases of atrioventricular (AV) valve endocardiosis with third-degree AV block. In all cases, gross examination revealed marked thickening and distortion of the base of the central fibrous body (CFB) and varying degrees of endocardial thickening of the upper portion of the ventricular septum (VS) as well as marked thickening of the mitral and tricuspid valve leaflets due to myxomatous degeneration. Microscopically, the thickened and distorted CFB had encased or trapped, either partly or totally, the underlying penetrating and branching portions of the AV bundle. The myxomatous and/or fibrofatty tissue, which had proliferated at the base of the extensive CFB, protruded into or encroached on the AV bundle, causing severe (51-75%) to very severe (76% or more) reduction of the conduction fibres. The upper portions of the left and right bundle branches were involved in the endocardial thickening due to degenerative and fibrotic changes at the uppermost VS; however, both bundle branches were much less severely affected than the AV bundle, the degree of reduction of the conduction fibres ranging from mild (25% or less) to moderate (26-50%). These observations suggest that the sites most vulnerable to lesions in the AV conduction system are the penetrating and branching portions of the AV bundle, which would represent the anatomical basis for third-degree AV block in canine cases of AV valve endocardiosis.

Correlations Between Endocardial Voltage Mapping, Diagnosis, and Genetics in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

The relations between endocardial voltage mapping and the genetic background of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) have not been investigated so far. A total of 97 patients with proved or suspected ARVC who underwent 3-dimensional endocardial mapping and genetic testing have been retrospectively included. Presence, localization, and size of scar areas were correlated to ARVC diagnosis and the presence of a pathogenic variant. A total of 78 patients (80%) presented with some bipolar or unipolar scar on endocardial voltage mapping, whereas 43 carried pathogenic variants (44%). Significant associations were observed between presence of endocardial scars on voltage mapping and previous or inducible ventricular tachycardia, right ventricular function and dimensions, or electrocardiogram features of ARVC. A total of 60 of the 78 patients (77%) with an endocardial scar fulfilled the criteria for a definitive arrhythmogenic right ventricular dysplasia diagnosis versus 8 of 19 patients (42%) without scar (p = 0.003). Patients with a definitive diagnosis of ARVC had more scars from any location and the scars were larger in patients with ARVC. In the 68 patients with a definitive diagnosis of ARVC, the presence of any endocardial scar was similar whether an ARVC-causal mutation was present or not. Only scar extent was significantly greater in patients with pathogenic variants. There was no difference in the presence and characteristics of scars in PKP2 mutated versus other mutated patients. The 3-dimensional endocardial mapping could have an important role for refining ARVC diagnosis and may be able to detect minor forms with otherwise insufficient criteria for diagnosis. The trend for larger scar extent were observed in mutated patients, without any difference according to the mutated genes.

Diagnosing myocarditis in endomyocardial biopsies: survey of current practice.

BACKGROUND: Dallas criteria (DC) and European Society of Cardiology criteria (ESCC) have provided valuable frameworks for the histologic diagnosis and classification of myocarditis in endomyocardial biopsy (EMB) specimens. However, the adaptation and the usage of these criteria are variable and depend on local practice settings and regions/countries. Moreover, several ancillary tests that are not included in the current criteria, such as immunohistochemistry (IHC) or viral polymerase chain reaction (PCR), have proven useful for the diagnosis of myocarditis. METHOD: As a joint effort from the Association for European Cardiovascular Pathology (AECVP) and the Society for Cardiovascular Pathology (SCVP), we conducted an online survey to understand the current practice of diagnosing myocarditis. RESULT: A total of 100 pathologists from 23 countries responded to the survey with the majority practicing in North America (45%) and Europe (45%). Most of the pathologists reported to examine less than 200 native heart biopsies per year (85%), and to routinely receive 3-5 fragments of tissue per case (90%). The number of hematoxylin-eosin-stained levels for each case varies from 1 to more than 9 levels, with 20% of pathologists routinely asking for more than 9 levels per case. Among the 100 pathologists, 52 reported to use the DC alone, 12 the ESCC alone, 28 both DC and ESCC and 8 reported to use neither the DC nor the ESCC. Overall, 80 pathologists reported to use the DC and 40 the ESCC. Use of DC alone is more common among North American pathologists compared to European ones (80% vs 32.6%) while use of ESCC alone is more common in Europe (20.9% vs 2.5%). IHC is utilized in either every case or selected cases by 79% of participants, and viral PCR is performed by 35% of participants. Variable terminologies are used in reporting, including both histological and clinical terms. The diagnosis of myocarditis is rendered even in the absence of myocyte injury (e.g., in cases of borderline or inactive/chronic myocarditis) by 46% respondents. The majority of the participants think it is time to update the current criteria (83%). CONCLUSIONS: The survey data demonstrated that pathologists who render a myocarditis diagnosis practice with variable tissue preparation methods, use of ancillary studies, guideline usage, and reporting. This result highlights the clinically unmet need to update and standardize the current diagnostic criteria for myocarditis on EMB. Additional studies are warranted to establish standard of practice.

[Endomyocardial biopsy in current practice: Technical Aspects, Indications and complications]. / Biopsia endomiocárdica en la práctica actual: Aspectos técnicos, indicaciones y complicaciones.

Endomyocardial biopsy (EMB) is an invasive procedure and a diagnostic tool used mainly on the follow-up of post-heart transplant rejection in the past years. Currently, it has an important role in the diagnosis of non-ischemic cardiomyopathies. EMB is frequently performed through a venous access to enter the right ventricle. Diagnostic performance has improved with advances in pathology analysis. Its complications risk, close to 1% in high-volume interventional centers, can be justified considering the potential benefit of an accurate diagnosis and prognosis.

Pulsed Field Ablation of the Porcine Ventricle Using a Focal Lattice-Tip Catheter.

BACKGROUND: Our understanding of catheter-based pulsed field ablation (PFA) of the ventricular myocardium is limited. We conducted a series of exploratory evaluations of ventricular PFA in swine ventricles. METHODS: A focal lattice-tip catheter was used to deliver proprietary biphasic monopolar PFA applications to swine ventricles under general anesthesia, with guidance from electroanatomical mapping, fluoroscopy, and intracardiac echocardiography. We conducted experiments to assess the impact of (1) delivery repetition (2×, 3×, or 4×) at each location, (2) epicardial PFA delivery, and (3) confluent areas of shallow healed endocardial scar created by prior PFA (4 weeks earlier) on subsequent endocardial PFA. Additional assessments included PFA optimized for the ventricle, lesion visualization by intracardiac echocardiography imaging, and immunohistochemical insights. RESULTS: Experiment no. 1: lesions (n=49) were larger with delivery repetition of either 4× or 3× versus 2×: length 17.6±3.9 or 14.2±2.0 versus 12.7±2.0 mm (P<0.01, P=0.22), width 13.4±1.8 or 10.6±1.3 versus 10.5±1.1 mm (P<0.01, P=1.00), and depth 6.1±2.1 or 5.1±1.3 versus 4.2±1.0 mm (P<0.01, P=0.21). Experiment no. 2: epicardial lesions (n=18) were reliably created and comparable to endocardial lesions: length 24.6±9.7 mm (n=5), width 15.6±4.6 mm, and depth 4.5±3.7 mm. Experiment no. 3: PFA (n=16) was able to penetrate to a depth of 4.8 (interquartile range, 4.5-5.4) mm in healthy myocardium versus 5.6 (interquartile range, 3.6-6.6) mm in adjacent healed endocardial scar (P=0.79), suggesting that superficial scar does not significantly impair PFA. Finally, we demonstrate, PFA optimized for the ventricle yielded adequate lesion dimensions, can result in myocardial activation, can be visualized by intracardiac echocardiography, and have unique immunohistochemical characteristics. CONCLUSIONS: This in vivo evaluation offers insights into the behavior of endocardial or epicardial PFA delivered using the lattice-tip catheter to normal or scarred porcine ventricular myocardium, thereby setting the stage for future clinical studies.

Transcatheter Myotomy to Relieve Left Ventricular Outflow Tract Obstruction: The Septal Scoring Along the Midline Endocardium Procedure in Animals.

BACKGROUND: Left ventricular outflow tract obstruction complicates hypertrophic cardiomyopathy and transcatheter mitral valve replacement. Septal reduction therapies including surgical myectomy and alcohol septal ablation are limited by surgical morbidity or coronary anatomy and high pacemaker rates, respectively. We developed a novel transcatheter procedure, mimicking surgical myotomy, called Septal Scoring Along the Midline Endocardium (SESAME). METHODS: SESAME was performed in 5 naive pigs and 5 pigs with percutaneous aortic banding-induced left ventricular hypertrophy. Fluoroscopy and intracardiac echocardiography guided the procedures. Coronary guiding catheters and guidewires were used to mechanically enter the basal interventricular septum. Imparting a tip bend to the guidewire enabled intramyocardial navigation with multiple df. The guidewire trajectory determined the geometry of SESAME myotomy. The myocardium was lacerated using transcatheter electrosurgery. Cardiac function and tissue characteristics were assessed by cardiac magnetic resonance at baseline, postprocedure, and at 7- or 30-day follow-up. RESULTS: SESAME myotomy along the intended trajectory was achieved in all animals. The myocardium splayed after laceration, increasing left ventricular outflow tract area (753 to 854 mm2, P=0.008). Two naive pigs developed ventricular septal defects due to excessively deep lacerations in thin baseline septa. No hypertrophy model pig, with increased septal thickness and left ventricular mass compared with naive pigs, developed ventricular septal defects. One animal developed left axis deviation on ECG but no higher conduction block was seen in any animal. Coronary artery branches were intact on angiography with no infarction on cardiac magnetic resonance late gadolinium imaging. Cardiac magnetic resonance chamber volumes, function, flow, and global strain were preserved. No myocardial edema was evident on cardiac magnetic resonance T1 mapping. CONCLUSIONS: This preclinical study demonstrated feasibility of SESAME, a novel transcatheter myotomy to relieve left ventricular outflow tract obstruction. This percutaneous procedure using available devices, with a safe surgical precedent, is readily translatable into patients.

Multielectrode Unipolar Voltage Mapping and Electrogram Morphology to Identify Post-Infarct Scar Geometry: Validation by Histology.

OBJECTIVES: This study sought to evaluate the ability of uni- and bipolar electrograms collected with a multielectrode catheter with smaller electrodes to: 1) delineate scar; and 2) determine local scar complexity. BACKGROUND: Early reperfusion results in variable endocardial scar, often overlaid with surviving viable myocardium. Although bipolar voltage (BV) mapping is considered the pillar of substrate-based ablation, the role of unipolar voltage (UV) mapping has not been sufficiently explored. It has been suggested that bipolar electrograms collected with small electrode catheters can better identify complex scar geometries. METHODS: Twelve swine with early reperfusion infarctions were mapped with the 48-electrode OctaRay catheter and a conventional catheter during sinus rhythm. BV electrograms with double components were identified. Transmural (n = 933) biopsy specimens corresponding to mapping points were obtained, histologically assessed, and classified by scar geometry. RESULTS: OctaRay UV (UVOcta) and BV (BVOcta) amplitude were associated with the amount of viable myocardium at a given location, with a stronger association for UVOcta (R2 = 0.767 vs 0.473). Cutoff values of 3.7 mV and 1.0 mV could delineate scar (area under the curve: 0.803 and 0.728 for UVOcta and BVOcta, respectively). The morphology of bipolar electrograms collected with the OctaRay catheter more frequently identified areas with 2 layers of surviving myocardium than electrograms collected with the conventional catheter (84% vs 71%). CONCLUSIONS: UV mapping can generate a map to delineate the area of interest when using a multielectrode catheter. Within this area of interest, the morphology of bipolar electrograms can identify areas in which a surviving epicardial layer may overlay a poorly coupled, potentially arrhythmogenic, endocardium.

Subendocardial hemorrhages in a case of complete avulsion of the heart.

We present a case of a 66-year-old man who died on the scene in a traffic accident. He was a car driver involved in a head-on collision with a bus. Autopsy performed 4 days after death showed multiple head, torso, and limb injuries, including complete avulsion of the heart from the great vessels and avulsion of both lungs from the tracheobronchial tree due to rapid deceleration. Gross examination of the heart was remarkable for patchy hemorrhages beneath the endocardium involving the left side of the interventricular septum and papillary muscles. Histological examination identified streaky subendocardial hemorrhages and perivascular hemorrhages in the subendocardial myocardium. Since the death, in this case, was instantaneous, the most likely mechanism of subendocardial hemorrhages involved a precipitous decrease in left ventricle pressure, as it is improbable that the timeline of events allowed for a catecholamine surge to occur and take effect. Findings in this case also suggest that subendocardial hemorrhages are an indicator of intravital trauma and that the time required for them to develop is very short.

Abdominal Fat Pad Fine-Needle Aspiration for Diagnosis of Cardiac Amyloidosis in Patients with Non-Ischemic Cardiomyopathy.

The diagnosis of cardiac amyloidosis is frequently delayed because histological confirmation is often challenging. Few studies have attempted to clarify the utility and safety of abdominal fat pad fine-needle aspiration (FPFNA) for an initial screening test in patients with suspected cardiac amyloidosis.This study included 77 consecutive patients with suspected non-ischemic cardiomyopathy who had left ventricular dysfunction and/or hypertrophy. All patients underwent abdominal FPFNA and an endomyocardial biopsy. In all patients, the abdominal FPFNA could be performed within less than 5 minutes with no complications; however, in 1 patient (1.3%), the obtained specimen was too small to evaluate. Among the remaining 76 patients, 5 (6.6%) were positive for amyloid (FPFNA[+]) and 7 (9.2%), including the 5 FPFNA[+], were diagnosed with cardiac amyloidosis (AL = 1, ATTR = 6) by endomyocardial biopsy. Positive abdominal FPFNAs indicated cardiac amyloidosis with high accuracy (sensitivity, 71.4%; specificity, 100%).Positive abdominal FPFNAs are directly linked to diagnoses of cardiac amyloidosis. Abdominal FPFNA is simple and useful for the initial screening test for cardiac amyloidosis in patients with non-ischemic cardiomyopathy.