Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant

COVID-19, the syndrome caused by the novel coronavirus SARS-CoV-2, has spread throughout the world, causing the death of at least three million people. For the over 81 million who have recovered, however, the long-term effects are only beginning to manifest. We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications. This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia. Pulmonologists and pulmonary pathologists should be aware of this possible association and look for the clinical, radiographic, and histologic criteria in the appropriate clinical setting.

Critical Role of Caveolin-1 Loss/Dysfunction in Pulmonary Hypertension

Pulmonary hypertension (PH) is a rare disease with a high morbidity and mortality rate. A number of systemic diseases and genetic mutations are known to lead to PH. The main features of PH are altered vascular relaxation responses and the activation of proliferative and anti-apoptotic pathways, resulting in pulmonary vascular remodeling, elevated pulmonary artery pressure, and right ventricular hypertrophy, ultimately leading to right heart failure and premature death. Important advances have been made in the field of pulmonary pathobiology, and several deregulated signaling pathways have been shown to be associated with PH. Clinical and experimental studies suggest that, irrespective of the underlying disease, endothelial cell disruption and/or dysfunction play a key role in the pathogenesis of PH. Endothelial caveolin-1, a cell membrane protein, interacts with and regulates several transcription factors and maintains homeostasis. Disruption of endothelial cells leads to the loss or dysfunction of endothelial caveolin-1, resulting in reciprocal activation of proliferative and inflammatory pathways, leading to cell proliferation, medial hypertrophy, and PH, which initiates PH and facilitates its progression. The disruption of endothelial cells, accompanied by the loss of endothelial caveolin-1, is accompanied by enhanced expression of caveolin-1 in smooth muscle cells (SMCs) that leads to pro-proliferative and pro-migratory responses, subsequently leading to neointima formation. The neointimal cells have low caveolin-1 and normal eNOS expression that may be responsible for promoting nitrosative and oxidative stress, furthering cell proliferation and metabolic alterations. These changes have been observed in human PH lungs and in experimental models of PH. In hypoxia-induced PH, there is no endothelial disruption, loss of endothelial caveolin-1, or enhanced expression of caveolin-1 in SMCs. Hypoxia induces alterations in membrane composition without caveolin-1 or any other membrane protein loss. However, caveolin-1 is dysfunctional, resulting in cell proliferation, medial hypertrophy, and PH. These alterations are reversible upon removal of hypoxia, provided there is no associated EC disruption. This review examined the role of caveolin-1 disruption and dysfunction in PH.

Male and Female High Fat Fed Dahl SS rats are largely protected from vascular dysfunctions: PVAT contributions reveal sex differences.

Vascular dysfunctions are observed in arteries from hypertensive subjects. The establishment of the Dahl SS male and female rat model to develop a reproducible hypertension with high fat (HF) diet feeding from weaning allows addressing the question of whether HF-diet associated hypertension results in vascular dysfunction similar to that of essential hypertension in both sexes. We hypothesized that dysfunction of three distinct vascular layers -- endothelial, smooth muscle and perivascular adipose tissue (PVAT) -- would be present in aorta from HF vs control diet fed male and female rats. Dahl SS rats were fed a control (10% Kcal from fat) or HF (60%) diet from weaning for 24 weeks. Male and female Dahl SS became equally hypertensive when placed on the HF diet. For males and females, the thoracic aorta exhibited medial hypertrophy in HF diet-induced hypertension vs control but did not display a hyperresponsive contraction to the alpha adrenergic agonist phenylephrine nor endothelial cell dysfunction as measured by acetylcholine-induced relaxation. A beneficial PVAT function, support of stress relaxation, was reduced in the male vs female fed a HF diet. PVAT in aorta of males but not females retained anticontractile activity. We conclude that this HF model does not display the same vascular dysfunctions observed in essential hypertension. Moreover, the male and female show significantly different vascular dysfunctions in this HF fat feeding model.

Intricacies of Upper Blepharoplasty in Asian Burden Lids

Differences between Oriental and Caucasian eyelids have been explained in great detail in several reports in the past. The purpose of this article is to discuss the functional aspects of Asian double fold upper blepharoplasty and to present techniques that help to improve both the functional and cosmetic outcomes and satisfaction after surgery. The eyes of Asians are relatively small with thick skin in the eyelids and periorbital area. They typically lack the upper eyelid crease (creating the so-called double eyelid) due to burden factors like thick skin, hypertrophied orbicularis oculi muscle (OOM), submuscular fibroadipose tissue, thick orbital septum, abundant preaponeurotic fat, and lower positioned transverse ligament. Asian eyes may also have a superior visual field defect due to skin overriding the upper lid margin (skin–OOM–fat complex slide down). These burden factors result in the eyelashes appearing short and becoming misdirected and pressed toward the globe, causing functional discomfort. As a compensatory mechanism, Asian people tend to engage the frontalis muscle to lift the eyebrow to help them open their eyes. Along with aesthetic enhancement, double-eyelid surgery in Asian burden lids can improve the functional deficiencies helping the patients to open the eyes more easily. In addition, treatment of the Mongolian fold (medial epicanthal fold), caused by medial hypertrophy of preseptal OOM, augments the surgical results. In this report, we present the appropriate preoperative assessment, surgical technique, and postoperative care that should be employed to achieve consistently good functional and aesthetic outcomes in these patients.

Characterization of Spontaneous Vascular Findings in the Papillary Muscles of Beagle Dogs

Standard histology trimming practices for toxicity studies in dogs include preparation of a section of the papillary muscle associated with the left ventricular free wall—the anteriolateral or anterior muscle. In contrast, the posteromedial or posterior papillary muscle, associated with the interventricular septum, is not commonly evaluated. In humans, the posterior papillary muscle is more often affected in ischemic myocardial disease, in large part due to the absence of collateral circulation, in contrast to the anterior muscle. Due to the differential vascular supply to the papillary muscles, we sought to determine whether there is a higher incidence of spontaneous coronary vascular changes in the posterior papillary muscle versus the anterior muscle in dogs. The hearts of 30 vehicle-treated or untreated beagle dogs that were euthanized for other purposes were collected and sectioned in a consistent manner to include both papillary muscles for histologic evaluation. The posterior muscle consistently had higher incidences of intramural coronary arteries affected by vascular medial hypertrophy, medial arteriosclerosis, intimal hyperplasia, and/or disruption or loss of the internal elastic lamina. This observation may have significant implications for the evaluation and characterization of spontaneous and xenobiotic-induced cardiovascular lesions in dogs.

Морфологические изменения в динамике легочной артериальной гипертензии, индуцированной монокроталином в эксперименте in vivo

Цель исследования - изучение временной динамики морфологических изменений легочной ткани и миокарда правого желудочка у крыс на модели легочной артериальной гипертензии, индуцированной монокроталином. Методика. Исследование выполнено на 80 беспородных белых крысах. Для моделирования легочной артериальной гипертензии крысам вводили подкожно монокроталин в дозе 60 мг/кг. Материал для морфологического исследования (образцы тканей легких и миокарда) брали через 2, 4, 6 и 8 нед после введения монокроталина. Контролем служили образцы соответствующих тканей интактных животных. Результаты. В течение первых 4 нед эксперимента выявлялись начальные признаки структурного ремоделирования легочной ткани и миокарда. Это проявлялось гипертрофией медиального слоя легочных артерий с сохранением сосудистого просвета на фоне незначительных периваскулярных лимфоцитарных инфильтратов, появлением признаков активации апоптотической гибели эндотелиоцитов, а также сегментарными повреждениями кардиомиоцитов с развитием гипертрофии правого желудочка. К концу эксперимента наблюдались необратимые прогрессирующие во времени патологические изменения в исследуемых тканях. В легочной ткани появлялись участки плексиформной артериопатии, а также полное закрытие просвета легочных сосудов с выраженной околососудистой реакцией. Облитерация просвета сосудов обусловлена как гипертрофией медии, так и выраженным фиброзом интимы. В правом желудочке были обнаружены признаки мелкоочагового некроза кардиомиоцитов с участками заместительного фиброза и развитием дилатации правых отделов сердца. Заключение. В эксперименте in vivo установлены временные интервалы обратимости морфологических изменений легочной ткани и миокарда правых отделов сердца, характерные для легочной артериальной гипертензии.Objective. To investigate the dynamics of pathomorphological changes in lung and right ventricular tissues in rats following injections of 60 mg/kg monocrotaline for 8 weeks. Methods. The study was performed on white mongrel male rats treated with monocrotaline 60 mg/kg, s.c. Samples of lung and heart tissues were collected for morphological studies every two weeks following the monocrotaline treatment. Results. In the first four weeks of the experiment, initial signs of structural remodeling were observed in the lungs and myocardium. These signs were evident as medial hypertrophy of pulmonary arteries with preserved lumen and minor perivascular infiltrates; increased apoptosis of endothelial cells; and segmental injury of cardiomyocytes with right ventricular hypertrophy. Irreversible, progressive pathology was observed in studied tissues by the end of experiment, which included occlusion of the vascular lumen in pulmonary arteries due to intimal fibrosis and medial hypertrophy in the lung tissue affected by perivascular inflammation. Plexiform arteriopathy was established in some samples at 8 weeks. Right ventricular cardiomyocytes showed aseptic necrosis with transformation into reactive fibrosis and right heart dilatation. Conclusion. This in vivo study established the time windows for reversibility of morphological alterations in lung and myocardial tissues characteristic of pulmonary arterial hypertension.

Novel Pathologic-Scoring for Charcot Arthropathy with Intraneural Observations

Category: Diabetes, Hindfoot, Midfoot/Forefoot Introduction/Purpose: Charcot arthropathy is a destructive joint disorder in patients with longstanding neuropathy, commonly related to Type II diabetes (T2DM). The diagnosis is historically classified via the radiologic Eichenholtz staging system (E-score). The purpose of this study is to examine histopathologic features and develop a correlative pathologic score for Charcot neuroarthropathy. Methods: Patients undergoing lower limb surgery with a clinical diagnosis of midfoot-ankle Charcot neuroarthropathy were included for study. Clinical data, radiology, E-score (1-3), and surgical pathology specimens were reviewed to evaluate skin, adipose, vessel, skeletal muscle, nerve, bone, and bone fragments embedded in synovium. Charcot pathology-score 1 (P-score, CPSI) = large bone fragments (> half 40x hpf objective) without host histiocytic response. CPSII = mixed large and small bone fragments with/without host histiocytic response, CPSIII = small to minute spicules to almost complete resorption/absence of bone fragments with histiocytic/fibrosis-reactive response, were scored by the authors in a blinded fashion. Results: Forty-two patients (32 males and 10 females) were included in analyses with a mean age of 59.9 years (median age: 60, range 28-83). Clinical risk factors for Charcot included T2DM and longstanding neuropathy. Elevated HbA1C, E-Score, preoperative American Society of Anesthesia score, and Charlson comorbidity index were predictors of amputation. Majority of pathologic specimens examined had superficial ischemic ulceration, dermal fibrosis, cellulitis, medial hypertrophy, atherosclerosis, skeletal muscle atrophy, and nerve hypertrophy with intraneural edema and perineural fibrosis. Osteomyelitis was present in >70%. P-scores CPSI = 6%, CPSII = 44%, CPSIII = 50% correlate with E-scores in 98% of cases without interobserver variability. Minor difference from E-score to P-score (2%) was due to sampling. Novel neuropathy change includes observation of intraneural vasculopathy (arteriolosclerosis) in evaluable nerves. Conclusion: CPS is reliable and reproducible and can be performed with adequate synovial sampling. Charcot progresses from large bone fragments in synovium to mixed size with histiocytic response, and final small/resorbed fragments with marked host response/fibrosis. Intraneural vasculopathy likely plays a role in Charcot. Charcot pathology-score (P-score) strongly correlates with clinicoradiologic Eichenholtz-score (E-score).

Parameters associated with outcome in pediatric patients with congenital heart disease and pulmonary hypertension subjected to combined vasodilator and surgical treatments

Management of pediatric pulmonary hypertension associated with congenital heart disease (PHT-CHD) is challenging. Some patients have persistently elevated pulmonary artery pressure (PAP) after cardiac surgery, an undesired condition that is difficult to predict. We investigated the value of clinical, hemodynamic, and histopathological data in predicting the outcome in a prospective cohort. Patients with PHT-CHD received sildenafil orally pre- and postoperatively for six months and then were subjected to a catheter study. Thirty-three patients were enrolled (age range = 4.6–37.0 months). Pulmonary vascular resistance (PVR) was 4.9 (range = 3.9–7.2) Wood units × m2 (median with IQR). Twenty-two patients had a ≥ 20% decrease in PVR and pulmonary-to-systemic vascular resistance ratio (PVR/SVR) in response to inhaled nitric oxide (NO). The response was directly related to the degree of medial hypertrophy of pulmonary arterioles ( P < 0.05) (morphometric analysis, intraoperative lung biopsy). Subsequently, five of the non-responders had a ≥ 30% increase in pulmonary blood flow in response to sildenafil (3.0 [2.0–4.0] mg/kg/day). Six months after surgery, PAP and PVR were significantly lower ( P < 0.001 vs. baseline), even in seven patients with Heath-Edwards grade III/IV pulmonary vascular lesions ( P = 0.018), but still abnormal in 12 individuals (>25 mmHg and >3.0 U × m2, respectively). A preoperative PVR/SVR of ≥24% during NO inhalation and a wall thickness of arteries accompanying respiratory bronchioli of ≥4.7 (Z score) were identified, respectively, as risk and protection factors for abnormal postoperative hemodynamics (hazard ratio [95% CI] = 1.09 [1.01–1.18], P = 0.036; and 0.69 [0.49–0.98], P = 0.040, respectively). Thus, in PHT-CHD patients receiving oral sildenafil pre- and post-surgical repair of cardiac lesions, mid-term postoperative outcome is predictable to some extent.

Relation of Macrophage Migration Inhibitory Factor to Pulmonary Hemodynamics and Vascular Structure and Carbamyl-Phosphate Synthetase I Genetic Variations in Pediatric Patients with Congenital Cardiac Shunts

Macrophage migration inhibitory factor (MIF) plays an important pathophysiological role in pulmonary hypertension (PHT). Previously, we demonstrated that serum MIF is increased in pediatric PHT associated with congenital heart disease (CHD). In the present study, we determined possible associations between MIF levels, hemodynamic and histological parameters, and mitochondrial carbamyl-phosphate synthetase I (CPSI) T1405N polymorphism in a similar population. The asparagine 1405 variant (related to A alleles in the C-to-A transversion) has been shown to be advantageous in pediatric PHT compared to the threonine 1405 variant (C alleles). Forty-one patients were enrolled (aged 2-36 months) and subsequently divided into 2 groups after diagnostic evaluation: the high-pulmonary blood flow (high PBF) group (pulmonary-to-systemic blood flow ratio 2.58 (2.21-3.01), geometric mean with 95% CI) and the high-pulmonary vascular resistance (high PVR) group (pulmonary vascular resistance 6.12 (4.78-7.89) Wood units×m2). Serum MIF was measured using a chemiluminescence assay. The CPSI polymorphism was analyzed by polymerase chain reaction followed by high-resolution melting analysis. Medial hypertrophy of pulmonary arteries was assessed by the histological examination of biopsy specimens. Serum MIF was elevated in patients compared to controls (p=0.045), particularly in the high-PVR group (n=16) (p=0.022) and in subjects with the AC CPSI T1405N genotype (n=16) compared to those with the CC genotype (n=25) (p=0.017). Patients with high-PVR/AC-genotype profile (n=9) had the highest MIF levels (p=0.030 compared with the high-PBF/CC-genotype subgroup, n=18). In high-PVR/AC-genotype patients, the medial wall thickness of intra-acinar pulmonary arteries was directly related to MIF levels (p=0.033). There were no patients with the relatively rare AA genotype in the study population. Thus, in the advantageous scenario of the asparagine 1405 variant (AC heterozygosity in this study), heightened pulmonary vascular resistance in CHD-PHT is associated with medial hypertrophy of pulmonary arteries where MIF chemokine very likely plays a biological role.