Alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and overgrowth - Association with a homozygous 2bp-insertion in LTBP2?

We present a male infant with alveolar capillary dysplasia without misalignment of pulmonary veins, hyperinflammation, megalocornea and macrosomia/macrocephaly at birth. Whole-exome sequencing revealed a homozygous 2bp-insertion in the latent transforming growth factor-beta binding protein 2 (LTBP2) (c.278_279dup, p.(Ser94Glyfs*187)). So far, LTBP2-variants have been frequently reported with an eye-restricted phenotype including primary congenital glaucoma and megalocornea/microspherphakia and ectopia lentis with/without secondary glaucoma. Hitherto reported systemic phenotypes showed, among others, features as tall stature, finger anomalies, high-arched palate and cardiovascular anomalies. The main pathophysiological finding of our patient was an alveolar capillary dysplasia (with pulmonary arterial hypertension and right ventricular impairment but without misalignment of pulmonary veins) resulting in almost continuous oxygen demand and prolonged dependence on mechanical ventilation. He died of respiratory failure at the age of seven months. This patient may extend the LTBP2-related phenotype with resulting diagnostic implications.

Correlación de la distancia recorrida en la caminata de 6 minutos y puntajes de comorbilidad Charlson y Elixhauser / Correlation of distance traveled in the 6 minute walk and Charlson and Elihauser comorbidity scores

Introduction: The walking test of 6 minutes (6MW) is a test that merges the answer of different systems (respiratory, cardiovascular, metabolic, skeletal muscle and neurosensorial) and offers an useful objective result to lead therapeutic measurements and stablish a prognosis, it's possible that the comorbid patient lowers their functional reserve and alters the result of the test not only because of the presence of pathologies cardiorespiratory, nevertheless, information about the correlation between the scores of comorbidity and the traveled distance in the 6MW is limited. Objective: Determine the correlation between the traveled distance in the 6MW and the scores of comorbidities of Charlson and Elixhauser. Methods: A cross-sectional study was made, in patients taken to the 6MW made between 2006 until March 2020, in a hospital of high complexity; there were included patients older than 18 years old, whose clinic history record and walk of 6 minutes were available. The index of Charlson and Elixhauser were calculated in the 6MW, a bivariate analysis was made between the antecedents of pathologies and the traveled distance, independently and adjusted, the spearman correlation coefficient was calculated for the different scores and the distance in meters of the 6MW, was considerate a significative p: <0,05. Results: to the final analysis 491 subjects entered, the average age was of 69 years old (sd: 14,9), 54% male, the 15,3% had an abnormal walk less than the 80% of the expected, the diseases that were considered had a statistically significant relation with the decrease of the distance in the 6MW were arterial hypertension (p: <0,001), chronic heart failure (p=0,037), heart arrhythmia (p=0,003), smoking (p=0,022), chronic pulmonary obstruction disease (p: <0,001), dementia (p=0,03diabetes mellitus with target organ damage (p=0,01), moderate to severe chronic kidney disease (p=0,012), obesity (p=0,036) y lymphoma (p=0,038 the spearman correlation coefficient between the traveled distances and Charlson was of -0,343 (IC95%:-0,420 -0,264)(p: < 0,001) and -0,213(IC95%:-0,285 -0,116)(p: <0,001) with the Elixhauser index. Conclusion: The distances walked in meters in the 6MW has a reverse low correlation with the comorbidity index, the diseases that were not cardiopulmonary and that related independently with changes in the traveled dist ance are smoking, dementia, diabetes mellitus, chronic kidney disease, obesity, and lymphoma. Key words: Comorbidities, Walk, Test, Cardiopulmonary, Charlson, Elixhauser

Endothelial-specific Loss of IFT88 Promotes Endothelial-to-Mesenchymal Transition and Exacerbates Bleomycin-induced Pulmonary Fibrosis.

Intraflagellar transport protein 88 (Ift88) is required for ciliogenesis and shear stress-induced dissolution of cilia in embryonic endothelial cells coincides with endothelial-to-mesenchymal transition (EndMT) in the developing heart. EndMT is also suggested to underlie heart and lung fibrosis, however, the mechanism linking endothelial Ift88, its effect on EndMT and organ fibrosis remains mainly unexplored. We silenced Ift88 in endothelial cells (ECs) in vitro and generated endothelial cell-specific Ift88-knockout mice (Ift88endo) in vivo to evaluate EndMT and its contribution towards organ fibrosis, respectively. Ift88-silencing in ECs led to mesenchymal cells-like changes in endothelial cells. The expression level of the endothelial markers (CD31, Tie-2 and VE-cadherin) were significantly reduced with a concomitant increase in the expression level of mesenchymal markers (αSMA, N-Cadherin and FSP-1) in Ift88-silenced ECs. Increased EndMT was associated with increased expression of profibrotic Collagen I expression and increased proliferation in Ift88-silenced ECs. Loss of Ift88 in ECs was further associated with increased expression of Sonic Hedgehog signaling effectors. In vivo, endothelial cells isolated from the heart and lung of Ift88endo mice demonstrated loss of Ift88 expression in the endothelium. The Ift88endo mice were born in expected Mendelian ratios without any adverse cardiac phenotypes at baseline. Cardiac and pulmonary endothelial cells isolated from the Ift88endo mice demonstrated signs of EndMT and bleomycin treatment exacerbated pulmonary fibrosis in Ift88endo mice. Pressure overload stress in the form of aortic banding did not reveal a significant difference in cardiac fibrosis between Ift88endo mice and control mice. Our findings demonstrate a novel association between endothelial cilia with EndMT and cell proliferation and also show that loss of endothelial cilia-associated increase in EndMT contributes specifically towards pulmonary fibrosis.

Application of a new pulmonary artery obstruction score in the prognostic evaluation of acute pulmonary embolism: comparison with clinical and haemodynamic parameters.

PURPOSE: Evaluation of computed tomography (CT) pulmonary angiography parameters revealing pulmonary embolism (PE) severity with particular attention to pulmonary obstruction indexes. Comparison with clinical and hemodynamic data and determination of predictive role in the development of chronic pulmonary heart disease. MATERIALS AND METHODS: This retrospective study analyzes 45 not consecutive patients from November 2007 to December 2008 with CT angiography diagnosis of acute PE. Included in the study are patients at the first documented episode of acute PE, with 6 month follow-up. Patients with severe pre-existent cardiopulmonary pathology or neoplastic diseases were excluded from the study. CT angiography evaluated right ventricular (RV)/left ventricular (LV) ratio, obstruction index according to Qanadli and Total Clot Burden (Ghanima score). PE indexes were compared with Troponin I measurement and echocardiography result; at last hospitalization and intensive care time were reported. RESULTS: A significant association was found between Ghanima and Qanadli score: the two indexes are equivalent in quantification of pulmonary arterial obstruction (p<0.001). Among others CT parameters, the new Ghanima score evidenced the best accuracy to detect patients evolving to chronic pulmonary heart disease (76%). This value is higher than that of echocardiography (71%). Troponins showed highest accuracy (82%). CONCLUSIONS: Ghanima score can be used in emergency CT angiography diagnosis as prognostic marker for a quickly risk stratification of pulmonary heart disease or death in patients with acute PE. This approach allows to obtain, with just one test, both the diagnosis and a rather accurate acute PE risk stratification.

The pathogenesis of functional tricuspid regurgitation.

Functional tricuspid regurgitation (TR) is a common etiology of TR. Functional TR results from geometrical distortion of the normal spatial relationships of the tricuspid leaflets, annulus, chords, papillary muscles, and right ventricular (RV) walls. Functional TR results most commonly from left-sided heart disease, including mitral valve abnormalities and cardiomyopathy and RV dysfunction secondary to pulmonary disease (Cor pulmonale). The tricuspid annulus, which has a normal bimodal or saddle shape, becomes larger, flatter, and more circular with the development of functional TR. RV dilation can lead to papillary muscle displacement and tethering of the tricuspid leaflets, resulting in incomplete coaptation and development of functional TR.

[Idiopathic and secondary pulmonary hypertension].

In the available literature, there are single papers on the association of the values of external respiratory function and the EchoCG sings of pulmonary hypertension with the morphological parameters of pulmonary arterial branches in idiopathic pulmonary hypertension (IPH) and secondary pulmonary hypertension (SPH). The present investigation comprised a comprehensive study of life-time functional changes in the cardiopulmonary system and postmortem morphometric changes in the heart and pulmonary vessels in idiopathic pulmonary fibrosis (IPF)-induced SPH and IPH. The investigation has indicated that PPH and SPH are characterized by the same-type rearrangement of pulmonary arterial branches as intimal hyperplasia and medial hypertrophy; however, IPH, as compared with SPH, induces a more significant cor pulmonale. The magnitude of right and left ventricular dysfunction corresponds to the degree of pulmonary hypertension (PH) and cor pulmonale. In IPF, the decreases in tidal volumes and pulmonary diffusion capacity favor PH progression.

Susceptibility to pulmonary hypertension in inbred strains of mice exposed to cigarette smoke.

Cor pulmonale is a significant cause of morbidity and mortality in patients with emphysema, but it is not known whether alveolar destruction is directly involved in the disease pathogenesis. The purpose of this study was to examine the relationship between susceptibility to smoking-induced cor pulmonale and alveolar destruction in eight inbred strains of mice: 129XI/SvJ, A/J, A/HeJ, BALB/cJ, C3H/HeJ, C57BL/6J, DBA/2J, and SWR/J. The mice were exposed to filtered air or mainstream cigarette smoke at a concentration of 250 mg/m(3) for 5.5 h/day, 5 days/wk for 5 mo, housed for 4 more months, and killed. The ratio of the weight of the right ventricle/left ventricle plus septum [RV/(LV + S)] was used to assess right ventricular hypertrophy. Alveolar mean linear intercept was used to quantify severity of alveolar destruction. Morphometric determination of blood vessel muscularization was done on sections from four mouse strains. Smoke exposure resulted in significant increases in RV/(LV + S) in the A/J and A/HeJ strains compared with air-exposed controls. The magnitude of the smoking-induced increase in RV/(LV + S) decreased as a function of the genetic distance of the other strains from the A/J and A/HeJ strains. Pulmonary vascular muscularization was significantly increased in smoke-exposed A/J and BALB/cJ mice but not in C3H/HeJ and C57BL/6 mice. Also, mouse strain susceptibility to smoking-induced pulmonary vascular muscularization did not correlate with changes in mean linear intercept. The data from this study suggest that alveolar destruction by itself is not sufficient to cause smoking-induced cor pulmonale in inbred mice.

Reconstruction of bilateral branch pulmonary artery stenosis caused by Takayasu's aortitis.

A 63 year-old female presented with dyspnea on exertion. Her chest X-ray showed cardiomegaly, and right ventricular overload and tricuspid regurgitation were detected. Her pulmonary ventilation and blood flow scintigraphy findings were suspicious of pulmonary vascular disease; the diagnosis was pulmonary hypertension and bilateral branch pulmonary artery stenosis. After the inflammation settled, the stenotic bilateral branch pulmonary artery was reconstructed with a prosthetic vessel and the pulmonary pressure normalized immediately. A resected specimen revealed that the stenotic changes were from Takayasu's disease. The patient's postoperative course was uneventful, and pulmonary ventilation and blood scintigraphy returned to an almost normal range. At follow-up 5 years and 6 months after the operation, there was no evidence of pulmonary artery disease (eg, stenosis and/or ischemia) or of any change in the central vessels of the retina, the so-called Takayasu's retinopathy.

Causes and clinical characteristics of chronic cor-pulmonale in Ethiopia.

OBJECTIVE: To determine the clinical characteristics and underlying causes of chronic cor-pulmonale in Ethiopian patients. DESIGN: A hospital based cross-sectional study. SETTING: Tikur Anbessa Hospital, a large referral hospital in Addis Ababa, Ethiopia. SUBJECTS: Fourty two consecutive patients referred to the chest clinic of Tikur Anbessa Hospital, Addis Ababa, Ethiopia. RESULTS: Bronchial asthma (36%), chronic fibrocavitary tuberculosis (31%) and chronic bronchitis/emphysema (33%) were the most frequent underlying causes and occurred either singly or in combination in 36(86%) of patients. Interstitial lung disease occurred in five (11.9%) patients. Right-sided heart failure and cyanosis were the most common clinical presentations. Secondary polycythemia was noted in 32 of 40 patients (80%). The role of pulmonary vascular diseases including pulmonary schistosomiasis as a cause of pulmonary heart disease could not be ascertained but appeared to be insignificant. CONCLUSION: Chronic persistent asthma is a frequent underlying cause of chronic obstructive pulmonary disease and chronic cor-pulmonale compared to smoking related chronic bronchitis/emphysema in Ethiopia. The preventive strategy of chronic cor-pulmonale includes optimal treatment of bronchial asthma, early diagnosis and effective treatment of tuberculosis and health education to avoid cigarette smoking.

Chronic sildenafil treatment inhibits monocrotaline-induced pulmonary hypertension in rats.

Sildenafil, a phosphodiesterase 5 inhibitor, is currently under investigation for therapy of pulmonary hypertension. This study was designed to investigate chronic effects of sildenafil in monocrotaline (MCT)-induced pulmonary hypertension in rats. Four weeks after a single subcutaneous injection of MCT, the animals displayed nearly threefold elevated pulmonary artery pressure and vascular resistance values, with a concomitant decline in central venous oxygen saturation and arterial oxygenation. Marked right heart hypertrophy was evident, and massive thickening of the precapillary artery smooth muscle layer was histologically apparent. Further deterioration of pulmonary hypertension occurred 6 weeks after MCT injection, with some animals dying during this period because of right heart failure. When chronically administered from Days 14-28, sildenafil significantly increased plasma cyclic guanosine monophosphate and inhibited the development of pulmonary hypertension and right heart hypertrophy, with preservation of gas exchange and systemic arterial pressure. A corresponding efficacy profile was also noted for long-term feeding with sildenafil from Days 28-42. Moreover, the death rate significantly decreased in those animals treated with sildenafil. We conclude that sildenafil attenuates MCT-induced pulmonary hypertension and cor pulmonale in rats.

Lack of alpha2-antiplasmin promotes pulmonary heart failure via overrelease of VEGF after acute myocardial infarction.

Identification of a novel therapy for prevention of sudden death by ischemic cardiac infarction is an area of intensive investigation. We here report that the mortality due to an experimental acute myocardial infarction (AMI) was markedly increased in mice deficient in alpha2-antiplasmin (alpha2-AP(-/-) mice) but not in mice deficient in other components acting in fibrinolysis (tissue-type PA, urokinase type PA, or plasminogen activator inhibitor-1) even if the infarct area in alpha2-AP(-/-) mice was not different from those in the other mice. Echocardiography showed in alpha2-AP(-/-) mice after AMI an overload of the right ventricle and that pulmonary permeability was increased. According to the experiments using explanted myocytes and vascular smooth muscle cells, it was found that the amount of secreted vascular endothelial cell growth factor (VEGF) in alpha2-AP(-/-) mice was markedly increased compared with that in wild-type mice. Finally, an injection of an anti-VEGF antibody decreased the mortality after AMI in alpha2-AP(-/-) mice. Plasmin cleaves extracellular matrix-bound VEGF to release a diffusible proteolytic fragment and is inactivated mainly by alpha2-AP. Therefore, lack of alpha2-AP could markedly result in overrelease of VEGF by the continuous activation of plasmin because of AMI and could result in an acute cor pulmonale. Our results provide new aspects on the role of alpha2-AP and VEGF in the pathogenesis of cardiac events.

Acute cor pulmonale due to microscopic tumour embolism as the first manifestation of hepatocellular carcinoma.

Microscopic pulmonary tumour embolism is a rare cause of pulmonary hypertension. In most of the reported cases, symptoms develop over several days or weeks in patients previously diagnosed with malignant diseases. In our case, a 41-year-old man with an unremarkable medical history presented with respiratory failure that led to death less than 48 h from the onset of symptoms. Autopsy revealed massive microscopic pulmonary tumour embolism and a multifocal hepatocellular carcinoma. This case report is exceptional because it describes a very rapid clinical progression, and because acute cor pulmonale was the first manifestation of a previously undiagnosed neoplastic disease.

Right heart failure as the dominant clinical picture in a case of primary amyloidosis affecting the pulmonary vasculature.

A 91-year-old female patient died of right heart failure and pulmonary hypertension. The autopsy revealed multi-organ vascular amyloidosis and pulmonary alveolar septal amyloidosis with no evidence of parenchymal myocardial amyloid deposition. This is a rare example of cor pulmonale secondary to pulmonary amyloidosis.

[A "typical" case of pulmonary embolism]. / Ein "typischer" Fall von Lungenembolien.

A 85-year-old woman was admitted to our hospital because of a presumtive diagnosis of pulmonary thromboembolism. The patient presented with a history of progressive dyspnoea and retrosternal pain. 3-4 weeks ago she had noticed a swollen left leg. On examination a 4/6-pansystolic murmur was found. An arterial blood gas analysis showed a reduced oxygen saturation. An electrocardiogram revealed deep S-waves in lead I and pathological Q-waves in lead III. The chest X-ray showed cardiomegaly, a pulmonary nodule and an ill-defined opacity inferioposteriorly. Ventilation-perfusion mismatch was demonstrated by lung ventilation-perfusion scanning. Transthoracic echocardiography showed pulmonary hypertension and tricuspid regurgitation. On the 20th hospital day the patient died from multi organ failure. Pulmonary thromboembolism secondary to deep venous thrombosis of the lower extremities was the most likely diagnosis. In view of the patients' history of night sweat, loss of appetite and weight loss a malignant process had to be taken into consideration. A tumor originating from the right ventricle, the right ventricular outflow tract or the pulmonary artery was compatible with the clinical picture of multiple pulmonary emboli. On autopsy a polymorph cellular sarcoma measuring 6 x 3 x 3 cm was found in the right ventricular outflow tract. Section of the lung revealed a single pulmonary metastasis and multiple thromboemboli of various age. Pulmonary artery sarcomas, as described in our case, are extremely rare. The prognosis is poor and often the diagnosis is only made on autopsy.

[Central lung embolism in chronic interstitial pneumopathy]. / Zentrale Lungenembolie bei chronisch interstitieller Pneumopathie.

An 80 year old patient with known interstitial pneumopathy of unknown etiology was hospitalized because of acute onset and rapid deterioration of dyspnea at rest within days. A foregoing neurologic investigation including CT and EEG because of prior syncopes and cramp attacks had not revealed pathologic findings. Thorax X-ray at admission showed homogenous loss of transparency on the left side, calcified basal plaques on both sides and prominent central pulmonary vessels with jumping caliber. A punctate of the leftsided pleural effusion revealed lymphocytic exsudate, normal pH, low glucose and an elevated LDH. The patient died shortly after a collapse at a bowel visit and pulmonary embolism was suspected in accordance to results from arterial blood gas analysis, ECG and chest X-ray. Neurologic symptoms could be explained by recurrent pulmonary embolism. Pleural plaques together with the punctate suggested a malignant etiology. A mesothelioma was taken into consideration, although there were no anamnestic reports on an exposition to asbestos. Autopsy revealed almost complete central embolism of the left pulmonary artery with acute cor pulmonale thus confirming the clinical suspicion. The embolus showed components of different ages of origin. Besides bronchitic and emphysematous alteration histology of the pulmonary tissue revealed interstitial and septal fibrosis with focal tissue consolidation. In one giant cell a typical asbestos body was found (in 1 out of 10 sections). In spite of missing information on an exposition to asbestos an abnormally high exposition must be taken into consideration because of the finding of an asbestos particle in relation to the amount of tissue studied. Apart from interstitial fibrosis asbestos may also cause consolidation of pulmonary tissue. Histology of plaquelike lesions revealed mesothelioma of fibrous type. This finding supports the suspicion that a major part of the pulmonary lesions was due to exposition to asbestos.