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.

A cross-sectional study of acute cor pulmonale in acute respiratory distress syndrome patients in China.

BACKGROUND: Increased right ventricle afterload during acute respiratory distress syndrome (ARDS) may induce acute cor pulmonale (ACP), which is associated with a poor clinical outcome. Echocardiography is now considered as a rapid and non-invasive tool for diagnosis of ACP. The aims of this study were to investigate the morbidity and mortality rates of ACP in ARDS patients in intensive care units (ICUs) across the mainland of China and to determine the severity and prognosis of ACP in ARDS patients through an ultrasound protocol (TRIP). And the association between ACP related factors and the ICU mortality will be revealed. METHODS: This study is a multicenter and cross-sectional study in China which will include ICU participants when diagnosed as ARDS. The ultrasound protocol, known as the TRIP, is proposed as severity assessment for ACP, which includes tricuspid regurgitation velocity (T), right ventricular size (R), inferior vena cava diameter fluctuation (I), and pulmonary regurgitation velocity (P). The 28-day mortality, ICU/hospital mortality, the length of stay in ICU, mechanical ventilation days, hemodynamic parameters and lab parameters of liver function and kidney function are all recorded. DISCUSSION: This large-scale study would give a sufficient epidemic investigation of ACP in ARDS patients in China. In addition, with the TRIP protocol, we expect that we could stratify ACP with more echocardiography parameters. TRIAL REGISTRATION: NCT03827863, https://clinicaltrials.gov/ct2/show/NCT03827863.

Ovine Models of Congenital Heart Disease and the Consequences of Hemodynamic Alterations for Pulmonary Artery Remodeling.

The natural history of pulmonary vascular disease associated with congenital heart disease (CHD) depends on associated hemodynamics. Patients exposed to increased pulmonary blood flow (PBF) and pulmonary arterial pressure (PAP) develop pulmonary vascular disease more commonly than patients exposed to increased PBF alone. To investigate the effects of these differing mechanical forces on physiologic and molecular responses, we developed two models of CHD using fetal surgical techniques: 1) left pulmonary artery (LPA) ligation primarily resulting in increased PBF and 2) aortopulmonary shunt placement resulting in increased PBF and PAP. Hemodynamic, histologic, and molecular studies were performed on control, LPA, and shunt lambs as well as pulmonary artery endothelial cells (PAECs) derived from each. Physiologically, LPA, and to a greater extent shunt, lambs demonstrated an exaggerated increase in PAP in response to vasoconstricting stimuli compared with controls. These physiologic findings correlated with a pathologic increase in medial thickening in pulmonary arteries in shunt lambs but not in control or LPA lambs. Furthermore, in the setting of acutely increased afterload, the right ventricle of control and LPA but not shunt lambs demonstrates ventricular-vascular uncoupling and adverse ventricular-ventricular interactions. RNA sequencing revealed excellent separation between groups via both principal components analysis and unsupervised hierarchical clustering. In addition, we found hyperproliferation of PAECs from LPA lambs, and to a greater extent shunt lambs, with associated increased angiogenesis and decreased apoptosis in PAECs derived from shunt lambs. A further understanding of mechanical force-specific drivers of pulmonary artery pathology will enable development of precision therapeutics for pulmonary hypertension associated with CHD.

Aerobic Exercise Promotes a Decrease in Right Ventricle Apoptotic Proteins in Experimental Cor Pulmonale.

Pulmonary arterial hypertension is characterized by progressive increases in resistance and pressure in the pulmonary artery and Cor pulmonale. The effect of exercise on hydrogen peroxide-dependent signaling in the right ventricle (RV) of Cor pulmonale rats was analyzed. Rats were divided into sedentary control (SC), sedentary monocrotaline (SM), trained control (TC), and trained monocrotaline (TM) groups. Rats underwent exercise training (60% of VO2 max) for 5 weeks, with 3 weeks after monocrotaline injection (60 mg/kg intraperitoneally). Pulmonary resistance was enhanced in SM (2.0-fold) compared with SC. Pulmonary artery pressure was increased in SM (2.7-fold) and TM (2.6-fold) compared with their respective controls (SC and TC). RV hypertrophy indexes increased in SM compared with SC. Hydrogen peroxide was higher in SM (1.7-fold) than SC and was reduced by 47% in TM compared with SM. p-Akt was increased in TM (2.98-fold) compared with SM. The Bax/Bcl-2 ratio and caspase 3 were also increased (2.9-fold and 3.9-fold, respectively) in SM compared with SC. Caspase 3 was decreased in TM compared with SM (P < 0.05). Therefore, exercise training promoted a beneficial response by decreasing hydrogen peroxide concentrations, and consequently, apoptotic signaling in RV.

Pulmonary artery dissection leading to cardiac tamponade as a cause of maternal death in a woman with pulmonary hypertension: a case report.

BACKGROUND: Severe pulmonary hypertension in pregnancy is known to carry a 40% risk of death for the mother. The most common cause of death in cases of pulmonary hypertension is heart failure. CASE: We present a case of maternal death due to dissection of the pulmonary artery resulting in cardiac tamponade. CONCLUSION: The sudden onset of severe chest pain radiating to the back should alert the clinician to the possibility of pulmonary artery dissection in pregnant patients with pulmonary hypertension. Severe chest pain may not be accompanied by changes in vital signs or oxygen saturation. Immediate delivery should be considered. However, delivery may worsen the mother's condition due to postpartum cardiovascular changes.

Right heart failure in the intensive care unit.

PURPOSE OF REVIEW: This review summarizes the approach to and recent developments in the evaluation and treatment of acute right heart failure in the ICU. Right heart failure, defined as failure of the right ventricle to provide sufficient blood flow through the pulmonary circulation at normal central venous pressure, is a common problem caused by a combination of increased right-ventricular afterload and right-ventricular contractile dysfunction. RECENT FINDINGS: Management of acute right heart failure continues to be challenging because of insufficient understanding of its pathophysiology, a lack of guidelines, and few available tools. Recent research has contributed to an improved understanding of its mechanisms, helping to guide therapy and suggest future options. Right-ventricular assist devices are emerging as a promising approach to treatment when optimization of hemodynamics and conventional medical therapy fail. SUMMARY: Right heart failure causes venous congestion and systemic hypoperfusion. Once right heart failure is identified, the primary goal is to alleviate any reversible cause of excessive load or right-ventricular contractile failure. When the underlying abnormalities cannot be alleviated, trials of diuretic, vasodilator, or inotropic therapy may be required. Invasive monitoring helps guide therapy. Medically refractory right heart failure may potentially be treated with right-ventricular assist devices.

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.

Pericardial plaque: a unique complication of silicosis.

The heart and the respiratory system are closely connected in such a way that disorders of one system would influence the function of the other. This unique case of silicosis complicated by corpulmonale associated with pericardial plaque formation in a young adult male is reported here due to an unknown complication of silicosis.

Cor pulmonale in a patient with Brown-Vialetto-Van Laere syndrome: a case report.

Brown-Vialetto-Van Laere syndrome (BVVLS) is a rare neurological disease characterized by sensorineural hearing loss and multiple cranial nerve palsies, usually involving the VIIth and IXth to XIIth cranial nerves. We describe the clinical and pathological features of a 33-year-old woman with BVVLS. The patient developed progressive exertional dyspnea, with clinical and laboratory findings of right-sided heart failure and pulmonary hypertension. She developed status epilepticus in the setting of cardiac deterioration and respiratory infection, and died of cardiogenic and septic shock. Autopsy disclosed bilateral neuronal loss and gliosis in the inferior colliculi, locus coeruleus and facial and vestibular nuclei. Cor pulmonale is a complication of hypoventilation-induced hypoxia and hypercapnia and had not yet been reported in BVVLS.

[The specific features of left cardiac cavity remodeling in patients with chronic obstructive pulmonary disease and chronic cor pulmonale].

AIM: To study left ventricular structural and functional changes in patients with chronic obstructive pulmonary disease (COPD) and chronic cor pulmonale (CCP) at different stages of a cardiac remodeling process. SUBJECTS AND METHODS: Echocardiography was used to examine 98 patients with COPD complicated by the development of CCP in a number of cases. The significant signs of CCP were absent in 19 patients; the signs of compensated and decompensated CCP in 41 and 38 patients, respectively. RESULTS: In the patients with COPD, the formation of CCP during remodeling of the heart involves its left cavities whose changes lie in the occurrence of left ventricular (LV) diastolic dysfunction, mainly of the restrictive type, in ventricular spherization, higher myocardial systolic tension, in tendencies towards increases in LV mass index, left atrial sizes, and in the indices reflecting LV systolic dysfunction. The LV diastolic dysfunction correlates with the degree of right ventricular hypertrophy and dilatation and the presence of complete right bundle-branch block. CONCLUSION: Progressive worsening of diagnostic filling of the left ventricle and its systolic function is an additional factor aggravating hemodynamic disorders in patients with COPD and CCP, which should be kept in mind on choosing an appropriate therapy for patients with CCP.

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.

Pulmonary alveolar microlithiasis with cor pulmonale: an autopsy case demonstrating a marked decrease in pulmonary vascular beds.

Pulmonary alveolar microlithiasis (PAM) is a very rare autosomal recessive disorder in which microliths are formed in the alveolar space. PAM is infrequently complicated by pulmonary hypertension, the cause of which is unclear. The author in this paper found that the pulmonary hypertension was caused by a marked decrease in pulmonary vascular beds. Here, an autopsy case of PAM with a marked cor pulmonale is reported. A 14-year-old woman was found to have an abnormal pulmonary shadow, but the cause was unclear. At 24 years, she was diagnosed with a diffuse pulmonary abnormal shadow. At 42 years, she was diagnosed with PAM by imaging techniques. Her condition gradually worsened and she had to be treated with oxygen. She died of respiratory failure at 54 years. An autopsy revealed severe PAM and marked cor pulmonale. The heart weighed 360 g and right ventricular thickness was 10 mm (normal, 2-3 mm). Microscopically, the alveolar space was diffusely filled with microliths, and heart failure cells were recognized. Bone formations were scattered. The alveolar walls showed fibrous thickening, and pulmonary arteries showed atherosclerosis. The right ventricle showed marked cardiac hypertrophy. Chronic severe liver congestion was noted. A morphometric analysis using CD34-stained specimens showed a marked decrease (one tenth) in pulmonary capillary beds (capillary number: 8.6 +/- 3.1 per image), compared with normal lungs obtained from two other autopsies (85.3 +/- 9.4 and 96.2 +/- 10,3). It was concluded that the cor pulmonale and pulmonary hypertension in the present case were caused by the marked decrease of the pulmonary arterial vascular beds. More research is required regarding the etiology and treatment of PAM.

[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.