scholarly journals MEK Inhibition in a Newborn with RAF1-Associated Noonan Syndrome Ameliorates Hypertrophic Cardiomyopathy but Is Insufficient to Revert Pulmonary Vascular Disease

Genes ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 6
Author(s):  
Alessandro Mussa ◽  
Diana Carli ◽  
Elisa Giorgio ◽  
Anna Maria Villar ◽  
Simona Cardaropoli ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Hypertrophic Cardiomyopathy ◽  
Pulmonary Artery ◽  
Vascular Disease ◽  
Noonan Syndrome ◽  
Therapeutic Option ◽  
Artery Aneurysm ◽  
Pulmonary Vascular Disease ◽  
Posthemorrhagic Hydrocephalus ◽  
Mek Inhibition

The RAF1:p.Ser257Leu variant is associated with severe Noonan syndrome (NS), progressive hypertrophic cardiomyopathy (HCM), and pulmonary hypertension. Trametinib, a MEK-inhibitor approved for treatment of RAS/MAPK-mutated cancers, is an emerging treatment option for HCM in NS. We report a patient with NS and HCM, treated with Trametinib and documented by global RNA sequencing before and during treatment to define transcriptional effects of MEK-inhibition. A preterm infant with HCM carrying the RAF1:p.Ser257Leu variant, rapidly developed severe congestive heart failure (CHF) unresponsive to standard treatments. Trametinib was introduced (0.022 mg/kg/day) with prompt clinical improvement and subsequent amelioration of HCM at ultrasound. The appearance of pulmonary artery aneurysm and pulmonary hypertension contributed to a rapid worsening after ventriculoperitoneal shunt device placement for posthemorrhagic hydrocephalus: she deceased for untreatable CHF at 3 months of age. Autopsy showed severe obstructive HCM, pulmonary artery dilation, disarrayed pulmonary vascular anatomy consistent with pulmonary capillary hemangiomatosis. Transcriptome across treatment, highlighted robust transcriptional changes induced by MEK-inhibition. Our findings highlight a previously unappreciated connection between pulmonary vascular disease and the severe outcome already reported in patients with RAF1-associated NS. While MEK-inhibition appears a promising therapeutic option for HCM in RASopathies, it appears insufficient to revert pulmonary hypertension.

PREOPERATIVE EVALUATION OF THE PULMONARY VASCULAR BED IN PATIENTS WITH PULMONARY HYPERTENSION ASSOCIATED WITH LEFT TO RIGHT SHUNTS

PEDIATRICS ◽  
1959 ◽  
Vol 24 (3) ◽  
pp. 448-454
Author(s):  
I. Hunter Crittenden ◽  
Forrest H. Adams ◽  
Harrison Latta
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Vascular Disease ◽  
Preoperative Evaluation ◽  
Pulmonary Arteries ◽  
Operative Risk ◽  
Pulmonary Vascular Disease ◽  
Vascular Bed ◽  
The Media ◽  
Index Of Severity

Eighteen patients with pulmonary hypertension associated with left to right cardiac shunts have been studied using acetylcholine injected into the pulmonary artery to determine the distensibility of the vascular bed. The response is considered as an index of severity of vascular disease and of operative risk. Six cases failed to respond to the drug. One of these had received atropine, and the data may not be reliable. Five were 6 years of age or older and had relatively less left to right shunting than the others. Surgery was performed in two of this group of six, and it proved fatal. The small pulmonary arteries in both patients had marked intimal disease. All of the 12 cases that responded to acetylcholine had shunting of at least 140% of the systemic flow, and in five patients tested the shunt increased following injection of the drug. The five cases operated upon from this group had hypertrophy of the media of the small pulmonary arteries and in two cases minimal proliferation of the intima was present. The pulmonary artery pressures were similar in both groups. These observations suggest that the severity of pulmonary vascular disease may be predicted by the method described.

Pulmonary Vascular Disease in Secundum Atrial Septal Defect with Pulmonary Hypertension

CHEST Journal ◽  
1986 ◽  
Vol 89 (5) ◽  
pp. 694-698 ◽  
Author(s):  
Shigeo Yamaki ◽  
Togo Horiuchi ◽  
Makoto Miura ◽  
Yasuyuki Suzuki ◽  
Eiji Ishizawa ◽  
...  
Keyword(s):  
Pulmonary Hypertension ◽  
Atrial Septal Defect ◽  
Vascular Disease ◽  
Septal Defect ◽  
Pulmonary Vascular Disease ◽  
Secundum Atrial Septal Defect

The pulmonary vasculature in a neonatal porcine model with increased pulmonary blood flow and pressure

2001 ◽  
Vol 11 (4) ◽  
pp. 420-430 ◽  
Author(s):  
Elisabeth V. Stenbøg ◽  
Daniel A. Steinbrüchel ◽  
Anne Bloch Thomsen ◽  
Ulrik Baandrup ◽  
Lene Heickendorff ◽  
...  
Keyword(s):  
Blood Flow ◽  
Pulmonary Artery ◽  
Vascular Disease ◽  
Pulmonary Blood Flow ◽  
Left Pulmonary Artery ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Systolic Pulmonary Arterial Pressure ◽  
Pulmonary Arterial ◽  
Circulating Levels

Introduction: Hypertension and hyperperfusion of the pulmonary vascular bed in the setting of congenital cardiac malformations may lead to progressive pulmonary vascular disease. To improve the understanding of the basic mechanisms of this disease, there is a need for clinically relevant animal models which reflect the disease process. Material and Results: We randomly allocated 45 newborn pigs, at the age of 48 hrs, to groups in which there was either construction of a 3 mm central aorto-pulmonary shunt, undertaken in 9, or ligation of the left pulmonary artery, achieved in 13. Controls included sham operations in 13, or no operations in 10 pigs. Follow-up was continued for three months. The interventions were compatible with survival in most pigs. The shunts resulted in an acute 85% increase in systolic pulmonary arterial pressure, and a more than twofold increase in pulmonary blood flow. By three months of age, nearly all shunts had closed spontaneously, and haemodynamics were normal. Ligation of the left pulmonary artery resulted in a normal total pulmonary blood flow, despite only the right lung being perfused, and a 33% increase in systolic pulmonary arterial pressure. These haemodynamic changes were maintained throughout the period of study. In both groups, histomorphometry revealed markedly increased muscularity of the intra-acinar pulmonary arteries. Circulating levels of endothelin were normal in the shunted animals, and elevated in those with ligation of the left pulmonary artery. Conclusion: In neonatal porcine models of pulmonary vascular disease, created by construction of 3 mm central aorto-pulmonary shunts and ligation of one pulmonary artery, we observed histopathological changes of the pulmonary vasculature similar to early hypertensive pulmonary vascular disease in humans. Elevated circulating levels of endothelin were associated with abnormal haemodynamics rather than abnormal pathology. These findings could be valuable for future studies on the pathogenesis of hypertensive pulmonary vascular disease associated with congenital cardiac malformations.

Abstract 15542: Late Pulmonary Hypertension in Surgically Palliated D-transposition of the Great Arteries: A 55-year Review

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Blair Suter ◽  
Dylan Hall ◽  
Eric S Ebenroth ◽  
Larry W Markham ◽  
Michael Johansen
Keyword(s):  
Pulmonary Hypertension ◽  
Pulmonary Artery ◽  
Late Onset ◽  
Systolic Dysfunction ◽  
Left Lung ◽  
Treatment Strategies ◽  
Lung Hypoplasia ◽  
Pulmonary Vascular Disease ◽  
Complete Evaluation ◽  
Lost To Follow Up

Introduction: Pulmonary hypertension (PH) has been described following surgical palliation for transposition of the great arteries (D-TGA). While early pulmonary vascular disease is associated with late repair, the increasing prevalence of late PH has been observed following the intra-atrial baffle procedure (ABP), Mustard/Senning. A previous study from our institution identified patients with precapillary PH. More recent studies have described predominately postcapillary PH, suggesting multiple, differing mechanisms for this complication. Hypothesis: While heart failure is a common complication following ABP and is associated with postcapillary PH, we hypothesize that precapillary PH can be identified in a subset of patients. Methods: A retrospective descriptive study was performed at a single institution. Using 6 th World Symposium on Pulmonary Hypertension definitions. PH was defined as a mean pulmonary artery pressure >20mmHg. Etiology of PH was defined as precapillary (≥3 Wood units) versus postcapillary (pulmonary artery wedge pressure >15 mmHg). Results: We reviewed 157 D-TGA patients following ABP, finding 33 patients with PH. Mean age at last evaluation was 36.6 (14-54) years. Current condition: 22 alive, 7 dead, and 4 lost to follow-up. Etiology of PH: 10 precapillary, 8 postcapillary, 8 mixed, 2 borderline PH, and 2 did not undergo catherization. Additionally, 2 patients had pulmonary venous baffle obstruction and 1 had left lung hypoplasia. Of patients with recent imaging, 21 of 25 had systemic RV systolic dysfunction on echocardiogram or MRI. Conclusions: Late-onset PH in D-TGA following ABP is a significant long-term complication and warrants vigilant surveillance. This highlights the limitations of imaging and need for catheterization for complete evaluation. In this study, we observed precapillary PH in a majority of patients with PH, which differs from some previous studies. Identifying the etiology of PH could drastically alter treatment strategies and has implications for transplant consideration. Further studies are needed to identify the clinical attributes that contribute to this process.

scholarly journals Lower DLco% identifies exercise pulmonary hypertension in patients with parenchymal lung disease referred for dyspnea

2020 ◽  
Vol 10 (1) ◽  
pp. 204589401989191 ◽  
Author(s):  
Richard H. Zou ◽  
William D. Wallace ◽  
S. Mehdi Nouraie ◽  
Stephen Y. Chan ◽  
Michael G. Risbano
Keyword(s):  
Pulmonary Hypertension ◽  
Lung Disease ◽  
Vascular Disease ◽  
Pulmonary Function Tests ◽  
Pulmonary Vascular Disease ◽  
Chronic Obstructive ◽  
Exertional Dyspnea ◽  
Pulmonary Arterial ◽  
Parenchymal Lung Disease ◽  
Parenchymal Lung

Exercise pulmonary hypertension is an underappreciated form of physical limitation related to early pulmonary vascular disease. A low diffusing capacity of lungs for carbon monoxide (DLco) can be seen in patients with resting pulmonary hypertension as well as parenchymal lung disease. It remains unclear whether low DLco% identifies early pulmonary vascular disease. We hypothesize that a reduced DLco% differentiates the presence of exercise pulmonary hypertension in patients with parenchymal lung disease. Fifty-six patients referred for unexplained exertional dyspnea with pulmonary function tests within six months of hemodynamic testing underwent exercise right heart catheterization. Exclusion criteria included resting pulmonary arterial or venous hypertension. Receiver operator characteristic curve determined the optimal DLco% cutoffs based on the presence or absence of parenchymal lung disease. Twenty-one (37%) patients had parenchymal lung disease, most common manifesting as chronic obstructive lung disease or interstitial lung disease. In patients with parenchymal lung disease, a DLco of 46% demonstrated 100% sensitivity and 73% specificity for detecting exercise pulmonary hypertension. In patients without parenchymal lung disease, a DLco of 73% demonstrated 58% sensitivity and 94% specificity for detecting exercise pulmonary hypertension. In both cohorts, DLco% below the optimum cutoffs were associated with higher peak mean pulmonary arterial pressure and peak total pulmonary resistance consistent with the hemodynamic definition of exercise pulmonary hypertension. Patients with a DLco < 46% were more often treated with pulmonary vasodilators and had a trend to higher mortality and lung transplant. DLco% is a simple non-invasive screening test for the presence of exercise pulmonary hypertension in our mixed referral population with progressive exertional dyspnea. DLco < 46% with parenchymal lung disease and DLco < 73% without parenchymal lung disease may play a role in differentiating the presence of pulmonary vascular disease prior to invasive hemodynamic testing.

scholarly journals P645 Familial restrictive cardiomyopathy and Noonan"s syndrome: a rare association

2020 ◽  
Vol 21 (Supplement_1) ◽  
Author(s):  
E Surkova ◽  
A Barradas-Pires ◽  
W Li
Keyword(s):  
Hypertrophic Cardiomyopathy ◽  
Pulmonary Artery ◽  
Noonan Syndrome ◽  
Genetic Disorder ◽  
Cardiopulmonary Exercise Testing ◽  
Family Members ◽  
Vena Cava ◽  
Systolic Pressure ◽  
Restrictive Cardiomyopathy ◽  
Reversal Flow

Abstract Background Noonan syndrome is a rare genetic disorder. Typical cardiac involvement include pulmonary stenosis and hypertrophic cardiomyopathy. We present the association of Noonan syndrome with familial non-hypertrophic cardiomyopathy with haemodynamic features of restrictive physiology. Case description. A 30-year old male patient presented to the outpatient clinic with clinical symptoms of heart failure which was slowly progressive since age 20. He was found to have features of restrictive cardiomyopathy aged 12 years at the time when his mother was diagnosed with Noonan syndrome and restrictive cardiomyopathy. On examination, his 1st and 2nd heart sounds were normal, however 3rd heart sound was present. Pulse was regular, 75 per minute, BP 110/70 mmHg. Chest was clear and saturation 98%. Echocardiography showed small left ventricle (LV) with preserved ejection fraction (EF), borderline LV wall thickness (10-11 mm), restrictive filling pattern with mitral valve E/A ratio 4.2 and deceleration time 68 ms; dilated both atria; and pulmonary artery systolic pressure of 37 mmHg (Figure, panels A-C; F). Prominent late diastolic reversal flow was noted in hepatic veins (Panel D). LV longitudinal strain was borderline in absolute value (-18%) however demonstrated ‘apical sparing’ pattern (Panel E). The right ventricle was small in size with mild hypertrophy and dynamic function, but normal flow through pulmonary valve. Prominent diastolic reversal flow was also noted in superior vena cava. Cardiac magnetic resonance confirmed echocardiographic findings and additionally demonstrated prominent trabeculations and myocardial crypts in the LV, small pericardial effusion; no signs of amyloidosis, myocardial infarction, infiltration or fibrosis. Right heart catheterisation showed borderline pulmonary hypertension with a mean pressure of 25 mmHg, raised pulmonary artery wedge pressure 18 mmHg, normal pulmonary vascular resistance 1.9 WU, and a ‘square root sign’ (Panel G). Patient underwent cardiopulmonary exercise testing, he stopped after 9 mins of Bruce protocol due to fatigue, reaching the Peak VO2 of 21.1ml/kg/min (49% of predicted value). No ST changes or arrhythmic events were noted. Patient was diagnosed with primary (non-infiltrative) familial restrictive cardiomyopathy and discussed at multidisciplinary team meeting with recommendation of close follow-up for timing for heart transplantation. Meanwhile he was encouraged to continue treatment with ramipril and start regular physical activity. Discussion There are only few reports describing familial non-hypertrophic cardiomyopathy in patients with Noonan syndrome and none in their family members. We review typical clinical and diagnostic features of restrictive cardiomyopathy involving both ventricles and raise awareness of clinicians of primary familial restrictive cardiomyopathy as a possible cardiac manifestation in patients with Noonan syndrome and their immediate family members. Abstract P645 Figure.

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