Congenital Cardiac Anesthesia Society
A Section of the the Society for Pediatric Anesthesia

{“questions”:{“wnlk5”:{“id”:”wnlk5″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children\u2019s Hospital – Edmonton, Canada \r\nA 25-year-old, G2P0 woman at 28 weeks gestation presents with three-pillow orthopnea. A transesophageal echocardiogram reveals severe mitral stenosis, which will require mitral valve replacement surgery. What is the expected maternal mortality after mitral valve replacement?\r\n\r\n”,”desc”:”EXPLANATION \r\nCardiovascular disease has become increasingly common during pregnancy and is one of the leading causes of maternal mortality in developed countries. This is due to both improved survival of children with congenital heart disease reaching childbearing age, as well as increased prevalence of acquired heart disease. The presence of cardiovascular disease during pregnancy increases the risk of maternal and fetal mortality and morbidity. The physiologic changes of pregnancy, including decreased systemic and pulmonary vascular resistance and increased cardiac output due to an elevation in heart rate and total blood volume, impose additional stress on the cardiovascular system. Ultimately, these physiologic changes may lead to clinical decompensation. Although most pregnant patients\u2019 cardiac disease can be managed medically, some require percutaneous intervention or surgery. Mitral and aortic valvular disease, cardiac tumors, and thromboembolic disease often require intervention during pregnancy. Historically, maternal morbidity and mortality after cardiac surgery were estimated to be 24% and 6%, respectively. Fortunately, more recent data seems to indicate perioperative maternal mortality is similar to that of non-pregnant patients undergoing non-urgent cardiac surgery, at roughly 1-5%. However, fetuses remain at high risk of mortality and morbidity. Schmitz et al. recently reported the Mayo Clinic experience on 29 pregnant patients undergoing cardiac surgery spanning from 1978 to 2023. Primary outcomes were maternal and fetal survival. The average gestational age at the time of surgery was 25 weeks. Fifty-five percent underwent surgery in the second trimester and 35% in the third trimester. More than half of the patients (55%) underwent aortic or mitral valve surgery. Only one woman died in the perioperative period (3%) in the context of emergent thrombectomy for thrombosis of a mechanical aortic valve. About one quarter of the patients underwent a cesarian section before cardiopulmonary bypass (CPB). Preterm delivery was the most common fetal outcome (68%), and fetal mortality remained high at 17%. Not surprisingly, fetal death was more common if delivery occurred after CPB.\r\n\r\n\r\n\r\nThe Modified World Health Organization classification is the most used risk-stratification tool in pregnant women with heart disease. The American Heart Association recommends that expecting mothers with class III or IV disease (significantly or extremely elevated risk of mortality or morbidity) receive care from a multidisciplinary team in an experienced center to determine the location, timing, and mode of fetal delivery. In general, the goal is to reach 39 weeks of gestation before delivery, but maternal or fetal well-being may dictate otherwise. Maternal mortality and morbidity tend to correlate with functional status. Predictors of worse outcomes include a history of stroke, transient ischemic attack or arrhythmia, severe fixed or dynamic left-sided obstruction, or an LV ejection fraction <40%.\r\n\r\n\r\n\r\nParturients with severe symptomatic mitral stenosis are at high risk of developing pulmonary edema, heart failure, arrhythmias, cerebrovascular events, pulmonary hypertension, and death. Medical management includes beta-blockers and diuretics. These patients may be treated with percutaneous balloon valvuloplasty with successful relief of valvular stenosis, with known favorable maternal and fetal outcomes. However, if the valvular stenosis is not amenable to balloon valvuloplasty, surgical replacement may be necessary. The preferable timing for cardiac surgery during pregnancy is thought to be the second trimester, as third-trimester surgery increases the risk of maternal complications. If the fetus has reached viability, pre-operative delivery or cesarian section may be indicated to increase the chances of fetal survival. \r\n\r\n\r\nCardiac surgery with cardiopulmonary bypass (CPB) in pregnant patients is uncommon. Management relies on physiological principles, experience, and expert opinion. General obstetric principles still apply, including maternal steroid administration to promote lung maturity if gestational age is less than 34 weeks and left uterine displacement to avoid aortocaval compression. Fetal heart rate and monitoring for uterine contractions, if possible, should be strongly considered. During CPB, maintenance of maternal homeostasis is essential, including acid-base status, oxygenation, and glucose levels. A mean arterial pressure greater than 70 mmHg should be targeted, which may be achieved with high CPB flow rates to sustain uteroplacental perfusion. Placental hypoperfusion is associated with fetal bradycardia, especially at the onset of CPB. Both fetal bradycardia and uterine contractions are strongly associated with fetal death. Normothermia is associated with improved fetal outcomes despite the potential challenges to myocardial and cerebral protection. A report by Jahangiri et al. on four women undergoing CPB during pregnancy seems to suggest that pulsatile flow may be better for the fetus, although good results have been achieved with non-pulsatile flows. Cardioplegia administration must be limited to avoid hyperkalemic arrest of the fetal heart. It is important to note that, following CPB, the fetus may experience significant metabolic acidosis from a rise in placental and fetal systemic vascular resistance, leading to low cardiac output, which may contribute to fetal demise. Some centers perform a cesarian section just before the sternotomy, pack the abdominal wound during CPB, and then close the abdomen after the reversal of heparin. \r\n\r\nThe correct answer is thus A. The risk of maternal mortality in pregnant patients after cardiac surgery is 1-8%. \r\n\r\n\r\n\r\n\r\n \r\nREFERENCES \r\nSchmitz KT, Stephens EH, Dearani JA, et al. Is Cardiac Surgery Safe During Pregnancy? A 40-Year Single-Institution Experience. Ann Thorac Surg<\/em>. 2024;S0003-4975. doi:10.1016\/j.athoracsur.2024.07.026\r\n\r\n\r\nMeng ML, Arendt KW, Banayan JM, et al. Anesthetic Care of the Pregnant Patient with Cardiovascular Disease: A Scientific Statement From the American Heart Association. Circulation<\/em>. 2023;147(11):e657-e673. doi:10.1161\/CIR.0000000000001121\r\n\r\n\r\n\r\nMehta LS, Warnes CA, Bradley E, et al. Cardiovascular Considerations in Caring for Pregnant Patients: A Scientific Statement from the American Heart Association [published correction appears in Circulation. 2020;141(23):e904. doi: 10.1161\/CIR.0000000000000845 \r\n\r\n\r\nKapoor MC. Cardiopulmonary bypass in pregnancy. Ann Card Anaesth<\/em>. 2014;17(1):33-39. doi:10.4103\/0971-9784.124133\r\n\r\n\r\nChandrasekhar S, Cook CR, Collard CD. Cardiac surgery in the parturient. Anesth Analg<\/em>. 2009;108(3):777-785. doi:10.1213\/ane.0b013e31819367aa\r\n\r\n\r\nJahangiri M, Clarke J, Prefumo F, Pumphrey C, Ward D. Cardiac surgery during pregnancy: pulsatile or nonpulsatile perfusion? [published correction appears in J Thorac Cardiovasc Surg. 2003 Nov;126(5):1680. Clark James [corrected to Clarke James]; Prefumo Frederico [corrected to Federico Prefumo]]. J Thorac Cardiovasc Surg<\/em>. 2003;126(3):894-895. doi:10.1016\/s0022-5223(03)00607-x\r\n\r\n”,”hint”:””,”answers”:{“5df8z”:{“id”:”5df8z”,”image”:””,”imageId”:””,”title”:”A.\t1-8%”,”isCorrect”:”1″},”x9g45″:{“id”:”x9g45″,”image”:””,”imageId”:””,”title”:”B.\t8-15%”},”mymf5″:{“id”:”mymf5″,”image”:””,”imageId”:””,”title”:”C.\t15-25%\r\n”}}}}}

{“questions”:{“wfi6c”:{“id”:”wfi6c”,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Authors: Kaitlin M. Flannery, MD, MPH – Stanford University AND Amy Babb MD – Monroe Carell Jr. Children\u2019s Hospital, Vanderbilt \r\n\r\nAn eight-month-old boy with a history of Williams syndrome underwent repair of supravalvar aortic stenosis 24 hours ago. The blood pressure is noted to be 124\/84 despite administration of additional analgesic and sedative medications. The last lactate was increased from 2.4 to 5.8, and the urine output is 0.6 cc\/kg\/hr. Liver transaminases have doubled over the last 24 hours. Which of the following antihypertensive medications is MOST appropriate to treat this patient?\r\n”,”desc”:”EXPLANATION \r\nAnti-hypertensive medications are frequently utilized in pediatric patients who undergo cardiac surgery. Causes of perioperative hypertension include activation of the sympathetic nervous system from excessive catecholamines, peripheral vasoconstriction, volume overload, and decreased baroreceptor sensitivity. Nitroglycerin, sodium nitroprusside, nicardipine, and clevidipine represent various vasodilator therapies used in pediatric patients after cardiac surgery. Nitroglycerin is a venodilator that is rarely effective as a monotherapy for elevated systemic vascular resistance. Sodium nitroprusside causes both arterial and venous dilatation. Due to its rapid onset of action, it is more likely to be associated with undesired hypotension during drug titration. In addition, there is a risk of cyanide toxicity with resultant hepatic dysfunction and thiocyanate toxicity with potential renal dysfunction. \r\nClevidipine is a dihydropyridine L-type calcium channel blocker that is used as an intravenous infusion to decrease systemic vascular resistance by direct arterial vasodilation. The mechanism of action is identical to nicardipine but with differing pharmacokinetics, which are detailed in the table below. \r\n\t\r\n\r\n\r\nClevidipine is rapidly metabolized by hydrolysis of ester linkages and occurs within the blood compartment and extravascular tissues. Therefore, drug metabolism is not affected by hepatic and\/or renal function. \r\nClevidipine is available in a lipid emulsion that appears similar to propofol. Due to its high lipid content, administration of clevidipine and propofol infusions over prolonged periods may warrant monitoring of triglyceride levels. In addition, lipid enteral infusions for nutrition may require dose adjusting with concomitant clevidipine use to avoid hypertriglyceridemia. It should also be noted that the clevidipine preparation contains soybean oil and egg yolk phospholipid, posing a question about food allergy cross-reactivity. \r\nThe correct answer is B. Clevidipine is the correct answer because its metabolism is not affected by renal or hepatic dysfunction, which are present in this patient. Nicardipine is metabolized by the liver and thus its action may be prolonged in the setting of rising lactate and hepatic dysfunction. Sodium nitroprusside should be avoided in this patient as it is associated with a risk of cyanide and thiocyanate toxicity, which can further worsen liver and renal dysfunction, respectively. \r\n\r\n \r\nREFERENCES \r\nMa M, Martin E, Algaze C, et al. Williams syndrome: supravalvar aortic, aortic arch, coronary, and pulmonary arteries: is comprehensive repair advisable and achievable? Semin Thorac Cardiovasc Surg Pediatr Card Surg Annu<\/em>. 2023;26:2-8. \r\nWu M, Ryan KR, Roesenthal DN, Jahadi O, Moss J, Kwiatkowski DM. The use of clevidipine for hypertension in pediatric patients receiving mechanical circulatory support. Pediatr Crit Care Med<\/em>. 2020;21(12):e1134-1139. \r\nAronson S, Dyke CM, Stierer KA, et al. The ECLIPSE trials: comparative studies of clevidipine to nitroglycerin, sodium nitroprusside, and nicardipine for acute hypertension treatment in cardiac surgery patients. Anesth Analg<\/em>. 2008;107(4):1110-1121. \r\n”,”hint”:””,”answers”:{“ih25y”:{“id”:”ih25y”,”image”:””,”imageId”:””,”title”:”A.\tNicardipine”},”3iiyj”:{“id”:”3iiyj”,”image”:””,”imageId”:””,”title”:”B.\tClevidipine”,”isCorrect”:”1″},”m8p6t”:{“id”:”m8p6t”,”image”:””,”imageId”:””,”title”:”C.\tSodium nitroprusside”}}}}}

{“questions”:{“akel6”:{“id”:”akel6″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children\u2019s Hospital -Edmonton AB Canada \r\n\r\nA 1-week-old girl with severe pulmonary stenosis, intact ventricular septum, and moderate tricuspid valve regurgitation is status post balloon pulmonary valvuloplasty. Two hours later, the heart rate was 188, with an arterial blood pressure of 46\/19 and oxygen saturation of 88%. A transthoracic echocardiogram demonstrates a large patent ductus arteriosus with left-to-right shunting, along with severe pulmonary and tricuspid regurgitation. Which of the following management options is MOST likely to improve the patient\u2019s hemodynamics?\r\n”,”desc”:”EXPLANATION \r\nThe most likely explanation for this patient\u2019s hemodynamic instability is the development of a circular shunt. This is an uncommon physiological phenomenon in which blood from the systemic circulation enters the pulmonary circulation through the patent ductus arteriosus (PDA). The blood then flows into the right ventricle (RV) and the right atrium (RA) in a retrograde fashion through regurgitant pulmonary and tricuspid valves. From the RA, blood flows across an atrial septal defect (ASD) or a patent foramen ovale (PFO). Thus, a circular shunt occurs in the presence of a PDA, a right to left atrial shunt, and significant pulmonary and tricuspid valve insufficiency, following the pathway of least resistance. This is illustrated in Figure 1 below. Circular shunts usually lead to significant hemodynamic instability as both the pulmonary and tricuspid regurgitation effectively steal blood from both the systemic and pulmonary circulations, leading to low cardiac output and desaturation.\r\n\r\n\r\n \r\n\r\n\r\n\r\nFigure 1. Pathway of blood flow in a circular shunt.\r\n\r\n\r\nCircular shunts are typically described in the setting of severe Ebstein\u2019s anomaly (EA), though they can also be seen after relief of right ventricular outflow tract obstruction (RVOTO) in patients with right-sided obstructive lesions. Bautista-Rodriguez et al. described two patients with severe pulmonary stenosis who developed circular shunt physiology following balloon dilation of the pulmonary valve. In both cases, the PDA failed to close, resulting in a low cardiac output state refractory to medical treatment after the procedure. PDA ligation was attempted to interrupt the circular shunt. However, upon complete occlusion of the PDA, the oxygen saturation decreased to 50%. At this point, the PDA was partially banded, targeting a systemic saturation of 70% and a mean systemic arterial pressure increase of greater than 20 mmHg. Both patients had good outcomes. The authors concluded that pulmonary insufficiency caused by balloon pulmonary valvuloplasty in the setting of tricuspid regurgitation and a small dysfunctional RV likely worsened RV function and favored retrograde flow in the presence of a PDA. Patients with severe EA who have a small, dysfunctional RV, significant TR, and a PDA may present similarly before intervention. Other susceptible patients include those with severe pulmonary stenosis (PS) and pulmonary atresia with intact ventricular septum (PA\/IVS). \r\n\r\n\r\nMedical management of a hemodynamically unstable circular shunt remains difficult and consists mainly of supportive treatment until an interventional or surgical procedure can take place. The goal is to optimize forward flow into the systemic and pulmonary circulation, mainly with inotropic support, reduction of systemic vascular resistance, and discontinuation of prostaglandin E1. Increasing pulmonary vascular resistance has also been described to decrease \u201csteal\u201d from the systemic circulation, although this might increase RV afterload and worsen pulmonary insufficiency. Definitive management depends on the underlying pathology. Options include PDA banding or ligation. In the case of EA, some options include pulmonary artery ligation or the Starne\u2019s procedure.\r\n\r\n\r\nThe correct answer is A, patent ductus arteriosus ligation. This functions to eliminate retrograde flow into the pulmonary artery to the RV. Supportive measures with vasoactive agents or pulmonary vasodilators, such as milrinone and nitric oxide, are likely to be of short-term benefit without addressing the underlying mechanism of the circular shunt.\r\n\r\n\r\n\r\n\r\n \r\nREFERENCES \r\n\r\nKonstantinov IE, Chai P, Bacha E, et al. The American Association for Thoracic Surgery (AATS) 2024 expert consensus document: Management of neonates and infants with Ebstein anomaly. J Thorac Cardiovasc Surg<\/em>. 2024;168(2):311-324. doi:10.1016\/j.jtcvs.2024.04.018\r\n\r\n\r\nBautista-Rodriguez C, Rodriguez-Fanjul J, Moreno Hernando J, Mayol J, Caffarena-Calvar JM. Patent Ductus Arteriosus Banding for Circular Shunting After Pulmonary Valvuloplasty. World J Pediatr Congenit Heart Surg<\/em>. 2017;8(5):643-645. doi:10.1177\/2150135116655122\r\n\r\n\r\nAndropoulos DB. Anesthesia for Congenital Heart Disease<\/em>. 2nd ed. Wiley-Blackwell; 2010. Chapter 28: Anesthesia for Right-Sided Obstructive Lesions. Accessed August 12, 2024.\r\n”,”hint”:””,”answers”:{“77kxm”:{“id”:”77kxm”,”image”:””,”imageId”:””,”title”:”A.\tPatent ductus arteriosus ligation”,”isCorrect”:”1″},”58mif”:{“id”:”58mif”,”image”:””,”imageId”:””,”title”:”B.\tInhaled nitric oxide”},”4yyqf”:{“id”:”4yyqf”,”image”:””,”imageId”:””,”title”:”C.\tMilrinone infusion\r\n”}}}}}

{“questions”:{“cw7s2”:{“id”:”cw7s2″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children\u2019s Hospital, Edmonton Canada \r\nA 15-month-old boy is started on a bivalirudin infusion after placement of a Berlin Heart ventricular assist device. Which of the following tests is MOST frequently used to monitor anticoagulation with bivalirudin? \r\n\r\n”,”desc”:”EXPLANATION \r\nBivalirudin is a direct thrombin inhibitor (DTI) that exerts its anticoagulant effect by binding both circulating and clot-bound thrombin, thus preventing cleavage of fibrinogen to fibrin. It is metabolized via proteolytic cleavage (80%) and renal excretion (20%), and its half-life is age-dependent, ranging from 15-18 minutes in children to 25 minutes in healthy adults. There are no reversal agents. While bivalirudin has been recently FDA-approved in adults in the setting of percutaneous coronary angioplasty, there are no approved indications in the pediatric population. It is, however, increasingly used in patients on mechanical circulatory support (MCS), including extracorporeal membrane oxygenation (ECMO). In most ICUs, bivalirudin is usually started at 0.3 mg\/kg\/h and titrated for an aPTT value of 1.5-2.5x normal. In contrast to unfractionated heparin (UFH), it does not depend on the action of antithrombin III (ATIII), thereby providing more stable levels of anticoagulation, which is particularly relevant in a population with highly variable ATIII levels. A study by Freniere et al. compared bivalirudin to UFH in children with Berlin Heart ventricular assist devices (VAD). Similar to other studies, they found there were no differences in thrombotic or hemorrhagic complications between both groups, but chest tube output was reduced in the bivalirudin group. Patients in the aPTT-monitored bivalirudin group had a shorter time to reach the therapeutic range (5.7 vs. 69.5 hours) and a greater percentage of test results and time in the therapeutic range compared to the anti-Xa-monitored UFH group. Interestingly, when anticoagulation was measured with aPTT for both drugs, the time to reach therapeutic levels was no longer statistically different, thus highlighting the importance of how anticoagulation is measured.\r\n\r\nAPTT is an assay that classically measures the activity of the tissue factor\/ extrinsic pathway. However, it is sensitive to a plethora of factors, including contact activation from artificial surfaces, inflammation, and variations in factor VIII levels. Moreover, anticoagulation with DTIs does not exhibit a linear correlation with commonly used tests, including aPTT, ACT, and kaolin-activated TEG, particularly at higher plasma concentrations. This may lead to erroneous dosing of bivalirudin, especially during MCS with ECMO or cardiopulmonary bypass (CPB). More recently, dilute thrombin time (dTT) has emerged as a more precise assay, as it provides a better correlation with bivalirudin plasma levels. A study by Engel et al. looked at several aPTT, dTT, and experimental bivalirudin-specific dTT assays in children on ECMO and with VADs who were anticoagulated with bivalirudin. They found the experimental and conventional dTT assays all correlated with the bivalirudin dosing but poorly correlated with aPTT. This supports the idea that while aPTT is widely used to measure bivalirudin anticoagulation due to its history and availability, it remains a suboptimal assay. \r\nUFH may also be monitored with a PTT, with a similar level of imprecision. The anti-Xa assay is used to measure UFH and low-molecular-weight heparin (LMWH) and is more sensitive than aPTT, leading to faster achievement of target anticoagulation and lower dose requirement. However, it cannot be used for bivalirudin monitoring as the latter does not exert its effect on factor X. The activated clotting time (ACT) is widely used to measure heparin anticoagulation during vascular or cardiac surgical procedures. It remains non-specific to any type of anticoagulant drug or physiologic disturbance and is unreliable to measure bivalirudin anticoagulation, even when used for CPB. \r\nThe correct answer is B. aPTT is the most commonly used test to monitor patients on bivalirudin. ACT and anti-Xa are used to monitor anticoagulation with UFH and LMWH. \r\n\r\n\r\n \r\nREFERENCES \r\nFaraoni D, DiNardo JA. Bivalirudin: The misunderstood alternative to heparin. Paediatr Anaesth<\/em>. 2024;34(5):394-395. doi:10.1111\/pan.14868 \r\nFreniere V, Salerno DM, Corbo H, et al. Bivalirudin Compared to Heparin as the Primary Anticoagulant in Pediatric Berlin Heart Recipients. ASAIO J<\/em>. 2023;69(5):e205-e211. doi:10.1097\/MAT.0000000000001921\r\n\r\nEngel ER, Perry T, Block M, Palumbo JS, Lorts A, Luchtman-Jones L. Bivalirudin Monitoring in Pediatric Ventricular Assist Device and Extracorporeal Membrane Oxygenation: Analysis of Single-Center Retrospective Cohort Data 2018-2022. Pediatr Crit Care Med<\/em>. 2024;25(7):e328-e337. doi:10.1097\/PCC.0000000000003527\r\n\r\nZaleski KL, DiNardo JA, Eaton MP. Bivalirudin: Are kids just adults to the \u00be power? Paediatr Anaesth<\/em>. 2021;31(6):628-630. doi:10.1111\/pan.14168\r\n\r\n”,”hint”:””,”answers”:{“7006r”:{“id”:”7006r”,”image”:””,”imageId”:””,”title”:”A.\tACT”},”drl3c”:{“id”:”drl3c”,”image”:””,”imageId”:””,”title”:”B.\taPTT”,”isCorrect”:”1″},”st0aa”:{“id”:”st0aa”,”image”:””,”imageId”:””,”title”:”C.\tAnti-Xa”}}}}}

{“questions”:{“6i5h4”:{“id”:”6i5h4″,”mediaType”:”image”,”answerType”:”text”,”imageCredit”:””,”image”:””,”imageId”:””,”video”:””,”imagePlaceholder”:””,”imagePlaceholderId”:””,”title”:”Author: Melissa Colizza, MD – Stollery Children’s Hospital, University of Alberta, Edmonton, Canada\r\n\r\nA 5-month-old girl with Noonan syndrome and confirmed RIT1 mutation presents with failure to thrive. A transthoracic echocardiogram demonstrates biventricular hypertrophy with a peak subaortic gradient of 88 mmHg. Which of the following medications is MOST likely to produce regression of the underlying pathology?\r\n”,”desc”:”EXPLANATION \r\nNoonan syndrome (NS) is a classic example of \u201cRASopathy,\u201d a family of genetic conditions characterized by the activation of rat sarcoma (RAS)virus protein\/mitogen-activated protein kinase (MAPK) cascade. RASopathies result in \u201cgain-of-function\u201d germline mutations and lead to congenital anomalies and a predisposition to malignancy. Typical clinical features involve a short stature, abnormal facies, congenital heart defects, developmental delay, lymphatic abnormalities, bleeding tendencies, and skeletal anomalies. Other RASopathies include Costello syndrome, cardiofaciocutaneous syndrome, and Legius syndrome. A plethora of responsible genes have been identified, including SOS1, RIT1, KRAS, RAF1and PTPN11. Approximately half of NS patients carry a mutation in the PNPT11 gene, which is more likely to be associated with the development of pulmonary valve stenosis. While overall, about 20% of NS patients have hypertrophic cardiomyopathy (HCM), 95% of individuals with RAF1 mutations, and 75% with RIT1 mutation have HCM. Animal models have shown a correlation between the strength of RAS\/MAPK signaling and the severity of manifestations. Mild to moderately increased activation from germline mutations will result in RASopathy, whereas moderate to severely increased activation stemming from somatic mutations will result in neoplastic disease. \r\n\r\nRoughly 80% of RASopathy patients will suffer from a cardiac anomaly, pulmonic valve stenosis being the most common. Approximately 22-29% will develop hypertrophic cardiomyopathy (HCM). As the pathology arises from a gain-of-function mutation, myocardial hypertrophy tends to be more severe and rapidly progressive than other forms of HCM and carries a poorer prognosis, with a 1-year survival of 34% in infants less than six months of age with severe obstruction and heart failure. Since mutations of the RAS\/MAPK pathway are the most common cause of human neoplasia, its inhibition has been the target of extensive research and resulted in the use of several mitogen-activated protein\/extracellular signal-regulated kinase (MEK) inhibitors such as trametinib, cobimetinib, and selumetinib. Animal models have subsequently shown that some RASopathy clinical features, including cardiac hypertrophy, may be altered by MEK inhibitors (MEKi). A case report by Andelfinger et al. described the compassionate use of trametinib in two NS infants with RIT1 mutations and severe, rapidly progressive HCM despite aggressive medical management. The authors noted a regression of the hypertrophy, as well as an improvement in clinical status and biological markers within four months following the initiation of therapy. Patients remained on trametinib for three and a half years before successful weaning. Other publications also report the effectiveness of MEKi in RASopathy-related HCM or lymphatic disease. In a review by Chaput and Andelfinger, the authors suggest the MEKi drugs should only be used in the context of a confirmed gain-of-function mutation of the RAS\/MAPK pathway in consultation with RASopathy specialists. The authors also highlight the fact that no single molecule would apply to all RASopathy patients, nor would one address all clinical manifestations in a single patient. \r\n\r\nWhile promising, the use of MEK inhibitors in RASopathies remains experimental, and most patients with HCM will be treated with conventional medical treatment, including beta-blockers, calcium channel blockers, and disopyramide. Beta-blockers reduce myocardial contractility and heart rate, thereby decreasing the dynamic subvalvular gradient and improving ventricular filling and ejection. Beta-blockers have been shown to decrease mortality in HCM. While some authors hypothesize that they might induce ventricular remodeling, beta blockers will not reverse the molecular process in the context of RASopathies. Calcium channel blockers may also be used as a treatment but have not been shown to decrease mortality or reverse underlying hypertrophy. \r\n\r\nThe correct answer is B. Trametinib is a mitogen-activated protein\/extracellular signal-regulated kinase (MEK) inhibitor that has been demonstrated to reverse the myocardial hypertrophy associated with NS. Propranolol and amlodipine provide symptomatic relief but do not alter the underlying pathological process.\r\n\r\n\r\n \r\nREFERENCES \r\nAndelfinger G, Marquis C, Raboisson MJ, et al. Hypertrophic cardiomyopathy in Noonan syndrome treated by MEK-inhibition. J Am Coll Cardiol<\/em>. 2019;73:2237-9. \r\n\r\nChaput D, Andelfinger G. MEK Inhibition for RASopathy-Associated Hypertrophic Cardiomyopathy: Clinical Application of a Basic Concept. Can J Cardiol<\/em>. 2024;40(5):789-799. doi:10.1016\/j.cjca.2024.02.020\r\n\r\nSaint-Laurent C, Mazeyrie L, Yart A, Edouard T. Novel therapeutic perspectives in Noonan syndrome and RASopathies. Eur J Pediatr<\/em>. 2024;183(3):1011-1019. doi:10.1007\/s00431-023-05263-y\r\n\r\n\r\n\u00d6stman-Smith I. Beta-Blockers in Pediatric Hypertrophic Cardiomyopathies. Rev Recent Clin Trials<\/em>. 2014;9(2):82-85. doi:10.2174\/1574887109666140908125158\r\n\r\n”,”hint”:””,”answers”:{“oht1p”:{“id”:”oht1p”,”image”:””,”imageId”:””,”title”:”A.\tPropranolol”},”jxr0x”:{“id”:”jxr0x”,”image”:””,”imageId”:””,”title”:”B.\tTrametinib”,”isCorrect”:”1″},”v4fqw”:{“id”:”v4fqw”,”image”:””,”imageId”:””,”title”:”C.\tAmlodipine\r\n”}}}}}