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Unusual cause of aborted sudden cardiac death in a teen athlete: homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene

Published online by Cambridge University Press:  12 December 2014

Susie B. Phillips,
Sarosh Batlivala and
Jarrod D. Knudson
Susie B. Phillips
Affiliation:
Department of Pediatrics, Children’s Heart Center, Children’s of Mississippi, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
Sarosh Batlivala
Affiliation:
Department of Pediatrics, Children’s Heart Center, Division of Cardiology, Children’s of Mississippi, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
Jarrod D. Knudson*
Affiliation:
Department of Pediatrics, Children’s Heart Center, Division of Critical Care, Children’s of Mississippi, University of Mississippi Medical Center, Jackson, Mississippi, United States of America
*
Correspondence to: Assistant Professor J. D. Knudson, MD, PhD, FAAP, FACC, Department of Pediatrics, Children’s Heart Center, Division of Critical Care, Children’s of Mississippi, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, United States of America. Tel: +601 815 8173; Fax: +601 984 5982; E-mail: jknudson@umc.edu; jarrodknudson@gmail.com
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Abstract

Common aetiologies of sudden cardiac death in children include coronary anomalies, channelopathies, and cardiomyopathies. Less frequently, hypercoagulable states cause sudden arrest. We report an unusual case of aborted sudden cardiac death in a teenager, ultimately found to have homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene.

Keywords

Sudden cardiac deathplasminogen activase inhibitorcoronary ischaemia

Information

Type
Brief Reports
Information
Cardiology in the Young , Volume 25 , Issue 7 , October 2015, pp. 1428 - 1430
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Copyright
© Cambridge University Press 2014 

Sudden cardiac death claims 300,000–400,000 lives annually in the United States.Reference Rubart and Zipes 1 Sudden cardiac death is rare in children; therefore, population-based data are scarce. Extrapolation from a comprehensive review of paediatric cardiac arrest cases suggests that ~16,000 children suffer from out-of-hospital cardiac arrest in the United States every year.Reference Young and Seidel 2 Children experiencing out-of-hospital cardiac arrest have a meaningful survival rate of only 6.4%, which nearly doubles with prompt resuscitation.Reference Atkins, Everson-Stewart and Sears 3 Common cardiac causes of sudden death in children include long QT syndrome, hypertrophic obstructive cardiomyopathy, and coronary artery anomalies. Other rare causes of sudden cardiac death include vasculopathy associated with undiagnosed remote Kawasaki disease or myocarditis.Reference Daniels, Gordon and Burns 4 Secondary causes include hypercoagulable states,Reference French, Van de Water and Sutton 5 resulting in myocardial infarction or pulmonary embolus. We report a case of sudden cardiac death in a teen athlete with collapse on the sports field secondary to myocardial infarction.

Case report

A 15-year-old Caucasian boy experienced a pulseless arrest on the sports field. Cardiopulmonary resuscitation was initiated immediately and defibrillation/cardioversion was performed with an automated external defibrillator within 10 minutes of arrest, resulting in the return of spontaneous circulation and normal mental status. The patient had past medical history of hiatal hernia, gastro-oesophageal reflux disease, remote history of peptic ulcer disease, and coeliac disease. A four-generation pedigree revealed no significant family history of cardiac disease. He denied illicit drug use, and his only medication was omeprazole. In the 24 hours leading up to cardiac arrest, he experienced burning, epigastric pain. Immediately before cardiac arrest, he experienced lightheadedness.

Initial work-up at an outside institution revealed ST segment elevation in the anterolateral leads, elevated cardiac enzymes (troponin I of 1 ng/ml), and globally depressed left ventricular systolic function. He was transferred to our facility for further evaluation and treatment.

Physical examination revealed a pleasant teenage boy resting comfortably in no distress with normal body mass index and vital signs. Cardiovascular examination revealed a quiet precordium with soft II/VI systolic ejection murmur at the left midsternal border without radiation, and the remainder of physical examination was unremarkable.

Blood counts, chemistry, urine drug screen, and lipid panel were unremarkable. Follow-up troponin I was 0.83 ng/ml. Repeat electrocardiogram revealed ST segment elevation in the anterolateral leads. Chest radiograph was normal. Owing to concern for coronary anomaly, CT angiography was performed and revealed normal coronary artery origins, but a dilated and thinned left ventricle with diffuse subendocardial flow attenuation suggestive of chronic myocardial ischaemia.

The patient was taken to the cardiac catheterisation laboratory immediately after the CT angiography results were obtained. Haemodynamics (Table 1) and endomyocardial biopsies were normal. Right coronary angiogram was normal. The proximal left coronary and circumflex arteries were normal; however, the mid-portion of the left anterior descending artery had a myocardial bridge immediately proximal to a left anterior descending filling defect with thrombolysis-in-myocardial-infarction flow grade IIReference Antman, Cohen and Bernink 6 – sluggish antegrade flow with normal distal filling (Fig 1a). Intravascular ultrasound confirmed the myocardial bridge with a patent lumen during diastole. The vessel had a flow defect consistent with thrombus. The vessel was manually aspirated, balloon dilated, intracoronary Integrilin was administered, and a subsequent dilation was performed, resulting in thrombolysis-in-myocardial-infarction flow grade III – normal flow (Fig 1b).

Figure 1

Panel (a) - Coronary lesion is marked by asterisk. There is sluggish antegrade flow with normal distal filling (arrows). Panel (b) - There is improvement in stenosis following intervention (asterisk) with normal filling of the vessel (arrows).

Table 1

Catheterisation haemodynamics.

AscAo=ascending aorta; DescAo=descending aorta; LPA=left pulmonary artery; LPCW=left pulmonary capillary wedge pressure; LV=left ventricle; RA=right atrium; RV=right ventricle

Atrial pressures reported as a-wave/v-wave/mean; others are systolic/diastolic or end-diastolic/mean

Following cardiac catheterisation, MRI revealed left ventricular systolic dysfunction, with 42% ejection fraction, and delayed enhancement in two adjacent regions of remote infarction.

Hypercoagulable work-up revealed homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene. Genetics work-up was negative for Fabry disease, chromosomal duplication/deletion syndromes, other metabolic disorders, and channelopathies. An automatic implantable cardioverter defibrillator was placed, and the patient was discharged in good condition on aspirin and clopidogrel. Clopidogrel was given for 3 months following catheterisation. The patient is currently on aspirin and metoprolol. He has not received therapy since his cardioverter defibrillator has been placed.

Discussion

The pathophysiology of homozygosity for the 4G allele of the plasminogen activase inhibitor type 1 gene is well-understood. Plasminogen activase inhibitor type 1 is a key physiological inhibitor of the fibrinolytic system. Known potentially pathologic genetic polymorphisms include 4G/4G and 4G/5G. The 5G allele has both a repressor-binding site as well as an activator site, allowing for more precise regulation of transcription and plasma concentration of plasminogen activator inhibitor type 1. In contrast, the 4G allele only has an activator site for binding; therefore, transcription of the 4G allele is associated with higher plasma concentrations of plasminogen activator inhibitor type 1.Reference Hoekstra, Geleijnse, Kluft, Giltay, Kok and Schouten 7 Individuals who are homozygous for the 4G allele have the highest plasma concentration of plasminogen activator inhibitor type 1, placing them at an increased risk for thrombotic eventsReference Isordia-Salas, Leanos-Miranda, Sainz, Reyes-Maldonado and Borrayo-Sanchez 8 secondary to stronger inhibition of fibrinolysis.

Our patient was found to have homozygosity for the 4G allele of the plasminogen activator inhibitor type 1 gene. There are reports of thrombotic events in young patients with this particular polymorphism. A right atrial thrombus in a 24-year-old womanReference Isordia-Salas, Leanos-Miranda, Sainz, Reyes-Maldonado and Borrayo-Sanchez 8 and myocardial infarctions in a set of newborn identical twinsReference De Lucia, Andreassi, Sabatini, Ait-Ali, Spadoni and Giusti 9 have been described. Larger studies evaluating the risk of 4G homozygosity in adults with myocardial infarction have not clearly demonstrated an association;Reference Leander, Wiman, Hallqvist, Sten-Linder and de Faire 10 however, Isordia-Salas et al performed a case–control study comparing genotype distribution between 127 patients with ST elevation myocardial infarction and an equal number of controls. The 4G allele occurred in higher frequency in the experimental group, suggesting that 4G homozygosity is an independent risk factor for myocardial infarction in young patients.Reference Isordia-Salas, Leanos-Miranda, Sainz, Reyes-Maldonado and Borrayo-Sanchez 8 Larger studies are needed to more clearly define the role of the 4G allele in early myocardial infarction in adults. In addition, with reports of life-threatening thrombotic events in children with the polymorphism, genetic testing and case reporting remain imperative to improving our understanding of this apparently hypercoagulable state in children.

Acknowledgements

None.

Financial Support

None.

Conflicts of Interest

None.

Ethical Standards

As a retrospective case report, Institutional Review Board approval was not required.

References

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Figure 0

Figure 1Panel (a) - Coronary lesion is marked by asterisk. There is sluggish antegrade flow with normal distal filling (arrows). Panel (b) - There is improvement in stenosis following intervention (asterisk) with normal filling of the vessel (arrows).

Figure 1

Table 1Catheterisation haemodynamics.