JACC: CASE REPORTS VOL. 2, NO.

1, 2020

ª 2020 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

THE CC BY-NC-ND LICENSE (http://creativecommons.org/licenses/by-nc-nd/4.0/).

CASE REPORT

CLINICAL CASE SERIES

Spontaneous Coronary Artery

Dissection in Females With the
Fragile X FMR1 Premutation
Forrest J. McKenzie, BS,a,b Nattaporn Tassanakijpanich, MD,c Kelly C. Epps, MD,d S. Kimara March, MD,e
Randi J. Hagerman, MDa,f

ABSTRACT

This paper reports 2 cases of female carriers of the FMR1 premutation for developing spontaneous coronary artery
dissection (SCAD). These women had classical presentations of premutation symptoms, including anxiety, depression,
and connective tissue problems, all of which can contribute to SCAD. These cases suggest a possible connection between
the fragile X premutation and a predisposition to SCAD. (Level of Difficulty: Intermediate.) (J Am Coll Cardiol Case Rep
2020;2:40–4) © 2020 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

S pontaneous coronary artery dissection (SCAD)

is defined as coronary dissection without
atherosclerotic and traumatic causes. This
complication is rare but is more prevalent in premen-
myocardial infarction without atherosclerotic risks
(1). Genetic disorders affecting connective tissue
such as Ehlers-Danlos syndrome or Marfan syndrome,
and as is suggested later, the fragile X premutation,
opausal and middle-aged women who present with may be an underlying cause of SCAD. Other factors
predisposing to SCAD include fibromuscular
LEARNING OBJECTIVES dysplasia (FMD), systemic inflammatory diseases,
 The objectives of this paper were to highlight use of hormones, psychological stress, and physical
the possible associations between female exertion (1).
carriers of the FMR1 premutation (55 to The fragile X premutation results from a 55 to 200
200 CGG repeats) and SCAD. CGG repeat in the promotor region of the FMR1 gene,
 An additional objective was to show that and this causes an elevation of FMR1 mRNA, leading
premutation carriers have a higher rate of to RNA toxicity. Medical problems can then occur,
hypertension, autoimmune problems, hor- including connective tissue problems, hypertension,
monal dysregulation, depression, anxiety,
autoimmune disorders, psychiatric problems (fragile
stress, and connective tissue problems that
X-associated neuropsychiatric disorders [FXAND]),
can predispose to SCAD.
fragile X-associated primary ovarian insufficiency

From the aMedical Investigation of Neurodevelopmental Disorders Institute, University of California Davis Medical Center, Sac-
ramento, California; bDepartment of Psychiatry and Behavioral Sciences, University of California Davis School of Medicine, Sac-
ramento, California; cDivision of Developmental and Behavioral Pediatrics, Department of Pediatrics, Faculty of Medicine, Prince
of Songkla University, Songkhla, Thailand; dInova Heart and Vascular Institute, Department of Cardiology, Falls Church, Virginia;
e
University of Minnesota Physicians, Department of Cardiology, Minneapolis, Minnesota; and the fDepartment of Pediatrics,
University of California Davis School of Medicine, Sacramento, California. This study was funded by National Institute of Child
Health and Human Development grant HD036071, MIND Institute Intellectual and Developmental Disabilities Research Center
grant U54 HD079125, and National Center for Advancing Translational Sciences and U.S. National Institutes of Health grant UL1
TR001860. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Informed consent was obtained for this case.

Manuscript received November 1, 2019; accepted November 27, 2019.

ISSN 2666-0849 https://doi.org/10.1016/j.jaccas.2019.11.058

JACC: CASE REPORTS, VOL. 2, NO. 1, 2020 McKenzie et al. 41
JANUARY 2020:40–4 SCAD in FMR1 Premutation Females

(FXPOI), and fragile X-associated tremor/ataxia syn- connective tissue problems or concerning ABBREVIATIONS

drome (FXTAS) (2–5). These disorders may predispose cardiac problems. The previous 6 years had AND ACRONYMS

to SCAD. In women in the general population, the been stressful for her because of severe
CAG = coronary angiography
prevalence of the premutation is approximately 1 in behavioral problems in her son with FXS. She
FMD = fibromuscular dysplasia
209 (6). had recently started an exercise program.
miRNA = microRNA
One previous case of SCAD was reported in a 45- DIFFERENTIAL DIAGNOSIS. Acute coronary
year-old female premutation carrier taking hormone SCAD = spontaneous coronary
syndrome. artery dissection
therapy for FXPOI (7). However, the authors described
INVESTIGATIONS. In the emergency room, ST = sinus tachycardia
this patient as having fragile X syndrome (FXS) which
an electrocardiogram (ECG) was performed TIMI = Thrombolysis In
is a different disorder from the premutation. The FXS
and revealed ST-segment elevation in the Myocardial Infarction
is caused by a CGG repeat of >200, and the FMR1 gene
inferior leads (Figure 1). Coronary angiography (CAG)
becomes methylated and silenced so that little or no
was obtained by right radial approach. There was a
mRNA or fragile X mental retardation protein (FMRP)
right dominant system with normal right coronary
is produced. Therefore, intellectual disability and
artery (Figure 2). The left anterior descending artery
autism are the phenotypic features of FXS. This paper
was normal, but a large circumflex obtuse marginal
reports 2 additional cases of female premutation car-
branch revealed typical appearance of SCAD with
riers who presented with SCAD.
Thrombolysis In Myocardial Infarction (TIMI) flow
CASE 1 PRESENTATION grade 3 (Figure 3). Echocardiography showed mild
inferolateral hypokinesis with an ejection fraction of
A 56-year-old woman presented with sudden chest 55% to 60% without significant valve disease.
pressure as she was walking up stairs and described MANAGEMENT. Repeated ECG confirmed resolution
the pain as though something was sitting on her of inferior ST-segment changes, thus no instrumen-
chest. tation of the vessel was performed. The patient was
MEDICAL HISTORY. This patient had the fragile X discharged after 2 days with an aspirin, metoprolol,
premutation of 88 CGG repeats. She had anxiety and and ticagrelor (Brilinta) therapy.
depressed mood which was being treated with ven- FOLLOW-UP. To assess underlying arteriopathies,
lafaxine. She had been in good health without known she underwent a computed tomography angiogram

F I G U R E 1 The Standard 12-Lead Electrocardiography Demonstrated ST-Segment Elevation in the Inferior Leads
42 McKenzie et al. JACC: CASE REPORTS, VOL. 2, NO. 1, 2020

SCAD in FMR1 Premutation Females JANUARY 2020:40–4

F I G U R E 2 Coronary Angiography Showing a F I G U R E 3 Coronary Angiography Showing Appearance of

Right-Dominant System Spontaneous Coronary Artery Dissection

Coronary angiography revealed typical appearance of sponta-

Coronary angiography revealed a right-dominant system with neous coronary artery dissection (arrow) at the large circum-
normal right coronary artery. flex first obtuse marginal branch with Thrombolysis In
Myocardial Infarction flow grade 3.

from head to pelvis that revealed a saccular aneurysm treated with bupropion, armodafinil, zolpidem, and
of the mid splenic artery measuring 7 mm. She had meclizine. She had no significant cardiovascular risk
patent renal and splenic arteries, but she did have factors, except for a remote history of tobacco use,
evidence of FMD in bilateral internal carotid arteries smoking 3 to 5 cigarettes per day in her 20s and 30s.
without stenosis. The patient has not had recurrent
DIFFERENTIAL DIAGNOSIS. Acute coronary syndrome.
SCAD.
INVESTIGATIONS. In the emergency room, ECG
CASE 2 PRESENTATION showed no ischemic changes. She was admitted for
observation, and subsequent troponin assay came
A 64-year-old woman presented with mild chest back mildly elevated at 0.05 ng/ml. CAG was obtained
heaviness and shortness of breath which developed and revealed a long 99% narrowing in the distal left
while hiking and resolved with rest. Three days later, circumflex artery with TIMI flow grade 2 (Figure 4A).
she noted intermittent symptoms of chest pain while Her coronary arteries were otherwise normal, without
at work. Later that day, while hiking, she developed evidence of atherosclerotic disease.
heavy, crushing chest pain that radiated to her right MANAGEMENT. A 2.25-  12-mm drug-eluting stent
shoulder and down her right arm. was deployed successfully in the left circumflex ar-
MEDICAL HISTORY. This patient had the fragile X tery, with good angiographic results (Figure 4B). She
premutation with 71 CGG repeats and loose connec- was discharged with a prescription for aspirin,
tive tissue problems including hyperextensible finger 81 mg/day, clopidogrel (Plavix), 75 mg/day, and
joints, inguinal hernia, chronic back problems with atorvastatin, 40 mg/day.
pain, and right thumb subluxation. She had autoim- FOLLOW-UP. The following day, she returned to the
mune thyroid disease and took levothyroxine daily. emergency room with recurrent chest pain. ECG
FXPOI was diagnosed at age 35 years, and she was showed no ischemic changes. Serial troponin con-
prescribed an estradiol vaginal ring (Estring) every centrations were stable at 0.09 to 0.1 ng/ml. The
3 months. She had a long history of anxiety, depres- previous angiograms were reviewed and appeared to
sion, insomnia, and migraine headaches. She was be consistent with type II SCAD and not
JACC: CASE REPORTS, VOL. 2, NO. 1, 2020 McKenzie et al. 43
JANUARY 2020:40–4 SCAD in FMR1 Premutation Females

F I G U R E 4 Coronary Angiography Images of Pre- and Post-Treatment of Spontaneous Coronary Artery Dissection

(A) A 99% narrowing is shown in the distal circumflex artery (arrow). (B) Post-treatment consisted of a stent (arrow).

atherosclerotic disease. Her treatment regimen was sequester proteins such as DROSHA and DGCR8,
therefore modified. Atorvastatin was discontinued, which leads to dysregulation of maturing micro-RNAs
given her normal lipids, and no evidence of athero- (miRNAs) (4,5). Additionally, hormonal replacement
sclerotic disease was observed on angiography. therapy is common in premutation-carrying women
Metoprolol 25 mg/day was added to her regimen. The as approximately 16% to 20% develop FXPOI (5).
patient has not had recurrent SCAD. Autoimmune problems and hormone replacement
therapy may predispose to SCAD (1).
DISCUSSION
Long-term management of SCAD is essential to
prevent recurrence. Arteriopathies in other sites (i.e.,
Women with the fragile X premutation can experi-
intracranial, renal, and iliac arteries in FMD) should
ence multiple medical problems related to their
be assessed by physical examination and imaging
elevated mRNA levels (4). Some of these problems
studies (1). SCAD is frequently aggravated by physical
overlap with possible causes of SCAD, including
and psychological stressful events (1). Effective psy-
connective tissue problems, autoimmune disorders,
chological intervention is crucial because depression,
hormone replacement therapy for FXPOI, psycholog-
anxiety, and stress are common in premutation car-
ical stress, and hypertension (1,5,8).
riers (3). Because the mechanism of SCAD is non-
Most cases of SCAD are highly associated with
atherosclerotic, medications conventionally used to
FMD (1). FMD and the premutation share clinical
treat acute coronary syndromes have unclear benefits
features of connective tissue problems (2,8). The
(1). Hypertension is a risk factor for recurrent SCAD.
connective tissue problems in the premutation are
Beta-blockers lower this risk by 60% (10). Because
related to a mild deficiency of FMRP. Decreased
fragile X premutation carriers have a higher risk of
FMRP expression increases matrix metallopeptidase
hypertension than the general population, moni-
9, which has a role in extracellular matrix degrada-
toring for hypertension can help prevent recurrent
tion and may contribute to dissection (9). Addition-
SCAD (4).
ally, elastin and actin are regulated by FMRP, so if
FMRP is lowered, the elastin matrix in connective CONCLUSIONS
tissue is abnormal (9).
Autoimmune problems are more common in pre- These cases suggest a possible association between
mutation carriers because elevated mRNA levels can SCAD and the fragile X premutation. SCAD should be
44 McKenzie et al. JACC: CASE REPORTS, VOL. 2, NO. 1, 2020

SCAD in FMR1 Premutation Females JANUARY 2020:40–4

considered in women with the premutation who

present with chest pain. DNA testing for the fragile X ADDRESS FOR CORRESPONDENCE: Dr. Randi J.
premutation should be considered in women who Hagerman, MIND Institute, University of California
present with SCAD and features of carriers described Davis Medical Center, 2825 50th Street, Sacramento,
here. California 95817. E-mail: rjhagerman@ucdavis.edu.

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