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Case Report/Case Series
May 2015

Familial Spontaneous Coronary Artery DissectionEvidence for Genetic Susceptibility

Author Affiliations
  • 1Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota
  • 2Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
  • 3Division of Anatomic Pathology, Mayo Clinic, Rochester, Minnesota
JAMA Intern Med. 2015;175(5):821-826. doi:10.1001/jamainternmed.2014.8307
Abstract

Importance  Spontaneous coronary artery dissection (SCAD) is a major cause of acute coronary syndrome in young women, especially among those without traditional cardiovascular risk factors. Prior efforts to study SCAD have been hampered by underrecognition and lack of registry-based studies. Risk factors and pathogenesis remain largely undefined, and inheritability has not been reported.

Observations  Using novel research methods, patient champions, and social media, the Mayo Clinic SCAD Registry has been able to better characterize this condition, which was previously considered rare. Of 412 patient enrollees, we identified 5 familial cases of SCAD comprising affected mother-daughter, identical twin sister, sister, aunt-niece, and first-cousin pairs, implicating both recessive and dominant modes of inheritance. The mother-daughter pair also reported fatal myocardial infarction in 3 maternal relatives. None of the participants had other potential risk factors for SCAD, including connective tissue disorders or peripartum status.

Conclusions and Relevance  To our knowledge, this series is the first to identify a familial association in SCAD suggesting a genetic predisposition. Recognition of SCAD as a heritable disorder has implications for at-risk family members and furthers our understanding of the pathogenesis of this complex disease. Whole-exome sequencing provides a unique opportunity to identify the molecular underpinnings of SCAD susceptibility.

Introduction

Spontaneous coronary artery dissection (SCAD) is a nonatherosclerotic disease of the coronary arteries and usually presents as acute coronary syndrome.1,2 The pathogenesis of SCAD involves development of a dissection plane within the coronary artery wall with concurrent intramural hematoma and/or intimal flap, ultimately obstructing flow and causing myocardial ischemia and infarction. Spontaneous coronary artery dissection was previously considered rare, with only individual cases and small case series published.35 However, the advent of dedicated online SCAD patient communities and social media communication has led to increased awareness of the condition and robust patient-initiated research activity. More recent studies6,7 with advanced intracoronary imaging suggest that 1% to 4% of patients with acute coronary syndrome may have SCAD. More importantly, SCAD may be responsible for one-third of the acute coronary syndromes in females younger than 50 years and is the most common cause of peripartum myocardial infarction.69 The emerging recognition that both the treatment and outcomes of SCAD differ from those of acute coronary syndrome caused by atherosclerosis1,10,11 highlights the need to increase awareness and diagnostic acumen among health care professionals.

Spontaneous coronary artery dissection occurs most commonly in young women with no or minimal cardiovascular risk factors. The exact pathophysiologic mechanisms associated with SCAD are unclear, but associations with the peripartum period, extreme exercise or emotion, connective tissue disorders, and fibromuscular dysplasia have been reported.1,2,12 Because the estimated 10-year incidence of major adverse cardiovascular events, including death, recurrent SCAD, heart failure, and myocardial infarction after initial SCAD, is high (47%),1 identification of novel risk factors is critical. To our knowledge, the significance of family history in SCAD has not been previously reported.

Methods

This study was approved by the Mayo Clinic institutional review board. Written informed consent was obtained for participation in the "Virtual" Multicenter Mayo Clinic SCAD Registry,1,13 which included obtaining medical records from other institutions. We reviewed the medical records of 412 participants with SCAD in the Registry for a history of SCAD or coronary artery disease in another family member. The Mayo Clinic SCAD Registry was established in 2010 in response to an organized effort by an online community of patients with SCAD seeking further research on their condition. A pilot study13 reported the development and feasibility of this novel international virtual rare-disease registry. We were able to confirm SCAD diagnoses via coronary angiographic review and gain new insights into the condition through comprehensive assessment of medical records and patient narratives of their experiences. Since then, the Mayo Clinic SCAD Registry has evolved to include hundreds of patients with SCAD who have learned about the study via the Internet, social media, or referrals by their physicians. Registry inclusion criteria require confirmation of SCAD diagnosis by review of coronary angiography by at least 2 interventional cardiologists; patients with dissections that are iatrogenic or secondary to coronary atherosclerosis are excluded. Data collection includes extensive medical records, detailed questionnaires, ancillary images, and prospective follow-up. Moreover, hundreds of participants and their family members have contributed specimens to an ongoing Mayo Clinic SCAD DNA biorepository.

Results

We identified 5 pairs of relatives with angiographically confirmed SCAD: 3 pairs of first-degree relatives, including mother-daughter, identical twin sisters, and sisters, and 2 pairs of second-degree relatives, including aunt-niece and first cousins. The details of their demographics, risk factors, presentation, location of SCAD, and management are presented in the Table.

Table.  
Clinical Characteristics of Patients With Family History of SCAD
Clinical Characteristics of Patients With Family History of SCAD
Case Series
Pair 1 (Mother and Daughter)
Mother

A 54-year-old woman presented with substernal chest pain and left arm discomfort. An electrocardiographic (ECG) recording revealed ST-elevation in the precordial leads. Emergent coronary angiography revealed a spiral dissection of the proximal left anterior descending artery (LAD) and absence of atherosclerotic disease. Attempted percutaneous revascularization was unsuccessful, so she underwent emergency coronary artery bypass grafting (CABG) surgery with left internal mammary artery (LIMA) to LAD. Her cardiovascular risk factors included current smoking, hypertension, and type 2 diabetes mellitus. She also had a history of anxiety and depression.

Daughter

A 42-year-old woman presented with left-sided chest and axillary pain along with elevated troponin levels and ECG changes consistent with non–ST-elevation myocardial infarction (NSTEMI). Coronary angiography revealed a spontaneous mid-LAD dissection, and she underwent CABG with LIMA to LAD. Her only cardiovascular risk factor was smoking. She reported a history of anxiety and depression.

Fatal myocardial infarction was reported in 3 additional family members including a 62-year-old maternal grandmother, 62-year-old maternal great-grandmother, and 42-year-old maternal grandaunt. None of the relatives had an autopsy.

Pair 2 (Identical Twin Sisters)
Sister 1

A 59-year-old woman was admitted to the hospital with chest pain, normal troponin levels, and unremarkable ECG findings. That night, she awoke with severe, crushing chest pain radiating down her left arm. Coronary angiography showed SCAD of the mid-LAD and left circumflex arteries (Figure, A), which was managed conservatively without revascularization. She reported significant emotional stress due to the death of her mother 5 days before this event. Her cardiovascular risk factors included hypertension and hyperlipidemia.

Figure.
Spontaneous Coronary Artery Dissection
Spontaneous Coronary Artery Dissection

A, Mid–left anterior descending artery (LAD); arrowhead indicates contrast staining in the false lumen. B, LAD; histopathologic evaluation exhibited an acute dissection with fresh blood in the false lumen. C, Mid-LAD extending distally; arrowhead points to contrast staining in false lumen with nearby luminal narrowing due to intramural hematoma. D, First diagonal branch of the LAD; arrowhead points to the dissection.

Sister 2

One year following her identical twin sister’s myocardial infarction, a 60-year-old woman was witnessed by an adjacent driver to slump while driving on the highway and crash her vehicle. First responders identified ventricular fibrillation arrest, and on-site cardiopulmonary resuscitation was started with transfer to the nearby hospital. She died the next day due to multiorgan failure, and her autopsy indicated blunt force injuries of the abdomen and chest wall as the cause of death, although acute dissection of the LAD and left circumflex arteries was noted. Review of the autopsy specimens by a cardiovascular pathologist (J.J.M.) confirmed coronary artery dissection, with an acute and evolving myocardial infarction (Figure, B). These findings, in conjunction with the history of SCAD in her identical twin, suggest SCAD as the cause of sudden death. Her only cardiovascular risk factor was hypertension. The sisters’ parents had no known coronary or extracoronary vascular disease.

Pair 3 (Sisters)
Sister 1

A 35-year-old woman underwent a stress test to assess chest pain radiating to her left arm. The baseline ECG tracing showed deep, anterolateral T-wave inversions, with results of a baseline echocardiography demonstrating apical hypokinesis. Coronary angiography, performed immediately, showed mid-LAD SCAD (Figure, C), which was treated successfully with 4 drug-eluting stents. The patient had used clomiphene citrate to enhance fertility prior to her pregnancy and childbirth 18 months before her SCAD. Pregnancy was complicated by preeclampsia and subsequent hypertension.

Sister 2

A 47-year-old woman was admitted to the hospital with exertional chest pain, jaw tightness, and troponin level elevation; NSTEMI was diagnosed. Coronary angiography revealed SCAD of the first diagonal branch of the LAD (Figure, D), which was treated with 2 bare-metal stents. She had a history of hypertension and had used clomiphene for treatment of infertility many years before the SCAD event. The sisters’ parents had no known coronary or extracoronary vascular disease.

Pair 4 (Aunt and Niece)
Aunt

A 45-year-old woman with a history of STEMI experienced chest pain and developed ventricular fibrillation cardiac arrest in the ambulance. She received prompt cardiopulmonary resuscitation and defibrillation (6 times), and thrombolytic agents were administered. Coronary angiography revealed LAD dissection extending proximally into the left main coronary artery. She underwent urgent CABG with LIMA to the LAD and right internal mammary artery to the first obtuse marginal artery. Her only cardiovascular risk factor was a remote history of smoking. She described extreme emotion involving the death of a family member preceding the episodes of STEMI and SCAD. Eleven years later, coronary angiography performed for chest pain and inferior STEMI showed a new spontaneous dissection of the right posterolateral artery. This event was managed conservatively, and coronary angiography performed 1 year later showed recanalization of the right posterolateral artery.

Niece

A 39-year-old woman presented with sudden-onset chest discomfort and shortness of breath. An initial ECG recording did not show any acute ischemic changes, but the troponin level was elevated. Her chest pain worsened, and a second ECG demonstrated anterior STEMI. Emergent coronary angiography showed SCAD of the midsection of the LAD. Treatment with stenting was complicated by stent malapposition with proximal and distal extension of the dissection. She had no cardiovascular risk factors at the time of SCAD. She had a history of treatment for infertility, including in-vitro fertilization, 8 years before her SCAD event. Her mother (sister of the affected aunt) underwent coronary angiography at age 60 years for atypical chest pain in the context of type 2 diabetes, hypertension, and hyperlipidemia. Atherosclerosis was ruled out, but coronary tortuosity was observed, potentially attributable to hypertension and/or an intermediate phenotype of SCAD.

Pair 5 (First Maternal Cousins)
Cousin 1

A 36-year-old woman presented with intermittent chest pain for 24 hours, which ultimately awakened her. The results of an ECG recording were unremarkable; however, her troponin level was elevated, and NSTEMI was diagnosed. Coronary angiography revealed spontaneous dissection of the obtuse marginal branch of the left circumflex artery with presence of an intimal flap. Conservative management was used. Coronary angiography performed 4 days later showed evolution of the dissection with intramural hematoma formation causing 50% obstruction, which was again managed conservatively. She had 1 episode of chest pain 2 months later, and acute coronary syndrome was excluded with serial ECG recordings and troponin measurements. Her only cardiovascular risk factor was hypertension. Subsequent imaging studies revealed right internal carotid artery dissection and the presence of fibromuscular dysplasia. The patient had been training for a triathlon in the week before her SCAD event.

Cousin 2

A 44-year-old woman presented with 2 hours of midsternal chest pain radiating to her upper back. An ECG recording revealed STEMI in the inferior leads. Emergent coronary angiography revealed dissection of the right posterolateral artery with an intimal flap and grade 1 Thrombolysis in Myocardial Infarction flow, which was treated successfully with 2 bare metal stents. Her only cardiovascular risk factor was a history of smoking. Factor V Leiden mutation and fibromuscular dysplasia were subsequently diagnosed. The patient reported participating in a 75-mile bicycle ride 3 days before her SCAD event.

The cousins’ mothers are sisters. The first cousin’s mother had a myocardial infarction and CABG surgery at age 60 years in the setting of type 2 diabetes and hypertension. The second cousin’s mother had a coronary angiogram with normal results at age 72 years.

Discussion

To our knowledge, this is the first study to report familial SCAD. Distribution of SCAD in these 5 families implicates both recessive and dominant modes of inheritance with incomplete penetrance and variable expression. Although previously published series1,12,14 on patients with SCAD have identified female sex, fibromuscular dysplasia, hormonal influences, and connective tissue diseases as possible risk factors, the present study identifies a probable genetic predisposition in some individuals as well as familial occurrence of fibromuscular dysplasia (pair 5).15 In our clinical experience, many patients who have experienced SCAD report a family history of early, unexpected, or peripartum death or premature cardiovascular events occurring in young or low-risk relatives, similar to the mother and daughter in pair 1. In the absence of clinical or postmortem confirmation, it may not be possible to ascertain the cause of death in these cases, but one may speculate that some of these deaths might have occurred as a result of SCAD. Family history may facilitate better risk stratification and accurate diagnosis of myocardial infarction or sudden death of unclear etiology in the families of patients with SCAD, as in the twin sister of pair 3. This history may also help health care professionals recognize the risk of SCAD in young women with symptoms suggestive of acute coronary syndrome and the need for prompt attention in low-risk relatives.

Chest pain in young individuals is often initially diagnosed as noncardiac or stress related. Early identification of SCAD requires a high degree of suspicion among health care professionals, especially internists and emergency department physicians since they are frequently the first point of contact. The demographics, cause, and treatment of SCAD differ from those of atherosclerotic coronary artery disease.7,8,11,16 Spontaneous coronary artery dissection should be considered as a potential cause in young persons with minimal traditional risk factors who present with acute coronary syndrome or cardiac arrest, particularly if they have a history of fibromuscular dysplasia, connective tissue disease, the peripartum state, or extreme physical exertion or stress.1,2,7,17 Coronary angiography with selective use of advanced intracoronary imaging techniques, including optical coherence tomography and intravascular ultrasonography, is the criterion standard for diagnosis of SCAD.10 An additional clue to the diagnosis of SCAD is the presence of coronary artery tortuosity, which may be a marker of a more widespread vasculopathy or a potential mechanism for SCAD.16 Accurate diagnosis of SCAD has important implications for the management of treatment in these patients, although much is yet to be determined. Percutaneous coronary intervention has a much lower technical success rate in patients with SCAD compared with those who have atherosclerotic coronary artery disease.1,7,11,17,18 Therefore, conservative management with close surveillance is generally preferred in most patients with preserved coronary flow, unless they have ongoing ischemic symptoms or cardiovascular instability. No intervention has yet been identified to reduce the risk of recurrent SCAD; therefore, medical management should be predicated on non-SCAD indications or symptoms. For instance, dual antiplatelet therapy is indicated if percutaneous coronary intervention is performed, but only low-dose aspirin is recommended in conservative management. Similarly, β-blockers and angiotensin-converting enzyme inhibitors are recommended if left ventricular dysfunction is present. Although routine statin administration is not recommended for SCAD,1,7 patients with hyperlipidemia should probably receive treatment. Nitrates or calcium channel blockers can be useful for angina, which may be due to post-SCAD coronary vasospasm. Cardiac rehabilitation is recommended for all patients with SCAD,7 although data collection and analysis to fully support this recommendation and potential protocol modification is ongoing.

Because there has been an association between extreme physical activity and SCAD, patients are advised to avoid weight lifting, body building, competitive racing, or athletic pursuits at high intensity levels and instead are encouraged to pursue moderate daily aerobic activity and resistance training with low weight and more repetitions. Because the prevalence of extracoronary vasculopathy, such as fibromuscular dysplasia, aneurysms, and dissections, is substantial in patients with SCAD,14 screening of the brain, neck, and visceral vessels with computed tomographic angiography or magnetic resonance angiography is advised. This is particularly important in patients who have symptoms or signs suggestive of extracoronary vascular disease, diagnosis of fibromuscular dysplasia,15 and a family history of aneurysms, dissections, or premature or unexplained sudden death. Patients with SCAD may also benefit from formal medical genetics consultation for familial assessment and genetic panel testing since it has been associated with genetic connective tissue diseases.1

Finally, this study also highlights the novel approach of the Mayo Clinic SCAD Registry, which began as a patient-driven initiative to raise awareness and better understanding of what was then classified as a rare disease. Through the use of online patient support communities, social media, and engaged SCAD survivors and families, we have been able to recruit, confirm the diagnosis in, and enroll more than 400 patients with SCAD from all over the world to the Mayo Clinic SCAD Registry. Through our work, we now know that instead of being rare, SCAD is a relatively uncommon and frequently unrecognized cause of acute coronary syndrome.1,11,16 Without this large SCAD cohort, novel observations, such as the familial pattern described in the present study, would be unlikely. Furthermore, through this registry we have created a robust SCAD DNA biorepository to further determine familial contributions and clarify the underlying pathophysiology of this disease. This unique research method may be broadened to the study of other diseases, particularly those that are considered rare or for which study recruitment has been challenging.

Conclusions

Although this study is descriptive and does not directly indicate management strategies for the family members of patients with SCAD, it is hypothesis generating. Identification of familial SCAD and fibromuscular dysplasia underscores genetically mediated vulnerability to the pathophysiology of this complex disorder. Conceivably, de novo or recessively inherited genetic variants may contribute to the more prevalent sporadic cases. The recent technological advance of whole-exome sequencing provides an unprecedented opportunity to discover genetic underpinnings of SCAD, which may lead to new mechanism-informed therapeutic interventions. Novel research methods that leverage the enthusiasm and motivation of patients and families, the growth of online patient communities, and the power of social media have the potential to transform the study and our understanding of uncommon conditions.

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Article Information

Accepted for Publication: December 27, 2014.

Corresponding Author: Sharonne N. Hayes, MD, Division of Cardiovascular Diseases, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (hayes.sharonne@mayo.edu).

Published Online: March 23, 2015. doi:10.1001/jamainternmed.2014.8307.

Author Contributions: Drs Goel and Hayes had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Goel, Tweet, Olson, Gulati, Hayes.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Goel, Tweet.

Critical revision of the manuscript for important intellectual content: All authors.

Obtained funding: Hayes.

Administrative, technical, or material support: Goel, Maleszewski, Hayes.

Study supervision: Olson, Maleszewski, Gulati, Hayes.

Conflict of Interest Disclosures: None reported.

Additional Contributions: Jill Boyum and Sue Ward, RN (Cardiovascular Research Unit, Mayo Clinic), assisted with patient recruitment as well as data collection and management; Matthew D. Hoplin, CCRC (Mayo Clinic), assisted with data acquisition; and Michelle M. Schoeppner (Women’s Heart Clinic) assisted with patient recruitment. None of the contributors received financial compensation. We sincerely thank all the patients and their families who are participants in the Mayo Clinic SCAD Registry.

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