Loeys-Dietz syndrome and isolated severe ostial left main coronary stenosis presenting as ventricular fibrillation arrest and biventricular takotsubo syndrome in a 25-year-old patient

Abstract

We present the case of a previously healthy 25-year-old woman who presented with an out-of-hospital ventricular fibrillation arrest. Postresuscitation ECG did not show any evidence of ST segment elevation. Echocardiogram showed regional wall abnormalities in keeping with takotsubo syndrome (TTS). Urgent coronary angiogram to rule out malignant congenital coronary artery anomaly revealed an isolated severe ostial left main coronary artery (LMCA) stenosis, a rare disease, approximately 0.2% in previous case series. The LMCA was aneurysmal. Genetic studies revealed a novel frameshift pathogenic variant in the transforming growth factor B two ligand gene (TGFB2) gene, suggestive of Loeys-Dietz syndrome (LDS) type 4, an aggressive vascular disease. Ostial LMCA stenosis has not been previously reported in LDS, and we outline the management of this unique disease combination. We also reflect on its presentation as TTS and infer that TTS and acute coronary syndromes are not mutually exclusive.

Background

Loeys-Dietz syndrome (LDS) is an autosomal dominant aortic aneurysm syndrome with widespread systemic involvement. It is defined by the triad of arterial tortuosity and aneurysms, bifid uvula/cleft palate and hypertelorism.¹ It is caused by heterozygous mutations in the genes encoding transforming growth factor B receptor 1 (TGFBR1) and transforming growth factor B receptor 2 (TGFBR2), mothers against decapentaplegic homolog 3 (SMAD3) and transforming growth factor B 2 ligand gene (TGFB2), respectively.¹ The hallmark of this syndrome is aggressive vascular disease and premature death from cardiovascular emergencies and cerebral haemorrhages. Average life expectancy of LDS is 36 years.² These patients require close surveillance imaging for aortic aneurysms in particular and often require early interventions.¹

Acute coronary syndromes associated with LDS are almost exclusively associated with aortic aneurysms complicated by dissections involving the coronary arteries; however, spontaneous coronary artery dissections (SCADs) have also been reported.³ Isolated ostial left main coronary artery (LMCA) stenosis is a rare condition that has an incidence of only 0.2% in patients with coronary artery dissection.⁴ The aetiology of the disease is typically atherosclerotic in origin but can be seen in inflammatory conditions, fibromuscular dysplasia, aortitis (particularly from syphilis), congenital anomaly or iatrogenic.⁵ As reported in previous case series, these patients frequently present with features of typical angina.^{5 6}

We present the case of a 25-year-old woman with an out-of-hospital ventricular fibrillation (VF) arrest who was then found to have biventricular takotsubo syndrome (TTS) on echocardiography.

Diagnostic coronary angiogram showed isolated severe ostial LMCA stenosis as well as aneurysm of her LMCA. Given her young age, negative inflammatory markers and negative autoimmune workup, a genetic panel was ordered, and she was found to have a novel pathogenic variant in the first exon of the TGFB2 gene for Loeys-Dietz syndrome type 4 (LDS4), an aggressive vascular disease. This variant induces a frameshift mutation resulting in protein truncation and defective protein synthesis.

We discuss the importance of this diagnosis on the management of this patient and the potential for transmission of the pathogenic variant, highlight potential complications and emphasise the role of surveillance imaging in the prevention of complications.

We also reflect on the finding of biventricular TTS in our patient and how this relates to her presentation with out-of-hospital VF arrest. Based on this and a few other case reports, we propose a revision of the diagnostic criteria for TTS.

Case presentation

A 25-year-old woman presented to the hospital post-VF arrest after being found unresponsive by her boyfriend who had seen her well moments previously. She was previously healthy and not taking any medications. Prompt bystander cardiopulmonary resuscitation was immediately started, and on arrival of emergency medical services, she was found to be in VF arrest (figure 1). She was successfully defibrillated with a single shock with prompt return of spontaneous circulation. She did not receive any epinephrine or antiarrhythmics. She was intubated and was eventually transferred to the coronary care unit (CCU) at the tertiary centre. Initial investigations revealed a normal complete blood count, renal panel and electrolytes. Cardiac enzymes were only mildly elevated. Creatine kinase peaked at 444 U/L. Troponins peaked at 161 ng/L. The most significant finding on admission was a persistently prolonged QTc of 635 ms on ECG (figure 2). She was haemodynamically stable, mechanically ventilated, with a temperature of 36.8°C, heart rate of 101 beats/min and a blood pressure of 123/76 mm Hg. She was on minimal ventilatory support (FiO₂ 25%, positive end-expiratory pressure (PEEP) 5) and was breathing spontaneously. She was rapidly weaned off mechanical ventilation.

Figure 1.

ECG showing ventricular fibrillation prior to defibrillation.

Figure 2.

Postresuscitation ECG shows T-wave inversions anterolaterally with prolonged QT interval.

Postextubation, a more thorough history was obtained. She did not have any medical history, denied any drug use and was a healthy child growing up according to the patient and her parents. She did have extensive dental surgery done as a child for overcrowding of teeth. There was no history of congenital heart disease or arrhythmia syndromes. More importantly, she revealed that she had experienced episodes of chest tightness consistent with typical angina for several years. In fact, she had been on the high school volleyball team and she mentioned that she had to request time out after episodes of exertional chest pain during competitive games.

On physical examination, it was noted that she had a tall stature (183 cm) and her arm span was 185 cm. She had discrete micrognathia and a high-arch palate. Her joints were hypermobile (figure 3). She had long and slender fingers. There was no evidence of flat feet. Her skin was hyperextensible. She had pectus excavatum. There was no scoliosis.

Figure 3.

Hypermobility of the wrist joint with positive thumb sign.

In terms of her family history, her brother is 6 feet, 6 inches tall and has long fingers and joint hypermobility. He has a history of hypertension and a congenital ureter malformation, as well as an abnormality of his kidney that was not clear on history. Her father is 6 feet, 4 inches tall, but proportionate in size, while her paternal aunt has a history of pectus carinatum. Her maternal grandfather had died quite suddenly in his 50s.

Investigations

High-sensitivity troponin was elevated at 161 ng/L, and creatine kinase was elevated at 279 U/L. She had a haemoglobin of 149 g/L, with a white count of 18.52×10⁹/L. Her electrolyte panel and creatinine were unremarkable, and her venous blood gas showed that she had lactic acidosis with a pH of 7.24 and a lactate of 3.7 mmol/L.

Repeat ECG, done on arrival to the CCU, showed sinus tachycardia with a prolonged QT interval of 635 ms and diffuse ST-T wave changes in the precordial leads (figure 2). Given this initial finding of a prolonged QTc with no underlying aetiology at the time, genetics was consulted for possible channelopathy and possibly a connective tissue disease.

Echocardiogram showed extensive wall motion abnormalities consistent with TTS. There was anteroapical akinesis with basal hyperkinesis of the left ventricle (video 1). The right ventricle showed a reverse TTS picture, namely, apical hyperkinesis with basal akinesis (video 2). The estimated left ventricular ejection fraction was about 30%. The aortic root was dilated at 42 mm, and the ascending aorta was mildly dilated at 38 mm.

Video 1.

bcr-2021-245566supp001.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-245566.video01

Video 2.

bcr-2021-245566supp002.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-245566.video02

Urgent coronary angiogram showed severe ostial LMCA stenosis (video 3) and a poststenotic aneurysm of the LMCA (video 4). There was marked damping of aortic pressures with ventricularisation on engaging the LMCA (figure 4). Intravascular ultrasound study confirmed severe ostial stenosis of the LMCA (figure 5). The ostial lesion was focal and ring-like and non-atheromatous (figure 5). The right coronary artery had a normal origin from the right sinus of valsalva and its ostium and course were normal. It was the dominant coronary artery.

Video 3.

bcr-2021-245566supp003.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-245566.video03

Video 4.

bcr-2021-245566supp004.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-245566.video04

Figure 4.

Severe damping of coronary pressure with ventricularisation after cannulation of the left main coronary ostium.

Figure 5.

Intravascular ultrasound (IVUS) showing severe ostial left main stenosis (blue arrow) and fibrous plaque (red arrow). Measurements confirmed severe stenosis (right image).

Given the correlation of this diagnosis with connective tissue diseases, she underwent a CT angiogram of her carotid, vertebral, iliac and renal arteries, which did not show any evidence of fibromuscular dysplasia or aneurysmal disease. However, it did show tortuous internal carotid arteries bilaterally with two 180° turns, but no beading, outpouching or stenosis (figure 6). MRI of her brain did not comment on any signs of ischaemia, but did note scaphocephaly.

Figure 6.

Right and left internal carotid arteries with two 180° turns (red arrows).

Genetics

A custom cardiology panel was ordered including genes related to long QT syndrome (LQTS), connective tissue disorders and TTS. A pathogenic variant was identified in the TGFB2 gene. This gene is associated with LDS4. This particular variant has not been reported previously in the genetic database. It causes a frameshift mutation resulting in a protein truncation located in the first exon of the gene. Frameshift mutations are caused by the insertion or deletion of nucleotides in a DNA sequence, resulting in a completely different reading frame from the original. Genotyping is ongoing and a full report is awaited.

Differential diagnosis

At the time of presentation, the aetiology of the cardiac arrest was unknown and, due to the inability to obtain a history, we were left with a diagnostic dilemma and therefore maintained a broad differential. Given the patient’s age and lack of comorbidities in addition to a mention in her chart of possible history of substance abuse in the past, our initial thought was that she had overdosed on a toxic substance. She had a complete cardiac and toxicology workup. Her 12-lead ECG (figure 2) showed a long QTc of about 635 ms. This was supportive of our diagnosis of a possible substance-induced cardiac arrest; however, her toxicity screen was negative. With this in mind, we considered the possible diagnosis of polymorphic ventricular tachycardia (VT) arrest degenerating into VF in the setting of an LQTS and channelopathy (ie, torsades de pointes VT/VF). The most common cause of a prolonged QT interval is medications followed by electrolyte abnormalities; however, in her case, she was on no medications and had no electrolyte abnormalities, so we were left with the possible diagnosis of congenital LQTS at the top of our differential. We also considered connective tissue diseases such as Marfan syndrome or Ehlers-Danlos syndrome, given her physical examination findings.

Although congenital LQTS was our working diagnosis, we completed the full workup for a patient with an out-of-hospital arrest, which includes an evaluation for possible structural heart disease. Her echocardiogram was rather abnormal and in keeping with TTS as described earlier.

At this point, we were able to obtain more of a history from the patient and her father, and she did note a several-year history of typical exertional chest pain, in fact a textbook picture of angina. We noted that her brother and father were also very tall; particularly her brother was 6 feet and had slender, long fingers, which further raised our suspicion of a genetic connective tissue disease syndrome as a possible aetiology. However, there was no family history of any genetic syndrome. The history of possible premature sudden cardiac death in the maternal grandfather was concerning for a genetic syndrome.

Given the echo findings and the classic history of exertional chest pain, coronary disease (likely a congenital anomaly but possible atherosclerotic disease) was included in the differential and needed to be excluded with a diagnostic angiogram. As mentioned previously, she and a few of her family members were noted to have Marfanoid features, which could possibly explain her presentation had she suffered a dissection complicated by an ischaemic cardiac arrest.

Given the rare and unusual findings on coronary angiography and her presentation with an out-of-hospital cardiac arrest in an otherwise healthy 25-year-old woman, we were strongly considering the aetiology of her presentation being genetic in origin. The possibility of her having Marfan syndrome, vascular Ehlers-Danlos syndrome or LDS became very high on our differential. The patient’s genetic workup revealed that she had LDS4, a connective tissue disease characterised by aortic root enlargement, bicuspid aortic valve, arterial tortuosity and cleft palate.¹ This diagnosis would explain her initial presentation to the hospital and the incidental findings we found on history and physical examination. Interestingly, she had corroborative findings on imaging such as scaphocephaly, bronchiectasis and tortuous internal cerebral arteries, which would also be explained by her underlying connective tissue disorder.

Treatment

She underwent urgent in-hospital coronary artery bypass grafting. The surgeon commented on her tissues being ‘baby-like’. Left internal mammary graft was placed on the left anterior descending coronary artery, and sequential saphenous venous graft was placed on the left circumflex and diagonal coronary arteries. Postoperative course was uneventful.

Outcome and follow-up

The patient was discharged home on metoprolol 12.5 mg two times per day, atorvastatin 40 mg/day and enteric coated aspirin 81 mg/day. She was doing well clinically and her blood pressure and heart rate were optimally controlled as per her log. Her sternotomy and saphenectomy had healed well. Quite remarkably, she has returned to complete her training as a millwright.

Implications of her diagnosis was explained to her in detail, including her high risk of acute vascular events with potential threat to life. The genetics of LDS were discussed briefly, and she was referred for genetic counselling. Screening of family members and first-degree relatives was also discussed.

Discussion

First described in 2005, LDS is an autosomal dominant connective tissue disorder characterised by aortic aneurysms, generalised arterial tortuosity, hypertelorism, and bifid uvula or cleft palate.^{7 8} Mutations in four genes have been described, namely, TGFBR1, TGFBR2, SMAD3 and TGFB2. These result in altered transforming growth factor-B (TGF-B) signalling.^9–12 Phenotypical features of affected individuals show similar craniofacial, cardiovascular, cutaneous and skeletal features. An aggressive vascular course is the rule with widespread arterial anomalies, vascular tortuosity and high risk of aneurysms and dissections throughout the arterial tree. Paradoxically, there are currently no specific clinical diagnostic criteria for this malignant arteriopathy, and diagnosis can only be confirmed by molecular testing. LDS4 represents the mildest form of the disease spectrum, and aneurysms are usually observed in the fourth decade with slow progression of disease.¹³ However, Mazzella et al have challenged this observation in their case report.¹⁴ Based on our report, we too disagree with this observation.

MacGarrick et al have proposed that a mutation in any of these four genes plus either aneurysm/dissection or a positive family history of LDS should establish the diagnosis.¹

Cardiovascular involvement in LDS is dominated by aggressive and rapidly progressive aortic aneurysmal disease. Patients with LDS1/LDS2 with severe craniofacial manifestations are at particularly high risk, including aortic dissection and rupture. Compared with other aortic aneurysm syndromes, they may experience potentially lethal vascular events at a younger age (as young as 3 months) and at smaller aortic dimensions.^{7 8} In fact, there is no aortic dimension that is deemed ‘safe’, and dissections have been reported at aortic dimensions of 39–40 mm in LDS1, LDS2 and LDS3 syndromes.^{7 9} LDS4 is the least aggressive vascular disease, but dissections have been reported at dimensions less than 50 mm.¹⁵ However, this is disputed by Mazella et al, who have reported on the ‘phenotypic variability and diffuse arterial lesions in a family with LDS4’.¹⁴ They describe lesions in medium-calibre and small-calibre arteries.¹⁴

While dissections are well documented in the large-sized and medium-sized arteries, it is interesting to note that SCAD has also been reported in at least one case report. In fact, Rynkiewicz et al have reported SCAD in a young woman with atypical chest pain.³ Thus, acute coronary syndromes may have different pathogenic mechanisms in these patients.

The pertinent issue is that of timing for valve-sparing aortic root replacement in these patients. Decision for surgical intervention focuses on the absolute dimension of the aorta, rate of progression of dilatation, presence of valvular dysfunction, severity of non-cardiac features, family history and genotype.^{7 16} Guidelines seem to favour prophylactic replacement at root dimensions of 40 mm, the more so in patients with LDS1, LDS2 and LDS3. In the absence of guidelines for LDS4 and early studies suggesting that the ‘threshold for dissection’ may be higher than 40 mm, indications for surgery may focus on family history and/or adult aortic dimensions in the mid-40 mm range. Valve-sparing surgery avoids the need for chronic anticoagulation. We would like to underline the fact that we did not have the genetic report on our patient when she underwent surgery and retrospectively she should have had a prophylactic valve-sparing aortic root surgery at the time of GABG as her root is dilated at 42 mm (2.16 cm/m²).

Bicuspid aortic valve, atrial septal defect, patent ductus arteriosus, mitral valve prolapse, atrial fibrillation (24%) and left ventricular hypertrophy have also been reported in patients with LDS, and management of these follows the usual guideline-based protocols.^{15 17–19}

Generalised arterial tortuosity, typically in cervical arteries, has been reported in LDS. These are not risk factors for acute vascular events in the concerned arteries; however, it has been reported that increased vertebral arterial tortuosity is a marker of adverse aortic outcome.^{17 20}

LMCA aneurysms have not been reported in the few case reports in LDS, and we believe ours is the first case report describing this condition. Coronary button aneurysms have been described in patients after valve-sparing aortic root replacement. These are not believed to be LDS-related complications but rather secondary to the surgery itself.¹

The diagnostic waters were further muddied by the finding of severe ostial LMCA stenosis in our patient, another finding never reported in LDS. This finding raised important questions with respect to pathogenesis and management of her cardiac arrest. There was debate on whether the lesion was severe and clinically relevant in her presentation. Even though the haemodynamic hallmark (severe damping on cannulation, figure 4) of severe ostial LMCA stenosis was unmistakable, we opted to pursue an IVUS study to confirm our findings. This confirmed the severity of the LMCA stenosis and guided our management decision. Since LDS is an aneurysmal disease, how does the severe ostial LMCA stenosis fit the scenario? We highlight this as a novel finding in LDS4 and underline the phenotypical variability of the disease.

Isolated LMCA ostial stenosis is a rare disease of unknown aetiology, accounting for 17.9% of the overall LMCA stenosis population in one large series.²¹ In one large series of patients undergoing coronary angiography, the reported incidence was 0.2%.²² The cause of isolated coronary ostial stenosis is unknown. No specific aetiology could be established in 18 out of 19 patients in the series referred to previously.²¹ Most cases are presumed to be atherosclerotic in origin, but aetiological factors include syphilitic and non-syphilitic aortitis, congenital ostial stenosis, as well as iatrogenic lesions of the coronary ostia after coronary angiography or selective coronary perfusion at operation.⁴ Isolated bilateral coronary ostial stenosis is even more uncommon, and only nine cases have been reported in the literature.²³ A particularly high incidence is reported in patients with homozygous familial hypercholesterolaemia. The clinical and angiographic profile appears unique, suggesting a natural history distinct from that usually seen in atheromatous disease.²² Diagnostic coronary angiography is potentially risky, and serious complications including death have been reported.²² The possibility of coronary ostial stenosis should be considered if (1) there is difficulty in cannulating the coronary ostium; (2) there is a profound decrease in distal coronary pressure after coronary engagement with or without angina or the appearance of ST segment changes on the monitor; and (3) there is failure to observe return of contrast medium into the sinus of valsalva.

Another possible mechanism of acute coronary ischaemia in patients with connective tissue disease and left main ostial stenosis may be related to anatomical factors, namely, distortion of the LMCA. This mechanism may have played a pathogenic role in precipitating VF arrest in our patient as she had a significantly stenotic left main ostium and poststenotic aneurysmal dilatation of the same artery. A hinge-like mechanism, from anatomical distortion and aggravated by systole, may have been the tipping point in our patient.

Management options include conventional coronary artery bypass grafting (CABG), surgical arterioplasty and angioplasty of the ‘unprotected’ LMCA. Conventional CABG is the most widely performed operation and considered the standard surgical treatment for these patients. However, conventional CABG carries with it the potential risks associated with reoperative address especially in patients operated at a younger age; as in the case discussed. This prompted the exploration of alternative modalities in the definite management of this specific disease entity. Surgical arterioplasty or patch angioplasty has emerged as an alternate attractive surgical option for these patients, and Bortolotti et al recommend surgical ostioplasty as an initial strategy in carefully selected patients with isolated ostial stenosis but no distal coronary artery disease.²³ Bonacchi et al have confirmed excellent results with surgical angioplasty in their series of 23 patients who underwent surgical ostial angioplasty, including 15 with LMCA stenosis. In their series, patients were followed up with postoperative thallium-201 stress Single-Photon Emission Computerised Tomography (SPECT) within a 6-month period, as well as control diagnostic coronary angiography.²⁴ They reported an overall success rate of 96% after a follow-up period of 49 months.²⁴

While we considered surgical patch angioplasty in our patient, it is noteworthy that there are very few surgeons adept at this technique, and after discussing with our surgeons, consensus opinion recommended conventional CABG.

Unprotected LMCA angioplasty and stenting is fast gathering momentum in the interventional arena and offers the attractive option of a non-surgical approach. Ostial left main lesions, with a long and wide truncus, are particularly accessible to percutaneous coronary intervention.²¹ With the recent encouraging results of unprotected LMCA stenting, this might become the preferred initial strategy in the management of this life-threatening disease. High rates of restenosis and in-hospital mortality remain concerning.²⁵ In our patient, this strategy was discarded because of the LMCA aneurysm, which would cause a mismatch in stent sizing.

Medical management forms a crucial aspect of secondary prevention and focuses on beta-blockade to reduce the shear stress (dp/dt (rate of change of pressure per unit time)) on the vasculature and optimisation of blood pressure control. Angiotensin receptor blockers (ARBs) may be especially useful due to their effects on the TGF-B signalling cascade.²⁶ Dietz recommends optimal titration of these drugs and also advises the use of supratherapeutic doses of newer ARBs in patients with aggressive vascular disease. We note that our patient has a dilated ascending aortic root and she is at high risk of vascular complications. Secondary prevention also focuses on regular surveillance imaging with magnetic resonance angiography and CT angiography. Restrictions on strenuous physical activity and overexertion also form an important component of secondary prevention, and we have counselled our patient from this perspective as she is training to be a millwright.

VF cardiac arrest and other malignant ventricular arrhythmias have not been previously described as an initial clinical presentation of LDS. This suggests it is less likely a primary manifestation of disease. Rather, this case is supportive of a pathophysiological consequence of coronary artery tortuosity, ectasia, aneurysm and ostial LMCA stenosis leading to ischaemia-induced ventricular arrhythmias. There is one reported case in a European retrospective review series of late cardiac arrest 24 years following cardiac surgery in a patient with LDS2.²⁷ The patient was admitted with atrial fibrillation and subsequently developed cardiac arrest and was unable to be resuscitated. No further details were elaborated. An increase in mortality with a median survival of 37 years has been reported.⁷ Death was attributable to thoracic aortic dissection/rupture, abdominal aortic dissection and cerebral bleeding, but not arrhythmic death.⁷ Although coronary involvement is unusual in more commonly known pathological genetic variants, the incidence of vascular disease outside of the ascending aorta and whether this differs with LDS types are unknown.²⁷

MacCarrick et al recommend managing arrhythmias in LDS as per standard treatment and management protocols.¹ As in this case, long-term management of ventricular arrhythmias focuses on treating reversible ischaemia with complete revascularisation. Indefinite beta blocker use is recommended to concurrently reduce myocardial demand as well as aortic shear stress. An implantable cardioverter defibrillator (ICD) was not recommended due to the corrected reversible aetiology and considering the potential long-term risk:benefit ratio of ICD therapy in young patient populations.¹ To our knowledge, there are no reports of either primary or secondary prevention ICD in patients with LDS. It was felt that robust arrhythmia surveillance with an implantable loop recorder be performed.

Our case report also begs reflection on the very pertinent issue of acute myocardial ischaemia in the diagnosis of TTS. Echocardiogram documented apical TTS of the left ventricle with reverse TTS of the right ventricle (videos 1 and 2). This finding is quite unique too and has not been reported before. Borchert et al have recently reported highly relevant variants in cardiac genes, namely, RNA-binding motif protein 20 (RBM20) and encoding calsequestrin 2 (CASQ2) in two of their TTS study patients, raising the pertinent issue of a genetic predisposition to TTS. They further hypothesise that patients with TTS are genetically susceptible and at high risk under high adrenergic stress.²⁸ TTS is currently a diagnosis of exclusion; acute coronary syndrome has to be ruled out. Our case report disproves this. From an initial syndrome of exclusion, TTS is slowly but surely evolving into one of inclusion—acute coronary ischaemia notwithstanding. ‘The heart has its reasons’, to paraphrase theologian Blaise Pascal. Diagnostic criteria need to follow this evolution!

Finally, we highlight that the fact that LDS is an autosomal dominant condition, and screening and genotyping of family members and first-degree relatives form an important component of management. Genetic counselling and screening are ongoing in our patient’s family members.

Learning points.

• Loeys-Dietz syndrome type 4 (LDS4) is an aggressive aneurysmal vascular disease with broad phenotypical variability and diffuse arterial anomalies that may manifest as aneurysms in the large-sized, small-sized and medium-sized arteries. Complications, namely, dissections, are the rule and may pose threat to life.

• Ostial left main coronary artery stenosis may form part of the arterial lesions and is a novel finding in LDS4.

• Ischaemic ventricular fibrillation arrest may present as takotsubo syndrome (TTS). A genetic predisposition to TTS is suggested, irrespective of the acute trigger.

• Secondary prevention in LDS4 focuses on regular surveillance imaging, beta-blockade and rigorous control of blood pressure. Strenuous physical activities should be avoided.

• Screening and genotyping of family members and first-degree relatives as well as counselling form an important aspect of therapy of these unfortunate patients.

Ethics statements

Patient consent for publication

Consent obtained directly from patient(s).