Non-compaction cardiomyopathy, Becker muscular dystrophy, neuropathy and recurrent syncope

Abstract

We present the case of a 50-year-old man presenting with new heart failure symptoms. He had no evidence of any ischaemic cardiomyopathy, however, further cardiac imaging showed a left ventricular non-compaction cardiomyopathy. He was noted to have muscular weakness and an exhaustive search for associated comorbidities yielded a diagnosis of Becker muscular dystrophy. In this report, we review the pathophysiology, comorbidities and diagnostic workup in patients presenting with left ventricular non-compaction in the context of dystrophinopathy. Ultimately, we suggest the consideration of rare cardiomyopathies in all patients presenting with neuromuscular syndromes and vice versa.

Background

Left ventricular non-compaction (LVNC) is an anatomical abnormality seen in the left ventricle (LV), which is characterised by intertrabecular recesses communicating with the ventricular cavity, a thin epicardium and prominent trabeculations.¹ With improvements in cardiac testing and diagnostic modalities, it seems that the disease has garnered more attention over the past few decades.^{2 3} LVNC has been linked to several conditions including cardiomyopathies, congenital heart disease, conduction system disease and neuromuscular conditions.^{4 5}

Becker muscular dystrophy (BMD) is a genetic disorder, which results in loss of skeletal muscle integrity.⁶ The condition involves a partial inability to form functional dystrophin, an essential protein needed for cellular architecture.⁷ A closely related condition is known as Duchenne muscular dystrophy (DMD), which involves complete inability to form dystrophin.⁷ Both dystrophinopathies have X-linked recessive inheritance, with worldwide prevalence of BMD estimated to be between 0.4 and 3.6 per 100 000 males.⁸ The typical presentation includes progressive and symmetric muscular weakness (predominantly proximal limb girdles).⁹ The American Pediatric Association recommends a cardiac functional assessment in all patients diagnosed with BMD and DMD, as the limitations in mobility can often mask any cardiac dysfunction.¹⁰

Our case illustrates a patient who was diagnosed with LVNC and later found to have BMD, highlighting the uncommon coexistence of these two rare disease processes. We aim to outline the pathophysiology of the co-occurrence as well as the overall challenges in management from a functional cardiac and neurological perspective, with special emphasis on advanced heart failure therapy.

Case presentation

A 50-year-old male with a medical history of hypertension, gastro-oesophageal reflux disease, gout, hypothyroidism and anxiety presented to the emergency department with a 4-month history of progressive New York Heart Association (NYHA) class IV heart failure symptoms including dyspnoea, orthopnoea and paroxysmal nocturnal dyspnoea. He had been previously well, but recovered from a viral prodrome the previous month. He was a lifetime non-smoker, non-alcohol consumer and no other illicit drug use. His family history included an unspecified cardiac septal defect. On examination, the patient was afebrile, appearing comfortable in no distress on 3 L of nasal cannula oxygen, with normal blood oxygen saturations, a blood pressure of 119/79 mm Hg, heart rate of 104 bpm and normal respiratory rate. He had normal S1 and prominent S2 heart sounds with an S3 gallop and his jugular venous pressure (JVP) was elevated to the level of his earlobes, with course crackles in his chest. His abdomen was soft and nontender with no organomegaly and he had pitting oedema in his lower legs.

He had multiple episodes of pronounced gait unsteadiness and at times would experience mechanical falls. These symptoms had been there throughout his adolescence and he endorsed he would require more upper limb strength to lift him off a chair and if on the floor he would need to get on his limbs first and push up with his arms. He also mentioned that as a child he would get muscle weakness and cramping during activity and had large calves. His neurological examination yielded a normal cranial nerve examination, reflexes were 2+ and symmetric with downgoing plantars bilaterally. His sensation was also grossly normal. He had atrophy of his quadriceps bilaterally, calf hypertrophy and normal strength in the upper extremities. He had mild weakness in his hip flexors (4/5) and hip abductors (4+/5), quadriceps (4+/5) and hamstrings (4/5) with preserved full distal strength in his lower extremities (graded in MRC muscle power scale). He had a waddling gait

Investigations

ECG showed normal sinus rhythm, evidence of left atrial enlargement and left anterior fascicular block, with no signs of acute or chronic ischaemia or infarction. Transthoracic echocardiogram (TTE) showed severe LV dysfunction with moderate secondary mitral regurgitation (MR) with an estimated ejection fraction (EF) of 20% and right ventricular systolic pressure (RVSP) of 74 mm Hg. CT coronary angiogram and pulmonary embolism study (CT-CA) that showed no significant epicardial coronary artery disease and no evidence of pulmonary emboli. He had a negative haemochromatosis workup. His initial telemetry findings showed few runs of asymptomatic non-sustained ventricular tachycardia (NSVT).

His 24-hour outpatient Holter was unremarkable. Cardiac MRI showed gross dilation of the LV with an EF of 17%. The LV was thin and hypertrabeculated in the anterior, lateral and inferior segments with delayed enhancement, suggestive of LVNC (figure 1, video 1). His repeat TTE showed severe global reduced LV function with EF of 20%–25%, LV dilation and eccentric hypertrophy with grade II diastolic dysfunction. The RV was hypokinetic with RVSP of 40 mm Hg, restricted mitral leaflets and mild MR and tricuspid regurgitation. The atria were also mildly dilated. Given the findings of new onset heart failure and the delayed enhancement seen on cardiac MRI, a CA was performed, which demonstrated normal coronary arteries and left ventriculogram showing severe global hypokinesis and EF of 15%–20%. Contrast echocardiogram showed features consistent with LVNC (videos 2 and 3).

Figure 1.

Cardiac MRI horizontal long axis view showing region in left ventricle (LV) delayed myocardial enhancement of trabeculated appearance (yellow arow).

Video 1.

bcr-2021-244745supp001.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-244745.video01

Video 2.

bcr-2021-244745supp002.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-244745.video02

Video 3.

bcr-2021-244745supp003.mp4 ^{(668.9KB, mp4)}

DOI: 10.1136/bcr-2021-244745.video03

On review, the patient had recurrent syncopal episodes, prompting further risk stratification for sudden cardiac death (SCD), as well as candidacy for an implantable cardiac defibrillator (ICD). An 123I- Meta-iodobenzylguanidine (MIBG) scintigraphy scan showed decreased cardiac 123I-MIBG activity suggestive of moderate to severe cardiac sympathetic denervation, implying high risk for SCD.

With regard to his muscular weakness, he had a normal CT brain and normal MRI brain and spine. He subsequently had an electromyogram (EMG) showing features consistent with nonspecific proximal lower extremity predominant myopathy, which led to a left quadriceps muscle biopsy. Histological examination revealed skeletal muscle with increased epimysial and perimysial fibroadipose tissue (figure 2A). An increased range of muscle fibre dimensions was evident, with many hypertrophic fibres measuring up to 150 µm in diameter (figure 2B), along with scattered single and very small collections of muscle fibres. Larger fibres were commonly rounded in appearance while normal and small-sized fibres were found to generally retain their usual polygonal contours. Occasional scattered degenerating or necrotic as well as regenerating fibres were identified, with several associated with collections of lymphocytes and macrophages. Blood vessels were unremarkable, and periodic-acid Schiff (PAS) and Oil Red O (ORO)-stained sections did not exhibit an apparent increase in glycogen or lipid, respectively. Myofibrillar ATPase-reacted sections demonstrated the normal checkerboard-like pattern of types 1 and 2 fibres, with all populations of fibres containing both types 1 and 2 fibres. An immunohistochemistry panel of merosin, beta-dystroglycan, alpha-sarcoglycan, beta-sarcoglycan, delta-sarcoglycan, dystrophin-1, and dystrophin-2 did not identify a definitive pathological abnormality (figure 2C). However, immunohistochemical analysis with dystrophin-3 antibodies demonstrated diminished to absent sarcolemmal positivity in most muscle fibres (figure 2D). Taken together, these findings were consistent with a nonspecific dystrophic/myopathic process with no inflammatory components, no rimmed vacuoles or inclusions noted.

Figure 2.

Histopathological findings consistent with dystrophy/myopathy. (A) H&E-stained section at low magnification showing increased epimysial and perimysial adipose tissue within a bundle of skeletal muscle fibres. (B) H&E-stained section demonstrating muscle fibre hypertrophy. (C) Immunostaining for dystrophin-2 demonstrates normal sarcolemmal positivity; inset, positive control. (D) Dystrophin-3 sarcolemmal positivity is reduced to absent; inset, positive control.

Genetic studies were considered and a gene panel for limb girdle muscular dystrophy turned out to be negative. He was found to have a hemizygous pathogenic variant in the DMD gene, which is designated as an in-frame deletion consistent with a diagnosis of BMD (c.5439_8237del, predicted to cause p.Glu2247_Gln2739del signifying deletions in exons 45–53 that results in truncated and dysfunctional dystrophin). He also was heterozygous for a variant of uncertain significance in the MYBPC3 gene that could potentially be responsible for his LVNC.

Differential diagnosis

In this gentlemen’s presentation of cardiomyopathy, an important distinction needed to be made between ischaemic and non-ischaemic aetiology. Ischaemia was essentially negated with a normal initial CT -CA and normal CA. A question of viral myocarditis as the causative trigger in the initial hospital presentation (given his viral prodrome) was considered, however, his LV systolic function did not improve over time. He subsequently had a cardiac MRI and contrast TTE which showed features consistent with LVNC.

With respect to this patient’s weakness and ataxia, there could have been a multifactorial aetiology including a primary structural central nervous system lesion such as a stroke or multiple sclerosis, which was ruled out by a normal CT and MRI of his brain. He did have EMG evidence of lower limb myopathy and the quadriceps biopsy further showed that he had a nonspecific dystrophic process. Thus, he had a symmetric limb-girdle distribution myopathy. He had no contractures, militating a diagnosis of Emery-Dreifuss syndrome. Inclusion body myositis was ruled out as the biopsy showed no inflammatory features, no rimmed vacuoles and no inclusions. Danon disease was considered given the dyad of cardiomyopathy and skeletal myopathy, however, given the lack of any evidence suggesting cognitive dysfunction and no LAMP2 gene mutations, it made it less likely. Further genetic workup yielded a pathogenic variant in the DMD gene consistent with BMD.

Treatment

This patient was optimised medically and switched to sacubitril/valsartan with good response. He was deemed high risk for SCD and was booked for an elective primary prevention ICD. Unfortunately he experienced an out-of-hospital cardiac arrest from pulseless VT. He was successfully resuscitated and subsequently received a dual chamber ICD for secondary prevention. He was concomitantly placed on amiodarone as an antiarrhythmic for shock suppression therapy and subsequently switched to sotalol due to amiodarone intolerance. The patient went on to have recurrent syncopal VT episodes requiring multiple hospital admissions. His Interagency Registry for Mechanically Assisted Circulatory Support score was 2–3, which prompted an urgent referral for a LV assist device (LVAD) and he had a HeartMate 3 LVAD implanted.

With regard to his BMD, the patient had no specific pharmacotherapy, however, he did attend regular follow-ups with neurology, physiatry, as well as speech pathology to monitor for any neurological and functional complications. This therapy formed an important aspect in preparing him for an eventual cardiac transplantation.

His cardiac medications are as follows: sotalol, warfarin, sertraline, aspirin, metoprolol, furosemide, spironolactone and sacubitril/valsartan.

Outcome and follow-up

This patient follows up regularly with both the heart function clinics. He thinks his management of his activities of daily living are slowly improving. He will have occasional orthostatic light-headedness but denies any syncopal events. He states that he is limited more by leg weakness than any dyspnoea. He denies any ICD shocks or LVAD alarms.

Discussion

The normal human LV has up to three prominent trabeculations and is much less trabeculated than the RV.¹¹ Diagnosis of LVNC can be challenging and focuses on non-invasive imaging with echocardiography and cardiac MRI.¹² TTE is the most common modality used in diagnosis of LVNC and several criteria such as Chin, Jenni and Vienna have been developed, but non have been validated as a gold standard.^{4 5} The Jenni criteria has been generally accepted and relies on the end-systolic ratio between noncompacted:compacted layer to be >2 in short axis.¹³ The challenges surrounding echocardiographic criteria revolve around miscalculation of mass, thickness or volume ratios depending on planes and prominence and thickness of trabeculae.^{4 5} Cardiac MRI is a modality mainly used for confirmation and to look for associated congenital cardiac disease.^{5 14} It can also provide information on kinetics and fibrosis of the myocardial layers.¹⁴ The Peterson criteria are generally accepted and include an end-diastolic ratio between noncompacted:compacted to be greater than 2.3. The main obstacle to accurate diagnosis is interobserver variability, up to 35% even among experienced observers.^{15 16} There is a tendency to overdiagnoses LVNC by these two modalities, more so with cardiac MRI.¹⁷

LVNC can be isolated, in which apart from non-compaction, there is otherwise normal cardiac size and function or in the absence of any congenital cardiac disease.¹⁸ The non-isolated forms of LVNC can be associated with LV dilation/dysfunction, cardiomyopathies, congenital cardiac disease or other metabolic/neuromuscular conditions.¹⁵ LVNC seems to have a dynamic acquired pathophysiology as it may develop during pregnancy or athletic training.^{19 20} Even more puzzling is the fact that it may disappear post partum.²⁰

Dystrophinopathies such as DMD and BMD are conditions known to be linked with varying degrees of cardiac dysfunction in affected individuals.²¹ Most common associated cardiac diseases include conduction system abnormalities as well as dilated cardiomyopathy.^{22 23} LVNC has also been similarly linked to several neuromuscular disorders (NMD) and up to two thirds of patients with LVNC have an NMD.²⁴ When considering the pathophysiological interface of both cardiac and skeletal myopathies, it is important to consider the importance of dystrophin in the development of cytoskeletal architecture and extracellular matrix.²⁵ It is well known that the cardiac compaction process in the fetus involves the extracellular matrix and thus dysfunctional or absent dystrophin can lead to compaction anomalies.^{26 27}

If detected early, patients identified with LVNC and DMD are shown to have delayed onset and slower decline in LV function.²⁸ The phenotypic penetrance varies among patients with dystrophinopathy and LVNC, as such there seems to be no correlation between severity of musculoskeletal (MSK) limitations and cardiac dysfunction.²⁹ This is evident in our patient as over the years he deteriorated from the cardiovascular standpoint with malignant dysrhythmias leading to advanced heart failure therapies, with relatively stable MSK function.

Cohort studies have shown that systolic dysfunction, heart failure, malignant ventricular arrhythmias, left bundle branch block, right bundle branch block, atrial fibrillation and associated NMDs have prognostic importance and the presence of NMDs was an adverse prognostic diagnostic finding.³⁰ Our patient presented with most of these adverse risk factors.

Potential causes for NMD patients having a worse prognosis include (1) Increased arrhythmogenicity because of involvement of cardiac electrical system, (2) compromised respiratory status from respiratory muscle affliction, (3) multisystem involvement, namely endocrine, gastrointestinal and immune systems, (4) lower aerobic capacity in these patients from diminished mobility and (5) autonomic neuropathy.¹⁵

Malignant cardiac arrhythmias most likely result from the development of fibrosis in the non-compacted myocardium.³¹ Re-entrant circuits may be established at the border of fibrotic areas with normal myocardium.³² Arrhythmic complications may range from conducting system disease to supraventricular tachycardias to ventricular arrhythmias including ventricular fibrillation.³² Monomorphic VT, polymorphic VT, bidirectional VT and fascicular VT have been described.³² Interestingly one case of catecholaminergic polymorphic VT has also been reported in a patient who subsequently developed LVNC, further lending credence to the dynamic nature of this cardiomyopathy.³³ Unfortunately stratification with electrophysiology studies has not yielded robust clinical indicators for appropriate ICD therapy in these patients, and thus clinical gestalt prevails.

MIBG scan is an emerging non-invasive tool to assess cardiac sympathetic activity and quantified myocardial MIBG parameters have proved to be of prognostic value in heart failure.³⁴ Patients with reduced heart-to-mediastinum ratio and increased MIBG myocardial washout fared worse. Specifically, Boogers et al proved that single-photon derived emission tomography (SPECT)-derived summed myocardial denervation score was associated with an increased risk of malignant ventricular arrhythmias and SCD.³⁵ Our patient had evidence of severe denervation based on a high risk MIBG scan as described. Thus, MIBG scan may be an effective tool to stratify these patients with respect to escalation of therapy. Our patient did not respond to optimisation of guideline-based medical therapy and his LV systolic function continued to deteriorate. Though he had a class 1 indication for ICD therapy for primary prevention of SCD and a high-risk MIBG scan, he did not receive the same initially because it was reasoned that he had a limited life-span due to the BMD, a faulty assumption.

LV hypertrabeculation is a pathognomonic process in search of a disease! In LVNC it attains cardiomyopathy status; full expression of which may or may not be linked with other pathological processes in or outside the heart. Thus, it may cohabit with other cardiomyopathies. Our case report describes its malignant association with BMD. NMDs have prognostic import in LVNC and vice versa. Life-threatening complications is the rule. Cardiac transplantation remains a challenging procedure in such patients and destination LVAD seems the more practical and feasible strategy.

Patient’s perspective.

As a kid I did not like sports as I was not good at running. My parents had me examined by a doctor and were told I was flat footed, and that is why I had foot problems. I am diagnosed with left ventricular noncompaction and Becker muscular dystrophy. I lived a good life, and never had to go to the doctor for anything, except the odd physical.

I had trouble sleeping because I was not able to breathe when I laid flat. I had an echocardiogram and then they ordered a CT scan, which showed left ventricular noncompaction. They were treating me for heart failure and running tests to see why I had this.

They did a muscle biopsy on me, which showed I had Becker muscular dystrophy. They did family history and genetic testing but did not find anything.

I had an ICD implanted and subsequently ended up in hospital with heart failure. This was the worst I had ever felt, and they said I was in the end stage. I remained in hospital and was placed on a device to let my right heart heal for about a month. Then they implanted a LVAD, which has given me my life back.

Now it’s time to decide whether to keep LVAD or get a heart transplant. With how I feel and the trouble I had to get back on my feet, I am thinking of keeping the LVAD, unless some complication arises. I will follow the advice of all the great doctors that have treated me. I am so impressed and grateful to each doctor I’ve met. They were all awesome and have kept me ALIVE, and I will always follow what they recommend.

Learning points.

• Left ventricular non-compaction is a diagnosis of interest and should lead to screening and surveillance of patients for dystrophinopathies.

• A multidisciplinary approach is recommended in patients diagnosed with neuromuscular disorders (NMDs) and cardiomyopathies, with particular emphasis on rehab.

• Life-threatening complications is the rule in these unfortunate patients. Cardiac transplantation is limited by the severity of NMD and capacity for rehabilitation. Destination therapy with left ventricular assist device offers a viable and practical option.

• MIBG scan may have value in identifying patients with high risk for sudden cardiac death (SCD). Electrophysiological stratification is of limited value for primary prevention implantable cardiac defibrillator (ICD).

• ICD is indicated for the primary and secondary prevention of SCD in high-risk patients.

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