Smartwatch bradycardia alarms leading to a diagnosis of lamin A/C cardiomyopathy: a case report

Abstract

Background

Genetic aetiologies of early-onset arrhythmias and cardiomyopathy (CM) are common, but timely diagnosis requires a high index of suspicion.

Case summary

An asymptomatic 47-year-old man presented to cardiology clinic for smartwatch low-rate alarms. His brother had exertional syncope and died in his 20s from heart failure. Transthoracic echocardiogram showed reduced left ventricular ejection fraction (35%). A Holter monitor showed third-degree atrioventricular block and frequent pauses (longest 4.9 s). He was admitted to the hospital and following a cardiac magnetic resonance imaging with late gadolinium enhancement a cardiac resynchronization therapy-defibrillator was placed. Genetic testing identified a pathogenic variant in the lamins protein A and C (LMNA) gene.

Discussion

Left ventricular dysfunction with or without arrhythmias should raise concern for familial CM and warrants further evaluation. Lamin A/C cardiomyopathy is the second most prevalent cause of familial dilated CM and is notable for an indolent course with conduction disturbances that frequently precede left ventricular dysfunction. Smartwatch alarms can potentially help with the early identification of patients with risk factors for familial CM before the development of overt symptoms.

Learning points.

• Lamin A/C cardiomyopathy is the second most prevalent cause of familial dilated cardiomyopathy and is notable for an indolent course with conduction disturbances often preceding systolic dysfunction.

• Wearables, including smartwatches, may help with early identification in patients at risk of familial dilated cardiomyopathy.

Introduction

Lamin A/C cardiomyopathy (LMNA-CM) is the second most prevalent cause of familial dilated cardiomyopathy (DCM) and is notable for a progressive course where conduction disturbances often precede systolic dysfunction.¹ An estimated 5%–8% of genetic DCM is attributed to LMNA missense and truncating variants.¹ Lamin proteins have both a critical nuclear structural role and act as deoxyribonucleic acid (DNA) repair, replication, and transcription regulators through interactions with inner nuclear membrane proteins.² Pathogenic disruption of these functions results in aberrant nuclear morphology and early-onset programmed cell death.³

The 2021 European Society of Cardiology (ESC) Heart Failure Guidelines added a new focus on genetic testing and outline disease specific recommendations for genetic CMs.⁴ Wearables, including smartwatches, may help with early identification in patients at risk of familial DCM.

Summary figure

Case presentation

An asymptomatic 47-year-old man from Costa Rica presented to cardiology clinic for evaluation of recurrent bradycardia alarms on his smartwatch (Apple Watch). He remained very active, exercising vigorously multiple times per week without shortness of breath, chest pain, or palpitations. He had no history of pre-syncope or syncope. The patient’s family history was significant for a younger brother with exertional syncope who ultimately died from heart failure in his 20s, a sister diagnosed with ventricular ectopy in her 20s, and his mother with a bundle branch block. There was no family history of neuromuscular disorders. At the time of his brother’s death, 3 years prior to the current presentation, the patient had a cardiac magnetic resonance imaging (cMRI) which showed low-normal left ventricular ejection fraction (LVEF) (53%) with linear septal fibrosis. The patient was started on an angiotensin-converting-enzyme inhibitor at this time. He denied alcohol or illicit substance use. Physical exam was notable for bradycardia with an irregular pulse, blood pressure of 127/72 mmHg, no murmurs, and no peripheral oedema. Electrocardiogram (ECG) was obtained which showed sinus bradycardia with marked first-degree atrioventricular block (AVB) and premature ventricular complexes (Figure 1). Transthoracic echocardiogram (TTE) showed a non-dilated [left ventricular internal diameter, diastole (LVIDD) 5.2 cm, left ventricular internal diameter, systole (LVIDS) 4.6 cm] left ventricle with reduced function LVEF 35%, global longitudinal strain (GLS) −10.2%), mild right ventricular dysfunction, and mild-moderate mitral regurgitation.

Figure 1.

Electrocardiogram. Sinus bradycardia with first-degree atrioventricular block and multiple premature ventricular complexes with different morphologies.

The differential diagnosis for this presentation of conduction disease and CM was broad. His family history raised concern for a familial CM, specifically LMNA-CM. We also considered infiltrative aetiologies like sarcoidosis, inflammatory conditions like viral or giant cell myocarditis, and infectious causes including Chagas disease as the patient was born in Central America.

The patient left clinic with a 72-h Holter monitor which showed 56 pauses (longest 4.9 s) and multiple episodes of third-degree AVB, 2:1 AVB, and second-degree AVB type 1. The patient was then admitted to the hospital for an expedited work-up and a cMRI was obtained (Figure 2) which showed an LVEF of 32%, normal LV wall thickness, and mildly enlarged atria. Delayed enhancement was notable for mid-myocardial late gadolinium enhancement of the basal and mid-septum and adjacent basal inferior wall suggestive of an idiopathic or familial CM. The electrophysiology team was consulted, and a cardiac resynchronization therapy-defibrillator (CRT-D) was implanted. The defibrillator was added given his reduced LVEF, non-ischaemic CM, and family history of sudden cardiac death (SCD). The patient was started on guideline directed medical therapy (GDMT)—spironolactone 25 mg daily, sacubitril-valsartan 24–25 mg twice daily, and dapagliflozin 10 mg daily—for his reduced LVEF.

Figure 2.

Cardiac magnetic resonance imaging. Delayed enhancement with mid myocardial late gadolinium enhancement in basal and mid-septum (A and B) and adjacent basal inferior wall (C) suggestive of idiopathic dilated cardiomyopathy or familial/genetic cardiomyopathy.

Genetic testing revealed a pathogenic loss of function mutation in the LMNA gene c.364A>T (pLys122*). This mutation results in a premature translational stop signal in the LMNA gene resulting in a loss of function in the protein.⁵ Follow-up device interrogation showed 8.7% atrial fibrillation burden, and the patient was started on apixaban. He has had no ICD discharges. Repeat TTE 6 months following his initial presentation showed mild recovery of his ejection fraction to 40%–45% (GLS −15%) with mild left ventricular dilation (LVIDD 5.9 cm, LVIDS 4.7 cm), and he remained asymptomatic.

Discussion

Clinicians must have a high index of suspicion for a familial CM in cases like this where patients under 50 present with early-onset high degree AVB, non-ischaemic CM, and/or a positive family history of SCD. Unlike other familial CMs, atrial and ventricular arrhythmias often precede ventricular dysfunction in LMNA-CM and around one-third of patients will present with normal LV function.⁶ Though this patient had a reduced LVEF, he was asymptomatic without signs or symptoms of heart failure at the time of presentation. Notably, previous reports have found smartwatches to have high sensitivity for the detection of bradycardia.⁷ Wearable devices rely on either single-lead ECG or photoplethysmography (PPG) for arrhythmia detection. While single-lead ECG devices capture electrical activity, PPG uses peripheral blood volume changes to indirectly assess pulse rate and rhythm and is more prone to artefact. Though these wearable devices were initially utilized primarily for the detection of atrial fibrillation, they also have utility in the detection of other arrhythmias including bradycardia. Others have reported the ability of artificial intelligence algorithms to detect low LVEF based on smartwatch ECGs.⁸ This case with bradycardia alarms leading to the discovery of pauses and subsequent LMNA-CM diagnosis illustrates another potential benefit of these technologies. As these technologies evolve, additional applications will likely emerge.

The most recent ESC Heart Failure Guidelines recommend genetic testing in patients with DCM and AV conduction delay under 50 years of age or those with a family history of DCM or SCD in first-degree relative under 50 years of age (Class I).⁴ As this patient met all listed criteria, he had a clear indication for genetic testing. The most recent iteration of the Guidelines added these recommendations, signalling a new awareness and emphasis on genetic CM.

This case highlights the many implications of establishing a LMNA diagnosis through genetic testing. First, the decision on what type of permanent pacemaker was impacted by his LMNA-CM diagnosis. A 2019 Heart Rhythm Society Expert Consensus Statement recommends implantable cardiac defibrillator (ICD) in patients with LMNA variants who are either (i) having a device implanted for other reasons or (i) have >2 risk factors (LVEF < 45%, male, NSVT).⁹ These recommendations, reflective of the heightened risk of SCD associated with LMNA-CM, led to the addition of an ICD for this patient. Next, remote device monitoring revealed paroxysmal atrial fibrillation, another common occurrence in patients with LMNA-CM. While there are no specific guidelines for anticoagulation in LMNA-CM, there is an elevated risk of stroke in LMNA-CM compared to other types of dilated CM. This stroke risk is felt to be related to an intrinsic atrial myopathy associated with LMNA variants.¹⁰ As this patient had a low bleeding risk, we elected to start him on anticoagulation for his atrial fibrillation despite a CHA2DS2-VASc score of 0. Additionally, at discharge from his hospitalization, he was started on GDMT, though there is evidence that GDMT may not be as beneficial in patients with LMNA-CM compared to those with other aetiologies of heart failure.¹¹ Finally, in LMNA-CM, an autosomal dominant condition with high penetrance (90%), the discovery of a likely pathogenic variant guides risk predictive genetic testing in offspring.¹² We discussed cascade screening with our patient as he has children who could potentially benefit from testing. While there are no specific treatments currently available for LMNA-CM, risk predictive genetic testing for the specific LMNA mutation has the potential to stratify his first-degree relatives into either low risk (no pathogenic LMNA variant) or guide lifelong monitoring and follow-up (LMNA pathogenic variant present).

At follow-up in our advanced heart failure clinic, the patient experienced some LVEF recovery, though we cautioned him that the overall prognosis of LMNA-CM is poor and frequently requires heart transplant. Previous cohort studies have reported ranges of 13%–26% of patients with LMNA-CM ultimately undergoing heart transplant.¹ In addition to serial imaging and ICD monitoring, we discussed monitoring for proximal muscle weakness or gait impairment given the association of LMNA disease with neuromuscular syndromes. As the patient was without high risk features and was quite active at baseline, we encouraged him continue with light to moderate activity but cautioned him against strenuous exertion or competitive sports.¹³

Left ventricular dysfunction with or without arrhythmias in the context of family history should raise concern for familial CM and warrants further evaluation. Lamin A/C cardiomyopathy is the second most common familial CM and frequently presents with arrhythmia, often preceding the development of left ventricular dysfunction. Smartwatch alarms, especially low HR alarms, in patients with a family history of CM and/or SCD may be helpful in identifying patients with risk factors for familial CM before developing overt heart failure symptoms or SCD.

Lead author biography

Dr Rushakoff is currently a cardiology fellow at Duke University. He is interested in heart failure and heart transplant and plans to complete an additional fellowship in advanced heart failure and transplant cardiology.

Author contributions

Joshua A. Rushakoff (Conceptualization [equal], Writing—original draft [lead], Writing—review & editing [lead]), Karen Flores Rosario (Conceptualization [equal], Supervision [equal], Writing—review & editing [supporting]), Phoenix Grover (Conceptualization [supporting], Data curation [supporting], Writing—review & editing [supporting]), and Andrew Wang (Conceptualization [equal], Supervision [lead], Writing—original draft [supporting], Writing—review & editing [supporting])

Consent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained the patient, in line with the COPE guidance.

Funding: None declared.

Data availability

The data underlying this article are available in the article and in its online supplementary material.