Left Ventricular Hypertrophy With Pre-Excitation

Abstract

Background

PRKAG2 cardiomyopathy is a genetic cardiomyopathy that phenotypically resembles hypertrophic cardiomyopathy (HCM) and results from myocardial glycogen accumulation. In addition to left ventricular hypertrophy (LVH), PRKAG2 cardiomyopathy is associated with ventricular pre-excitation, cardiac conduction disease, and ventricular tachyarrhythmias.

Case Summary

A 34-year-old woman with a family history of HCM and Wolff-Parkinson-White syndrome presented with exertional dyspnea, chest discomfort, and near-syncope. Electrocardiogram revealed LVH, T-wave inversions, and pre-excitation. Echocardiography demonstrated severe LVH with outflow tract obstruction. Based on family history, LVH, and pre-excitation, PRKAG2 syndrome was suspected and later confirmed by genetic testing.

Discussion

PRKAG2 cardiomyopathy results from glycogen accumulation rather than sarcomeric hypertrophy. This case highlights the diagnostic importance of electrocardiography-detected pre-excitation in a patient with severe LVH, raising suspicion for nonsarcomeric HCM.

Take-Home Messages

Consider PRKAG2 mutations in HCM patients with pre-excitation or conduction disease. Early genetic diagnosis guides management and informs family screening.

Visual Summary

Visual Summary.

Case Presentation, Diagnosis, and Take-Home Points

Although PRKAG2-associated cardiomyopathy phenotypically resembles sarcomeric HCM, the primary mechanism of LVH development is accumulation of myocardial glycogen stores. A diagnosis of PRKAG2-associated cardiomyopathy should be considered in patients with a personal or family history of both HCM and ventricular pre-excitation. HCM = hypertrophic cardiomyopathy; LGE = late gadolinium enhancement; LV = left ventricle; LVH = left ventricular hypertrophy; LVOT = left ventricular outflow tract; WPW = Wolff-Parkinson-White.

History of Presentation

A 34-year-old woman with no significant prior medical history presented to the emergency department with acute-on-chronic symptoms of dyspnea and chest discomfort, which had progressed from occurring only with exertion to occurring at rest and with new associated palpitations and near-syncope. At baseline, she was an athlete who enjoyed running and walking; however, her exercise tolerance had progressively declined over several months.

Take-Home Messages

• •Consider PRKAG2 variant in patients with hypertrophic cardiomyopathy phenotype with pre-excitation or conduction disease and a strong family history of hypertrophic cardiomyopathy and Wolff-Parkinson-White syndrome.
• •Early genetic diagnosis guides management and informs family screening.

Physical examination revealed a harsh systolic murmur that increased with Valsalva maneuver. High-sensitivity troponin T was mildly elevated but stable at 100 ng/L. Laboratory tests were otherwise normal. Electrocardiogram demonstrated sinus rhythm with a short PR interval (96 ms) in the setting of ventricular pre-excitation (QRS duration: 120 ms) and diffuse left ventricular hypertrophy (LVH) by voltage criteria (meeting Sokolow-Lyon and Cornell criteria) with associated deep T-wave inversions (Figure 1). Coronary computed tomography angiography demonstrated no evidence of obstructive coronary artery disease. Transthoracic echocardiography showed severe LVH, with a maximal proximal anteroseptal wall thickness of 28 mm, near-complete systolic left ventricular cavity obliteration, and a resting left ventricular outflow tract (LVOT) gradient of 47 mm Hg that increased to 70 mm Hg with Valsalva maneuver.

Figure 1.

Presenting Electrocardiogram

Electrocardiogram demonstrates diffuse left ventricular hypertrophy by voltage criteria (meeting Sokolow-Lyon and Cornell criteria), associated with deep T-wave inversions; a short PR interval (96 ms) with evidence of ventricular pre-excitation; and a mildly prolonged QRS duration of 120 ms.

Her symptoms improved on treatment with low-dose metoprolol succinate (25 mg/d), and she was discharged with plans to follow up at the Johns Hopkins Hypertrophic Cardiomyopathy Center.

Past Medical History

She had a history of hypertension (not on medications) and polycystic ovarian syndrome.

Family History

The patient had a prominent family history of hypertrophic cardiomyopathy (HCM), atrioventricular (AV) conduction block, and Wolff-Parkinson-White (WPW) syndrome (Figure 2). Her maternal grandmother had HCM and third-degree heart block requiring pacemaker implantation. Her mother was diagnosed with HCM and WPW syndrome. Her sister had HCM with WPW syndrome and an implantable cardioverter-defibrillator (ICD). No male relatives were known to be affected. The genetic status of other relatives was unknown.

Figure 2.

Family Pedigree

The patient's maternal grandmother had HCM and third-degree heart block requiring pacemaker implantation. Her mother was diagnosed with HCM and WPW syndrome. Her sister had HCM with WPW syndrome and an ICD. No male relatives were affected. The black arrow indicates the patient. HCM = hypertrophic cardiomyopathy; ICD = implantable cardioverter-defibrillator; WPW = Wolff-Parkinson-White.

Differential Diagnoses

Given the strong family history of HCM and conduction disorders including both AV block and WPW syndrome, a nonsarcomeric genetic etiology of LVH was strongly suspected. Glycogen storage–related cardiomyopathies, including LAMP2 (Danon disease) and PRKAG2 syndromes, were important considerations given the coexistence of hypertrophy and pre-excitation. Fabry disease was also in the differential diagnosis given the severity of LVH.

Investigations

The patient underwent additional risk stratification with cardiac magnetic resonance imaging, which demonstrated a maximal left ventricular wall thickness of 41 mm, a left ventricular mass of 380 g, and late gadolinium enhancement involving approximately 10% to 14% of the left ventricular mass, distributed throughout the hypertrophied segments of the left ventricle, particularly in the mid-to-apical anterior and lateral walls (Figure 3). After genetic counseling, she underwent 30-gene HCM panel cardiac testing. This revealed a pathogenic variant in the PRKAG2 gene (p.Tyr487His), confirming the diagnosis of PRKAG2-related cardiomyopathy. She underwent 7-day ambulatory cardiac monitoring, which revealed rare premature ventricular contractions (<1%) and 1 episode of nonsustained ventricular tachycardia lasting 5 beats, with a maximum rate of 167 beats/min.

Figure 3.

Imaging Features of PRKAG2 Syndrome

(A) Transthoracic echocardiogram parasternal long-axis view demonstrating diffuse left ventricular hypertrophy. (B) Continuous-wave Doppler interrogation of the left ventricular outflow tract demonstrating a peak resting gradient of 47 mm Hg. Cardiac magnetic resonance imaging showing (C) significant left ventricular hypertrophy and (D) late gadolinium enhancement demonstrating myocardial fibrosis within hypertrophied left ventricular segments.

Management

Based on the presence of massive LVH and high-risk genotype, she was referred for dual-chamber ICD placement. In addition to low-dose metoprolol, she was started on verapamil 240 mg once daily, with resolution of exertional symptoms. Treatment escalation with cardiac myosin inhibitors (eg, mavacamten) or septal reduction therapy were discussed, but the patient declined owing to her perceived low burden of symptoms. She underwent cardiopulmonary exercise testing but completed only 6 minutes and 48 seconds on a Bruce protocol given onset of shortness of breath, resulting in subadequate heart rate (117 beats/min; 63% of predicted). Maximum recorded oxygen consumption was 18.6 mL/kg/min under these limitations.

Discussion

This case illustrates a classic but often under-recognized presentation of PRKAG2-related cardiomyopathy, a rare autosomal dominant glycogen storage disease that mimics HCM phenotype while exhibiting distinct genetic, electrophysiologic, and pathophysiologic features.¹ The combination of severe LVH, dynamic LVOT obstruction, and ventricular pre-excitation in a young patient—particularly in the setting of a strong family history of HCM and WPW syndrome—should prompt consideration of nonsarcomeric etiologies of LVH rather than classic sarcomeric HCM.²

The PRKAG2 gene encodes the γ2 regulatory subunit of 5′ AMP-activated protein kinase (AMPK), a key cellular energy sensor involved in myocardial metabolism. Pathogenic variants result in constitutive AMPK activation, leading to excessive myocardial glycogen accumulation rather than true myocyte hypertrophy.³ This glycogen infiltration produces marked ventricular wall thickening and cavity obliteration that closely mimic sarcomeric HCM on imaging but lack the myocyte disarray characteristic of sarcomeric disease.⁴ These mechanistic differences are clinically important, as disease progression, arrhythmic risk, and response to therapy differ from those of traditional HCM.

Ventricular pre-excitation is often considered a hallmark of PRKAG2 cardiomyopathy; however, its prevalence is variable and not uniformly observed across affected individuals. Earlier reports describing familial WPW syndrome suggested pre-excitation in up to 70% to 80% of patients with PRKAG2 mutation, although these observations were derived from small familial cohorts enriched for conduction phenotypes.⁵ In contrast, contemporary multicenter data from a large cohort of patients with genetically confirmed PRKAG2 variant demonstrated pre-excitation in approximately one-third of the participants, highlighting phenotypic heterogeneity and emphasizing that absence of pre-excitation does not exclude the diagnosis.⁶ Emerging genotype-phenotype correlations suggest that pre-excitation may be variant dependent, with many pathogenic mutations involving cystathionine beta-synthase domains of the AMPK γ2 subunit, including Arg302Gln and Asn488Ile variants.^6,7 The Tyr487His variant identified in our patient is likewise located within a cystathionine beta-synthase regulatory domain, which may influence nucleotide binding and AMPK activation, potentially predisposing to accessory pathway formation.

Pre-excitation is thought to result from disruption of the annulus fibrosus by glycogen-laden myocytes, permitting persistence of accessory AV pathways. In addition to WPW syndrome, affected patients are also at risk for progressive conduction disease including complete heart block (which may be masked by pre-excitation) and atrial and ventricular tachyarrhythmias. Family history of pacemaker implantation further highlights the electrophysiologic derangement associated with PRKAG2 variants. In this patient, massive hypertrophy (LVH ≥30 mm), borderline extensive late gadolinium enhancement (10%-14%), and high-risk genotype prompted ICD placement.

Although PRKAG2 cardiomyopathy may resemble HCM, LVOT obstruction appears to be uncommon in published cohorts. In the largest contemporary series of 64 individuals with PRKAG2 cardiomyopathy, none had LVOT obstruction >30 mm Hg or evidence of systolic anterior movement of the mitral valve.⁶ Mechanistic studies suggest that glycogen accumulation typically produces diffuse or concentric hypertrophy rather than the asymmetric septal remodeling characteristic of sarcomeric obstructive HCM.⁸ The presence of dynamic obstruction in our patient therefore represents a less typical but clinically important manifestation within the PRKAG2 spectrum. While comprehensive 30-gene panel testing did not reveal additional sarcomeric variants, the contribution of genetic modifiers or currently unidentified loci cannot be excluded. Such background variation may partially explain phenotypic diversity among individuals harboring PRKAG2 variants.

Although affected individuals in this family were female, PRKAG2 cardiomyopathy is inherited in an autosomal-dominant manner, and this apparent female predominance most likely reflects chance, small family size on the maternal side, and incomplete ascertainment rather than true sex-limited expression. Variable penetrance and phenotypic heterogeneity are well described in PRKAG2-related cardiomyopathy and can contribute to uneven expression across pedigrees.¹ This underscores the importance of comprehensive genetic testing and cascade screening in families with atypical HCM features, particularly when LVH coexists with pre-excitation or conduction disease.

Accurate identification of PRKAG2 cardiomyopathy has important clinical implications. Conventional HCM risk stratification algorithms may not fully apply, and patients require vigilant monitoring for conduction system disease and malignant arrhythmias. Early genetic diagnosis facilitates arrhythmia-appropriate surveillance, informs family counseling, and prevents misclassification as sarcomeric HCM or other infiltrative cardiomyopathies such as Fabry or Danon disease.⁹ Dual-chamber ICD selection may be preferred in PRKAG2 cardiomyopathy given high risk for the development of AV block. Furthermore, acute strenuous exercise may be avoided in these patients, as there are reports that physical exercise can enhance glycogen deposition in mitochondria.¹⁰ Finally, PRKAG2 cardiomyopathy is associated with higher rates of ventricular dysfunction and progression to advanced heart failure compared with sarcomeric HCM, likely reflecting cumulative glycogen deposition and adverse remodeling.⁶ Accordingly, gene-specific management mandates close longitudinal surveillance for systolic dysfunction and heart failure progression, early referral to advanced heart failure programs when appropriate, and timely transplant evaluation in selected patients.

Conclusions

This case underscores the importance of recognizing PRKAG2 cardiomyopathy as a distinct, nonsarcomeric cause of HCM, particularly when LVH coexists with ventricular pre-excitation or conduction disease. Early genetic diagnosis is essential to guide appropriate surveillance, tailor management, and enable accurate risk stratification and family screening.

Funding Support and Author Disclosures

Dr Bukhari is supported by NIH/NHLBI grant T32HL007227. Dr Carrick is a recipient of the Semyon and Janna Friedman Fellowship award. Drs Madrazo and Carrick have received support from the Talles Family Hypertrophic Cardiomyopathy Research Fund. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.