Aetiology and clinical manifestations of patients with non‐dilated left ventricular cardiomyopathy

Abstract

Non-dilated left ventricular (LV) cardiomyopathy (NDLVC) is a new entity introduced in the recently published 2023 European Society of Cardiology (ESC) guidelines for the management of cardiomyopathies.1 It is an umbrella term encompassing the presence of (i) non-ischaemic LV fibrosis or fatty replacement in the absence of LV dilatation, with or without global or regional motion abnormalities, or (ii) isolated global LV hypokinesia (i.e. LV ejection fraction [LVEF] <50%) without fibrosis. The cardiac phenotype should be not solely explained by coronary artery disease or abnormal loading conditions (i.e. hypertension or valve disease).1 According to the recent classification of cardiomyopathy phenotypes proposed by the ESC guidelines, which is based on detailed morpho-functional characterization by a comprehensive multimodality imaging approach, the NDLVC phenotype was introduced to provide a starting disease phenotype, the identification of which should trigger the investigation of the underlying aetiology. This new phenotype was suggested to overcome some limitations related to previous entities, including isolated LV scar, arrhythmogenic LV cardiomyopathy (ALVC),2 and hypokinetic non-dilated cardiomyopathy (HNDCM),3 and avoid contradictory, confusing, or overlapping terminology. The introduction of the NDLVC phenotype allows for an easy diagnosis, which can be performed using echocardiography or cardiac magnetic resonance (CMR). However, there is limited knowledge about this condition, particularly regarding its underlying aetiology. This study aims to define the underlying aetiologies and clinical manifestations of patients with NDLVC to enhance understanding and management of this condition. An observational, longitudinal cohort study was conducted. All patients gave written consent, and the institutional ethics review board approved the study (Comitato Etico Università Vanvitelli – A.O.R.N. dei Colli, approval code AOC113/2023). The cohort included consecutive patients, identified retrospectively, who met echocardiographic or CMR diagnostic criteria for NDLVC and were referred to the Inherited and Rare Cardiovascular Diseases Unit (Naples, Italy) from January 2021 to July 2023. To be eligible for enrolment, patients had to meet the following inclusion criteria: diagnosis of NDLVC according to the 2023 ESC guidelines for the management of cardiomyopathies1; and age at diagnosis of 16 years or older. The diagnosis of NDLVC was defined by the presence of echocardiographic or CMR evidence of non-ischaemic LV scarring or fatty replacement in the absence of LV dilatation, with or without global or regional wall motion abnormalities, or isolated global LV hypokinesia without scarring. Patients were excluded if they had significant coronary artery disease or abnormal loading conditions sufficient to explain the disease phenotype. Patients fulfilling inclusion criteria underwent a comprehensive and standardized clinical and genetic evaluation including family history, medical history, clinical examination, resting 12-lead electrocardiography (ECG), conventional M-mode, two-dimensional and Doppler echocardiography with Doppler tissue imaging, 24-h ambulatory ECG monitoring, CMR imaging, and genetic testing. The prospective evaluation occurred between August 2023 and July 2024. Molecular genetic testing was conducted using a next-generation sequencing (NGS) panel containing 202 genes, as previously described.4 Genetic variant interpretation was curated following the American College of Medical Genetics and Genomics and the Association for Molecular Pathology recommendations.5 According to the final aetiology, patients were classified into four main diagnostic categories: (1) genetic, in the presence of pathogenic/likely pathogenic (P/LP) variants in genes encoding for cytoskeletal, desmosomal, sarcomeric, and calcium-handling proteins associated with the NDLVC phenotype1; (2) inflammatory, including patients with acute and chronic myocarditis, with a ring-like pattern on CMR and without P/LP variants in desmosomal and non-desmosomal genes, and patients with cardiac sarcoidosis; (3) neuromuscular, including patients with X-linked muscular dystrophies, limb-girdle muscular dystrophies, and myotonic dystrophies; (4) idiopathic, when genetic analysis did not find P/LP variants in NDLVC-associated genes and an integrated diagnostic work-up excluded phenocopies. The 2024 updated Padua criteria for the diagnosis of ALVC were also applied to patients included in the study to evaluate how many patients would have been diagnosed with this condition starting from the NDLVC phenotype. Normally distributed continuous variables are described as mean ± standard deviation, while categorical variables as number (percentage). All statistical analyses were performed using IBM SPSS Statistics for Macintosh, Version 27.0. A total of 42 patients with a diagnosis of NDLVC fulfilled the inclusion criteria and represented the final study cohort (Figure 1). The average age at the first evaluation was 42.9 ± 17.0 years, and 29 (69.0%) were male. Family history of cardiomyopathy and sudden cardiac death was observed in 17 (40.5%) and 13 (30.9%) cases, respectively. Genetic testing was performed in all cases. After a comprehensive clinical and genetic evaluation, patients were classified as having: genetic aetiology in 16 cases (38.0%), with P/LP variants in NDLVC-associated genes (DES [n = 2], FLNC [n = 2], LMNA [n = 3], JUP [n = 1], DSP [n = 3], PLN [n = 1], MYH7 [n = 2], TNNT2 [n = 1], and TTN [n = 1]); inflammatory aetiology in five cases (11.9%), with four patients fulfilling diagnostic criteria for myocarditis and one for cardiac sarcoidosis; neuromuscular aetiology in four cases (9.5%), with two cases diagnosed with Duchenne muscular dystrophy and two with myotonic dystrophy type 1; idiopathic NDLVC in 17 cases (40.5%). Eight patients (19%) exhibited a myocarditis-like clinical presentation. Among these, three patients showed a P/LP variant in DSP and were classified as genetic NDLVC, while the remaining were diagnosed with myocarditis (n = 4) or cardiac sarcoidosis (n = 1). Thirty-four patients underwent CMR imaging. Among these, the diagnosis of NDLVC was based on the presence of: LV fibrosis with normal LV systolic function (LVEF >50%) in 21 cases (61.7%); LV fibrosis with LV systolic dysfunction (LVEF <50%) in 2 cases (5.9%); isolated LV systolic dysfunction without fibrosis in 11 cases (32.4%). Patients with LV fibrosis were more likely to have a genetic aetiology, while those with isolated LV systolic dysfunction without fibrosis had largely unidentified aetiology (idiopathic NDLVC). Among the 34 patients who underwent CMR, a definitive diagnosis of ALVC according to the 2024 updated Padua criteria was reached in 14 cases (41.2%). This diagnosis was mainly based on the presence of a ring-like pattern of fibrosis on CMR and a P/LP variant in an ALVC-associated gene. These 14 cases were distributed as follows: 11 patients with genetic NDLVC, 2 patients with idiopathic NDLVC, and 1 patient with inflammatory NDLVC. Thus, the diagnosis of ALVC was common among patients with genetic NDLVC (11/15 cases [73.3%] who underwent CMR) and uncommon in those with inflammatory or neuromuscular NDLVC (1/5 cases [20.0%] and 0/2 cases [0.0%], respectively). This study describes for the first time the aetiological spectrum of consecutive patients with NDLVC. The findings reveal that the aetiology is heterogeneous, with more than one-third having an underlying genetic aetiology, nearly one-fifth having an inflammatory or neuromuscular condition, and in the remaining cases, a comprehensive diagnostic work-up fails to identify an underlying aetiology. A genetic cause was more frequent in patients with LV fibrosis at CMR compared with patients with isolated LV systolic dysfunction without fibrosis. Myocarditis-like onset is a common clinical presentation, with nearly one-third of cases uncovering a P/LP variant in DSP, confirming the emerging notion that myocarditis can uncover a genetic cardiomyopathy.6 Finally, while most patients with genetic NDLVC fulfilled diagnostic criteria for ALVC, the diagnosis of ALVC was rarely observed in patients with an inflammatory or neuromuscular aetiology. These observations support the concept of the 2023 ESC guidelines that the NDLVC phenotype represents a starting disease phenotype. It should be considered as a working diagnosis that promptly triggers a multiparametric approach leading to an aetiological diagnosis and, ultimately, individualized management. Indeed, risk stratification for adverse cardiovascular events and treatment can vary significantly among patients presenting with the same NDLVC phenotype but different underlying aetiologies.1 This study has several limitations, including a small sample size and its retrospective nature. Larger multicentre cohort studies are needed to confirm these findings. Furthermore, future research on the role of clinical, molecular, and imaging features in predicting the underlying aetiology will be crucial for guiding the diagnostic work-up and is essential for early diagnosis and management. Additionally, assessing the pattern of disease progression in patients with NDLVC could provide valuable information for a tailored management of affected patients. We are grateful to Dr. Santo Dellegrottaglie and Dr. Alessandra Scatteia for their valuable contribution as cardiac magnetic resonance experts in the field. We are also grateful to our nurses Michela Piscopo and Daniela Lafera for their precious contribution in managing patients with cardiomyopathies. Conflict of interest: none declared.

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