Non-Dilated Left Ventricular Cardiomyopathy: Exploring the Spectrum from Phenotype to Disease Entity

Figures

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  Figure 5. CMR LGE patterns across the DCM–NDLVC–ACM spectrum. Four representative non-ischemic late gadolinium enhancement (LGE) patterns are shown: (1) mid-wall septal linear LGE, (2) subepicardial LGE, (3) ring-like subepicardial LGE, and (4) multifocal patchy LGE. The anatomical distribution shown is representative rather than exclusive; mid-wall LGE is most commonly observed in the interventricular septum, whereas subepicardial LGE more frequently involves the inferolateral and lateral LV wall. The figure illustrates the substantial overlap of LGE patterns across dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), and arrhythmogenic cardiomyopathy (ACM). Genotype associations are presented as relative tendencies rather than disease-specific relationships; their position reflects reported associations or relative frequencies and does not imply diagnostic specificity. RV insertion point enhancement is shown separately because of its non-specific nature. Abbreviations: ACM, arrhythmogenic cardiomyopathy; ARVC, arrhythmogenic right ventricular cardiomyopathy; BAG3, BCL2-associated athanogene 3; CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy;…

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  Figure 6. What weighs toward phenotype versus disease. Each central element is a line of evidence in the NDLVC debate; the arrow’s direction indicates whether that element weighs toward interpreting NDLVC as a shared morpho-functional phenotype (left) or as a distinct disease entity (right). The distinct genotypic setting element refers to the higher frequency of pathogenic variants in pro-arrhythmogenic genes reported in NDLVC than in DCM and to the frequency of guideline-designated high-risk genotypes among genotype-positive patients. In the prognostic element, the notation controls NDLVC; DCM denotes the reported ordering of adverse event rates, and RV insertion point LGE is abbreviated as RV insertion. The overlapping statements shown in the figure refer to reported occurrence and are deliberately summaries; as detailed in Table 3 and Figure 7, the strength of the association with ACM varies substantially between genes, and RV insertion point enhancement, although seen across these phenotypes, is excluded from the ACM diagnostic criteria as non-specific and accordingly placed outside of the ACM circle in Figure 7. See Section 7.1 and Section 7.2. Abbreviations: ACM, arrhythmogenic…

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  Figure 7. Neither genotype (left panel) nor CMR LGE pattern (right panel) is specific to NDLVC, DCM, or ACM. Genes and LGE patterns are positioned according to their reported occurrence across phenotypes; displacement within a circle indicates relative frequency and does not imply exclusivity or diagnostic specificity. Mid-wall, subepicardial, ring-like, and patchy LGE patterns overlap across the DCM–NDLVC–ACM spectrum, whereas RV insertion point enhancement is shown outside of the ACM circle because it is non-specific and excluded from ACM diagnostic criteria [2,3]. In the genotype panel, ACM circle membership reflects the strength of evidence for an arrhythmogenic cardiomyopathy phenotype rather than arrhythmic risk; therefore, guideline-designated high-risk genotypes such as LMNA and RBM20 may lie outside of the ACM circle [1,24]. TMEM43 is positioned at the margin of the NDLVC circle because it is not commonly reported with a non-dilated presentation [1]. Associations represent reported patterns rather than deterministic or diagnostic relationships. Abbreviations: ACM, arrhythmogenic cardiomyopathy; CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; DES, desmin; DMD,…

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  Figure 1. Index case: taxonomic divergence in a single patient. A 39-year-old man with a family history of premature sudden cardiac death, NSVT with right bundle branch block morphology, a non-dilated LV, mildly reduced LVEF (43%), regional inferolateral wall motion abnormalities, subepicardial basal inferior and inferolateral LGE, preserved RV structure and function, and a pathogenic DES variant is classified differently across four major frameworks. (A) ESC 2023 [1]: NDLVC with systolic dysfunction based on non-ischemic LV scarring in the absence of LV dilatation or an alternative loading or ischemic cause. (B) Padua Criteria [2,3]: Left-dominant arrhythmogenic left ventricular cardiomyopathy (ALVC), supported by LV morpho-functional, tissue characterization, arrhythmic, and genetic criteria. (C) AHA 2006 [5]: Primary cardiomyopathy of genetic etiology without a fitting phenotypic category for this non-dilated, non-hypertrophic presentation. (D) HRS 2019 [4]: Left-dominant arrhythmogenic cardiomyopathy within the broader ACM spectrum. Abbreviations: ACM, arrhythmogenic cardiomyopathy; AHA, American Heart Association; ALVC, arrhythmogenic left ventricular cardiomyopathy; CAD, coronary…

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  Figure 2. Classification frameworks over time and their respective vantage points. Seven frameworks are shown in chronological order: the 1995 WHO/ISFC definition, the 2006 AHA Scientific Statement, the 2008 ESC morpho-functional classification, the 2016 ESC Position Statement, the 2019 HRS consensus, the 2020 Padua Criteria with their 2023 European Task Force refinement, and the 2023 ESC Guidelines. For each framework, the upper card summarizes the perspective it contributes, whereas the lower card summarizes the question that remains open; these residual uncertainties reflect current gaps in evidence rather than contradictions between systems. Classification schemes specific to hypertrophic cardiomyopathy are deliberately not considered here, as they lie outside of the scope of this review, which concerns the non-dilated, non-hypertrophic left ventricular phenotype. Abbreviations: ACM, arrhythmogenic cardiomyopathy; AHA, American Heart Association; ALVC, arrhythmogenic left ventricular cardiomyopathy; DCM, dilated cardiomyopathy; ESC, European Society of Cardiology; HNDC, hypokinetic non-dilated cardiomyopathy; HRS, Heart Rhythm Society; LV, left ventricle; NDLVC, non-dilated left…

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  Figure 3. Phenotypes of the 2008 and 2023 ESC classifications. The two overlapping circles represent the phenotypes of each classification. Four phenotypes lie in the intersection and are shared by both: hypertrophic, dilated and restrictive cardiomyopathy, and arrhythmogenic right ventricular cardiomyopathy. The two classifications differ in one category each, shown in the non-overlapping regions. The 2008 classification included an unclassified group comprising left ventricular non-compaction and takotsubo syndrome, which the 2023 Guidelines no longer retain as a distinct phenotype, non-compaction being regarded as a morphological trait that may accompany other phenotypes rather than a phenotype in itself. Conversely, the non-dilated left ventricular phenotype introduced in 2023, highlighted in amber, had no counterpart in 2008: a patient with this presentation could only be assigned to the unclassified group or left outside of the classification altogether. Abbreviations: ARVC, arrhythmogenic right ventricular cardiomyopathy; DCM, dilated cardiomyopathy; ESC, European Society of Cardiology; HCM, hypertrophic cardiomyopathy; LV, left ventricular; NDLVC, non-dilated left ventricular…

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  Figure 4. Phenotypic classification of a patient with non-ischemic LV scarring without dilatation. A 52-year-old man with preserved LVEF (~58%), a non-dilated LV of normal wall thickness, no regional wall motion abnormalities, normal RV, limited focal subepicardial inferolateral LGE, and NSVT with RBBB morphology, with negative genetic testing and no history of myocarditis. (A) 2023 ESC Guidelines [1]: NDLVC, based on non-ischemic LV scarring in the absence of LV dilatation. (B) 2008 ESC classification [7]: No corresponding phenotype. (C) 2006 AHA classification [5]: No specific phenotypic category for this presentation. (D) Padua Criteria and subsequent European Task Force revision [2,3]: Criteria insufficient for a definite diagnosis of ALVC/ACM; under the 2020 Padua Criteria, a pathogenic ACM gene variant is required in the absence of RV involvement, whereas the subsequent European Task Force revision no longer requires a pathogenic variant but the available structural and arrhythmic criteria remain insufficient for a definite diagnosis. This case illustrates how NDLVC may capture a myocardial phenotype that remains unclassified or incompletely classified by previous frameworks.…

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  Figure 8. From the NDLVC phenotype to a probable biological trajectory. Proposed conceptual framework illustrating how integration of genotype, multiparametric CMR tissue characterization, including LGE pattern and burden, native T1, T2, and ECV mapping, longitudinal left ventricular remodeling, right ventricular involvement, and arrhythmic phenotype may estimate the most probable biological trajectory of patients presenting with NDLVC. Alternative and potentially reversible secondary causes should be considered and excluded when clinically appropriate before attributing the phenotype to a primary cardiomyopathy. The integrated assessment yields a probability-weighted assignment, that is, a qualitative judgement of which trajectory a given patient is most likely to be following, which serves as a first approximation of the conceptual trajectory rather than a calculated probability. Three conceptual trajectories are proposed, evolving DCM, evolving arrhythmogenic cardiomyopathy, and stable NDLVC, each associated with different follow-up priorities. Within the arrhythmogenic trajectory, the associated late gadolinium enhancement pattern differs by genotype, being subepicardial or ring-like…