Abstract
Background
Disease‐causative variants in LMNA‐encoded lamin A/C cause a genetic cardiomyopathy characterized by atrioventricular block, atrial fibrillation, ventricular arrhythmias, and systolic dysfunction. The influence of LMNA variant type/localization on late gadolinium enhancement (LGE) patterns and clinical outcomes remains unclear.
Methods
Retrospective analysis of 822 genotype‐positive patients with arrhythmogenic/dilated cardiomyopathy was used to identify those with disease‐causative variants in LMNA. Data on LGE distribution and prevalence of advanced heart failure, thromboembolic and sudden cardiac death/major ventricular arrhythmia events were extracted from the electronic record and analyzed by variant type/localization.
Results
Among the 72/116 (62%) LMNA variant‐positive patients with cardiac magnetic resonance imaging data, LGE was observed in 40/72 (56%) cases. Most exhibited a nonischemic, midmyocardial or subepicardial pattern (73%), and 6/40 (15%) showed a unique “pseudo‐infarct” transmural pattern, predominantly affecting the apical segments. All 6 patients with this distinct LGE pattern harbored C‐terminal IgD (immunoglobulin‐like domain) variants (p.Arg471His or p.Arg541His). In patients with clinically manifest disease (76/116), those with IgD‐localizing variants had a lower prevalence of atrioventricular block (25% versus 72%, P=0.002) and atrial fibrillation (50% versus 81%, P=0.019) but higher rates of thromboembolic events (42% versus 16%, P=0.038). During a median follow‐up of 37 months, IgD variant presence independently predicted sudden cardiac death/major ventricular arrhythmia (hazard ratio, 2.391 [95% CI, 1.046–5.464]; P=0.039).
Conclusions
LMNA missense variants localizing to IgD present a distinct apical pseudo‐infarct LGE pattern associated with increased risk of ventricular arrhythmias and thromboembolic events but reduced atrioventricular block and atrial fibrillation. Multicenter studies are warranted to develop variant‐specific risk‐stratification strategies in cardiac laminopathy.
Keywords: arrhythmogenic cardiomyopathy, genotype–phenotype correlation, laminopathy
Subject Categories: Arrhythmias, Genetics, Precision Medicine, Cardiomyopathy
Nonstandard Abbreviations and Acronyms
- IgD
immunoglobulin‐like domain
- LGE
late gadolinium enhancement
- MVA
major ventricular arrhythmias
- SCD
sudden cardiac death
- VA
ventricular arrhythmias
CLINICAL PERSPECTIVE.
What Is New?
Cardiac laminopathy patients harboring disease‐causative missense variants involving the IgD (immunoglobulin‐like domain) often present with a distinct apical pseudo‐infarct variant characterized by transmural fibrosis and apical aneurysm.
IgD‐localizing LMNA missense variants conferred an increased risk of major ventricular arrhythmias and thromboembolic events; the increased thromboembolic risk is likely related to a higher propensity for apical left ventricular thrombus formation, despite a reduced prevalence of atrial fibrillation.
What Are the Clinical Implications?
IgD‐localizing LMNA missense variants are associated with an increased risk of stroke/thromboembolism and major ventricular arrhythmias/sudden cardiac death; patients with cardiac laminopathy caused by IgD‐localizing LMNA missense variants may benefit from an individualized approach that involves serial cardiac magnetic resonance imaging monitoring, lower threshold for use of primary prevention implantable cardioverter‐defibrillators, and consideration of prophylactic anticoagulation once transmural apical fibrosis/apical aneurysm is detected.
The increased risk of major ventricular arrhythmia events observed in cardiac laminopathy patients with IgD‐localizing LMNA missense variants is not accounted for in current LMNA‐specific ventricular arrhythmia risk calculators and should prompt consideration of a revised variant‐specific LMNA risk score that accounts for higher risk IgD‐localizing missense variants.
LMNA‐encoded lamin A and C are nuclear intermediate filament proteins that ensure mechanical stability of the nuclear envelope and modulate gene expression through effects on chromatin organization and cell signaling. 1 Structurally, these proteins are characterized grossly by 3 domains: an N‐terminal head domain, a central a‐helical rod domain that contains 4 distinct coiled‐coil domains and C‐terminal tail domain that contains an IgD (immunoglobulin‐like domain) thought to enhance the flexibility of lamin A/C allowing it to bind other substrates during mechanical stress. 1 , 2
Disease‐causative variants in LMNA‐encoded lamin A/C cause a genetic cardiomyopathy characterized clinically by conduction disease, atrial arrhythmias, ventricular arrhythmias (VAs), and ventricular systolic dysfunction. 3 Prior studies have shown that missense variants largely result in protein misfolding and the accumulation of abnormal protein aggregates that impede the integrity of wild‐type proteins resulting in a dominant negative effect. 4 In contrast, frameshift variants tend to result in generation of a truncated product leading to haploinsufficiency. 4 However, how these divergent mechanisms both lead to similar clinical phenotypes is not well understood.
Clinically, the presence of nonsustained ventricular tachycardia, a left ventricular (LV) ejection fraction <45%, male sex, and nonmissense (ie, frameshift, nonsense, etc.) variants have been associated with an increased risk for major VA (MVA) events and are incorporated into a LMNA‐specific score card that aids in the selection of LMNA variant‐positive patients who would derive the greatest benefit from implantation of a primary prevention implantable cardioverter‐defibrillator (ICD). 4 , 5 Furthermore, late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (cMRI) is associated with an increased risk of MVA events. 6 Typically, fibrotic involvement in cardiac laminopathy presents with LGE predominantly involving the midmyocardium of the interventricular septum. 6 However, a small case series showed that patients with disease‐causative variants involving the p.Arg541 residue in the C‐terminal IgD of lamin A/C have a unique transmural LGE pattern 7 and additional studies have described the presence of an apical LV aneurysm in the absence of atrioventricular block in p.Arg541 variant‐positive patients. 7 , 8 , 9
Whether LMNA missense variants residing outside the p.Arg541 “hotspot” result in variant‐ or domain‐specific LGE patterns and clinical outcomes remains poorly understood and were the aims of the current study in a large single‐center cohort of patients with cardiac laminopathy.
METHODS
In this institutional review board‐approved single‐center study, a retrospective analysis of 822 patients with genotype‐positive arrhythmogenic cardiomyopathy and dilated cardiomyopathy evaluated between January 2015 and June 2024 was performed to identify all patients with a disease‐causative variant in LMNA‐encoded lamin A/C. All subjects provided informed consent for participation in the study. Dilated cardiomyopathy was defined as the presence of LV systolic dysfunction (LV ejection fraction ≤50%) accompanied by LV dilation, indicated by an LV end‐diastolic diameter or LV end‐diastolic volume >2 SDs above the normal range, adjusted for age and body surface area. In adults, LV end‐diastolic diameter >58 mm in men and >52 in women, and an LV end‐diastolic volume index of ≥75 mL/m2 in men and ≥62 mL/m2 in women in the absence of either pressure or volume overload or significant coronary artery disease, met criteria for LV end‐diastolic volume enlargement. 5 According to 2023 European Society for Cardiology guidelines for the management of cardiomyopathies, we distinguished the phenotype as dilated cardiomyopathy or nondilated LV cardiomyopathy. 5 Arrhythmogenic cardiomyopathy with LV involvement was defined according to the Padua criteria as outlined in a recent international expert consensus statement. 10
In patients with available cMRI data, LGE images were acquired in the same views using segmented T1‐weighted inversion‐recovery prepared gradient‐ inversion recovery pulse sequence, individually adjusting inversion time to optimize nulling of apparently normal myocardium. LGE imaging was performed beginning 8 to 10 minutes after the administration of 0.2 mmol/kg of gadobutrol (Gadavist, Bayer Heathcare LLC, Whippany, NJ). cMRI imaging was performed at 1.5T (Optima 450W or Artist, GE Healthcare, Milwaukee, WI; Aera, Siemens Healthineers, Erlangen, Germany). LGE presence was defined by the identification of areas of visually increased signal intensity confirmed in 2 orthogonal planes.
After reviewing the most recent cMRI exam available and retrospectively extracting the information from the clinical report, LGE distribution (visually classified as subepicardial, midmyocardial, subendocardial, or transmural), location (septal, free wall, or apical) patterns 11 and clinical outcomes were then analyzed by variant type (missense versus truncating) and missense variant localization (central rod domain versus tail domain). In addition, a focused analysis was performed on the subset of LMNA variant‐positive patients with available cMRI data to evaluate LGE patterns and their associations with genotype and clinical features. Pertinent demographic, electrocardiographic, genetic, and imaging data were extracted from the electronic medical record. Detailed information regarding family history of cardiomyopathies and sudden cardiac death (SCD), with a ≥3 generation pedigree, were recorded. Atrioventricular block was defined as any degree of atrioventricular AV conduction block, including first‐, second‐, and third‐degree atrioventricular block, to capture the full spectrum of atrioventricular conduction system involvement.
Statistical Analysis
Summary statistics of clinical and instrumental variables were expressed as mean±SD, median and interquartile range, and counts and percentage, as appropriate. The comparison between groups was performed using the Student's t test for gaussian distributed continuous variables, or the nonparametric Mann–Whitney test for nongaussian continuous variables. The chi‐square or Fisher's exact tests were calculated for discrete variables. For categorical variables with small cell sizes (<5 events per group), Fisher's exact test was used to ensure robustness of statistical comparisons. A P value <0.05 was considered as statistically significant.
Univariable and multivariable Cox proportional hazards regression models were used to assess associations between candidate variables and the composite outcome. Variables with a P value <0.05 in univariable analysis were included in the multivariable model. The proportional hazards assumption was assessed using log‐minus‐log survival plots, and no violations were observed.
Analyses were conducted using IBM SPSS Statistics software (IBM Corp. Released 2021. IBM SPSS Statistics for Macintosh, Version 28.0. Armonk, NY).
Clinical outcomes were extracted from health records by a clinical expert. SCD/MVA were selected as study end points and assessed retrospectively. Advanced heart failure events and prevalence of thromboembolic events were also analyzed. Advanced heart failure events were defined as heart transplant or LV assist device implantation. SCD was defined as an unexpected death occurring usually within an hour of onset of symptoms, arising from an underlying cardiac disease. 12 MVA events were defined as successfully resuscitated ventricular fibrillation or ventricular tachycardia, sustained (>30 s) ventricular tachycardia causing hemodynamic instability, or appropriate ICD therapies, defined as shock or antitachycardia pacing for termination of sustained ventricular tachycardia or ventricular fibrillation. Thromboembolic events were defined by embolic stroke or LV thrombi requiring anticoagulation. The data, methods used in the analysis, and materials used to conduct this research are not publicly available due to privacy and ethical restrictions. We followed the Strengthening the Reporting of Observational Studies in Epidemiologycohort reporting guidelines for the design, conduct, and reporting of this study. 13
RESULTS
Overall, 116 LMNA variant‐positive patients (mean age 36±15, 43% male, 95% White, 76 [66%] with an overt cardiac phenotype, 64 [55%] with missense variants, 52 [45%] with truncating variants, and 47 [41%] probands) were identified.
cMRI Findings, LGE Distribution, and Associated Clinical Features
Among the 72/116 (62%) patients with available cMRI data, LGE (subendocardial in 5 [7%], mid‐myocardial in 36 [50%], subepicardial in 13 [18%], transmural in 7 [10%], apical in 10 [14%], septal in 33 [46%], and free wall in 25 [35%]) was observed in 40/72 (56%) of the cases (Figure 1). Among these 40 LMNA variant‐positive patients with LGE on cMRI, a nonischemic midmyocardial or subepicardial (29/40, 73%) delayed enhancement pattern was observed most frequently (Figure 1B and 1C). However, 6/40 (15%) patients had a unique “pseudo‐infarct” transmural LGE pattern involving the apical segments and to varying degrees the free wall, with 1 out of 6 patients also having a basal septal midwall LGE (6/6 with LGE >15%) (Figure 1D through 1G).
Figure 1. Late gadolinium enhancement patterns observed in cardiac laminopathy patients.
A, Schematic/illustrative summary of regional myocardial fibrosis distribution by anatomic location and myocardial layer observed as detected by cMRI in pathogenic/likely pathogenic LMNA variant‐positive patients in our cohort. B, C, p.Tyr211Cys‐LMNA‐positive patient, cMRI showing midmyocardial septal LGE (yellow arrow) in the 4‐chamber (B) and midventricular short‐axis (C) postcontrast images. D–G, p.Arg471His‐LMNA‐positive patient, on baseline cMRI apical aneurism and LV thrombus (yellow arrow) on 4‐chamber (D) and apical short‐axis (E) views. At follow‐up cMRI after initiation of anticoagulation therapy, evidence of clear extensive transmural LGE involving the apex and the free wall at 4‐chamber (F) and apical short‐axis (G) postcontrast images. cMRI indicates cardiac magnetic resonance imaging; LGE, late gadolinium enhancement; and LV, left ventricular.
Interestingly, in comparison to all LMNA variant‐positive patients with cMRI data, LMNA variant‐positive patients with this distinct apical transmural LGE pattern were more likely to be male (5 [83%] versus 26 [39%], P=0.049), have a higher LV end‐diastolic volume (232±66 mL versus 150±62 mL, P=0.003), lower LV ejection fraction (35±8 versus 50±15%, P=0.014) and more likely to experience thromboembolic events (3 [50%] versus 5 [8%], P value=0.016) (Table 1). Moreover, LMNA variant‐positive patients with apical transmural LGE pattern were also less likely to have atrioventricular block (0 versus 35 [57%], P=0.019) (Table 1).
Table 1.
Baseline Characteristic of the LMNA Variant‐Positive Patients With Cardiac Magnetic Resonance Data Comparing Those With an Apical Pseudo‐Infarct Transmural LGE Pattern to Those Without
| Total 72 | Apical “pseudo‐infarct” LGE Present 6 | Apical “pseudo‐infarct” LGE Absent 66 | P value | |
|---|---|---|---|---|
| Male sex, n (%) | 31 (43) | 5 (83) | 26 (39) | 0.049 |
| Age, y | 36±15 | 40±17 | 36±15 | 0.471 |
| White race, n (%) | 68 (95) | 6 (100) | 62 (94) | 0.825 |
| Family history of sudden cardiac death, n (%) | 43 (60) | 4 (67) | 39 (59) | 0.538 |
| IgD‐localizing variants, n (%) | 10 (14) | 6 (100) | 4 (6) | <0.001 |
| Non‐IgD‐localizing variants, n (%) | 62 (86) | 0 (0) | 62 (94) | <0.001 |
| Family history of cardiomyopathy, n (%) | 55 (76) | 4 (67) | 51 (77) | 0.436 |
| History of syncope, n (%) | 15 (21) | 2 (33) | 13 (20) | 0.366 |
| Dilated cardiomyopathy, n (%) | 16 (22) | 4 (67) | 12 (19) | 0.006 |
| Nondilated LV cardiomyopathy, n (%) | 35 (49) | 2 (33) | 33 (50) | 0.434 |
| History of thromboembolic event, n (%) | 8 (11) | 3 (50) | 5 (8) | 0.016 |
| Advanced heart failure, n (%) | 5 (7) | 0 (0) | 5 (8) | 0.639 |
| Atrial fibrillation, n (%) | 38 (53) | 2 (33) | 36 (55) | 0.285 |
| Implantable cardioverter‐defibrillator, n (%) | 42 (58) | 5 (83) | 37 (56) | 0.197 |
| Atrioventricular blocks, n (%) | 36 (53) | 0 (0) | 36 (57) | 0.019 |
| Left bundle‐branch block, n (%) | 5 (7) | 1 (17) | 4 (6) | 0.375 |
| LV ejection fraction, % | 49±14 | 35±8 | 50±15 | 0.014 |
| LV end‐diastolic volume, ml | 157±66 | 232±66 | 150±62 | 0.003 |
IgD indicates immunoglobulin‐like domain; and LV, left ventricular.
Given the potential association between the apical transmural LGE pattern and a ventricular‐predominant clinical phenotype, we sought to determine if specific LMNA genetic variant(s), or variants localizing to a distinct region(s) of the lamin A/C protein, were more likely to generate a transmural LGE pattern by correlating these variants and their predominant associated LGE pattern with the major protein domains (tail and central rod) and by mapping their fibrotic phenotype on the linear structure of lamin. (Figure 2A). Interestingly, a “pseudo‐infarct” transmural LGE pattern was more common in patients harboring missense variant localizing to the C‐terminal tail region of lamin A/C, compared with missense variant localizing to the central rod and nonmissense variants (P<0.001) (Figure 2B).
Figure 2. Relationship between variant localization and predominant late gadolinium enhancement patterns in patients with cardiac laminopathy.
A, Schematic depicting the location of disease‐causative LMNA variants on the linear topology of lamin A and predominant LGE pattern observed on cMRI. B, Bar graph comparing the prevalence of the apical transmural “pseudo‐infarct” LGE pattern in the LGE positive patients (n=40) with disease‐causative LMNA missense variants localizing to the C‐terminal tail domain (n=8/40), N‐terminal central rod domain (n=15/40), and those with nonmissense variants (n=17/40). cMRI indicates cardiac magnetic resonance imaging; and LGE, late gadolinium enhancement.
In particular, a higher prevalence of transmural (6 [60%] versus 1 [2%]; P≤0.001) and apical involvement (7 [70%] versus 3 [5%]; P<0.001) was observed in patients with missense variants localizing to the C‐terminal IgD (n=10) when compared with those with other variants localizing outside the IgD (n=62: Table 2). Furthermore, the presence of a distinct apical‐predominant pseudo‐infarct LGE pattern (n=6) appeared to be restricted to patients harboring 2 specific variants involving arginine residues in the C‐terminal IgD, p.Arg471His‐LMNA (n=5) and p.Arg541His‐LMNA (n=1) (Figure 2B).
Table 2.
Baseline Characteristic of the LMNA Variant‐Positive Patients With Cardiac Magnetic Resonance Imaging Data Comparing Those With IgD‐Localizing Missense Variants to All Other Variants
| Total 72 | IgD‐localizing missense variants 10 | Other disease causative variants 62 | P value | |
|---|---|---|---|---|
| Male sex, n (%) | 31 (43) | 5 (50) | 26 (42) | 0.736 |
| Age, y | 36±15 | 36±14 | 36±15 | 0.94 |
| White race, n (%) | 68 (95) | 10 (100) | 58 (94) | 0.711 |
| Family history of sudden cardiac death, n (%) | 43 (60) | 6 (60) | 37 (60) | 0.633 |
| Family history of cardiomyopathy, n (%) | 55 (76) | 7 (70) | 48 (77) | 0.608 |
| History of syncope, n (%) | 15 (21) | 2 (20) | 13 (21) | 0.656 |
| Dilated cardiomyopathy, n (%) | 16 (22) | 6 (60) | 10 (16) | 0.002 |
| Nondilated LV cardiomyopathy, n (%) | 35 (49) | 2 (20) | 33 (53) | 0.052 |
| History of thromboembolic event, n (%) | 8 (11) | 3 (30) | 5 (8) | 0.042 |
| Advanced heart failure, n (%) | 5 (7) | 0 (0) | 5 (8) | 0.462 |
| Atrial fibrillation, n (%) | 38 (53) | 4 (40) | 34 (55) | 0.298 |
| Atrioventricular blocks, n (%) | 36 (53) | 2 (20) | 34 (55) | 0.049 |
| LV ejection fraction, (%) | 49±14 | 42±13 | 50±15 | 0.115 |
| LV end‐diastolic volume, (ml) | 157±66 | 214±66 | 149±62 | 0.009 |
| Presence of LGE, n (%) | 40 (56) | 8 (80) | 32 (52) | 0.096 |
| Subendocardial LGE, n (%) | 5 (7) | 1 (10) | 4 (7) | 0.538 |
| Midmyocardial LGE, n (%) | 36 (50) | 5 (50) | 31 (50) | 0.633 |
| Subepicardial LGE, n (%) | 13 (18) | 2 (20) | 11 (18) | 0.578 |
| Transmural LGE, n (%) | 7 (10) | 6 (60) | 1 (2) | <0.001 |
| Apical LGE, n (%) | 10 (14) | 7 (70) | 3 (5) | <0.001 |
| Septal LGE, n (%) | 33 (46) | 6 (60) | 27 (44) | 0.336 |
| Free wall, n (%) | 25 (35) | 8 (80) | 17 (27) | 0.002 |
IgD indicates immunoglobulin‐like domain; LGE, late gadolinium enhancement; and LV, left ventricular.
Given these observations, we sought to determine if missense variants such as p.Arg471His‐LMNA and p.Arg541His‐LMNA that localize to the C‐terminal IgD of lamin A/C are associated with differential phenotypic manifestations and clinical outcomes in comparison to patients with cardiac laminopathy with nonmissense variants and missense variants localizing outside the IgD within our larger LMNA variant‐positive cohort.
Among the 76/116 (66%) of patients with overt structural phenotype (Table 3), the 12 patients with disease‐causative variants localizing to the IgD of lamin A/C (p.Arg471His‐LMNA [n=6], p.Ile497Thr‐LMNA [n=1], p.Arg541His‐LMNA [n=3], and p.Arg453Trp‐LMNA [n=2]) had an increased prevalence of thromboembolic events (5 [42%] versus 10 [16%], P=0.038) despite a reduced prevalence of AF (6 [50%] versus 52 [81%], P=0.019). No differences in advanced heart failure events were found.
Table 3.
Baseline Characteristic of the LMNA Variant‐Positive Patients With Overt Structural Phenotype, Comparing Those IgD‐Localizing Missense Variants to Those With All Other Variant Types
| Total 76 | IgD‐localizing missense variants 12 | Other disease causative variants 64 | P value | |
|---|---|---|---|---|
| Male sex, n (%) | 31 (41) | 5 (42) | 26 (41) | 0.946 |
| Age, y | 42±13 | 37±12 | 43±13 | 0.186 |
| White race, n (%) | 72 (95) | 11 (92) | 61 (95) | 0.052 |
| Family history of sudden cardiac death, n (%) | 42 (55) | 7 (58) | 35 (55) | 0.536 |
| Family history of cardiomyopathy, n (%) | 57 (75) | 9 (75) | 48 (75) | 0.626 |
| History of syncope, n (%) | 25 (33) | 4 (33) | 21 (33) | 0.607 |
| Dilated cardiomyopathy, n (%) | 28 (37) | 8 (67) | 20 (21) | 0.020 |
| Nondilated LV cardiomyopathy, n (%) | 48 (63) | 4 (33) | 44 (69) | 0.020 |
| History of thromboembolic events, n (%) | 15 (20) | 5 (42) | 10 (16) | 0.038 |
| Advanced heart failure, n (%) | 15 (20) | 1 (8) | 14 (22) | 0.258 |
| Atrial fibrillation, n (%) | 58 (76) | 6 (50) | 52 (81) | 0.019 |
| Inferior T negative waves, n (%) | 11 (17) | 5 (46) | 6 (11) | 0.005 |
| Lateral T negative waves, n (%) | 9 (14) | 4 (36) | 5 (9) | 0.036 |
| Anterior T negative waves, n (%) | 6 (9) | 2 (18) | 4 (7) | 0.260 |
| Atrioventricular blocks, n (%) | 49 (65) | 3 (25) | 46 (72) | 0.002 |
| Implantable cardioverter‐defibrillator, n (%) | 64 (84) | 10 (83) | 54 (84) | 0.606 |
| LV ejection fraction, (%) | 41±15 | 38±10 | 42±16 | 0.435 |
| LV end‐diastolic diameter, mm | 55±8 | 58±9 | 55±7 | 0.155 |
IgD indicates immunoglobulin‐like domain; and LV, left ventricular.
Furthermore, this group of patients showed an increased prevalence of LV thrombi (2 [17%] versus 0, P<0.001) and inferior and lateral T wave inversions (5 [46%] versus 6 [11%], P=0.005 and 4 [36%] versus 5 [9%], P=0.036, respectively), and a reduced prevalence of atrioventricular block (3 [25%] versus 46 [72%], P=0.002) (Figure 3, Table 3).
Figure 3. Common 12‐lead ECG patterns observed in patients with LMNA‐related cardiomyopathy‐causative missense variants.
A, Baseline ECG of a p.Arg471His‐LMNA‐positive patient showing normal PR interval and negative T waves in the anterolateral leads, II and aVF (blue arrows). B, Baseline ECG of a p.Arg72Leu‐LMNA‐positive patient showing long PR interval (blue arrows).VT, ventricular tachycardia.
Univariable and Multivariable Predictors of SCD/MVA in Cardiac Laminopathy
Univariable and multivariable Cox regression analyses in the overall population are shown in Table 4. Over a median follow‐up of 37 (interquartile range, 5–106) months, the study outcome of SCD/MVA occurred in 40 patients (35%). The presence of IgD‐localizing disease‐causative variants was independently associated to the study outcome in the overall population in univariate (hazard ratio [HR], 3.066 [95% CI, 1.349–6.968]; P=0.015) and multivariate analysis (HR, 2.391 [95% CI, 1.046–5.464]; P=0.039).
Table 4.
Univariable and Multivariable Analysis for the Composite Primary End Point of SCD/MVA in the Overall Population
| Univariable | Multivariable | |||
|---|---|---|---|---|
| HR (95% CI) | P value | HR (95% CI) | P value | |
| Male sex | 1.349 (0.715–2.547) | 0.358 | ||
| Immunoglobulin‐like domain‐localizing variants. | 3.066 (1.349–6.968) | 0.015 | 2.391 (1.046–5.464) | 0.039 |
| All other LMNA variants | 0.417 (0.125–1.387) | 0.179 | ||
| Missense variants | 0.727 (0.385–1.373) | 0.326 | ||
| Nonmissense variants | 0.838 (0.449–1.565) | 0.579 | ||
| Family history of SCD | 0.645 (0.343–1.212) | 0.173 | ||
| Family history of cardiomyopathy | 0.600 (0.302–1.191) | 0.159 | ||
| Left bundle‐branch block | 0.576 (0.176–1.885) | 0.325 | ||
| Atrial fibrillation | 2.434 (1.004–5.903) | 0.031 | 2.095 (0.807–5.438) | 0.129 |
| Nonsustained ventricular tachycardia | 4.315 (1.313–14.177) | 0.003 | 2.643 (0.767–9.108) | 0.124 |
| Atrioventricular blocks | 0.878 (0.449–1.717) | 0.706 | ||
| LV ejection fraction | 0.979 (0.960–0.998) | 0.035 | 0.979 (0.957–1.003) | 0.082 |
| LV end‐diastolic diameter | 1.034 (0.992–1.077) | 0.109 | ||
HR indicates hazard ratio; LV, left ventricular; MVA, major ventricular arrhythmias; and SCD, sudden cardiac death.
DISCUSSION
Over the past 2 decades, cMRI has emerged as a key imaging modality for the evaluation, risk stratification, and management of patients with an array of cardiomyopathies. Although LGE in nonischemic cardiomyopathies usually involves the subepicardium and the midmyocardium, transmural ischemic‐like patterns have been described. 14
The current study, which uses one of the largest single‐center cohorts of patients with cardiac laminopathy assembled to date, provides further evidence that an atypical LGE pattern characterized by the presence of transmural/near transmural LGE predominantly involving the apical and lateral left ventricular walls on cMRI is associated with disease‐causative LMNA missense variants, specifically p.Arg541His‐LMNA and p.Arg471His‐LMNA, that localize to the well‐characterized IgD within the C‐terminal tail of lamin A/C.
The distinct apical “pseudo‐infarct” LGE pattern/imaging phenotype was described previously in patients with cardiac laminopathy‐causative variants involving the p.Arg541 residue that localizes to the C‐terminal IgD of lamin A/C by Di Marco et al. and Wang et al. in 2 small case series. Interestingly, most of the patients with cardiac laminopathy‐causative variants involving the p.Arg541 residue in the reports by Di Marco et al. 15 and Wang et al. 7 appeared to follow a more malignant clinical course characterized by an increased burden of MVA events and lower prevalence of conduction disease akin to that observed in p.Arg541His‐LMNA‐ and p.Arg471His‐LMNA‐positive patients in the current study. 7 , 15
Furthermore, these observations are in line with the prior functional study by Al‐Saaidi et al. where the ratio of wild‐type to mutant lamin A/C in patient‐specific cultured skin fibroblasts was higher for p.Arg471Cys‐LMNA and p.Arg471His‐LMNA (50:50) than p.Arg216Cys‐LMNA (70:30). 4 In addition, p.Arg471Cys/His‐LMNA fibroblasts had a more pronounced increase in lamin C protein expression and resulting decreased/skewed lamin A to lamin C ratio than that observed in p.Arg216Cys‐LMNA and p.Arg321*‐LMNA fibroblasts. 4 , 16 Collectively, this led Al‐Saaidi et al. to conclude that the increased incorporation of mutant p.Arg471Cys/His‐LMNA into the nuclear envelope may lead to greater destabilization of the nucleus resulting in worse clinical outcomes. 4 Although Al‐Saaidi did not perform/report a statistical analysis of clinical outcomes between their p.Arg216Cys‐LMNA‐positive and p.Arg471Cys/His‐LMNA‐positive patients, p.Arg471Cys/His‐LMNA appeared to be associated with an increased risk of dilated cardiomyopathy (11/15 [65%] versus 12/36 [33%]) and SCD (3/15 [20%] versus 2/36 [6%]) and decreased prevalence of conduction disease (4/15 [24%] versus 17/36 [47%]). 4
As such, the current study coalesces and builds upon the findings of Al‐Saaidi et al., 4 Di Marco et al., 15 and Wang et al. 7 by providing compelling evidence that LMNA missense variants localizing to the C‐terminal IgD of lamin A/C, specifically those involving the p.Arg541 and p.Arg471 residues, result in a distinct LV predominant phenotype characterized clinically by a so‐called apical pseudo‐infarct LGE pattern on cMRI and a decreased prevalence of atrioventricular block/conduction disease and atrial fibrillation in comparison with the cardiac laminopathy with nonmissense variants and missense variants localizing to the central rod domain.
Importantly, this imaging “genotype–phenotype” association appears to carry prognostic significance for both stroke/thromboembolism and VA/SCD as IgD‐localizing LMNA missense variants conferred (1) an increased risk of thromboembolic events, likely related to an increased propensity for apical left ventricular thrombus formation, despite a reduced prevalence of atrial fibrillation and (2) an independent association with MVA events in both univariable and multivariable regression analyses. Of note, the increased SCD/MVA risk associated with cardiac laminopathy‐causative variants involving the p.Arg471 and p.Arg541 residues is likely to be downplayed/underestimated in the widely used LMNA genotype‐specific risk calculator developed by Wahbi et al. 17 that assigns increased risk to nonmissense/truncating (ie, frameshift, non‐sense, and splice) rather than missense LMNA variants. This is due, at least in part, to the fact that IgD‐localizing variants such as p.Arg471His‐LMNA and p.Arg541His‐LMNA are lumped together with and therefore diluted by lower risk/later onset central rod domain‐localizing missense variants such as p.Arg216Cys‐LMNA that are commonly observed in our cohort and other cardiac laminopathy cohorts.
Mechanistically, we hypothesize that the arginine residues, at positions 471 and 541, are likely to be critical for the normal function of the protein. In the specific cases of p.Arg471His and p.Arg541His, mutations in these positions could disrupt ionic interactions or the overall charge distribution within the protein since arginine is a positively charged amino acid and histidine has a partial positive charge and is less basic.
The study by Scharner et al. highlights that mutations in the C‐terminal IgD, which accounted for 16% of LMNA variants in their cohort—including those affecting conserved arginine residues—can disrupt the overall stability of the domain and its interactions with other nuclear proteins, potentially contributing to more severe disease phenotypes. 18 This change can disrupt the electrostatic interactions and hydrogen bonding that are critical for maintaining lamin structure with subsequent impairment of mechanotransduction and potential DNA‐protein interactions. Additionally, Mukherjee et al. demonstrated that mutations in the C‐terminal IgD, such as p.Arg453Trp‐LMNA, lead to significant changes in protein flexibility, supporting the critical role of arginine and of the IgD in maintaining the structural integrity of lamin A/C. 19
Collectively, impaired mechanical support of the cellular nucleus resulting from disease causative variants affecting the IgD of the protein may explain, at least in part, our finding of higher fibrosis burden with transmural LGE pattern especially in areas of mechanical stress such as the apical and lateral segments as observed in our patients.
However, the precise mechanisms by which LMNA missense variants involving p.Arg471, p.Arg541 and perhaps other residues in the IgD result in the distinct apical “pseudo‐infarct” transmural LGE pattern described in the current study remains unclear and requires further investigation. Interestingly, disruption of the LINC (linkers of nucleoskeleton to the cytoskeleton) complex, which mediates force transmission between the nucleus and cytoskeleton via genetic knockout of the SUN1‐encoded SUN1 (Sad1 and UNC84 domain containing 1) nuclear envelope protein or adeno‐associated virus serotype 9 transduction of a dominant‐negative SUN1 protein slows disease progression and results in a 5‐fold increase in the survival of LMNA conditional knockout and homozygous p.Asn195Lys‐LMNA mice. 20 As such, understanding how specific cardiac laminopathy‐causative LMNA variants differentially affect or maladaptively respond to force transmission between nucleus and cytoskeleton could help identify those patients who would derive the most substantive benefit from emerging therapies aimed at disrupting the LINC complex in cardiac laminopathy.
More immediately, patients with cardiac laminopathy with the IgD‐localizing p.Arg471His‐LMNA and p.Arg541His‐LMNA variants, characterized by extensive LV apical involvement, appear to be at increased risk for stroke/thromboembolic events despite a reduced prevalence of AF that appears to be secondary to a proclivity for developing apical LV thrombi. This raises the question whether stroke risk‐stratification and the use of chronic anticoagulation should be variant/region specific as the presence or absence of clinically or device‐documented AF does not appear to fully reflect the risk of thromboembolic events in cardiac laminopathy. In this light, it stands to reason that patients with disease‐causative variants in LMNA‐encoded lamin A/C involving the IgD would benefit from a more individualized approach that includes serial cMRI monitoring, potentially adoption of a lower threshold for use of primary prevention ICDs and initiation of chronic anticoagulation if there is extensive transmural apical LGE that may potentially give rise to or the presence of a left ventricular apical aneurysm.
Conclusions
In summary, disease‐causative LMNA missense variants that localize to lamin A/C's IgD within the C‐terminal tail region, specifically p.Arg471His‐LMNA and p.Arg541His‐LMNA, cause a distinct “apical variant” of LMNA‐related cardiomyopathy characterized clinically by the presence of an apical pseudo‐infarct LGE pattern on cMRI, inferolateral T‐wave inversions on 12‐lead ECG, increased risk of MVA and thromboembolic events and a decreased risk of high‐grade atrioventricular block and AF. Given the increased risk of MVA and thromboembolic events in this group of patients, a risk‐stratification approach that takes into consideration not only variant type (ie missense versus nonmissense/truncating), but potentially for LMNA missense variant‐positive patients domain, specifically the C‐terminal IgD fold, merits consideration and may lead to more individualized genotype‐guided care particularly as it pertains to ICD placement and chronic anticoagulation.
Limitations
Like many observational studies, the current study is affected inherently by the common bias of its retrospective design. Due to the retrospective nature of the study, the temporal relationship between cMRI findings and clinical events could not be uniformly established. Although the pseudo‐infarct LGE pattern was present before SCD/MVA or thromboembolic events in several patients, in others, cMRI was performed shortly after or at the time of the event. Additionally, although nonsustained ventricular tachycardia episodes are common in arrhythmogenic cardiomyopathy, variability in ICD programming strategies, which are difficult to track, summarize, and correct for, may influence the prognostic significance of device‐detected nonsustained ventricular tachycardia episodes and represents an inherent limitation of this study. Finally, the study is limited by being a single‐center study involving a relatively small population size and these findings ideally would be assessed/reproduced in the context of a larger multicenter cohort whose goal is to determine the role of region‐ or variant‐specific arrhythmic risk‐stratification/anticoagulation indications in cardiac laminopathy.
Sources of Funding
This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program (Michael J. Ackerman) and the Paul and Ruby Tsai and Family Fund for Hypertrophic Cardiomyopathy Research (Michael J. Ackerman and John R. Giudicessi).
Disclosures
Dr. Ackerman is a consultant for Abbott, BioMarin Pharmaceutical, Boston Scientific, Bristol Myers Squibb, Illumina, Invitae, Medtronic, Tenaya Therapeutics, and UpToDate. Dr. Ackerman and Mayo Clinic Ventures are involved in an equity/intellectual property/royalty relationship with AliveCor, Anumana, ARMGO Pharma, Prolaio, Solid Biosciences, and Thryv Therapeutics. However, none of these entities have contributed to this study in any manner. The other authors report no conflicts.
Dr. Giudicessi is a consultant for Avidity Biosciences, Citizen Health and Nuevocor Therapeutics. Dr. Giudicessi serves as the principal investigator for clinical trials sponsored by Tenaya Therapeutics. Dr. Giudicessi and/or Mayo Clinic are involved in an equity/intellectual property/royalty relationship with Prolaio.
This article was sent to Timothy C. Wong, MD, MS, Associate Editor, for review by expert referees, editorial decision, and final disposition.
For Sources of Funding and Disclosures, see page 11.
REFERENCES
- 1. Mounkes LC, Burke B, Stewart CL. The A‐type lamins: nuclear structural proteins as a focus for muscular dystrophy and cardiovascular diseases. Trends Cardiovasc Med. 2001;11:280–285. doi: 10.1016/s1050-1738(01)00126-8 [DOI] [PubMed] [Google Scholar]
- 2. Ahn J, Jo I, Kang S‐m, Hong S, Kim S, Jeong S, Kim Y‐H, Park B‐J, Ha N‐C. Structural basis for lamin assembly at the molecular level. Nat Commun. 2019;10:3757. doi: 10.1038/s41467-019-11684-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Nishiuchi S, Makiyama T, Aiba T, Nakajima K, Hirose S, Kohjitani H, Yamamoto Y, Harita T, Hayano M, Wuriyanghai Y, et al. Gene‐based risk stratification for cardiac disorders in LMNA mutation carriers. Circ Cardiovasc Genet. 2017;10:e001603. doi: 10.1161/circgenetics.116.001603 [DOI] [PubMed] [Google Scholar]
- 4. Al‐Saaidi RA, Rasmussen TB, Birkler RID, Palmfeldt J, Beqqali A, Pinto YM, Nissen PH, Baandrup U, Mølgaard H, Hey TM, et al. The clinical outcome of LMNA missense mutations can be associated with the amount of mutated protein in the nuclear envelope. Eur J Heart Fail. 2018;20:1404–1412. doi: 10.1002/ejhf.1241 [DOI] [PubMed] [Google Scholar]
- 5. Arbelo E, Protonotarios A, Gimeno JR, Arbustini E, Barriales‐Villa R, Basso C, Bezzina CR, Biagini E, Blom NA, de Boer RA, et al. 2023 ESC guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44:3503–3626. doi: 10.1093/eurheartj/ehad194 [DOI] [PubMed] [Google Scholar]
- 6. Peretto G, Barison A, Forleo C, Di Resta C, Esposito A, Aquaro GD, Scardapane A, Palmisano A, Emdin M, Resta N, et al. Late gadolinium enhancement role in arrhythmic risk stratification of patients with LMNA cardiomyopathy: results from a long‐term follow‐up multicentre study. EP Europace. 2020;22:1864–1872. doi: 10.1093/europace/euaa171 [DOI] [PubMed] [Google Scholar]
- 7. Wang S, Peng D. Case series: LMNA‐related dilated cardiomyopathy presents with reginal wall akinesis and transmural late gadolinium enhancement. ESC Heart Fail. 2020;7:3179–3183. doi: 10.1002/ehf2.12822 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Forissier JF, Bonne G, Bouchier C, Duboscq‐Bidot L, Richard P, Wisnewski C, Briault S, Moraine C, Dubourg O, Schwartz K, et al. Apical left ventricular aneurysm without atrio‐ventricular block due to a lamin a/C gene mutation. Eur J Heart Fail. 2003;5:821–825. doi: 10.1016/s1388-9842(03)00149-1 [DOI] [PubMed] [Google Scholar]
- 9. Hookana E, Junttila MJ, Särkioja T, Sormunen R, Niemelä M, Raatikainen MJ, Uusimaa P, Lizotte E, Peuhkurinen K, Brugada R, et al. Cardiac arrest and left ventricular fibrosis in a Finnish family with the lamin a/C mutation. J Cardiovasc Electrophysiol. 2008;19:743–747. doi: 10.1111/j.1540-8167.2007.01017.x [DOI] [PubMed] [Google Scholar]
- 10. Corrado D, Perazzolo Marra M, Zorzi A, Beffagna G, Cipriani A, Lazzari M, Migliore F, Pilichou K, Rampazzo A, Rigato I, et al. Diagnosis of arrhythmogenic cardiomyopathy: the Padua criteria. Int J Cardiol. 2020;319:106–114. doi: 10.1016/j.ijcard.2020.06.005 [DOI] [PubMed] [Google Scholar]
- 11. Castrichini M, De Luca A, De Angelis G, Neves R, Paldino A, Dal Ferro M, Barbati G, Medo K, Barison A, Grigoratos C, et al. Magnetic resonance imaging characterization and clinical outcomes of dilated and Arrhythmogenic left ventricular cardiomyopathies. J Am Coll Cardiol. 2024;83:1841–1851. doi: 10.1016/j.jacc.2024.02.041 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Gray B, Ackerman MJ, Semsarian C, Behr ER. Evaluation after sudden death in the young. Circ Arrhythm Electrophysiol. 2019;12:e007453. doi: 10.1161/CIRCEP.119.007453 [DOI] [PubMed] [Google Scholar]
- 13. von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J Clin Epidemiol. 2008;61:344–349. doi: 10.1016/j.jclinepi.2007.11.008 [DOI] [PubMed] [Google Scholar]
- 14. Aquaro GD, De Gori C, Faggioni L, Parisella ML, Cioni D, Lencioni R, Neri E. Diagnostic and prognostic role of late gadolinium enhancement in cardiomyopathies. Eur Heart J Suppl. 2023;25:C130–c136. doi: 10.1093/eurheartjsupp/suad015 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15. Di Marco A, Ruiz‐Cueto M, Salazar‐Mendiguchía J, Claver E, Roura G, Dallaglio PD, Anguera I. Genotype‐phenotype correlation of LMNA variants involving the Arg541 residue: a case report with multimodality imaging and literature review. ESC Heart Fail. 2020;7:3169–3173. doi: 10.1002/ehf2.12776 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16. Al‐Saaidi R, Rasmussen TB, Palmfeldt J, Nissen PH, Beqqali A, Hansen J, Pinto YM, Boesen T, Mogensen J, Bross P. The LMNA mutation p.Arg321Ter associated with dilated cardiomyopathy leads to reduced expression and a skewed ratio of lamin A and lamin C proteins. Exp Cell Res. 2013;319:3010–3019. doi: 10.1016/j.yexcr.2013.08.024 [DOI] [PubMed] [Google Scholar]
- 17. Wahbi K, Ben Yaou R, Gandjbakhch E, Anselme F, Gossios T, Lakdawala NK, Stalens C, Sacher F, Babuty D, Trochu JN, et al. Development and validation of a new risk prediction score for life‐threatening ventricular tachyarrhythmias in laminopathies. Circulation. 2019;140:293–302. doi: 10.1161/circulationaha.118.039410 [DOI] [PubMed] [Google Scholar]
- 18. Scharner J, Lu HC, Fraternali F, Ellis JA, Zammit PS. Mapping disease‐related missense mutations in the immunoglobulin‐like fold domain of lamin A/C reveals novel genotype‐phenotype associations for laminopathies. Proteins. 2014;82:904–915. doi: 10.1002/prot.24465 [DOI] [PubMed] [Google Scholar]
- 19. Mukherjee C, Sengupta D, Maganti L, Mahendar M, Bhattacharyya D, Sengupta K. Slower diffusion and anomalous association of R453W lamin A protein alter nuclear architecture in AD‐EDMD. RSC Adv. 2022;12:32129–32141. doi: 10.1039/d2ra05620h [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Chai RJ, Werner H, Li PY, Lee YL, Nyein KT, Solovei I, Luu TDA, Sharma B, Navasankari R, Maric M, et al. Disrupting the LINC complex by AAV mediated gene transduction prevents progression of lamin induced cardiomyopathy. Nat Commun. 2021;12:4722. doi: 10.1038/s41467-021-24849-4 [DOI] [PMC free article] [PubMed] [Google Scholar]