AIMS:To determine the prevalence of asymmetric septal hypertrophy(ASH) across health and in diseases associated with left ventricular hypertrophy(LVH), including hypertrophic cardiomyopathy(HCM). METHODS AND RESULTS:We analysed two complementary datasets. First, a large UK Biobank healthy reference cohort(n = 4,020) was used to model demographic determinants of septal-to-lateral wall thickness ratio(SLR) and to provide the reference group for age-, sex-, and body-surface area-adjusted comparisons. Second, a multi-cohort clinical CMR dataset included 1,655 subjects comprising local healthy volunteers, athletes, patients with hypertension, aortic stenosis, Fabry disease, AL amyloidosis, ATTR amyloidosis, and HCM. LVH was defined by maximum wall thickness(MWT) ≥ 15 mm and asymmetry defined as SLR≥1.3. Left ventricular morphology was classified as normal, asymmetric remodelling(SLR≥1.3;MWT<15 mm), symmetric hypertrophy(SLR<1.3;MWT≥15 mm) or ASH(SLR≥1.3;MWT≥15 mm). ASH was highly prevalent in HCM(61%) but was also observed in ATTR amyloidosis(37%), AS(26%), and AL amyloidosis(23%). In the healthy reference cohort, a higher septal-to-lateral ratio was independently associated with older age, female sex, and larger BSA(p < 0.001). After adjustment for these demographic factors, only HCM retained a clinically meaningful excess in septal asymmetry(ΔSLR=+0.27;p < 0.001). In contrast, the apparent asymmetry in non-HCM cohorts was partly explained by demographic variation. After adjustment, only HCM showed a clinically meaningful excess in SLR, whereas other disease cohorts showed either no material difference or small negative differences relative to healthy controls. CONCLUSION:ASH is a common but non-specific finding in diseases associated with LVH. Septal asymmetry increases with age and body-size and is more pronounced in women. After adjusting for age, sex, and body-size, disproportionate septal asymmetry was most characteristic of HCM.

BACKGROUND:Incidental findings are often found in imaging research, especially in older people (aged ≥75 years). Understanding their prevalence is essential to inform consent and disclosure protocols as well as anticipate onward investigation balanced against minimising unnecessary anxiety and health-care burden. The aim of this study was to determine the prevalence of incidental findings in a population-based sample of individuals aged 75-77 years using cardiovascular magnetic resonance (CMR) imaging and to inform duty-of-care frameworks for their reporting. METHODS:MyoFit46 was a prospective imaging cohort substudy of the National Survey of Health and Development (NSHD) study. Participants were prospectively recruited from the NSHD study, between May 18, 2020, and March 15, 2024, and underwent 3-Tesla contrast-enhanced CMR. An incidental finding was defined as a previously unknown abnormality that had not been identified by the participant or the research team before the study date. Incidental findings were classified into cardiac, non-cardiac, and clinical, and predefined according to the required urgency of follow-up as routine (reported to participants and their general practitioners within 28 days) or or immediate (reported within 48 hours). This study is registered with ClinicalTrials.gov, NCT05455125. FINDINGS:Of 505 participants prospectively recruited, 484 (96%) completed a full CMR scan. Of these, 432 (89%) had at least one incidental finding, including 58 (12%) immediate and 429 (89%) routine findings. Incidental findings were more common in male participants than in female participants (routine: 250 [92%] of 271 men vs 182 [85%] of 213 women, p=0·018; immediate: 39 [14%] of 271 men vs 19 [9%] of 213 women, p=0·069). The commonest routine cardiac incidental finding was late gadolinium enhancement (145 [43%] of 334 participants) and the commonest immediate cardiac finding was a left ventricular ejection fraction lower than 40% (seven [2%] of 334 participants). Non-cardiac incidental findings were predominantly routine (203 [42%] of 484) whereas immediate non-cardiac incidental findings were very uncommon (four [1%] of 484). Clinical findings were found in 201 (42%) of 484 participants, of which 28 (6%) were classified as immediate and 187 (39%) classified as routine. INTERPRETATION:CMR and baseline assessments revealed that incidental findings are common in imaging research in adults aged 75 years and older, underscoring the need for robust duty-of-care frameworks to ensure timely, ethical, and appropriate management of these findings in older age. These findings provide a population benchmark that can inform the design, governance, and resource planning of future large-scale imaging studies in ageing cohorts. FUNDING:British Heart Foundation and Medical Research Council.

AIMS:Assessing cardiac function is critical for managing cardiovascular disease, guiding treatment, monitoring progression, and risk stratification. While left ventricular (LV) ejection fraction (LVEF) is firmly established, it has limitations. Myocardial contraction fraction (MCF)-the ratio of stroke volume to myocardial volume, is simple to compute without additional analysis and offers a promising alternative to LVEF. METHODS AND RESULTS:MCF was assessed across four datasets spanning healthy controls and chronic structural cardiac disease, with direct comparison to LVEF. Association between age, sex, and MCF were investigated in 3541 healthy subjects from the UK Biobank and sex-specific reference ranges derived. Several cohorts were recruited to investigate the discriminative power of MCF and LVEF between health and physiological adaption (n = 278 veteran athletes), pathological hypertrophy [hypertrophic cardiomyopathy, amyloid, Fabry, severe aortic stenosis (AS), and hypertension (HTN); n = 633], and dilatation [n = 103 dilated cardiomyopathy (DCM)]. Ability to track disease severity was assessed by looking at 41 558 subjects from the UK Biobank. Finally, prognostication was assessed on 1277 consecutive patients from an independent external dataset. All images were analysed using the same validated artificial intelligence algorithm. MCF varied with sex (mean MCF: 0.94 male; 1.1 female) but not age. Sex-specific reference ranges were established: [0.68-1.20] for male and [0.82-1.38] for female. MCF decreased in pathological disease (e.g. mean MCF: 0.72 HCM; 0.69 severe AS; 0.5 amyloid; 0.9 HTN) but there was no significant decrease in LVEF other than in amyloid (mean EF: 76% HCM; 64% severe AS; amyloid 56%; 65% HTN). Both MCF and ejection fraction (EF) decreased in DCM (EF 34%; MCF 0.58). MCF decreased with worsening HTN, whereas LVEF increased (P < 0.05). MCF had superior prognostic ability to LVEF (MCF vs. LVEF: HR = 0.772 vs. HR = 0.816; χ2 = 198 vs. χ2 = 151; P < 0.001). CONCLUSION:We established MCF reference ranges, showing superior performance for detecting early disease and tracking progression compared with LVEF. MCF offers enhanced prognostic utility, complementing established metrics of LV function.

BACKGROUND:The presence of midwall septal fibrosis (MSF) in dilated cardiomyopathy (DCM) has been shown to be associated with adverse clinical outcomes, but the underlying pathophysiological mechanisms are incompletely understood. We investigated whether MSF associates with a distinct pattern of myocardial microstructural and microvascular abnormalities using advanced cardiovascular magnetic resonance (CMR). METHODS:This was a prospective, multi-referral, single-center study comparing the hearts of patients with a current or prior diagnosis of DCM with and without MSF ("MSF+"/"MSF-"), to a control cohort of a similar age and sex distribution. All underwent single-magnet 3 Tesla CMR, including cardiac diffusion tensor imaging (cDTI), quantitative rest perfusion, and multiparametric tissue characterization. Prespecified analyses compared DCM with controls, and MSF+ with MSF-; secondary analyses included regional septal and within-subject segmental comparisons. RESULTS:About 121 participants were studied: 34 MSF+ (51±14years; 74% male), 27 MSF- (48±15 years; 63% male), and 60 controls (45±13 years; 58% male). Compared with controls, the DCM cohort demonstrated increased mean diffusivity (MD) (1.49 v 1.43 ×10-3mm2/s, p<0.001) and reduced second eigenvector angle (E2A) (34.7 vs. 40.2°, p=0.001), consistent with microstructural abnormality, along with reduced resting myocardial blood flow (rMBF) (0.66 vs. 0.70 mL/g/min, p=0.045). Within the DCM cohort, MSF+ patients exhibited increased MD (1.51 vs. 1.46 ×10-3mm2/s, p=0.006) and decreased rMBF (0.64 vs. 0.71 mL/g/min, p=0.013) compared to MSF-. Septal analyses demonstrated increased MD, decreased E2A, decreased FA, and reduced rMBF in DCM. Within-patient comparisons showed decreased perfusion in fibrotic segments compared with non-fibrotic myocardium. In exploratory analyses, decreased rMBF was associated with greater ventricular ectopic burden. CONCLUSION:Midwall septal fibrosis in DCM identifies a distinct myocardial phenotype characterized by microstructural remodeling and impaired myocardial perfusion, with regional and segmental specificity. These findings provide mechanistic insight into the adverse prognostic associations of MSF and highlight a potential imaging-guided pathway for risk stratification and therapies.

Distinguishing the intrinsic electrophysiological remodeling of healthy cardiac aging from early pathology is a prerequisite for preventive cardiology in older adults, yet no population-scale 3D normative reference exists. Leveraging the life-course design of the MyoFit46 birth cohort, community-dwelling adults aged 75 + born within the same week of 1946, we combined cardiovascular magnetic resonance with 256-lead electrocardiographic imaging (ECGI) and a deterministic mapping framework to construct subject-specific digital twins (DTs) encoding myocardial conduction velocity, endocardial activation sequences, and regional repolarization heterogeneities. An aging repolarization layer was required in all 30 selected participants, demonstrating that standard adult cellular models do not reproduce the repolarization dynamics of healthy aging hearts and that explicit age-related ionic remodeling is systematically necessary. Population-level analysis revealed structured Purkinje-myocardial junction distributions consistent with classical anatomical landmarks, distinct apico-basal repolarization gradients, and sex-specific repolarization scaling reflecting age-related hormonal decline. The DTs replicated in vivo epicardial dynamics within established clinical ECGI uncertainties. As a proof-of-concept, the atlas was compared against an age-matched, non-fibrotic early-stage hypertensive group, identifying a directional shift toward action potential prolongation before overt structural disease. These findings establish the first normative electrophysiological DT atlas of the healthy aging heart for assessing pathological remodeling in older adults. *Jazmín Aguado-Sierra & Gabriella Captur are joint last authors.

Background: High blood pressure (BP) leads to coronary artery disease. Aim: We explored the impact of life-course BP, especially the steepness of BP increase and cumulative BP burden, on later-life stress myocardial blood flow (sMBF) and perfusion reserve (MPR) by cardiovascular magnetic resonance (CMR). Methods: MyoFit46 prospectively undertook stress perfusion and late gadolinium enhancement (LGE) CMR at age 76 in age-matched participants of the National Survey of Health and Development 1946 birth cohort. Myocardial perfusion was quantified as global sMBF normalized (sMBF N ) to contemporaneous rate pressure product (heart rate x central aortic BP) and MPR. Systolic (SBPs) and diastolic BPs (DBPs) were recorded at 36, 43, 53, 62, 69, and 76 years. For each participant, annual rates of BP change (steepness) and the area under the BP trajectory curve (AUC BP ; cumulative burden) were calculated using mixed-effect models. Participants were clustered by BP trajectory using latent class mixed models. Associations between BP and CMR metrics were tested using generalized models, adjusted for antihypertensive use, demographics, lifestyle, and comorbidities. Mediation analyses explored mechanistic pathways. Results: Among 459 participants (53% male), each 10mmHg SBP increase at 36, 43, 53, 62, and 69 years associated with a 3-6% lower sMBF N at 76. For midlife BPs (43-62 years), associations were independent of SBP at 76 and the decrease in sMBF N was steepest as SBPs rose from 120 to 140mmHg ( Figure 1 ). Having a sustained higher SBP by 10mmHg from 36 to 76 years associated with an 11% (95% CI: 8-14) lower sMBF N . Exemplar CMR perfusion maps based on AUC SBP are shown in Figure 2 . Each 1 mmHg/year steeper SBP rise during age intervals 36–43, 43–53, 53–62, and 62–69 was associated with a 2–5% lower sMBF N at age 76, independent of baseline or final BPs in each interval. sMBF N mediated 20-40% of the life-course SBPs and myocardial fibrosis by LGE associations. Results were similar for DBP, MPR, or unnormalized sMBF. Participants with the steepest BP rises from 36 to 53 years had the lowest myocardial perfusion at 76 ( Figure 3 ). Conclusion: Higher life-course BPs (even from age 36), steeper increases (regardless of final BP), and more years spent at higher BP levels associate with lower myocardial perfusion in older age. This underscores the importance of early-life BP screening, guiding treatment based on BP trajectories and cumulative burden, and rigorous midlife BP control.

BACKGROUND:Elevated blood pressure (BP) is a major contributor to coronary artery disease. We explored the impact of life-course BP on later-life normalized stress myocardial blood flow (sMBFN) and myocardial perfusion reserve by cardiovascular magnetic resonance (CMR). METHODS:MyoFit46 prospectively recruited ≈500 National Survey of Health and Development 1946 birth cohort participants, aged ≈77 years, to undergo stress perfusion and late gadolinium enhancement CMR. Systolic (SBPs) and diastolic BPs were recorded at 36, 43, 53, 63, 69, and 77 years. For each participant, the annual rates of BP change (steepness of BP increase) and area under the BP trajectory curve (cumulative life-course BP burden) were derived using mixed-effects models. The associations between BP measures and CMR metrics were tested using generalized linear and additive models, adjusted for antihypertensive use, demographics, lifestyle choices, and comorbidities. Cross-sectional associations between CMR metrics and major adverse cardiovascular events (myocardial infarction, stroke, and heart failure) were also tested. Mediation analyses explored the mechanistic pathways linking life-course BPs, myocardial perfusion, and myocardial fibrosis. RESULTS:Among 459 included MyoFit46 participants, each 10 mm Hg higher SBP at 36 to 69 years was associated with 3% to 6% lower sMBFN by CMR at 77 years. At 43 to 63 years, as SBPs rose from 120 to 140 mm Hg, sMBFN was 18% to 24% lower. Having a sustained higher SBP by 10 mm Hg from 36 to 77 years was associated with 11% (95% CI, 8-14) lower sMBFN at 77 years. Each 1 mm Hg/y steeper SBP rise during age intervals 36 to 43, 43 to 53, 53 to 63, and 63 to 69 years was associated with 2% to 6% lower sMBFN at 77 years, associations not conditional on baseline or final BPs in each age interval. Associations may be clinically relevant as each 1% lower sMBFN was associated with 3% higher odds of major adverse cardiovascular events. sMBFN mediated ≈20% to ≈40% of the associations between life-course SBPs and late gadolinium enhancement at 77 years. Results were similar for diastolic BP, myocardial perfusion reserve, or sMBF (not normalized). CONCLUSIONS:Higher life-course BPs, steeper increases, and greater cumulative BP burden associate with lower myocardial perfusion by CMR at 77 years, which can be linked with higher odds of major adverse cardiovascular events and greater myocardial fibrosis burden. This underscores the importance of early life BP screening and guiding hyperetension treatment based on longitudinal BP trajectories (rather than relying solely on cross-sectional BPs). REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05455125.

Background Aircraft noise is a growing concern for communities living near airports. Objectives This study aimed to explore the impact of aircraft noise on heart structure and function. Methods Nighttime aircraft noise levels (Lnight) and weighted 24-hour day-evening-night aircraft noise levels (Lden) were provided by the UK Civil Aviation Authority for 2011. Health data came from UK Biobank (UKB) participants living near 4 UK major airports (London Heathrow, London Gatwick, Manchester, and Birmingham) who had cardiovascular magnetic resonance (CMR) imaging starting from 2014 and self-reported no hearing difficulties. Generalized linear models investigated the associations between aircraft noise exposure and CMR metrics (derived using a validated convolutional neural network to ensure consistent image segmentations), after adjustment for demographic, socioeconomic, lifestyle, and environmental confounders. Mediation by cardiovascular risk factors was also explored. Downstream associations between CMR metrics and major adverse cardiac events (MACE) were tested in a separate prospective UKB subcohort (n = 21,360), to understand the potential clinical impact of any noise-associated heart remodeling. Results Of the 3,635 UKB participants included, 3% experienced higher Lnight (≥45 dB) and 8% higher Lden (≥50 dB). Participants exposed to higher Lnight had 7% (95% CI: 4%-10%) greater left ventricular (LV) mass and 4% (95% CI: 2%-5%) thicker LV walls with a normal septal-to-lateral wall thickness ratio. This concentric LV remodeling is relevant because a 7% greater LV mass associates with a 32% greater risk of MACE. They also had worse LV myocardial dynamics (eg, an 8% [95% CI: 4%-12%] lower global circumferential strain which associates with a 27% higher risk of MACE). Overall, a hypothetical individual experiencing the typical CMR abnormalities associated with a higher Lnight exposure may have a 4 times higher risk of MACE. Findings were clearest for Lnight but were broadly similar in analyses using Lden. Body mass index and hypertension appeared to mediate 10% to 50% of the observed associations. Participants who did not move home during follow-up and were continuously exposed to higher aircraft noise levels had the worst CMR phenotype. Conclusions Higher aircraft noise exposure associates with adverse LV remodeling, potentially due to noise increasing the risk of obesity and hypertension. Findings are consistent with the existing literature on aircraft noise and cardiovascular disease, and need to be considered by policymakers and the aviation industry.

BACKGROUND:Gestational diabetes mellitus (GDM) and preeclampsia are common complications of pregnancy, for which overweight/obesity is a common risk factor. Both conditions are associated with a two-to-four-fold increase in future incident heart failure, which may be linked to early maladaptive myocardial changes. OBJECTIVE:To determine maternal myocardial structural, functional, and energetic responses to pregnancies complicated by GDM or preeclampsia compared to healthy pregnancies (HP) at third-trimester of pregnancy and 12-months postpartum. STUDY DESIGN:Thirty-eight women with HP, 30 GDM, 20 preeclampsia, 10 nonpregnant controls with overweight (Overweight-NC), and 10 with normal-weight were recruited. Cardiovascular magnetic resonance spectroscopy and imaging were used to define myocardial energetics (phosphocreatine: ATP ratio [PCr/ATP]), left ventricular (LV) volumes, mass, and ejection fraction and global longitudinal shortening (GLS). Pregnancy groups underwent repeat scans 12-months postpartum, nulliparous-controls were assessed once. RESULTS:During third-trimester, compared to HP, women with either GDM or preeclampsia displayed higher BMI, higher LV-mass (HP: 90 [85, 94] g, GDM: 103 [96, 112], Preeclampsia: 118 [111, 125] g; P=.001) and lower PCr/ATP (HP: 2.2 [2.1, 2.4], GDM: 1.9 [1.7, 2], Preeclampsia: 1.9 [1.8, 2.1]; P=.0004) and GLS (HP: 20 [18, 21]%, GDM: 18 [17, 19]%, Preeclampsia: 16 [14, 17]%; P=.01). Post-pregnancy, no group saw significant changes in LV-mass, PCr/ATP, or GLS. There were no significant differences in LV-mass, PCr/ATP or GLS between the GDM and preeclampsia groups during or post-pregnancy. Moreover, the Overweight-NC showed no significant differences in LV-mass (53 [43, 63])g, PCr/ATP (2.0 [1.8, 2.2]), or GLS (-19 [17, 21]%) compared to GDM or preeclampsia groups during or post-pregnancy. CONCLUSION:Women with GDM or preeclampsia exhibit similar myocardial phenotypes during pregnancy with persistent subclinical alterations in LV mass, energetics, and GLS 12-months postpartum. These myocardial alterations are similar to those detected in Overweight-NC, potentially suggesting the myocardial changes may predominantly be driven by overweight/obesity.

BACKGROUND:Measurements of cardiac size and function drive clinical decisions. Left ventricular (LV) metrics can be derived from cardiac MR images by delineating the blood pool and myocardium, by either drawing a rounded contour to approximate the compacted myocardial border, or by delineating the papillary muscles and trabeculae (trabecular segmentation). There is no consensus as to which is best, particularly in the emergent AI era. We developed machine-learning (ML) approaches for both and compared them for clinically important metrics (error rate, precision, and prognosis). METHODS:Separate ML models were developed for rounded and trabecular segmentation, using U-net models trained on 1923 subjects (mixed pathology, multiple scanners, multiple centers). Blood and myocardial volumes for each segmentation method were compared on 4118 healthy UK biobank subjects. Model segmentation quality was evaluated subjectively on a real-world clinical dataset of 1594 consecutive CMR scans, with all scans included regardless of image quality and artifacts. Scan-rescan precision was measured on a multi-center, multi-disease dataset of 109 subjects scanned twice and compared to human performance. Finally, prognostication ability was evaluated on 1215 clinical patients, using a primary outcome of all-cause mortality and hospitalization with heart failure. RESULTS:Error rates (where a human disagreed by >1 mL) were the same, occurring in 0.6% (184/29680) of images and 3.6% (60/1594) of patients. In health, the mean EF was 4% higher for trabecular vs rounded segmentation. On test-retest data, there was no difference between rounded and trabecular ML models for precision, apart from end-diastolic and end-systolic volume, which was better for rounded segmentations. ML rounded and trabecular precision exceeded clinician performance for EF. There were marginal differences in prognostication between rounded and trabecular models. CONCLUSION:We developed an automated method for annotating papillary muscles and trabeculae from cardiac MR images with low error rates. We found higher precision than clinicians in ejection fraction. There was similar precision and prognostication to an ML rounded model with similarly low error rates. Findings support the feasibility of automated trabecular segmentation in clinical care and clinical trials.

Background Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden cardiac death. Current diagnosis emphasizes the detection of left ventricular hypertrophy (LVH) using a fixed threshold of ≥15-mm maximum wall thickness (MWT). This study proposes a method that considers individual demographics to adjust LVH thresholds as an alternative to a 1-size-fits-all approach. Methods Left ventricular MWT was measured in 3 cohorts: a Reference Cohort of healthy adults (n = 5,067, no comorbidities), a Population Cohort (n = 43,239, with comorbidities), and an HCM Cohort from 6 international centers (n = 2,424). Measurement used cardiovascular magnetic resonance (CMR) and a validated artificial intelligence algorithm. The Reference Cohort was used to developed demographically adjusted LVH thresholds, and individualized z-scores based on age, sex, and body surface area (BSA), which were used to explore the other cohorts. Results The traditional ≥15-mm threshold classified 4.3% (n = 1,854) of the Population Cohort as hypertrophic, with a significant sex skew (89% male). Demographic-adjusted LVH thresholds (range: 10-17 mm) reduced ascertainment to 2.2% (n = 945), reducing the sex skew (56% male). Similar reductions in bias with height, weight, and age also occurred. The HCM cohort was found to have a 2:1 male-to-female ratio. A significant proportion of patients received diagnoses of HCM despite having MWT below the traditional LVH threshold (<15 mm): 27% of female individuals and 18% of male individuals. Using demographic-adjusted LVH thresholds reduced these proportions to 7% of female individuals and 15% of male individuals (P < 0.0001). Female patients had lower absolute MWT (18 mm vs 19 mm; P < 0.001) but higher MWT z-scores (5.1 vs 4.5; P = 0.05). Conclusions Age, sex, and body size influence the normal heart MWT. Using a fixed LVH threshold ≥15 mm biases LVH ascertainment in both population and HCM cohorts. A demographic-adjusted approach for LVH improves ascertainment and diagnostic accuracy.

Introduction Truncating (nonsense) variants of the lamin gene (LMNA) are predicted to be more aggressive than missense variants, as are variants upstream as opposed to downstream of its nuclear localization signal (NLS). However, whether impaired myocardial mechanics in vivo is influenced by variant subtype or by their coding DNA location relative to the NLS is unknown. Moreover, whether mechanics is impaired in subclinical LMNA variant carriers is yet to be elucidated. Materials and Methods This multi-centre CMR study (NCT03860454) prospectively recruited 3 cohorts: patients with pathogenic LMNA variants (LMNA); patients with dilated cardiomyopathy but wild-type LMNA gene (DCMwt) and healthy volunteers (Controls). Left ventricular (LV) cines were analysed using 3D feature tracking strain in cvi42 and 3D cartesian coordinates for epi/endocardial meshes were exported. Shapes were reconstructed using generalized procrustes analysis in the size and shape space at homologous times. To compare myocardial mechanics between subjects, procrustes trajectory sizes (PTS) were calculated at each homologous time and for the overall cardiac cycle. Conventional strain metrics (longitudinal, radial, circumferential) were also derived. Results 187 were recruited: 67 LMNA (42% male, 42.1 ±15.2 years)-29 of which had good LV function (i.e., subclinical LMNA carriers); 73 DCMwt (53% male, 45.0 ±15.0 years); and 47 Controls (43% male, 44.1 ±20.2 years). As expected, in LMNA, principal strains were worse compared to Controls but better than in DCMwt (figure 1). Compared to the diastolic reference, LMNA truncating variant carriers had smaller PTS only during systole compared to splice and missense variant carriers suggesting poorer myocardial mechanics (figure 2A). Carriers of an LMNA variant upstream of the NLS had significantly worse myocardial mechanics compared to those with downstream variants (PTS across the whole cardiac cycle 0.16 vs 0.14, p = 0.024; figure 2B). Compared to Controls, subclinical LMNA carriers had smaller (worse) circumferential strain values at the base (by 7% 95% [CI]: [1–13], p=0.025), mid (by 8% [2–14], p=0.015), and apical segments (by 14% [7–20], p<0.001) (table 1). Discussion 4-Dimensional procrustes motion analysis of standard CMR cines provides unprecedented insights into myocardial deformation. Applied to lamin heart disease, it links the LMNA genetic landscape to deranged myocardial mechanics, with truncating variants and those upstream of the NLS emerging as particularly aggressive. Moreover, abnormal myocardial mechanics can be detected in subclinical LMNA carriers prior to any decline in ejection fraction. Conclusion In lamin heart disease, myocardial mechanics is impaired in subclinical gene carriers, and it is influenced by the variant subtype. Acknowledgements The authors would like to thank all the study participants for their participation and engagement in this study. Your contribution to science is extremely valued and appreciated. Authors are grateful to their funders: NIHR Rare Disease Translational Research Collaboration, Barts Charity (HeartOME project grant) and SCMR Seed Grant.