Topriceanu Constantin-Cristian, Al-Farih Mashael, Joy George, Chan Fiona, Webber Matt, Ilie-Ablachim Denis C, Shiwani Hunain, Tamang Mansoon, Banks Catherine, Pettit Stephen, Petersen Steffen E, O'Brien Ben, Hughes Alun D, Pierce Iain, Moody William E, Steeds Richard P, Puddu Paolo E, Kellman Peter, Savvatis Konstantinos, Mohiddin Saidi, Moon James C, Barison Andrea, Piras Paolo, Captur Gabriella
MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom; Cardiac MRI Unit, Barts Heart Centre, London, United Kingdom.
MRC Unit for Lifelong Health and Ageing, University College London, London, United Kingdom; Institute of Cardiovascular Science, University College London, London, United Kingdom.
JACC Cardiovasc Imaging. 2025 Jun;18(6):644-660. doi: 10.1016/j.jcmg.2025.01.004. Epub 2025 May 14.
BACKGROUND: Lamin (LMNA) heart disease is a lethal form of dilated cardiomyopathy (DCM). OBJECTIVES: The authors explored its cardiovascular magnetic resonance (CMR) phenotype to discover prognostically useful and subclinical biomarkers. METHODS: This prospective multicenter study recruited 4 groups: LMNA carriers with left ventricular ejection fraction ≥55% (Lamin+EF), LMNA carriers with left ventricular ejection fraction <50% (Lamin-EF), individuals with DCM with wild-type LMNA (DCMwt), and healthy volunteers. Phantom-calibrated CMR comprising cines, late gadolinium enhancement, and multiparametric mapping was undertaken. Left ventricular shapes were reconstructed using generalized Procrustes analysis. Serum biomarkers were collected at the time of CMR. Using a major adverse cardiovascular events (MACE) outcome of cardiovascular death, life-threatening ventricular tachyarrhythmia, heart transplantation, or atrioventricular block requiring pacing, we explored the prognostic value of CMR metrics using Cox regression. RESULTS: A total of 187 individuals were recruited (50% male): 29 with Lamin+EF (38 ± 14 years), 38 with Lamin-EF (45 ± 17 years), 73 with DCMwt (45 ± 15 years), and 47 healthy volunteers (44 ± 20 years). Compared to HVs, Lamin+EF had longer phantom-normalized T by 10 (95% CI: 2-20), higher ECV by 3% (95% CI: 1%-6%), and worse myocardial dynamics. Compared with DCMwt participants, Lamin+EF participants had better myocardial dynamics, higher phantom-normalized T (20 vs 12; P = 0.010), higher serum troponin (27 ng/L vs 5 ng/L; P < 0.001), and higher C-reactive protein (8 mg/L vs 3 mg/L; P = 0.021). Lamin-EF participants had similar myocardial dynamics but higher serum troponin (13 ng/L vs 5 ng/L; P < 0.001), higher N-terminal pro-B-type natriuretic peptide (668 pg/mL vs 228 pg/mL; P = 0.025), longer phantom-normalized T by 16 (95% CI: 1-31), and higher extracellular volume by 5% (95% CI: 1%-9%) than DCMwt participants. Over 4 years, 21% of lamin and 6% of DCMwt participants experienced MACE (P < 0.001). In lamin participants, each 1% increase in global late gadolinium enhancement and each 1% decrease in Procrustes trajectory sizes associated with HRs for MACE of 1.15 (95% CI: 1.02-1.30) and 1.01 (95% CI: 1.01-1.02), respectively (both P ≤ 0.025). CONCLUSIONS: The CMR phenotype of LMNA carriers with preserved left ventricular systolic function consists of longer T, higher serum troponin levels, higher extracellular volume, and impaired strain. CMR-derived focal fibrosis and strain biomarkers are prognostic, and future studies should explore their added clinical utility beyond the currently available MACE risk prediction tools. (The Deep Phenotype of Lamin A/C Cardiomyopathy; NCT03860454).
背景：核纤层蛋白（LMNA）心脏病是扩张型心肌病（DCM）的一种致死形式。 目的：作者探究了其心血管磁共振（CMR）表型，以发现具有预后价值的亚临床生物标志物。 方法：这项前瞻性多中心研究招募了4组人群：左心室射血分数≥55%的LMNA携带者（Lamin+EF）、左心室射血分数<50%的LMNA携带者（Lamin-EF）、野生型LMNA的DCM患者（DCMwt）以及健康志愿者。进行了包括电影成像、延迟钆增强和多参数映射的体模校准CMR检查。使用广义普罗克汝斯分析重建左心室形状。在CMR检查时收集血清生物标志物。以心血管死亡、危及生命的室性快速心律失常、心脏移植或需要起搏的房室传导阻滞等主要不良心血管事件（MACE）作为结局，我们使用Cox回归探究CMR指标的预后价值。 结果：共招募了187名个体（50%为男性）：29名Lamin+EF患者（38±14岁），38名Lamin-EF患者（45±17岁），73名DCMwt患者（45±15岁），以及47名健康志愿者（44±20岁）。与健康志愿者相比，Lamin+EF患者的体模标准化T值延长10（95%CI：2-20），细胞外容积增加3%（95%CI：1%-6%），心肌动力学更差。与DCMwt参与者相比，Lamin+EF参与者的心肌动力学更好，体模标准化T值更高（20对12；P=0.010），血清肌钙蛋白更高（27 ng/L对5 ng/L；P<0.001），C反应蛋白更高（8 mg/L对3 mg/L；P=0.021）。Lamin-EF参与者的心肌动力学相似，但血清肌钙蛋白更高（13 ng/L对5 ng/L；P<0.001），N末端B型利钠肽前体更高（668 pg/mL对228 pg/mL；P=0.025），体模标准化T值延长16（95%CI：1-31），细胞外容积比DCMwt参与者增加5%（95%CI：1%-9%）。在4年时间里，21%的LMNA患者和6%的DCMwt参与者发生了MACE（P<0.001）。在LMNA参与者中，整体延迟钆增强每增加1%和普罗克汝斯轨迹大小每减少1%，与MACE的风险比分别为1.15（95%CI：1.02-1.30）和1.01（95%CI：1.01-1.02）（均P≤0.025）。 结论：左心室收缩功能保留的LMNA携带者的CMR表型包括T值延长、血清肌钙蛋白水平升高、细胞外容积增加和应变受损。CMR衍生的局灶性纤维化和应变生物标志物具有预后价值，未来的研究应探索它们在现有MACE风险预测工具之外的额外临床效用。（核纤层蛋白A/C心肌病的深度表型；NCT03860454）
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