Early phenotype identification - the key to taming genetic cardiomyopathies

Dilated cardiomyopathy (DCM) has a significant genetic basis (1) and causes substantial morbidity and mortality.(2) DCM typically manifests as heart failure or arrhythmias; however, this represents an advanced phase of the disease after significant myocardial alterations have occurred. Identifying early DCM, particularly in genetically at-risk individuals, and initiating therapy may delay advanced disease. Lamin (LMNA) cardiomyopathy is associated with a particularly malignant phenotype resulting in early cardiac dysfunction and ventricular arrhythmias.(3) The LMNA risk VTA (ventricular tachyarrhythmia) calculator (4) is a validated risk prediction tool to help guide device-based therapies in this high-risk population. The challenge is that this risk tool relies on left ventricular (LV) function as the only imaging variable and does not consider myocardial tissue alterations as can be observed with cardiovascular magnetic resonance (CMR). Patients with LMNA heart disease are known to have a high burden of fibrosis by late gadolinium enhancement (LGE) and this has been shown to be associated with arrhythmic outcomes.(5) Additionally, interstitial fibrosis as evaluated by CMR based extracellular volume fraction (ECV), which is thought to demonstrate a subclinical stage of disease, has already been noted in LMNA carriers with preserved LV function even without LGE.(6) These tissue-based changes may be the key to identifying LMNA patients at the earliest stage of disease to have the greatest therapeutic impact.

In this issue of the Journal of the American College of Cardiology: Cardiovascular Imaging, Topriceanu and colleagues phenotyped patients with lamin heart disease utilizing multiparameteric CMR and myocardial tissue dynamics. The authors prospectively recruited 4 groups of patients who underwent contrasted CMR exams: 38 LMNA carriers with reduced ejection fraction (EF)<55% (Lamin-EF), 29 LMNA carriers with preserved EF≥55% (Lamin+EF), 73 patients with DCM and no disease-causing variants in LMNA (DCMwt), and 47 healthy volunteers. Even though the 73 patients negative for pathogenic variants in LMNA were termed DCM-wild type, 40 and 15 had disease-associated variants in TTN or RBM20, respectively. Additionally, LMNA carriers underwent variant classification (missense, truncating, splice-site), as well as quantification of the LMNA risk VTA score. Image postprocessing included standard volumes and function, strain via feature tracking, LGE quantification (3 standard deviations method), as well as absolute and T1MES(7) phantom normalized T1 and T2 mapping values. In addition, 4D heart shape and size evaluation was performed utilizing Procrustes motion analysis. Patients were followed for a median of 4 years to evaluate major adverse cardiovascular events (MACE) including sudden cardiac death, resuscitated cardiac arrest, VTA, high degree atrioventricular block, and heart transplant.

The main findings of this study highlight the strength of CMR in identifying an early cardiomyopathy phenotype in LMNA carriers with preserved LVEF. In comparison to healthy volunteers, Lamin+EF carriers had a lower preserved EF, worse myocardial dynamics, longer T2, higher ECV, and a higher prevalence of LGE. As expected, Lamin-EF patients had worse myocardial dynamics, higher ECV and more LGE than Lamin+EF carriers. Compared to DCMwt patients, mostly comprised of TTN- and RMB20-related DCM, Lamin-EF patients had higher troponin and NT-proBNP levels, and higher T2 and ECV, despite similar LGE burden and EF. Patients with LMNA truncating variants demonstrated worse myocardial dynamics vs missense and splice-site variants. Lamin-EF patients had more conduction disease and arrhythmias than Lamin+EF carriers. However, in both Lamin+EF and Lamin-EF groups, fibrosis (both replacement fibrosis by LGE and interstitial fibrosis by ECV), and worse myocardial dynamics were associated with higher odds of ventricular arrhythmias and bundle branch block. In total 14 (21%) LMNA carriers experienced MACE, including 5 events in the Lamin+EF group (vs 6% MACE in the DCMwt group). Main predictors of MACE included bundle branch block, non-sustained ventricular tachycardia, larger ventricular volumes and mass, and higher LGE burden.

The authors are to be congratulated on their comprehensive analysis of tissue characteristics and dynamics in LMNA heart disease. The study has multiple strengths, particularly the rigorous analytical approach, well planned comparison groups for the LMNA population (healthy volunteers and non-LMNA DCM patients), standardized myocardial tissue evaluation, and the detailed myocardial dynamics analysis. Inclusion of LMNA variant status into the analysis is applauded, as is the genotype information provided on the DCMwt cohort to put the findings into a broader context of DCM genetics. Identification of the earliest changes with parametric mapping (myocardial edema / inflammation and interstitial fibrosis) are a much-needed addition beyond LGE imaging. Although the lack of patients with implantable cardioverter defibrillators or significant LV dysfunction may be considered a limitation to some, others may argue that a study focused on those with mild, early disease is exactly what we need to move science forward and motivate earlier therapeutic actions. Parametric mapping across scanners and field strengths posed a challenge but the use of phantoms and standardization was the key to overcoming this hurdle. The myocardial dynamics approach utilized here was detailed and sophisticated, but its use would be challenging in routine clinical care; however, standard strain analysis did demonstrate early dynamic changes in LMNA carriers.

As we move into a gene-first era of precision medicine, we will strive to identify familial cardiomyopathies at their earliest stages and perform this amidst phenotypic heterogeneity.(8) Detection of the earliest myocardial tissue and dynamic alterations is key to improving outcomes in the high-risk LMNA population. The main finding of the study by Topriceanu and colleagues is to again confirm with advanced imaging that the LMNA carriers with preserved EF have significant early myocardial changes including myocardial edema / inflammation (T2 mapping), early activation of the profibrotic pathways (interstitial and replacement fibrosis), and worse myocardial strain. A proactive approach routinely integrated into clinical care for the screening of LMNA carriers to identify these myocardial tissue alterations is needed. As evidenced in the current study, events occurred in 21% of the LMNA group despite a relatively preserved EF across both cohorts (median LVEF 48% in Lamin-EF, median LVEF 58% in Lamin+EF) – thus highlighting the need for further optimization of current risk stratification tools. Prior studies have also shown that even in patients with a similar LMNA risk VTA score, LGE presence provided further risk stratification for arrhythmic events.(5) Large multicenter studies will be needed to evaluate the performance of incorporating CMR parameters into the LMNA risk VTA calculator.

Several questions arise from this otherwise rigorous study. Given the myocardial changes seen in this young LMNA carrier population (median 38 years), at what age should the recommended screening begin, and should this remain every 1-2 years?(9) The data to address this important question has not been available as the historical focus has been on LV systolic function rather than on tissue characterization. But with CMR imaging this can change. The more important question is once early disease is detected, can an early intervention slow or halt the progression of LMNA cardiomyopathy? In the era of expanding access to CMR centers, and likely growth due to more low field systems, studies such as this one add to a rapidly expanding body of literature that indicates that CMR should be the modality of choice for screening. Timely CMR scans can more carefully define the natural progression of lamin heart disease, and from these data more thoughtful recommendations can be made for the intervals needed for surveillance imaging. Other opportunities include novel non-contrast approaches to identify fibrosis and assessment of changes in left atrial function that have been shown to precede atrial dilation and ventricular dysfunction.(10)

In summary, the authors provide compelling evidence for an early aggressive approach to evaluating LMNA carriers with CMR imaging. We await further multicenter data to optimize LMNA arrhythmia risk scores by incorporating CMR measures. Future studies will need to focus on therapy-based trials to determine best strategies to halt the progression of myocardial tissue-based and structural changes.