Author + information
- Marianna Fontana, MD,
- Andrea Barison, MD,
- Nicoletta Botto, PhD,
- Luca Panchetti, MD,
- Giulia Ricci, MD,
- Matteo Milanesi, PhD,
- Roberta Poletti, MD,
- Vincenzo Positano, MSc,
- Gabriele Siciliano, MD, PhD,
- Claudio Passino, MD, PhD,
- Massimo Lombardi, MD,
- Michele Emdin, MD, PhD and
- Pier Giorgio Masci, MD⁎ ()
- ↵⁎Fondazione CNR/Regione Toscana G. Monasterio, Via Giuseppe Moruzzi 1, 56124 Pisa, Italy
Lamin A/C (LMNA) gene mutation, identified in 10% of familial dilated cardiomyopathy (DCM) patients, is associated with an increased risk of sudden cardiac death (SCD), which may be the first clinical manifestation (1). Myocardial fibrosis (MF) has been identified in the hearts of LMNA mutation carriers experiencing arrhythmias or conduction disturbances, irrespective of left ventricular (LV) dilation and/or dysfunction (2). Thus, MF may be a precocious primary phenomenon responsible for the subsequent development of electrical instability and LV dysfunction. Cardiovascular magnetic resonance (CMR) allows the depiction of gross MF by late gadolinium enhancement (LGE), whereas extracellular/extravascular volume (ECV) fraction of the myocardium by pre- and post-contrast T1 mapping was recently demonstrated to detect interstitial MF (3). We aimed to investigate the incidence and pattern of MF using comprehensive CMR in LMNA mutation carriers.
We prospectively studied 7 families whose probands with the DCM phenotype were referred to our hospital between 2009 and 2011. We found 5 missense, 1 frame, and 1 splicing mutations (Online Appendix). All LMNA mutation carriers underwent biohumoral assays (hematocrit, N-terminal pro–B-type natriuretic peptide, plasma catecholamine, aldosterone, and plasma renin activity [PRA]), 12-lead electrocardiography, 24-h Holter monitoring, a cardiopulmonary exercise test, and CMR. All 6 probands received beta-blocker and/or an angiotensin-converting enzyme inhibitor therapy. A group of 16 age-matched healthy volunteers without a clinical history of cardiovascular disease was recruited as controls and underwent CMR, 12-lead electrocardiography, and blood sampling for hematocrit determination.
Participants were examined by 1.5-T unit (CVi, GE-Healthcare, Milwaukee, Wisconsin). Standard protocols for LV volume and function and late gadolinium enhancement (LGE) were performed. For myocardial ECV determination, T1 values of myocardium and blood cavity were measured in a single mid ventricular short-axis slice using modified-cine inversion-recovery sequence before and at fixed time intervals (5, 10, and 15 min) after a bolus of contrast agent (Gadodiamide-OMNISCAN,0.2 mmol/kg). Protocols, sequence parameters, T1-mapping, and myocardial ECV calculation are detailed in the Supplemental Material.
Baseline characteristics of LMNA mutation carriers and healthy controls are outlined in Tables 1 and 2, respectively. LMNA mutation carriers and healthy controls showed comparable age (46 ± 18 vs. 45 ± 13 years, p = 0.717) and body mass index (23.4 ± 4.1 vs. 24.0 ± 3.9 kg/m2, p = 0.659), although a lower prevalence of male sex was observed in LMNA mutation carriers compared with healthy controls (37% vs. 75%, p = 0.042). LMNA mutation carriers had slightly larger LV end-diastolic volume and lower ejection fraction than healthy controls (87 ± 20 vs. 76 ± 12 ml/m2 and 60 ± 8% vs. 68 ± 5%, respectively; both p < 0.05) (Online Fig. 1).
Five (26%) LMNA mutation carriers with an enlarged and dysfunctional left ventricle were older (67 ± 8 vs. 39 ± 14 years) and had a higher pro–B-type natriuretic peptide level (median 333 ng/l [25th to 75th percentiles: 62 to 1,943] vs. median 66 ng/l [25th to 75th percentiles: 29 to 107]) than LMNA mutation carriers with normal LV dimension and function (both p < 0.05). In all LMNA mutation carriers, PRA and catecholamine levels were within normal range, whereas the plasma aldosterone level was close to the upper normal limit (median 140 pg/ml [25th to 75th percentiles: 75 to 170], reference values: 20 to 180 pg/ml). Eight LMNA mutation carriers (42%) showed myocardial LGE with a patchy (n = 3) or mid wall (n = 5) pattern. In LMNA mutation carriers, LGE was more frequently detected in carriers with LV dysfunction (4 of 5 patients, 80%) compared with those with normal LV dimension and function (4 of 14 [29%], p < 0.05). Myocardial LGE was more common in carriers with first-degree atrioventricular block (4 of 5 [80%]) than those with normal atrioventricular conduction (1 of 14 [7%], p < 0.05).
Myocardial ECV was higher in LMNA mutation carriers than healthy controls (28.0 ± 2.9% vs. 22.7 ± 3.0%, p < 0.001) even after excluding LV segments with LGE (27.9 ± 3.7% vs. 22.7 ± 3.5%; p < 0.001). Myocardial ECV remained higher in LMNA mutation carriers after excluding carriers with LGE (28.6 ± 3.2% vs. 22.7 ± 3.5%, p < 0.001) or overt LV dysfunction (28.6 ± 2.9%, p < 0.001) (Online Fig. 1).
We demonstrated that interstitial MF represents a subclinical marker of cardiac involvement in genotype-positive LMNA carriers, likely determined by the expression of the mutated gene. This was substantiated by the fact that LMNA mutation carriers showed increased myocardial ECV than healthy controls also when the analysis was confined to carriers without LV dysfunction, electrical abnormalities, or LGE. Additionally, in LMNA mutation carriers, the PRA and aldosterone levels were not significantly increased, indicating that interstitial MF was unlikely related to the activation of the renin-angiotensin-aldosterone axis. These findings are concordant with previous studies reporting that LMNA mutation is associated with myocardial and skeletal muscle fibrosis (2), indicating that MF may occur as primary phenomenon due to mutated gene expression. On the other hand, myocardial LGE was more common in carriers with LV dysfunction and/or electrical disturbances rather representing an unspecific marker of myocardial damage (4).
In conclusion, CMR showed that MF is an intrinsic feature of LMNA cardiomyopathy ranging from interstitial to gross MF. Interstitial MF may represent a subclinical marker preceding the overt structural, functional, and electrical abnormalities. In contrast, gross MF is more commonly detected in carriers already expressing the typical cardiac phenotype.
For supplemental material, please see the online version of this article.
Please note: Drs. Fontana and Barison contributed equally to this paper.
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