Left Ventricular Non-compaction Cardiomyopathy Patients Research Articles

Renal dysfunction and outcome in left ventricular non-compaction.

While renal function has been observed to inversely correlate with clinical outcome in other cardiomyopathies, its prognostic significance in patients with left ventricular non-compaction cardiomyopathy (LVNC) has not been investigated. The aim of this study was to determine the prognostic value of renal function in LVNC patients. Patients with isolated LVNC as diagnosed by echocardiography and/or magnetic resonance imaging in 4 Swiss centers were retrospectively analyzed for this study. Values for creatinine, urea, and estimated glomerular filtration rate (eGFR) as assessed by the CKD-EPI 2009 formula were collected and analyzed by a Cox regression model for the occurrence of a composite endpoint (death or heart transplantation). During the median observation period of 7.4 years 23 patients reached the endpoint. The ageand gender-corrected hazard ratios (HR) for death or heart transplantation were: 1.9 (95% confidence interval [CI] 1.4-2.6) for each increase over baseline creatinine level of 30 μmol/L (p < 0.001), 1.6 (95% CI 1.2-2.2) for each increase over baseline urea level of 5 mmol/L (p = 0.004), and 3.6 (95% CI 1.9-6.9) for each decrease below baseline eGFR level of 30 mL/min (p ≤ 0.001). The HR (log2) for every doubling of creatinine was 7.7 (95% CI 3-19.8; p < 0.001), for every doubling of urea 2.5 (95% CI 1.5-4.3; p < 0.001), and for every bisection of eGFR 5.3 (95% CI 2.4-11.6; p < 0.001). This study provides evidence that in patients with LVNC impairment in renal function is associated with an increased risk of death and heart transplantation suggesting that kidney function assessment should be standard in risk assessment of LVNC patients.

Long-Term Prognosis of Different Subtypes of Left Ventricular Noncompaction Cardiomyopathy Patients: A Retrospective Study in China.

Left ventricular noncompaction (LVNC) is a heterogeneous cardiomyopathy that can be classified into different subtypes based on morphologic and functional features. However, the prognosis of the dilated and isolated subtypes of non-pediatric LVNC remains unknown. We retrospectively studied 101 patients with LVNC diagnosed at Peking Union Medical College Hospital from 2006 to 2022 using the Jenni criteria of transthoracic echocardiography. The patients were grouped into those with dilated LVNC (n = 64) or isolated LVNC (n = 37), and 88 patients (54 with dilated LVNC and 34 with isolated LVNC) were followed up successfully. The primary outcome was major adverse cardiovascular events (a composite of cardiovascular mortality, heart failure, severe ventricular arrhythmia, and systolic embolism). The median follow-up time was 5.24 years. The incidence of major adverse cardiovascular events was 43.2%; patients with dilated LVNC had a higher risk (adjusted hazard ratio, 4.43; 95% confidence interval, 1.24-15.81; p = 0.02) than those with isolated LVNC. None of the isolated LVNC patients had cardiovascular deaths or severe ventricular arrhythmias. The risk of systemic embolism was similar between patients with dilated and isolated LVNC. Our findings indicate that transthoracic echocardiography is a useful tool for classifying LVNC into subtypes with distinct clinical outcomes. Dilated LVNC is associated with a poor prognosis, while the isolated subtype is probably a physiological condition.

Noncompaction Cardiomyopathy and Embolic Events

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent ventricular trabeculations and deep intertrabecular recesses. Patients with LVNC have an increased risk of embolic events. The presence of symptoms at the time of diagnosis can be a risk marker for stroke/embolic events. Left ventricular ejection fraction (LVEF), as measured by transthoracic echocardiography and left atrial diameter, has been found to be a significant predictor of systemic embolism in LVNC patients. Furthermore, CHADS2 (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus and stroke or transient ischemic attack) and CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes, stroke, vascular disease, age 65–74 years and sex category [female]) scores were significantly higher in patients with stroke or embolism. Although the difference was not statistically significant, pediatric patients with LVNC combined with other congenital heart defects had more thromboembolic events compared to patients with isolated LVNC. On the other hand, stroke/transient ischemic attacks did not differ significantly between patients with isolated apical LVNC and mid-basal noncompaction. Furthermore, no differences in the prevalence of stroke between the quantiles of the maximal ratio of noncompacted to compacted myocardium have been revealed. Additionally, current data show no association between N-terminal pro-B-type natriuretic peptide levels and stroke/embolic events. Current evidence suggests anticoagulation treatment in LVNC patients with prior embolic events, atrial fibrillation, presence of left ventricular (LV) thrombus, and/or LV dysfunction. In patients with LVNC without a clear indication for anticoagulation, anticoagulant therapy may be considered in patients with CHADS2 score ≥2. More data are needed to identify patients at higher risk of embolic events who will be benefited from anticoagulation treatment.

Left ventricular non-compaction cardiomyopathy associated with the PRKAG2 mutation

Left ventricular non-compaction cardiomyopathy (LVNC) is one of the most common inherited cardiovascular diseases. The genetic backgrounds of most LVNC patients are not fully understood. We collected clinical data, family histories, and blood samples and performed genetic analysis using next-generation sequencing (NGS) from a Chinese family of 15 subjects. Clinically LVNC affected subjects showed marked cardiac phenotype heterogeneity. We found that these subjects with LVNC carried a missense heterozygous genetic mutation c.905G>A (p.R302Q) in γ2 subunit of AMP-activated protein kinase (PRKAG2) gene through NGS. Individuals without this mutation showed no symptoms or cardiac structural abnormalities related to LVNC. One subject was the victim of sudden cardiac death. To sum up, PRKAG2 mutation c.905G>A (p.R302Q) caused familial LVNC. Our results described a potentially pathogenic mutation associated with LVNC, which may further extend the spectrum of LVNC phenotypes related to PRKAG2 gene mutations.

Characteristics and long-term survival of patients with left ventricular non-compaction cardiomyopathy.

Left ventricular non-compaction cardiomyopathy (LVNC) is a poorly understood entity resulting in heart failure. Whether it is a distinct form of cardiomyopathy or an anatomical phenotype is a subject of discussion. The current diagnosis is based on morphologic findings by comparing the compacted to non-compacted myocardium. The study aimed to compare demographic and prognostic variables of patients with dilated cardiomyopathy (DCM) and LVNC. Emphasis was given to cardiac magnetic resonance (CMR) imaging analysis. Data on survival were also assessed. We retrospectively evaluated the characteristics and outcomes of 262 non-ischaemic cardiomyopathy patients with LVNC and DCM phenotypes. Petersen's CMR criteria of non-compacted to the compacted myocardial ratio 2.3 were used to diagnose LVNC. The primary endpoint was a composite endpoint of major adverse cardiovascular events comprising cardiovascular-related death, left ventricular assisted device implantation, or heart transplantation. A total of 262 patients with CMR data were included in the study. One hundred fifty-five patients who fulfilled CMR criteria were diagnosed as LVNC. CMR findings revealed that LVNC patients had higher left ventricular end-diastolic (137.2±51.6, 116.8±44.6, P=0.002) and systolic volume index (98.4±49.5, 85.9±42.7, P=0.049). Cardiac haemodynamics, cardiac output (5.61±2.03, 4.96±1.83; P=0.010), stroke volume (73.9±28.8, 65.1±25.1; P=0.013), and cardiac index (2.85±1.0, 2.37±0.72; P<0.0001), were higher in LVNC patients. Of all the 249 patients, 102 (40.9%) patients demonstrated late gadolinium enhancement (LGE). According to Petersen's criteria, the Kaplan-Meier survival outcome did not reveal significant differences (hazard ratio [HR]: 1.53, 95% confidence interval [CI]: [0.89-2.63], P=0.11). The presence or pattern of LGE did not show significant importance for endpoint-free survival. Most of the sub-epicardial LGE pattern was found in LVNC patients (94.4%). When receiver operator characteristics analysis was applied to NC/C ratio to discriminate the primary endpoint, a higher NC/C ratio of 2.57 was associated with adverse events (HR: 1.90, 95% CI: [1.12-3.24], P=0.016). Our study questions the criteria being used for the diagnosis of LVNC. Further evaluation of CMR variables and association of these findings with demographic variables and survival is mandatory.

Predictors of fatal arrhythmic events in patients with non-compaction cardiomyopathy: a systematic review.

Left ventricular non-compaction cardiomyopathy (LVNC) is a congenital heart disease with autosomal dominant inheritance. This review aims to summarize the existing data about the predictors of fatal arrhythmias in patients with LVNC. Medline and Cochrane library databases were searched from inception to November 2021 for articles on LVNC. The reference lists of the relevant research studies as well as the relevant review studies and meta-analyses were also searched. Clinical symptoms and electrocardiogram findings such as left bundle branch block are significantly associated with ventricular arrhythmias. Other non-invasive tools such as Holter monitoring, echocardiography, and cardiac magnetic resonance (CMR) can provide additional value for risk stratification. CMR-derived left and right ventricular ejection fraction, left ventricular end-diastolic diameter, late gadolinium enhancement, and non-compacted to compacted myocardium ratio are predictive of ventricular arrhythmias. An electrophysiological study can provide additional prognostic data in patients with LVNC who are at moderate risk of ventricular arrhythmias. Risk stratification of LVNC patients with no prior history of a fatal arrhythmic event remains challenging. Symptoms assessment, electrocardiogram, Holter monitoring, and cardiac imaging should be performed on every patient, while an electrophysiological study should be performed for moderate-risk patients. Large cohort studies are needed for the construction of score models for arrhythmic risk stratification purposes.

RBM20-mutations induce disturbed splicing of calcium relevant genes and guides clinically therapy in different cardiomyopathies

Abstract Background Mutations in the splice factor RBM20 account for ∼3% of genetic cardiomyopathies. Mutations at position R634 in the hotspot RS-domain were found to cause dilative cardiomyopathy (DCM) (R634W) or left ventricular non-compaction cardiomyopathy (LVNC) (R634L), but the pathophysiological mechanisms that govern the heterogeneity in phenotype presentation remain unknown. Purpose We aimed here to identify the molecular events caused by the distinct RBM20 mutations from DCM and LVNC patients using a patient-specific induced stem cell model (iPSC) and test if the currently clinically used β-blockers (Metroprolol) are suitable for different RBM20-dependent cardiomyopathies. Methods We generated iPSC-cardiomyocytes of 2 DCM- and 2 LVNC-patients harboring the RBM20-mutations R634W (DCM) or R634L (LVNC). We investigated alternative splicing, sarcomeric regularity, cAMP-level, kinase-specific phosphorylation of Ca2+ players and Ca2+ handling. To investigate the impact of the genetic background, isogenic rescue lines were generated by CRISPR/Cas9. Different clinical drugs as Metoprolol and Verapamil were used to analyze the pharmacological improvement in vitro. Results We investigated the splicing pattern of the 2 RBM20 mutations in DCM and LVNC iPSC-CMs and observed common isoform changes in titin and a 24bp-insertion in the gene RYR2. The Ca2+ handling gene triadin is misspliced in LVNC-CMs, whereas the structural gene LDB3 is misspliced in DCM-CMs. As a possible consequence of splice defects in sarcomeric genes, both DCM and LVNC-CMs exhibited an irregular sarcomeric structure. The Ca2+ handling gene CAMK2δ was predominantly misspliced in LVNC-CMs leading to CAMK2δ-dependent hyperphosphorylation of its target PLN-Thr17 and subsequently to shortened Ca2+ elimination time and weakened response to β-adrenergic stimulation. By contrast, DCM-CMs exhibited increased Ca2+ sparks and decreased systolic and diastolic Ca2+ levels. RBM20 expression itself was decreased in LVNC-CMs, but not in DCM-CMs. This highlights that 2 distinct RBM20 mutations can lead to different pathological Ca2+ phenotypes. Isogenic CRISPR/Cas9 repair of both RBM20 mutations in LVNC and DCM demonstrated a rescue in gene missplicing, sarcomeric regularity and the Ca2+ handling aberrations and underscored the causative nature of the 2 mutations and their diverging effects. Ca2+ channel blockage with Verapamil showed a significant improvement of some of the LVNC disease characteristics compared to commonly clinically used β-blocker Metoprolol and underpins the potential clinical use of this drug in patients with LVNC. Conclusion We show the first iPSC-model of splice-defect associated RBM20-dependent LVNC and DCM. In summary, our results suggest that the molecular aberrations in alternative splicing differ depending on the distinct mutation in RBM20 and lead to shared and differential pathologies. Verapamil could be a good candidate in the treatment of RBM20-dependent LVNC. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Bunderministerium für Bildung und Forschung BMBFGerman Center for Cardiovascular Research DZHK

Generation and cardiac differentiation of a human induced pluripotent stem cell line UALGi002-A from a female patient with Left-Ventricular Noncompaction Cardiomyopathy

Left Ventricular Noncompaction Cardiomyopathy (LVNC) is characterized by abnormal number and prominence of trabeculations of the left ventricle of the heart. Although LVNC has been associated with mutations in several genes encoding for transcriptional regulators, ion channels, sarcomeric and mitochondrial proteins, approximately 60% of LVNC patients do not present these genetic alterations. Here, we describe an induced pluripotent stem cell (hiPSC) line (UALGi002-A) originated from a LVNC female patient (LVNC-hiPSC) who does not present any previously known mutations associated to LVNC. The LVNC-hiPSC exhibited full pluripotency and differentiation potential and retained a normal karyotype after reprogramming. Moreover, the LVNC-hiPSC differentiated into contracting cardiomyocytes. This cellular model will be useful to study the molecular, genetic and functional aspects of LVNC in vitro.

Molecular analysis of dilated and left ventricular noncompaction cardiomyopathies in Egyptian children.

Paediatric cardiomyopathy is a progressive, often lethal disorder and the most common cause of heart failure in children. Despite its severe outcomes, the genetic aetiology is still poorly characterised. High-throughput sequencing offers a great opportunity for a better understanding of the genetic causes of cardiomyopathy. The current study aimed to elucidate the genetic background of cardiomyopathy in Egyptian children. This hospital-based study involved 68 patients; 58 idiopathic primary dilated cardiomyopathy and 10 left ventricular noncompaction cardiomyopathy. Cardiomyopathy-associated genes were investigated using targeted next-generation sequencing. Consanguinity was positive in 53 and 70% of dilated cardiomyopathy and left ventricular noncompaction cardiomyopathy patients, respectively. Positive family history of cardiomyopathy was present in 28% of dilated cardiomyopathy and 10% of the left ventricular noncompaction cardiomyopathy patients. In 25 patients, 29 rare variants were detected; 2 likely pathogenic variants in TNNI3 and TTN and 27 variants of uncertain significance explaining 2.9% of patients. The low genetic detection rate suggests that novel genes or variants might underlie paediatric cardiomyopathy in Egypt, especially with the high burden of consanguinity. Being the first national and regional report, our study could be a reference for future genetic testing in Egyptian cardiomyopathy children. Genome-wide tests (whole exome/genome sequencing) might be more suitable than the targeted sequencing to investigate the primary cardiomyopathy patients. Molecular characterisation of cardiomyopathies in different ethnicities will allow for global comparative studies that could result in understanding the pathophysiology and heterogeneity of cardiomyopathies.

Left Ventricular Dilatation Impacts Heart Transplant and Death in Left Ventricular Non-Compaction Cardiomyopathy

<h3>Purpose</h3> Patients with left ventricular non-compaction cardiomyopathy (LVNC) and end-stage heart failure (HF) are transplanted less often than dilated cardiomyopathy (DCM) patients. We aimed to describe a cohort of LVNC patients and to identify risk factors associated with death or heart transplant (HTX). <h3>Methods</h3> We reviewed all patients < 18 years included in our HF database (2001 - 2018) with LVNC, either isolated (I-LVNC) or with dilated phenotype (D-LVNC) and at least mildly reduced ejection fraction (EF). Patients with DCM were included as controls for comparison. Descriptive statistics, multivariate analysis, and time-to-event analysis were used. <h3>Results</h3> We included 239 patients, 37 (15%) with I-LVNC, 38 (16%) with D-LVNC, and 164 (69%) with DCM. The overall median age at diagnosis was 4.8 years (IQR 1.1 - 10.1) with a median follow-up of 1.2 (IQR 0.2-4.1) years. I-LVNC patients presented less often with HF than D-LVNC and DCM patients (24%, 45%, 76%; p=0.0001). As expected, baseline LV dimensions were smaller in I-LVNC than in the D-LVNC and DCM groups (median z-scores 0.8, 3.84, 3.76; p < 0.0001). I-LVNC patients had higher baseline EF (median EF 47%, 30%, 22%; p<0.0001), however 64% of these patients did develop moderate to severe LV dysfunction during follow-up. I-LVNC patients had less admissions to ICU (46%, 61%, 70%, p=0.0005), 1 patient required ECMO and none underwent VAD implant (0%, 11%, 18%; p = 0.01). Significantly less patients from the I-LVNC group underwent HTX, as compared to their D-LVNC and DCM counterparts (11%, 21%, 33%; p = 0.02). This resulted in a significantly improved HTX-free survival for the I-LVNC group (p<0.0001) - Figure 1. On multivariable analysis, baseline EF and LV dimension, ACE inhibitor therapy and ICU admission during follow-up were significantly associated with death or HTX -Table 1. <h3>Conclusion</h3> In this cohort of LVNC and DCM patients, LV dilation with dysfunction was associated with death or HTX. Further studies on the outcomes of LVNC subtypes are warranted.

Intraventricular synchronism assessment by gated-SPECT myocardial perfusion imaging in cardiac resynchronization therapy. Does cardiomyopathy type influence results?

PurposeTo analyze the evolution post-cardiac resynchronization therapy (CRT) in left ventricular non-compaction (LVNC) cardiomyopathy (CM) patients compared to other types of CM, according to clinical and functional variables, by using gated-SPECT myocardial perfusion imaging (MPI).MethodsNinety-three patients (60 ± 11 years, 28% women) referred for pre-CRT assessment were studied and divided into three groups: 1 (non-ischemic CM with LVNC, 11 patients), 2 (ischemic CM, 28 patients), and 3 (non-ischemic CM, 53 patients). All were studied by a 99mTc-MIBI gated-SPECT MPI at rest pre-CRT implantation and 6 ± 1 months after, including intraventricular dyssynchrony assessment by phase analysis. Quality of life was measured by the Minnesota Living with Heart Failure Questionnaire (MLHFQ).ResultsNo differences in sex, atherosclerotic risk factors other than smoking habit, and MLHFQ results were found among groups. LVNC CM patients were younger, with greater QRS width and lower left ventricular ejection fraction (LVEF) at baseline, but the differences were not significant. No significant differences were found at baseline regarding ventricular function, although end-systolic volume was slightly higher in LVNC CM patients. Mean SRS was significantly higher (p < 0.0001) in ischemic patients (14.9) versus non-ischemic ones (8.7 in group 1 and 9 in group 2). At baseline, LVNC CM patients were significantly more dyssynchronous: Their phase standard deviation (PSD) was higher (89.5° ± 14.2°) versus groups 2 (65.2° ± 23.3°) and 3 (69.7° ± 21.7°), p = 0.007. Although the quality of life significantly improved in all groups, non-ischemic patients (with or without LVNC) showed a higher LVEF increase and volumes reduction at 6 months post-CRT. Dyssynchrony reduced post-CRT in all groups. Nevertheless, those more dyssynchronous at baseline (LVNC CM) exhibited the most significant intraventricular synchronism improvement: PSD was reduced from 89.5° ± 14.2° at baseline to 63.7° ± 20.5° post-CRT (p = 0.028). Six months post-CRT, 89% of patients were responders: 11 (100%) of those with LVNC CM, 25 (86%) of those with ischemic CM, and 47 (89%) of patients with non-ischemic CM. No patient with LVNC CM had adverse events during the follow-up.ConclusionCRT contributes to a marked improvement in non-ischemic CM patients with non-compaction myocardium. Phase analysis in gated-SPECT MPI is a valuable tool to assess the response to CRT.

Biventricular imaging markers to predict outcomes in non-compaction cardiomyopathy: a machine learning study.

AimsLeft ventricular non‐compaction cardiomyopathy (LVNC) is a genetic heart disease, with heart failure, arrhythmias, and embolic events as main clinical manifestations. The goal of this study was to analyse a large set of echocardiographic (echo) and cardiac magnetic resonance imaging (CMRI) parameters using machine learning (ML) techniques to find imaging predictors of clinical outcomes in a long‐term follow‐up of LVNC patients.Methods and resultsPatients with echo and/or CMRI criteria of LVNC, followed from January 2011 to December 2017 in the heart failure section of a tertiary referral cardiologic hospital, were enrolled in a retrospective study. Two‐dimensional colour Doppler echocardiography and subsequent CMRI were carried out. Twenty‐four hour Holter monitoring was also performed in all patients. Death, cardiac transplantation, heart failure hospitalization, aborted sudden cardiac death, complex ventricular arrhythmias (sustained and non‐sustained ventricular tachycardia), and embolisms (i.e. stroke, pulmonary thromboembolism and/or peripheral arterial embolism) were registered and were referred to as major adverse cardiovascular events (MACEs) in this study. Recruited for the study were 108 LVNC patients, aged 38.3 ± 15.5 years, 48.1% men, diagnosed by echo and CMRI criteria. They were followed for 5.8 ± 3.9 years, and MACEs were registered. CMRI and echo parameters were analysed via a supervised ML methodology. Forty‐seven (43.5%) patients had at least one MACE. The best performance of imaging variables was achieved by combining four parameters: left ventricular (LV) ejection fraction (by CMRI), right ventricular (RV) end‐systolic volume (by CMRI), RV systolic dysfunction (by echo), and RV lower diameter (by CMRI) with accuracy, sensitivity, and specificity rates of 75.5%, 77%, 75%, respectively.ConclusionsOur findings show the importance of biventricular assessment to detect the severity of this cardiomyopathy and to plan for early clinical intervention. In addition, this study shows that even patients with normal LV function and negative late gadolinium enhancement had MACE. ML is a promising tool for analysing a large set of parameters to stratify and predict prognosis in LVNC patients.

Right ventricle and outcome in left ventricular non-compaction cardiomyopathy

BackgroundThe risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. Information on prognostic factors, however, is limited. This study was designed to assess the prognostic value of right ventricular (RV) size and function in LVNC patients. MethodsCox regression analyses were used to determine the association of indexed RV end-diastolic area (RV-EDAI), indexed end-diastolic diameter (RV-EDDI), fractional area change (FAC), and tricuspid annular systolic excursion (TAPSE) with the occurrence of death or heart transplantation (composite endpoint). ResultsOut of 127 patients (53.2 ± 17.8 years; 61% males, median follow-up time was 7.7 years), 17 patients reached the endpoint. In a univariate analysis, RV-EDAI was the strongest predictor of outcome [HR 1.48 (1.24–1.77) per cm2/m2; p < 0.0001]. FAC was predictive as well [HR 1.44 (1.16–1.83) per 5% decrease; p = 0.0009], while TAPSE was not (p=ns). RV-EDAI remained an independent predictor in a bivariable analysis with indexed left ventricular ED volume [HR 1.41 (1.18–1.70) per cm2/m2; p = 0.0002], while analysis of FAC and left ventricular ejection fraction demonstrated that FAC was not independent [HR 1.20 (0.98–1.52); per 5% decrease; p = 0.0721]. RV-EDAI 11.5 cm2/m2 was the best cut-off value for separating patients in terms of outcome. Patients with RV-EDAI >11.5 cm2/m2 had a survival rate of 18.5% over 12 years as compared to 93.8% in patients with RV-EDAI <11.5 cm2/m2 (p < 0.0001). ConclusionIncreased end-diastolic RV size and decreased systolic RV function are predictors of adverse outcome in patients with LVNC. Patients with RV-EDAI >11.5 cm2/m2 exhibit a significantly lower survival than those <11.5 cm2/m2.

Clinical implications of sarcomere and nonsarcomere gene variants in patients with left ventricular noncompaction cardiomyopathy.

BackgroundRobust data regarding genotype–phenotype correlations in left ventricular noncompaction cardiomyopathy (LVNC) are lacking.MethodsAbout 72 cardiomyopathy‐related genes were comprehensively screened in a cohort of LVNC patients using targeted sequencing. Baseline and follow‐up data were collected. The primary endpoint was a composite of death and heart transplantation.ResultsA total of 83 unrelated adult patients were included in analyses. Following stringent classification according to the American College of Medical Genetics and Genomics (ACMG) guidelines, 36 pathogenic variants of 14 genes were detected in 32 patients. Among them, 12 patients carried at least one nonsarcomere variant (NSV). At baseline, NSV carriers had a higher frequency of atrial fibrillation, but lower left ventricular ejection fraction, than did noncarriers. During a median follow‐up of 4.2 years, NSV carriers experienced a higher rate of the primary endpoint compared with noncarriers. There was no significant difference in the rate between carriers of sarcomere variant (SV) and noncarriers, as well as between carriers of SV and NSV. The presence of NSV was associated with an increased risk of the primary endpoint independent of age, sex, and cardiac function (hazard ratio: 3.61, 95% confidence interval: 1.42–9.19, p = .002).ConclusionNSV may act as a genetic modifier and worsen the clinical phenotype in patients with LVNC.

Cardiac Segmental Strain Analysis in Pediatric Left Ventricular Noncompaction Cardiomyopathy

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by prominent left ventricular trabeculations, often leading to myocardial dysfunction and death or heart transplantation. Although diagnostic echocardiographic criteria exist for LVNC, segmental speckle-tracking strain patterns have not been described in pediatric LVNC. The objectives of this study were to characterize segmental noncompaction, evaluate segmental speckle-tracking strain, and characterize peak strain values in children with LVNC with adverse clinical outcomes. Echocardiographic noncompaction/compaction ratios and segmental radial, circumferential, and longitudinal strain were measured retrospectively in children with LVNC (January 2000 to June 2013). Segmental strain of the cohort was compared with that in control subjects matched by age and body surface area. One hundred one pediatric patients with LVNC were included (median age 2.8years; range, 0-19.4years); 71 patients survived (benign group) and 30 patients did not survive or required heart transplantation (adverse group). The adverse group was younger at diagnosis (P=.03), with lower ejection fractions (P<.0001) compared with the benign group. Both groups demonstrated increased noncompaction/compaction ratios within apical segments, with significantly increased involvement in antero- and inferolateral midpapillary segments in the adverse group (P<.005). Radial, circumferential, and longitudinal strain of nearly all left ventricular segments were significantly decreased in the adverse compared with the benign group and in pediatric LVNC patients compared with control subjects. Global radial (7.4±9.7% vs 19.6±16.5%, P<.0001), circumferential (-8.4±7.0% vs -18.9±6.9%, P<.0001), and longitudinal (-7.1±5.2% vs -11.8±5.3%, P<.0001) strain were all significantly decreased in the adverse group compared with the benign group. Segmental radial, circumferential, and longitudinal strain are decreased in pediatric patients with LVNC compared with control subjects and lowest in those with adverse compared with benign outcomes. LVNC appears to be a global disease affecting deformation in all regions, including compacted myocardial segments.

Clinical genetics and outcome of left ventricular non-compaction cardiomyopathy.

In this study, we aimed to clinically and genetically characterize LVNC patients and investigate the prevalence of variants in known and novel LVNC disease genes. Left ventricular non-compaction cardiomyopathy (LVNC) is an increasingly recognized cause of heart failure, arrhythmia, thromboembolism, and sudden cardiac death. We sought here to dissect its genetic causes, phenotypic presentation and outcome. In our registry with follow-up of in the median 61 months, we analysed 95 LVNC patients (68 unrelated index patients and 27 affected relatives; definite familial LVNC = 23.5%) by cardiac phenotyping, molecular biomarkers and exome sequencing. Cardiovascular events were significantly more frequent in LVNC patients compared with an age-matched group of patients with non-ischaemic dilated cardiomyopathy (hazard ratio = 2.481, P = 0.002). Stringent genetic classification according to ACMG guidelines revealed that TTN, LMNA, and MYBPC3 are the most prevalent disease genes (13 patients are carrying a pathogenic truncating TTN variant, odds ratio = 40.7, Confidence interval = 21.6-76.6, P < 0.0001, percent spliced in 76-100%). We also identified novel candidate genes for LVNC. For RBM20, we were able to perform detailed familial, molecular and functional studies. We show that the novel variant p.R634L in the RS domain of RBM20 co-segregates with LVNC, leading to titin mis-splicing as revealed by RNA sequencing of heart tissue in mutation carriers, protein analysis, and functional splice-reporter assays. Our data demonstrate that the clinical course of symptomatic LVNC can be severe. The identified pathogenic variants and distribution of disease genes-a titin-related pathomechanism is found in every fourth patient-should be considered in genetic counselling of patients. Pathogenic variants in the nuclear proteins Lamin A/C and RBM20 were associated with worse outcome.

Complications Associated With Implantable Cardioverter Defibrillators in Adults With Congenital Heart Disease or Left Ventricular Noncompaction Cardiomyopathy (From the NCDR® Implantable Cardioverter-Defibrillator Registry)

Patients with childhood heart disease are living longer and entering adulthood, and may undergo implantable cardioverter-defibrillator (ICD) implantation to reduce the risk of sudden death. We evaluated the characteristics of adult patients with congenital heart disease or left ventricular noncompaction cardiomyopathy (LVNC) in the National Cardiovascular Disease Registry ICD Registry and determined ICD-related in-hospital complications. Patients with LVNC or transposition of the great arteries, tetralogy of Fallot, Ebstein's anomaly, atrial septal defect, ventricular septal defect, or common ventricle were identified in the registry. In-hospital complications were compared among different diagnoses using the chi-square test for categorical variables and the F-test in analyses of variance for continuous variables. A total of 3,077 patients were identified. The mean age was 48.0 ± 16.0 years, and 39.9% were female. Single-chamber ICDs were implanted in 25.2%, dual chamber in 41.9%, and cardiac resynchronization in 30.8%. Intraprocedural or postprocedural complications occurred in 70 patients (2.3%); there were 6 in-hospital deaths (0.2%). The most frequent complications were acute lead dislodgments, pneumothorax, and hematomas. Patients with Ebstein's anomaly had the greatest complication rate (8.3%, p = 0.03). The complication rate was 1.55% in single-chamber devices, 1.86% in dual chamber, and 3.5% in cardiac resynchronization (p < 0.001). For initial implants, the complication rate was 2.55%, 1.62% in generator replacements, and 8.77% in lead revisions (p = 0.001). In conclusion, in this large contemporary adult cohort of congenital heart disease and LVNC patients who underwent ICD implant procedures, periprocedural complication rates were low. Lead-related risks predominated.

Prognostic power of NT-proBNP in left ventricular non-compaction cardiomyopathy

BackgroundThe risk of adverse events in patients with left ventricular non-compaction cardiomyopathy (LVNC) is substantial. This study was designed to determine the prognostic value of NT-proBNP, left ventricular ejection fraction (LVEF), NYHA class, and exercise capacity in LVNC patients. MethodsCox regression analyses were performed for evaluating the prognostic value of NT-proBNP, LVEF, NYHA class, and exercise capacity on the occurrence of death or heart transplantation. 153 patients were included. ResultsDuring 1013 person-years (longest follow-up 18.5years) 23 patients (15%) died or underwent heart transplantation. We observed a significant relationship of NT-proBNP (adjusted HR 2.44, 95% CI 1.45–4.09, for every NT-proBNP doubling, p=0.0007) and LVEF (adjusted HR for age 60years: 2.68, 95% CI 1.62–4.41, p=0.0001) with the risk of death or heart transplantation. Combined covariate analysis indicated a strong influence of NT-proBNP (adjusted 2.89, 95% CI 1.33–6.26, p=0.007), whereas LVEF was no longer significant (adjusted HR 0.82, 95% CI 0.42–1.67, p=0.66) demonstrating a favorable prognostic power of NT-proBNP over LVEF. An increase in NYHA class was associated with a worse outcome, and exercise capacity revealed a trend in the same direction. For all the abovementioned analyses, similar results were obtained when assessing the values at first presentation. ConclusionThis study provides evidence that an increase in NT-proBNP is a strong predictor of outcome in patients with LVNC. The prognostic power of NT-proBNP is at least as good as that of LVEF, indicating that routine NT-proBNP measurement may improve risk assessment in LVNC.

LVAD as a Bridge to Heart Transplantation in a Patient with Left Ventricular Noncompaction Cardiomyopathy and Advanced Heart Failure

Left ventricular noncompaction cardiomyopathy (LVNC) is a rare hereditary cardiomyopathy characterized by the formation of an outer compacted and inner noncompacted layer of the myocardium. The latter is characterized by prominent trabeculations and deep intertrabecular recesses and is functionally inferior to the compacted myocardium. As there is no specific treatment for patients with LVNC who develop heart failure, the management of these patients is limited and many patients progress to advanced stages of the disease. For LVNC patients with advanced heart failure, the data regarding the use of mechanical circulatory support are scarce. We report a case of a 29-year-old patient with LVNC and advanced refractory heart failure, who was successfully bridged to heart transplantation using a long-term continuous-flow left ventricular assist device.

Abstract 11621: Fibrillin-1 Gene Mutations in Left Ventricular Non-Compaction Cardiomyopathy

Introduction: Left ventricular non-compaction cardiomyopathy (LVNC) is a rare and unique cardiomyopathy. Its presentation can range from a benign phenotype to overt heart failure and sudden cardiac death. The genetics of LVNC are not completely understood and current genetic testing has a yield of about 30% in identifying a causative gene mutation. We present a series of patients with LVNC and fibrillin-1 (FBN1) gene mutations. Hypothesis: We hypothesize that FBN1 gene mutations can lead to LVNC by way of its role in the myocardial extracellular matrix during cardiac development. Methods: A retrospective review of all patients with LVNC at our institution was performed for purposes of another investigation. The process unexpectedly identified patients with LVNC and FBN1 gene mutations, as well as LVNC and Marfan syndrome. Results: Approximately 150 patients are followed in our clinic with LVNC. We screened this population and found 51 patients on medical therapy for reduced function. We retrospectively reviewed gene testing in these 51 patients, when available, and identified 5 patients (10%) with an FBN1 gene mutation. All 5 patients had a dilated LVNC phenotype and previous or current evidence of left ventricular dysfunction. Syndrome breakdown as follows: 3 with Marfan, 1 with Shprintzen-Goldberg, and 1 with no identifiable syndrome. Dilated cardiomyopathy/LVNC gene testing was performed in 3 patients; 2 had disease causing myosin heavy chain 7 gene defects and 1 had no defects. Conclusions: The role of FBN1 in the human myocardium is not completely understood but it is expressed in the developing fetal heart and is a component of the myocardial extracellular matrix. Although causation has not been proven by our report, it certainly raises interest in a mechanistic relationship between LVNC and FBN1 given the increased prevalence of Marfan syndrome and probable increased prevalence of FBN1 gene mutations in this cohort of LVNC patients in light of FBN1.