Left Ventricular Noncompaction Cardiomyopathy Research Articles

Circulating microRNAs as biomarkers for myocardial fibrosis in patients with left ventricular non-compaction cardiomyopathy.

IntroductionDespite the fact that cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) is a proven method for detecting myocardial fibrosis, there is a need for new and reliable serological biomarkers. Circulating miRNAs could be a practical and attractive alternative. The purpose of the study was to assess the miRNAs well established in myocardial fibrosis – miR-21, miR-29a, miR-30d and miR-133a – in the plasma of patients with left ventricular non-compaction (LVNC) that have areas of LGE assessed by CMR.Material and methodsWe prospectively enrolled 13 adult patients (9 males and 4 females; mean age: 39 ±11.7 years) considered to meet standard CMR criteria for LVNC and 10 healthy age- and sex-matched subjects. All LVNC patients and control subjects underwent CMR examination and the measurement of peripheral plasma levels of 4 miRNAs: miR-21, miR-29a, miR-30d and miR-133a.ResultsThe LGE was present in 9 of the 13 (69.2%) LVNC patients, and most often located in the ventricular septum. Compared with LGE-negative patients, LGE-positive patients had significantly lower LVEF (28.3 ±13.3% vs. 53.5 ±14.9%, p = 0.0113) and greater LV end-diastolic diameter (67.8 ±9.5 mm vs. 57 ±2.2 mm, p = 0.01). Significant up-regulation of all 4 miRNAs was observed among LGE-positive patients vs. LGE-negative patients: miR-21 (p = 0.007), miR-29a (p = 0.0001), miR-30d (p = 0.001) and miR-133a (p = 0.0003).ConclusionsThe up-regulation of miR-21, miR-29a, miR-30d and miR-133a indicates the presence of LGE in LVNC patients, and therefore they may serve as potential biomarkers for myocardial fibrosis.

Cardiomyopathies.

The most common cardiomyopathies often present to primary care physicians with similar symptoms, despite the fact that they involve a variety of phenotypes and etiologies (1). Many have signs and symptoms common in heart failure, such as reduced ejection fraction, peripheral edema, fatigue, orthopnea, exertion dyspnea, paroxysmal nocturnal dyspnea, presyncope, syncope and cardiac ischemia (1). In all cardiomyopathies, the cardiac muscle (myocardium) may be structurally and/or functionally impaired. They can be classified as hypertrophic, dilated, left-ventricular non compaction, restrictive and arrhythmogenic right ventricular cardiomyopathies. (www.actabiomedica.it)

左心室心肌致密化不全合并二尖瓣重度关闭不全1例报道并文献复习

左心室心肌致密化不全合并二尖瓣重度关闭不全1例报道并文献复习

Value of Cardiac Magnetic Resonance Fractal Analysis Combined With Myocardial Strain in Discriminating Isolated Left Ventricular Noncompaction and Dilated Cardiomyopathy.

Excessive trabeculation is present in isolated left ventricular noncompaction (LVNC) and dilated cardiomyopathy (DCM), which sometimes makes the differentiation between these two difficult. Fractal dimension (FD) is a unitless measure value of how completely the object fills space, which can assess the extent of myocardial trabeculae quantitatively. To compare the trabeculae features and myocardial strain derived from cardiac MR between LVNC and DCM. Respective case-control series. In all, 35 LVNC patients and 30 DCM patients were enrolled, and 20 healthy volunteers were selected as a control group. 5 T with 8-channel phased-array cardiac receiver coil including steady-state free precession cine imaging. The degree of left ventricular trabeculation was evaluated by a semiautomatic tool based on fractal analysis. Myocardial deformation was assessed by feature tracking. Independent samples Student's t-test, Mann-Whitney U-test, receiver operating characteristics (ROC) curves, and Spearman's rank coefficient were conducted. Max apical FD and mean global FD were higher in the LVNC group than in the DCM group (1.433 ± 0.074 vs. 1.341 ± 0.062, P < 0.001; 1.323 ± 0.036 vs. 1.267 ± 0.041, P < 0.001, respectively). For diagnosing LVNC, max apical FD was 1.392 (area under the curve [AUC] = 0.881, 95% confidence interval [CI]: 0.804-0.957), and the cutoff value of mean global FD was 1.283 (AUC = 0.895, 95% CI: 0.828-0.961). The global peak longitudinal strain value of the left ventricle (GPLS) showed significant differences between the LVNC group and DCM group [-6.49 (-11.41, -4.90) vs. -4.61 (-5.87, -3.61), P = 0.006]. The diagnostic accuracy for LVNC is highest when using FDs in coordination with GPLS (AUC = 0.93, 95% CI: 0.86-0.98, P < 0.001). Fractal analysis provides a quantitative measurement of myocardial trabeculation. The combination of fractal analysis with myocardial strain provides a novel biomarker in distinguishing LVNC from DCM. 3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019;50:153-163.

Abstract 17001: Nebulette Knock-Out in Mice Leads to Dilated Cardiomyopathy

Introduction: Cardiomyopathy is a serious heart condition that can lead to heart failure. Nebulette is a cardiac-specific Z-disk protein which plays a crucial role in mechanosensing and force generation in the heart. Previous studies have shown that nebulette mutations are associated with various cardiomyopathies including hypertrophic, left ventricular noncompaction and dilated cardiomyopathy. However, the molecular mechanisms by which nebulette affects the cardiac structure and function are not well-understood. Hypothesis: In this study, we tested whether decrease in nebulette causes cardiac remodeling, dysfunction and dilated cardiomyopathy in vivo. Methods: We generated a novel nebulette knockout (KO, excision of exon 3) mice using the Cre/loxP technique. Mice were characterized prior to being subjected to serial echocardiography and electrocardiogram (ECG) at 6 weeks, 3 months, 6 months and one year of age. A separate cohort of mice were used for histopathological and molecular studies. Results: KO mice were born following Mendelian laws. Western blot and qPCR data revealed significant decrease in nebulette expression in KO mouse hearts compared to heterozygous (Het) and WT mice. Confocal microscopy further elicited diminished nebulette expression and perturbed distribution in myocardial sections as well as isolated cardiomyocytes from KO mice. Echocardiography showed a deterioration of cardiac function in KO mice starting from 6 weeks of age to one year of age, which were characterized by reduced fractional shortening and MV E/A, increased LV diastolic dimension as compared with age-matched WT mice. KO mice showed tachycardia and lower QRS voltage at one year of age compared to WT and Het mice. KO hearts revealed increased fibrosis, sarcomere disorganization, enlarged t-tubules and less apparent M-lines. Western blot demonstrated reduced cardiac TnT and increased TnI levels in the KO mice whereas desmin, actin and cardiac ankyrin repeat protein (CARP) remained comparable between the genotypes. Conclusions: Taken together, these data provide evidence for the critical role of nebulette in maintaining cardiac structure and function. Further data that provides mechanistic insight will be presented.

Successful cardiac resynchronization therapy in a young patient with left ventricular non-compaction cardiomyopathy: a case report

Successful cardiac resynchronization therapy in a young patient with left ventricular non-compaction cardiomyopathy: a case report

Genotype-Positive Status Is Associated With Poor Prognoses in Patients With Left Ventricular Noncompaction Cardiomyopathy.

BackgroundLeft ventricular noncompaction cardiomyopathy (LVNC) is a genetically and phenotypically heterogeneous disease. This study aims to investigate the genetic basis and genotype‐phenotype correlations in a cohort of Chinese patients with LVNC.Methods and ResultsA total of 72 cardiomyopathy‐associated genes were comprehensively screened in 83 adults and 17 children with LVNC by targeted sequencing. Pathogenicity of the detected variants was determined according to their prevalence and American College of Medical Genetics and Genomics recommendations. Baseline and follow‐up clinical data were collected. The primary end point was a composite of death and heart transplantation. Overall, 42 pathogenic variants were identified in 38 patients (38%), with TTN,MYH7,MYBPC3, and DSP being the most commonly involved genes. At baseline, genotype‐positive adults had higher rates of atrial fibrillation and family history, and lower left ventricular ejection fraction, compared with genotype‐negative adults. During a median follow‐up of 4.2 years, more primary end points occurred in genotype‐positive adults than in genotype‐negative adults (50.0% versus 23.5%; P=0.013). Multivariable analysis demonstrated that genotype‐positive status was associated with higher risks of death and heart transplantation, independent of age, sex, and cardiac function at baseline in patients with LVNC (adjusted hazards ratio, 2.49; 95% confidence interval, 1.15–5.37; P=0.020).ConclusionsOur study revealed a distinct genetic spectrum in Chinese patients with LVNC, with variants in TTN,MYH7,MYBPC3, and DSP being the most common. The presence of pathogenic variants is an independent risk factor for adverse outcomes and may aid in risk stratification in adult patients. Larger studies are needed to confirm these findings.

Concise Review: The Current State of Human In Vitro Cardiac Disease Modeling: A Focus on Gene Editing and Tissue Engineering.

Until recently, in vivo and ex vivo experiments were the only means to determine factors and pathways involved in disease pathophysiology. After the generation of characterized human embryonic stem cell lines, human diseases could readily be studied in an extensively controllable setting. The introduction of human‐induced pluripotent stem cells, a decade ago, allowed the investigation of hereditary diseases in vitro. In the field of cardiology, diseases linked to known genes have successfully been studied, revealing novel disease mechanisms. The direct effects of various mutations leading to hypertrophic cardiomyopathy, dilated cardiomyopathy, arrythmogenic cardiomyopathy, or left ventricular noncompaction cardiomyopathy are discovered as a result of in vitro disease modeling. Researchers are currently applying more advanced techniques to unravel more complex phenotypes, resulting in state‐of‐the‐art models that better mimic in vivo physiology. The continued improvement of tissue engineering techniques and new insights into epigenetics resulted in more reliable and feasible platforms for disease modeling and the development of novel therapeutic strategies. The introduction of CRISPR‐Cas9 gene editing granted the ability to model diseases in vitro independent of induced pluripotent stem cells. In addition to highlighting recent developments in the field of human in vitro cardiomyopathy modeling, this review also aims to emphasize limitations that remain to be addressed; including residual somatic epigenetic signatures induced pluripotent stem cells, and modeling diseases with unknown genetic causes. Stem Cells Translational Medicine 2019;8:66–74

LEFT VENTRICULAR NONCOMPACTION CARDIOMYOPATHY: AN UNDERRECOGNIZED CAUSE OF HEART FAILURE

SESSION TITLE: Cardiovascular Disease SESSION TYPE: Med Student/Res Case Report PRESENTED ON: 10/09/2018 07:30 AM - 08:30 AM INTRODUCTION: Left ventricular noncompaction cardiomyopathy (LVNC) is a congenital abnormality of myocardial tissue characterized by prominent ventricular trabeculations with deep recesses, which communicate with the LV cavity. It is thought to be caused by the failure of the loose myocardial meshwork to undergo compaction during fetal development (1). Early diagnosis and correct management is crucial due to association with early onset heart failure, development of ventricular arrhythmias, and embolic events (1). CASE PRESENTATION: 53-year-old Caucasian male with history of untreated hypertension presented with chest tightness, dyspnea on exertion, and orthopnea. He had no known cardiac history. Upon presentation, he was hypertensive at 207/132 with heart rate of 97 beats/min and respiratory rate of 18 breaths/min. Troponin was normal at 0.03. BNP was elevated at 648 pg/ml. EKG showed normal sinus rhythm and left atrial enlargement. CXR showed pulmonary vascular congestion and interstitial edema. Hypertensive emergency was treated with nitroglycerin drip. TTE was performed, which showed LVEF of 35 to 40%, LV diastolic dysfunction, moderate asymmetric LVH, mild to moderate increase in LV chamber size and prominent trabeculation at the LV apex (Figs. 1, 2). Due to the echo findings, he underwent coronary angiography, which revealed nonobstructive CAD. He underwent cardiac MRI, which showed diffuse LVH, global LV hypokinesis, and LV noncompaction (Fig. 3). Patient was started on medical therapy for HFrEF, which consisted of aspirin, atorvastatin, carvedilol, furosemide, lisinopril, isosorbide mononitrate, spironolactone. He remained free of heart failure symptoms at 6 week follow up as outpatient. DISCUSSION: Echocardiography is the initial imaging modality used for diagnosis, which shows a 2 layered structure of compacted epicardial and noncompacted endocardial layers; the abnormal noncompacted layer consists of trabeculations with deep endomyocardial recesses (1). Jenni et al criteria are the most commonly used in clinical practice and these are as follows: 1) maximum end-systolic ratio of noncompacted to compacted myocardium >2.0 on short-axis views; 2) absence of other cardiac abnormalities; 3) color doppler showing perfusion of the intratrabecular recesses; 4) predominantly localized to mid-lateral, apical, or mid-inferior regions. CONCLUSIONS: LVNC must be considered within the differential diagnosis of new onset heart failure with nonobstructive findings on coronary angiography. Echocardiogram is the initial imaging modality of choice; however, the major limitation is that the diagnostic criteria have yet to be validated within a larger cohort (1-2). This is especially needed as there are some case reports that suggest conditions leading to high LV preload such as chronic renal failure, valvular heart disease, pregnancy, or sickle cell disease may lead to high prevalence of LV trabeculations (2). Reference #1: Jenni, R. (2001). Echocardiographic and pathoanatomical characteristics of isolated left ventricular non-compaction: a step towards classification as a distinct cardiomyopathy. Heart, 86(6), 666–671. https://doi.org/10.1136/heart.86.6.666 Reference #2: Gati, S., Rajani, R., Carr-White, G. S., & Chambers, J. B. (2014). Adult left ventricular noncompaction: Reappraisal of current diagnostic imaging modalities. JACC: Cardiovascular Imaging, 7(12), 1266–1275. https://doi.org/10.1016/j.jcmg.2014.09.005 Reference #3: Stöllberger, C., Gerecke, B., Engberding, R., Grabner, B., Wandaller, C., Finsterer, J., Balzereit, A. (2015). Interobserver agreement of the echocardiographic diagnosis of LV hypertrabeculation/noncompaction. JACC: Cardiovascular Imaging, 8(11), 1252–1257. https://doi.org/10.1016/j.jcmg.2015.04.026 DISCLOSURES: No relevant relationships by Mirza Ali, source=Web Response No relevant relationships by Abdisamad Ibrahim, source=Web Response

GW29-e0491 Value of fractal analysis in identification and further discrimination of isolated left ventricular non-compaction and dilated cardiomyopathy by cardiac magnetic resonance

GW29-e0491 Value of fractal analysis in identification and further discrimination of isolated left ventricular non-compaction and dilated cardiomyopathy by cardiac magnetic resonance

Light-sheet Fluorescence Microscopy to Capture 4-Dimensional Images of the Effects of Modulating Shear Stress on the Developing Zebrafish Heart.

The hemodynamic forces experienced by the heart influence cardiac development, especially trabeculation, which forms a network of branching outgrowths from the myocardium. Genetic program defects in the Notch signaling cascade are involved in ventricular defects such as Left Ventricular Non-Compaction Cardiomyopathy or Hypoplastic Left Heart Syndrome. Using this protocol, it can be determined that shear stress driven trabeculation and Notch signaling are related to one another. Using Light-sheet Fluorescence Microscopy, visualization of the developing zebrafish heart was possible. In this manuscript, it was assessed whether hemodynamic forces modulate the initiation of trabeculation via Notch signaling and thus, influence contractile function occurs. For qualitative and quantitative shear stress analysis, 4-D (3-D+time) images were acquired during zebrafish cardiac morphogenesis, and integrated light-sheet fluorescence microscopy with 4-D synchronization captured the ventricular motion. Blood viscosity was reduced via gata1a-morpholino oligonucleotides (MO) micro-injection to decrease shear stress, thereby, down-regulating Notch signaling and attenuating trabeculation. Co-injection of Nrg1 mRNA with gata1a MO rescued Notch-related genes to restore trabeculation. To confirm shear stress driven Notch signaling influences trabeculation, cardiomyocyte contraction was further arrested via tnnt2a-MO to reduce hemodynamic forces, thereby, down-regulating Notch target genes to develop a non-trabeculated myocardium. Finally, corroboration of the expression patterns of shear stress-responsive Notch genes was conducted by subjecting endothelial cells to pulsatile flow. Thus, the 4-D light-sheet microscopy uncovered hemodynamic forces underlying Notch signaling and trabeculation with clinical relevance to non-compaction cardiomyopathy.

P2251Long-term prognostic value of cardiac magnetic resonance imaging in patients with left ventricular non-compaction cardiomyopathy: a multicenter study

P2251Long-term prognostic value of cardiac magnetic resonance imaging in patients with left ventricular non-compaction cardiomyopathy: a multicenter study

Anticoagulation Therapy in Specific Cardiomyopathies: Isolated Left Ventricular Noncompaction and Peripartum Cardiomyopathy.

In 2 distinct entities, left ventricular noncompaction (LVNC) and peripartum cardiomyopathy (PPCM), routine anticoagulation therapy is often used in current practices. However, our systematic review showed that LVNC itself was not associated with the increase in thromboembolism event rates and therapeutic anticoagulation therapy should not be considered only for LVNC, unless there is risk factor for thromboembolism. Current literature justifies prophylactic therapeutic anticoagulation in LVNC with low left ventricular ejection fraction (EF < 40%) and/or atrial fibrillation. Although not specifically studied, the presence of intracardiac thrombi by echocardiography or other imaging studies should also prompt anticoagulation therapy. There is limited evidence available for the use of anticoagulation in patients with PPCM, but our systematic review showed that anticoagulation should be recommended only for patients with PPCM especially with an EF < 35% until EF is recovered, as well as for patients with PPCM treated with bromocriptine.

Potential Common Pathogenic Pathways for the Left Ventricular Noncompaction Cardiomyopathy (LVNC).

Ventricular trabeculation and compaction are two essential morphogenetic events for generating a functionally competent ventricular wall. A significant reduction in trabeculation is usually associated with hypoplastic wall and ventricular compact zone deficiencies, which commonly leads to embryonic heart failure and early embryonic lethality. In contrast, the arrest of ventricular wall compaction (noncompaction) is believed to be causative to the left ventricular noncompaction (LVNC), a genetically heterogeneous disorder and the third most common cardiomyopathy among pediatric patients. After critically reviewing recent findings from genetically engineered mouse models, we suggest a model which proposes that defects in myofibrillogenesis and polarization in trabecular cardiomyocytes underly the common pathogenic mechanism for ventricular noncompaction.

Atrial fibrillation in patients with inherited cardiomyopathies.

Atrial fibrillation (AF) often complicates the course of inherited cardiomyopathies and, in some cases, may be the presenting feature. Each inherited cardiomyopathy has its own peculiar pathogenetic characteristics that can contribute to the development and maintenance of AF. Atrial fibrillation may occur as a consequence of disease-specific defects, non-specific cardiac chamber changes secondary to the primary illness, or a combination thereof. The presence of AF can denote a turning point in the progression of the disease, promoting clinical deterioration and increasing morbidity and mortality. Furthermore, the management of AF can be particularly challenging in patients with inherited cardiomyopathies. In this article, we review the current information on the prevalence, pathophysiology, risk factors, and treatment of AF in three different inherited cardiomyopathies: hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia/cardiomyopathy, familial dilated cardiomyopathy, and left ventricular non-compaction cardiomyopathy.

Neddylation mediates ventricular chamber maturation through repression of Hippo signaling

During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2-E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle-regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP-deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling.

Neural Crest Derived Cardiomyocytes Regulate Cardiac Trabeculation and Adult Heart Function.

The cardiac neural crest arise from the multi‐potent, migratory neural crest cell population and contribute to cardiovascular development, including contributions to cardiac endothelium and myocardium, formation of the great vessels and their valves, as well as septation of the chambers. However, very little is known about the neural crest contribution to the myocardium. This study aims to selectively decipher the function of the neural crest derived cardiomyocytes (NC‐Cms) without the confounding roles of the contributions of neural crest to other tissues, including endocardium. Zebrafish provide a unique genetic model to study this population because of their developmental transparency and they have a relatively large neural crest contribution of NC‐Cms compared to mammals. By creating Zebrafish transgenic lines that both lineage label and allow for ablation of only NC‐Cms, we find that the embryonic NC‐Cms arrive early in zebrafish heart development, makeup ~10% of the embryonic cardiomyocyte population and are steady state by two days post fertilization (2dpf). A majority of this contribution is to the ventricle in a discrete pattern around the apex of the ventricle. To test the function of NC‐Cms during heart development, we genetically ablated them during their early stages (up to 2dpf) and then observed heart development and phenotype up to 14dpf and into adulthood. Surprisingly embryonic ablation of the NC‐Cms was largely dispensable for heart development with a non‐lethal but significant defect in patterning of ventricle trabeculation. Importantly, embryonic ablation of NC‐Cms yielded adults with hypertrabeculated hearts and impaired performance in cardiac stress tests. We investigated the relation of the NC‐Cms to known Notch and Neuregulin effectors of embryonic trabeculation and speculate on their mechanistic regulation of this pathway. These results present a new model of human left ventricular non‐compaction or hypertrabeculation cardiomyopathy, and adult heart failure. Importantly these results demonstrate how a subtle and relatively minor developmental cell population can have detrimental effects on adult cardiac function.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Myocardial T1 mapping and extracellular volume quantification in patients with left ventricular non-compaction cardiomyopathy.

From pathophysiological mechanisms to risk stratification and management, much debate and discussion persist regarding left ventricular non-compaction cardiomyopathy (LVNC). This study aimed to characterize myocardial T1 mapping and extracellular volume (ECV) fraction by cardiovascular magnetic resonance (CMR), and investigate how these biomarkers relate to left ventricular ejection fraction (LVEF) and ventricular arrhythmias (VA) in LVNC. Patients with LVNC (n = 36) and healthy controls (n = 18) were enrolled to perform a CMR with T1 mapping. ECV was quantified in LV segments without late gadolinium enhancement (LGE) areas to investigate diffuse myocardial fibrosis. Patients with LVNC had slightly higher native T1 (1024 ± 43 ms vs. 995 ± 22 ms, P = 0.01) and substantially expanded ECV (28.0 ± 4.5% vs. 23.5 ± 2.2%, P < 0.001) compared to controls. The ECV was independently associated with LVEF (β = -1.3, P = 0.001). Among patients without LGE, VAs were associated with higher ECV (27.7% with VA vs. 25.8% without VA, P = 0.002). In LVNC, tissue characterization by T1 mapping suggests an extracellular expansion by diffuse fibrosis in myocardium without LGE, which was associated with myocardial dysfunction and VA, but not with the amount of non-compacted myocardium.

PROGNOSTIC VALUE OF EXTENT OF NON-COMPACTION IN NON-ISCHEMIC CARDIOMYOPATHY

Left ventricular noncompaction is frequently seen in non-ischemic cardiomyopathy (NICM). The number of non-compacted segments determines the diagnosis of left ventricular noncompaction cardiomyopathy (LVNC). This study evaluates the impact of increasing number of noncompacted segments on structural

Whole-Exome Sequencing Reveals GATA4 and PTEN Mutations as a Potential Digenic Cause of Left Ventricular Noncompaction

A 48-year-old male proband presented with atypical chest pain. An echocardiogram revealed possible left ventricular apical noncompaction that was confirmed by cardiac magnetic resonance imaging as left ventricular noncompaction cardiomyopathy (LVNC; Figure 1A). His ejection fraction was initially preserved at 60% but declined to 45% over the subsequent 6 years despite optimal medical therapy. His asymptomatic 19-year-old son was diagnosed with LVNC at the time of a screening echocardiogram, and follow-up cardiac magnetic resonance imaging confirmed the diagnosis (Figure 1B). His ejection fraction was 50% at the time of diagnosis and was subsequently stable for 5 years with medical therapy. An echocardiogram from the proband’s father showed normal left ventricular structure and function with no excess trabeculation (Figure 1C and 1D). The proband’s daughter had a normal echocardiogram. There were no other family members with a known history of cardiomyopathy or heart failure (Figure 1E). Figure 1 . Clinical characteristics and whole - exome sequencing results of a family with left ventricular noncompaction cardiomyopathy (LVNC). Cardiac magnetic resonance imaging of a 48-year-old proband ( A ) and his 19-year-old son ( B ) showing extensive trabeculation in the left ventricle. Echocardiogram of the proband’s father showing no left ventricle trabeculation at rest ( C ) or during contraction ( D ). E , Pedigree of LVNC family showing individuals diagnosed with LVNC and those that carry the p.Arg260Trp variant in GATA4 , p.Pro191Arg variant in JPH2 , and p.Arg173Cys variant in PTEN . A standard dilated cardiomyopathy panel genetic test (27 genes) on a sample from the proband revealed no pathogenic mutations. Whole-exome sequencing was then performed for the proband, his parents, and his son. Analysis of whole-exome sequencing demonstrated 2 variants that were considered to be potentially causative. The first, GATA4 c.778 C>T, Arg260Trp, was present in the proband, his son, and his unaffected father (Figure 1E). The …