Identification of a novel de novo NONO variants causing X-linked syndromic intellectual developmental disorder-34 in a fetus.

Background: Cardiomyopathies are a heterogeneous group of heart muscle disorders with diverse genetic origins. Biallelic loss-of-function (LoF) variants in the nebulin-related anchoring protein (NRAP) gene have been linked to dilated cardiomyopathy (DCM) and left ventricular noncompaction cardiomyopathy, though only a few families have been described. NRAP, a member of the Nebulin family, plays a key role in cardiomyocyte development, structural integrity, and muscle function. Methods: We investigated two Italian siblings with DCM born to consanguineous parents from a small village in Campania. Exome sequencing, homozygosity mapping, and comparative analyses with other reported cases were performed. Genealogical research was conducted using civil registry data to reconstruct extended family pedigrees. Results: Both siblings were homozygous for a LoF variant in NRAP (NM_198060.4:c.619del; p.Val207TrpfsTer20). A third brother with tachycardia-induced cardiomyopathy, as well as their living mother, who did not have cardiac abnormalities, were found to be heterozygous. The same homozygous variant was recently identified in another Italian family with DCM coming from North-eastern Italy, whose proband also originated from a nearby village in Campania. These two families exhibited heterogeneity in clinical presentation. Homozygosity analysis revealed a >25 Mb shared region on chromosome 10 encompassing NRAP, supporting a common ancestral origin. While genealogical reconstruction did not allow identification of a shared ancestor, it confirmed consanguinity and enabled the recognition of potential carriers across both families. Conclusions: Our findings strengthen the evidence for NRAP as a disease-causing gene in cardiomyopathies and highlight a likely founder effect in Campania. Incorporating NRAP into genetic testing panels is warranted, especially in populations with high rates of consanguinity or suspected founder variants.

The current diagnostic criteria for noncompaction of the ventricular myocardium (NVM) remain inconsistent, and comprehensive cardiac magnetic resonance (CMR) imaging data on the disease are limited. Therefore, the purpose of this study is to evaluate the clinical utility of CMR imaging in the diagnosis and functional assessment of patients with NVM. Twenty patients with NVM and twenty age- and sex-matched healthy controls (HC) underwent comprehensive CMR imaging. Postprocessing software was used to quantify left ventricular longitudinal strain, both global longitudinal strain (GLS) and strain in the basal, middle, and apical segments (BLS, MLS, and ALS, respectively). Statistical analyses were performed to assess group differences. Compared with the HC group, patients with NVM presented significantly increased left ventricular end-diastolic volume (LVEDV), end-systolic volume (LVESV), stroke volume (LVSV), and myocardial mass index (LVMI) and a significantly reduced left ventricular ejection fraction (LVEF) (all P < 0.001). All NVM patients presented prominent trabeculations and deep intertrabecular recesses in the left ventricle during diastole. Cine imaging revealed direct blood flow communication between the recesses and the ventricular cavity. The myocardium exhibited a thin compacted outer layer (C) and a thickened noncompacted inner layer (NC), with an average NC/C ratio of 2.8 ± 0.5. For these patients, NVM primarily involved the apical and adjacent mid-ventricular free wall segments; in five patients, it also involved the basal segment. Right ventricular noncompaction was observed in five patients, and apical ventricular aneurysms were identified in two patients. Compared with the HC group, the NVM group presented a significantly lower ALS (P < 0.05); however, the BLS, MLS, and GLS values were not significantly different between the groups (P > 0.05). Our study demonstrated the feasibility of using CMR imaging to quantitatively assess left ventricular systolic function in NVM patients. The choice of longitudinal strain as a primary parameter was driven by the fact that NVM predominantly affects the endocardial myocardium, particularly the subendocardial fibers, which are primarily longitudinal. As such, longitudinal strain is particularly sensitive for detecting myocardial contractile dysfunction in NVM. Our results indicated that ALS apical longitudinal strain is a more significant marker of contractile dysfunction in NVM than MLS, which was not significantly altered in NVM patients relative to HCs. CMR imaging offers robust diagnostic capabilities for patients with NVM and, when combined with feature tracking, allows the quantitative assessment of left ventricular systolic function. The ALS may serve as a sensitive marker of early myocardial dysfunction and may be clinically important in guiding timely diagnosis and intervention.

Background/Objectives: Sodium glucose co-transporter 2 inhibitors (SGLT2is) improve outcomes in heart failure; however, data in left ventricular non-compaction cardiomyopathy (LVNC) patients are limited. We sought to analyze the clinical effects of the SGLT2is dapagliflozin and empagliflozin in patients with LVNC. Methods: Thirty consecutive LVNC patients diagnosed by CMR were prospectively enrolled. Clinical, biochemical and echocardiography data were obtained at the initiation of the SGLT2is and at the 12-month follow-up. All patients were on stable guideline-directed medical therapy. A response to SGLT2i therapy was defined as an improvement in LVEF ≥ 5% at 12 months. Results: Of the 30 enrolled patients, 25 were male, with a mean age of 49 ± 16 years and few comorbidities. Dapagliflozin 10 mg was prescribed to 23 patients and empagliflozin 10 mg to 7 patients. Five patients experiened an adverse event during follow-up (one sudden cardiac death; four heart transplantations or LVAD implantations). During follow-up, significant improvements were observed in LVEF (32.1 ± 6.9% vs. 43.5 ± 9.7%; p = 0.003), LVOT VTI (14.8 ± 6.5 cm vs. 17.6 ± 3.3 cm; p = 0.008), E/e′ (14.8 ± 4.7 vs. 10.0 ± 4.1; p < 0.001), and TAPSE (2.0 ± 0.4 cm vs. 2.3 ± 0.4 cm; p = 0.012). NT-proBNP levels decreased significantly (2025 ± 2198 pg/mL vs. 582 ± 803 pg/mL; p = 0.005). Eighteen patients responded favorably to SGLT2i therapy (Group A), whereas seven showed no significant LVEF improvement (Group B). The groups did not differ significantly in age, sex, baseline creatinine, or bilirubin. Compared to Group B, Group A had a smaller baseline LV end-diastolic diameter (6.3 ± 0.8 cm vs. 7.1 ± 0.9 cm; p = 0.025) and lower NT-proBNP levels (1720 ± 1662 pg/mL vs. 4527 ± 4397 pg/mL; p = 0.02). Conclusions: In patients with LVNC, SGLT2i therapy is associated with significant reverse remodeling and functional improvement. Benefits may be greater in those with less advanced disease.

Cardiomyopathies are rare diseases in children but are the primary indication for heart transplantation in this age group. Various causes of paediatric cardiomyopathies, ranging from gene-mediated to underlying infection or systemic disease, result in a wide spectrum of clinical presentations and imaging manifestations. Over the years, the classification and terminology of cardiomyopathy have evolved in children and are currently primarily based on the imaging phenotype (dilated, hypertrophic, and restrictive) and then subdivided based on pathogenesis, organ involvement, genetic or familial inheritance pattern, and aetiology. Dilated and hypertrophic cardiomyopathies are more common than non-compaction, restrictive, and arrhythmogenic cardiomyopathies. Echocardiography remains the first-line modality for functional and structural cardiac assessment. However, cardiac magnetic resonance imaging enhances diagnostic accuracy, provides serial cardiac functional evaluation and tissue characterization, and facilitates individual risk stratification and management in patients with heterogeneous phenotypes. This review provides an overview of paediatric cardiomyopathies with a focus on magnetic resonance imaging indications, technique, and key imaging findings that influence management decision-making.

Background: Noncompaction cardiomyopathy (NCCM) is a distinct myocardial disorder associated with a high risk of ventricular arrhythmias and sudden cardiac death. Although implantable cardioverter-defibrillators (ICDs) are frequently used in this population, data on predictors of shock therapy remain limited. Aim: Evaluation of a large cohort of patients with NCCM and ICDs to identify incidence and clinical factors associated with ICD shock Methods: This retrospective cohort study included patients with confirmed NCCM between 2002 and 2023 at all Mayo Clinic sites. Baseline clinical data, genetic findings, cardiac imaging parameters, and device-related outcomes were collected through detailed chart review. Multivariable Logistic regression was used to identify independent predictors. Results: Among 145 patients with NCCM who received ICDs, the median age was 45 years (IQR: 34–56), with 75 (52%) female and 120 (83%) White. The median left ventricular ejection fraction (LVEF) was 35% (IQR: 22.5–47.5%), and the median follow-up from ICD implantation was 6.4 years (IQR: 2.9–11.0). Most ICDs (124, 85.5%) were implanted for primary prevention. Appropriate shocks were observed in 37 patients (25.5%), with 14 (9.8%) experiencing three or more appropriate shocks. Inappropriate shocks occurred in 15 patients (10.3%). Device-related complications were reported in 22 patients (15.2%), including infections in 4 (2.8%), lead fractures or dislodgement in 17 (11.9%), and pneumothorax in 1 (0.7%). Clinical predictors of shocks are illustrated in the figure. Conclusion: ICD therapy for NCCM patients prevented SCD in 25.5% of patients. Syncope, RBBB, troponin T &gt;30 ng/L, and imaging-based apical trabeculations were independently associated with ICD shocks in patients with NCCM. These factors may aid in risk stratification and clinical decision-making.

Description of Case: A 36-year-old male with a history of intermittent palpitations and shortness of breath was referred for cardiology evaluation after an event monitor captured an episode of complete atrioventricular (AV) block. He was asymptomatic at the time and engaged in routine activities, including driving. The rhythm strip demonstrated AV dissociation with absent QRS complexes despite ongoing atrial activity, without any identifiable vagal or positional triggers. Baseline ECG revealed a known right bundle branch block and left anterior fascicular block. Cardiac magnetic resonance imaging showed prominent trabeculations in the apical and lateral walls of the left ventricle, with a non-compacted to compacted myocardial ratio of 3.5, consistent with noncompaction cardiomyopathy (NCCM). A prior transthoracic echocardiogram showed normal left ventricular systolic function (LVEF 60%) without any structural or regional wall motion abnormalities. As the patient remained asymptomatic without syncope or heart failure, device therapy was deferred. He was referred to cardiomyopathy clinic for outpatient follow-up, including genetic testing and extended rhythm monitoring. Discussion: This case highlights an uncommon presentation of NCCM, in which conduction system disease—specifically intermittent complete heart block—precedes overt systolic dysfunction. NCCM is a phenotypically diverse cardiomyopathy resulting from failed embryologic compaction of the myocardium. While it is often associated with heart failure, arrhythmias, and thromboembolism, early signs may include conduction abnormalities due to disrupted Purkinje architecture or myocardial fibrosis. These abnormalities can be silent and episodic, making diagnosis challenging in young patients without overt structural disease on echocardiogram. Recognition of NCCM in patients with unexplained AV block is critical, particularly when accompanied by fascicular block or a history of palpitations. Multimodality imaging, particularly cardiac MRI, enables accurate diagnosis when standard echocardiography appears normal. Early referral to cardiomyopathy specialists facilitates appropriate genetic testing, family screening, and longitudinal risk stratification, even in the setting of preserved ejection fraction. This case reinforces the importance of structural evaluation in young adults presenting with conduction disease to ensure timely identification and management of cardiomyopathies like NCCM.

Introduction: BAG3 pathogenic variants and Charcot-Marie-Tooth (CMT) have been linked with various cardiac conditions, but rarely hypertrophic cardiomyopathy (HCM). This case shows a unique presentation of BAG3 pathogenic variants, including CMT and HCM and highlights the importance of cardiac evaluation for BAG3 -related CMT. Description of Case: A 44-year-old female with CMT was referred to the department of genetics due to a family history of CMT. Genetic testing revealed a pathogenic variant in BAG3 , specified c. 1408C&gt;T ; this result prompted a referral to cardiogenomics clinic. During her cardiac evaluation, she reported a year-long history of palpitations, fatigue, orthopnea, and near-syncope. Echocardiography showed a left ventricular outflow tract (LVOT) gradient of 42 mmHg with Valsalva and asymmetric hypertrophy of the mid to apical left ventricular cavity. Cardiac MRI confirmed asymmetric HCM with thickening of the basal and mid interventricular septum and anterior segments of the myocardial wall, up to 19 mm, and mild LVOT flow acceleration. She was initiated on a cardiac myosin inhibitor for obstructive HCM, and after one year, her LVOT gradient decreased to 13 mmHg. At 1-year follow-up, she was feeling well with rare palpitations and fatigue. Discussion: The BAG3 gene encodes Bcl-2-associated athanogene 3 (BAG3), involved in sarcomere maintenance, apoptosis regulation, and mitochondrial function. While BAG3 -related cardiomyopathy is typically dilated in phenotype, other conditions, such as left ventricular noncompaction and peripartum cardiomyopathy, have been described. HCM is rare, with limited associations to specific BAG3 variants, such as C151R; this is distinct from the c. 1408C&gt;T variant mentioned above. BAG3 mutations may also lead to adult-onset CMT, often with associated cardiac findings, including arrythmias and conduction abnormalities. However, to our knowledge, HCM in the context of BAG3 -associated CMT has not been previously reported. This case expands the known cardiac phenotype of BAG3 -related disease and underscores the importance of cardiovascular evaluation in patients with neuromuscular manifestations of BAG3 variants.

Left ventricular non-compaction cardiomyopathy (LVNC) is an infrequent cardiac disorder characterized by prominent trabeculations, deep intertrabecular recesses, and thinning of the compacted myocardial layer, predisposing to heart failure, arrhythmias, and thromboembolic complications. The relationship between myocardial inflammation and chordae tendineae rupture is clinically relevant, as prior inflammatory processes may compromise valvular structures, leading to acute mitral regurgitation and ventricular overload. We present the case of a 45-year-old male with a history of severe mitral regurgitation and heart failure with preserved ejection fraction, who presented with progressive dyspnea, oppressive chest pain, diaphoresis, and lower extremity edema. Clinical assessment revealed arterial hypertension, tachycardia, hypoxemia, a loud systolic mitral murmur, jugular venous distension, and peripheral edema. Complementary studies demonstrated LVNC, severe prolapse of the posterior mitral leaflet with chordae tendineae rupture, acute mitral regurgitation, and pulmonary hypertension. Thoracic computed tomography revealed chronic lesions compatible with a previous viral infection, although specific SARS-CoV-2 testing results were unavailable. The patient underwent mitral valve replacement with a mechanical prosthesis, with postoperative complications including acute pulmonary edema, pleural effusion, renal insufficiency, and left ventricular dysfunction, which resolved favorably during hospitalization. This case highlights the importance of early recognition of LVNC and its valvular complications, as well as a comprehensive approach and timely surgical intervention to optimize clinical outcomes in complex cardiovascular scenarios.

Background Non-compaction cardiomyopathy is a rare disease. Its natural history includes heart failure, thromboembolic events, arrhythmias and sudden death (SD). In the absence of data from randomized studies or records, the ACC / AHA / HRS 2008 guidelines recommend the automatic implantable cardioverter defibrillator (AICD) in all patients with non-compaction cardiomyopathy to reduce the risk of suden death. Objective Describe the outcomes of patients with non-compaction cardiomyopathy according to selected criteria for risk stratification of sudden death to decide the implantation of an AICD. Material and Methods A total of 80 patients were analyzed. The diagnosis was established by echocardiography and nuclear cardiac magnetic resonance imaging criteria. The criteria for implantation of an AICD as a secondary prevention included sudden death and sustained ventricular tachycardia (SVT); as primary prevention included left ventricular ejection fraction (LVEF) &lt; 30% or ≥ 2 risk factors (family history of sudden death [FHSD], syncope and non-sustained VT). Results AICD group (n = 26) for secondary prevention (n = 3): 3 patients suffered sudden death (2 SVT). AICD group for primary prevention (n = 23): 10 patients had LVEF &lt;30%, 1 LVEF &lt;30% + FHSD, 1 LVEF &lt;30% + syncope, 5 LVEF &lt;30% + nonsustained VT, 3 non-sustained VT + syncope, 2 non-sustained VT + FHSD and 1 SVT in electrophysiological study. Follow up was a median of 16.61 months. Two patients underwent a heart transplant, 3 patients received appropriate shocks and 4 patients, inappropriate shocks. Group without AICD (n = 54): 4 patients had syncope and 4, nonsustained VT. Follow up was a median of 12.15 months. Two patients died due to heart failure and 3 underwent a heart transplant. Conclusions 32.5% of patients with non-compaction cardiomyopathy received an AICD, 88.5% for primary prevention; 11.5% received appropriate shocks. There was no sudden death in patients without AICD, these patients died due to heart failure progression. This record suggests that patients with non-compaction cardiomyopathy could be stratified to select those at higher risk of sudden death and who could be benefited from an AICD implantation.

Objectives: The aim of our study was to investigate the medical treatment and doses used in patients with a diagnosis of heart failure (HF) and whether these vital drugs were used by cardiologists at the required doses in patients with indications. Patients and methods: This single-center, prospective study included a total of 419 chronic HF (CHF) patients (275 males, 144 females; mean age: 65.2±13.8 years; range, 22 to 94 years) between April 1st, 2020 and November 15th, 2020. Patients and their relatives were interviewed and sociodemographic data of the patients were recorded. Routine hematological and biochemical parameters, electrocardiographic findings, electrocardiographic and echocardiographic findings, and systolic and diastolic pressure data were recorded during follow-up. The New York Heart Association (NYHA) functional classes were also determined. Results: The causes of CHF were as follows: 55.6% ischemic heart disease, 33.9% dilated cardiomyopathy (CMP), 3.8% valvular, 1.9% peripartum CMP, 1.9% post-chemotherapy (CT), 1% non-compaction CMP, and 1.9% other causes. The most common reason for not receiving medical treatment at the maximal doses recommended by the guidelines was "not recommended by the physician" (beta-blockers 49.6%, n=208, angiotensin-converting enzyme inhibitors/angiotensin receptor blockers [ACEI/ARBs] 44.6%, n=187, mineralocorticoid receptor antagonists [MRAs] 38.7%, n=162). The second most common reason was the lack of desired follow-ups due to socioeconomic reasons. Conclusion: The most common reason why HF patients do not receive optimal treatment, including beta-blocker, ACEI/ARB, and MRA groups is that clinicians do not recommend it. This study may be a reference to the fact that clinicians' maximal sensitivity in treatment optimization in fragile patient groups, such as HF, would significantly change patient outcomes.

Left ventricular noncompaction cardiomyopathy and mitral annular disjunction in patient undergoing cardiotoxic therapy for breast cancer.

Novel presentation of CACNA1C variant as neonatal complete atrioventricular block, heart failure and non-compaction cardiomyopathy with oligogenic influences.

Elamipretide in the Management of Barth Syndrome: Current Evidence and a Case Report.

Reviewing early troponin elevation as a risk marker in left ventricular noncompaction cardiomyopathy induced by chemotherapy: Current insights and future directions

Left ventricular non-compaction (LVNC) cardiomyopathy is a rare congenital cardiomyopathy which is characterized by prominent and extensive trabeculation and deep intertrabecular recesses communicating with left ventricular cavity. Here we present a rare case report of patient with severe secondary Mitral regurgitation (MR) and severe tricuspid regurgitation (TR) in LVNC cardiomyopathy who underwent MV Repair using ring annuloplasty with #28 CG future ring and kay's suture annuloplasty for severe TR and its postoperative management. Patient recovered well after surgery and was discharged with improved hemodynamics. The valve surgery in patients with such cardiomyopathy is very rare. This case will add to the small growing literature of surgery in severe secondary Mitral regurgitation in LVNC and the problems we faced while coming off bypass and its postoperative management.

Cardiac CT fractal analysis of LV noncompaction and common cardiomyopathies.

Abnormal aortic elasticity serves as a marker for cardiovascular mortality and has a negative impact on the left ventricular (LV) afterload. Noncompaction cardiomyopathy (NCCM) is characterized by hypertrabeculation of the LV endomyocardial wall, with an underdeveloped endocardial helix. This may result in absence of LV twist, disturbed aortic elasticity, LV dysfunction, and ultimately premature heart failure (HF). This study compared the aortic stiffness and clinical outcome in patients with NCCM to that of a control group with dilated cardiomyopathy (DCM). Sixty NCCM patients, matched by age and sex, were compared with 60 DCM controls. Transthoracic echocardiography was performed to measure the systolic (SD) and diastolic diameters (DD) of the ascending aorta. These measurements, along with systolic (SBP) and diastolic blood pressure (DBP), were utilized to calculate the aortic stiffness index defined as ln(SBP/DBP)/[(SD-DD)/DD]. This index was then compared to clinical features and outcome. The mean age was 49 ± 16 years (55% males) in the NCCM group and 49 ± 16 years (55% male) in the DCM group. Aortic stiffness index (ASI) was significantly higher in the NCCM group than in the DCM group (7.0 [5.8-10.2] vs. 6.2 [4.8-7.7], p = 0.011). This difference remained statistically significant after adjustment for established risk factors associated with aortic stiffness (β = 1.771; 95% CI [0.253-3.289], p = 0.023). Patients with NCCM demonstrated increased aortic stiffness when compared to those with DCM, which may reflect the underlying pathophysiological processes. Additional research is necessary to evaluate the impact of aortic stiffness on the advancement of LV dysfunction, the onset of heart failure, and long-term outcomes.

Reduced myocardial CARF and the underlying implications in left ventricular noncompaction cardiomyopathy.

Failure of proper embryonic myocardial trabeculation and compaction leads to left ventricular noncompaction cardiomyopathy (LVNC). Cardiac endothelial cells (CECs) play critical roles in supporting proper myocardial trabeculation and compaction. For instance, reduction of coronary angiogenesis in mice leads to LVNC. Previously, our group showed that global knockout (KO) of Zip8, a zinc importer, resulted in LVNC in mice, but the underlying cellular and molecular mechanisms await further investigation. Using various Cre driver mice, we found that only endothelial deletion of Zip8 recapitulated the LNVC phenotypes present in Zip8 global KO hearts. Intriguingly, we found that the proportions of endocardial endothelial cells (EECs) and coronary endothelial cells (CoECs) in Zip8 endothelial KO ( Zip8 eko ) hearts were skewed: there were significantly more EECs but significantly fewer CoECs in Zip8 eko hearts as compared to littermate controls. The number of coronary vessels was significantly reduced in Zip8 eko hearts as compared to controls, along with decreased expression of vascular endothelial growth factor receptor 2 (VEGFR2), a critical angiogenic factor. Further, the angiogenic defect was recapitulated in cultured Zip8 KO mouse CECs (MCECs), and this phenotype was successfully rescued by Vegfr2 overexpression. The transcriptional activity of Metal regulatory transcriptional factor 1 (MTF1) is subject to the regulation by ZIP8. Interestingly, we found that Mtf1 knockdown also resulted in angiogenetic defects in cultured MCECs along with VEGFR2 reduction. Finally, we found that MTF1 directly regulates Vegfr2 transcription. In conclusion, our findings illustrate that Zip8 in CECs regulates myocardial morphogenesis through the MTF1-VEGFR2 axis, providing new insights into the pathogenesis of LVNC.